Post acute COVID syndrome (PASC)

Approaches to healing

Persis Hope, FNP, IFMCP

Amy Trelease-Bell, MD, IFMCP

Disclosures

• Persis Hope FNP, IFMCP and Amy Trelease-Bell MD, IFMCP disclose that they have no relevant financial relationships with any organization producing, marketing, reselling, or distributing health care goods or services consumed by, or used on, patients relative to the content of this presentation.

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Perspective

• Functional medicine- a systems biology approach to health and healing
• “The functional medicine model is an individualized, patient-centered, science-based approach that empowers patients and practitioners to work together to address the underlying causes of disease and promote optimal wellness. It requires a detailed understanding of each patient’s genetic, biochemical, and lifestyle factors and leverages that data to direct personalized treatment plans that lead to improved patient outcomes.
• By addressing root cause, rather than symptoms, practitioners become oriented to identifying the complexity of disease. They may find one condition has many different causes and, likewise, one cause may result in many different conditions. As a result, functional medicine treatment targets the specific manifestations of disease in each individual.”

Goals and objectives

• Objective 1: a general understanding of the pathophysiology of covid infection and post covid acute syndrome (PACS)
• Objective 2: have an understanding of resources for information and treatments for PACS
• Objective 3: have a general view of some of the dietary options for patients with PACS
• Objective 4: be reminded of the role health care disparities play in PACS

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What is post acute COVID syndrome?

Estimates of the proportion of people who had COVID-19 that go on to experience post-COVID conditions can vary:

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13.3% at one month or longer after infection

2.5% at three months or longer, based on self-reporting

More than 30% at 6 months among patients who were hospitalized

Current case totals in the US: 93, 085,891 total in the US

Impacts of SARS-coV-19

• SARS-CoV-2's ability to spread throughout the body is largely tied to the spike proteins on its surface, which bind to ACE2 receptors — a protein on the surface of various types of human cells — like a key into a lock.
• ACE2 receptors are found on epithelial cells of the upper and lower respiratory tracts, intestines, kidney, testes, gallbladder, heart and vasculature
• That means the virus can reach far beyond the respiratory tract, causing inflammation wherever it spreads.

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Mucosal immunity -

• works to repel upper resp, also lung, GI tract – inter-related microbiota (so the resp microbiome is impacted by the GI microbiome, etc.). Studies in COVID patients show changes in microbiome of mucosa, feces compared to well samples
• Secretory IgA – prevents or limits binding by pathogens
• Role of microbiome—
• production of short chain fatty acids (SCFA) that help heal mucosa;
• toll-like receptor (TLR) activation
• regulation of T-cell populations
• regulation of systemic inflammation

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Innate immune system— inflammatory process, first line of defense if mucosal defenses are breached�

• sentinel cells- macrophages, dendritic cells, mast cells, Kupfer cells
• detection of PAMPs (Pathogen assoc molecular patterns) via TLR (pattern recognition)🡪
• stimulates production of – NF-kB, IFN-gamma (other interferons, too)
• NFkB- cytokine and chemokine production; phagocytosis; complement cascade; activation of adaptive immunity; activation of NLRP3 inflammasome
• In viral infections, type 1 interferons (IFN-1) are produced
• IFN-1 inactivates SARS-Cov-2 and upregulates ACE-2 in the lungs
• This is very key
• In viral infections, Natural Killer (NK) cells are activated

Adaptive immune system—B and T cell priming, increased specificity�

• lymphocytes
• T-cells- activated through antigen presentation (macrophages, dendritic cells)
• CD8 (cytotoxic T cells) attack infected cells
• CD4 (T helper) regulators of immune response
• Th1- production of IFN-gamma and increase cell-mediated immunity (virus specific)
• Th2- production of IL-4, IL-5
• B-cells- secrete antibodies (humoral immunity) takes 4-7 days
• Variable, may be transient
• Lymphopenia is predictive of severe disease
• Previous coronavirus infections may underlie some heterogeneous responses to COVID19

Cytokine storm

• Positive feedback loops of inflammation can be created by
• DAMPs ( damaged associated molecular patterns )
• Reactive oxygen and nitrogen species
• Leading to long term complications like

vascular endotheilitis

thrombosis

endothelial dysfunction

neurological impairments

chronic fatigue

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Impact of Pre-existing inflammation on COVID-19�

• Cytokines- involved in cell signaling meant to be therapeutic
• Prolonged stimulation leads to tissue damage and more triggering of this response
• TNF, IL-1B, IL-6, IL-8, G-CSF, GM-CSF are all elevated in COVID-19, higher if critically ill
• In ICU- we see these in COVID-19-- TNF, ganzyme B, heat shock protein 70 (specifically signals increased mortality), interleukin -18, IFN-gamma inducible protein 10, elastase 2

Oxidative stress�

• oxidative stress is a common response to resp viral exposure; overproduction of ROS (reactive oxidative species) and depleted antioxidant capacity contributes to the pathogenesis of severe COVID
• Overeating increases oxidative stress and lowers antioxidant capacity
• Glutathione-- deficiency is most likely cause of serious COVID illness
• Crucial factor in development of severe morbidity / mortality
• Impaired redox homeostasis increases free radicals (redox is oxidation-reduction)

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Post acute COVID syndrome

• Defined as new continuing or recurring symptoms that occur 4 or more weeks after initial coronavirus infection
• Symptoms may include fatigue, myalgia, poor sleep, cough, dyspnea, chest discomfort, palpitations, night sweats, generalized arthritis, sensory disturbance, mood disorders
• Marked variation in presentation
• Need to consider pulmonary embolism
• Autonomic dysfunction
• Post viral pericarditis/ myocarditis with heart failure
• Post-viral asthma or bronchiectasis
• The Post-acute COVID-19 Syndrome (Long COVID) Issa Al-Jahdhami, Khalid Al-Naamani, Adhra Al-Mawali Oman Med J. 2021 Jan; 36(1): e220. Published online 2021 Jan 26.

Sequelae�

• DKA
• Subacute thyroiditis with thyrotoxicosis, new onset Hashimoto’s or Graves
• Metabolic associated fatty liver
• Fibromyalgia
• neurological symptoms – brain fog, cognitive impairment, paresthesias
• Arthritis
• Dysautonomia
• New autoimmune-mediated disease- RA, IBD

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PASC – hypotheses around causes�

Cellular damage

Robust innate immune response with inflammatory cytokine production

Cytokine “rain”

Virus in short quantity in some organs

Immune system detects the virus

Mast cells and macrophages produce cytokine rain

Persistent inflammation causes fatigue , weakness and difficulty healing

(Chi Sono 2021) , (Schafer, et al)

Pro coagulant state induced by SARS coV-2 , (McElvaney 2020; )

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Is low cortisol a cause or an effect?

• Marked differences were noted in specific circulating myeloid and lymphocyte populations relative to matched control groups
• unexpected increases were observed in antibody responses directed against non-SARS-CoV-2 viral pathogens, particularly Epstein-Barr virus
• levels of cortisol being uniformly lower among participants with Long COVID relative to matched control groups
• Distinguishing features of Long COVID identified through immune profiling Jon Klein, et al

Disparities and inequities in health care

To promote high‐quality care in individuals with PACS, we need to ensure resources are equitably available for those affected to maintain physical and mental health.

Prevalence of PASC- demographics

• Age, race, comorbidities all matter
• BIPOC groups are statistically more likely to be exposed, to become sicker with COVID, and to have more comorbidities
• Older adults are more likely to have multiple comorbidities
• Groups that are economically burdened struggle more with prolonged symptoms
• Not as able to stop working to recover
• Lack of health insurance

Health care disparities

• Marginalized communities everywhere continue to be disproportionately affected as the pandemic amplifies longstanding health and healthcare disparities. As an example, in the United States, members of the Black, Indigenous and Latino communities remain two to three times more likely to be infected with SARS-CoV-2, to be hospitalized with COVID-19 and to die from this disease. Dismantling structural racism is necessary to improve neurological health, as greater attention is focused on understanding and addressing the post-acute neurological consequences of COVID-19, or the neurological manifestations of what is sometimes called long COVID.

Big picture !

Oxidative stress and inflammation contribute to COVID-19 severity

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Can we repurpose anti inflammatory immunomodulatory agents to mitigate inflammation in covid 19 ?

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Can we use mitochondria-targeted agents prophylactically to prevent inflammation and boost immunity in long haulers?

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Kalyanaranman, B. Reactive oxygen species, proinflammatory and immunosuppressive mediators induced in covid-19: overlapping biology with cancer. Royal Society of chemistry, 2012, 2, 1402-1414.

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Help is on the way

• The American Academy of Physical Medicine and Rehabilitation (AAPM&R) Multi‐Disciplinary PASC Collaborative (“PASC Collaborative”) was created, in part, to develop expert recommendations and guidance from established PASC centers with extensive experience in managing patients with PASC.
• There is an intentional focus on health equity as disparities in care and outcomes are critically important to address.
• Also the National Institute for Health and Care Excellence are publishing recommendations on therapeutics, so that healthcare staff and those planning and delivering services can find and use them more easily.

Work up

• The following basic lab workup should be considered in new patients or those without lab workup in the 3 months before visit including
• complete blood count with differential
• chemistries including renal and hepatic function tests
• thyroid stimulating hormone ( just my note here, no research on this but I like to get thyroid antibodies )
• c‐reactive protein or erythrocyte sedimentation rate
• creatinine kinase.
• Other tests as applicable to symptoms

Initial management

1. Begin an individualized and structured, titrated return to activity program.

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• Discuss energy conservation strategies.

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• Encourage a healthy dietary pattern and hydration.

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4 Treat, in collaboration with appropriate specialists, underlying medical conditions, such as pain, insomnia/sleep disorders (including poor sleep hygiene), and mood issues that may be contributing to fatigue.

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PACS Treatments- integrative

• Food as medicine
• Botanicals
• Resveratrol, Quercetin, Curcumin, Melatonin, ECGC
• There are others that have been well investigated. We chose these as some that are accessible
• Supplements
• Vitamin C, D, A, magnesium glycinate, zinc

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• Please see reference slides for many more resources

It’s all about the gut microbiome �

• Covid 19 alters gut microbiome
• Increased opportunistic microbe species
• Decreased beneficial microbe species
• Ability of gut microbiota to alter course of resp infections (gut-lung axis)
• Recognized with flu and other resp infections (Bradley, 2019)

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Standard Diet vs healthier choices

• pro-inflammatory states and chronic disease related fatigue.
• Single nutrients
• polyunsaturated fatty acids,
• anti oxidative vitamins
• specifically vitamins A, B12, and D, polyphenols, protein/amino acids)
• specific diets
• whole grains high in fibers
• polyphenol‐rich vegetables
• omega‐3 fatty acid‐rich foods) have been suggested to have anti‐inflammatory and fatigue‐reducing effects, although further confirmatory research is needed

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Nutrition and PACS muscle mass

• Acute sarcopenia is known to occur during COVID-19 especially in older adults
• This has implications for post COVID recovery
• Recent study of muscle mass recovery in older adults found protein supplementation and muscle strength training can be used
• Minimum daily protein requirement healthy elderly 0.83 g per kilo
• In this study, Leucine supplementation or balanced diet demonstrated best evidence

Nutrition and PACS fats

• Daily intake 1.5-3 grams of omega 3 FA for decreased inflammation
• Increased intake of olive oil which will provide monounsaturated fatty acids, tocopherols, polyphenols which have anti inflammatory properties

Nutrition and PACS carbs

• Low glycemic index carbs recommended
• High glycemic foods associated with increased inflammation and oxidative stress
• Intake of viscous & fermentable fibers ( B-glucan and arabinoxylans from whole grains, pectins from fruit, veg and legumes) should be increased for their prebiotic effect towards butyrate producing bacteria which has been associated with reduced inflammation

Micronutrients

• Pilot study showing micronutrient deficiency in hospitalized patient with COVID-19 especially vitamin D 76% and selenium 42%
• European Society for Clinical Nutrition and Metabolism-- patients should consume 100% of RDA and MVP for patient with micronutrient deficiency.

Nutraceuticals – a food containing health giving additives and medicinal benefit

• Antiviral activity mainly involving inhibition of inflammatory pathways as well as viral replication-
• Polyphenols – quercetin, resveratrol, catechins
• NAC (N-Acetyl cysteine), PEA (endocannabinoid-like lipid mediator)

Polyphenols food sources

• Quercetin- fruit and veg
• Apples
• Onions
• Parsley
• Sage
• Tea
• Red wine
• Olive oil
• Grapes
• Dark, cherries, dark berries ie blueberries, blackberries, bilberries

Polyphenols food sources cont

• Resveratrol
• Grapes
• Wine
• Grape juice
• Peanuts
• Cocoa
• Berries – blueberries, bilberries, cranberries

Polyphenols food sources cont

• Catechins
• Red wine
• Broad beans
• Black grapes
• Apricotes
• Strawberries
• Green tea and black tea
• Apples
• Chocolate

Food sources of NAC

• Meat, Fish, Seafood, Chicken and turkey
• Eggs
• Whole grains, oatmeal
• Cauliflower, broccoli, onions, legumes- lentils , asparagus
• Sunflower seeds

Nutritional recommendations

• Plant based diet
• High quality animal protein
• Extra virgin olive oil as principal fat
• Adequate hydration 30mL/kg actual body weight
• Fiber content

Mediterranean diet

• Dietary intake can modulate inflammation and the immune system
• A combination of different foods with these properties can be useful
• Mediterranean diet is characterized by many bioactive compounds with anti inflammatory and antioxidant activities
• Several studies confirm anti inflammatory and immunomodulatory effects of med diet on several disease associated with chronic low grade nutrition.
• Observational studies highlight an association between adherence to med diet and better outcomes in patient with COVID-19.

Short Chain Fatty Acids ( acetate and butyrate examples)

• Plant based diet increases short chain fatty acid intake
• Resistant starch – cooked cornmeal, potatoes, whole green or legume based pasta , green banana (green banana flour), cooked and cooled rice, potato, legumes
• Fiber, fiber , fiber
• Necessary for improved health of mucosal immunity – heal the gut
• Necessary for production of neurotransmitters

Fiber as a post covid Rx

• “high intake of dietary fibers with diverse physicochemical structures significantly alleviated severe GI symptoms in a patient with post-acute COVID-19 syndrome. The significant structural shifts in the patient’s gut microbiota induced by the high-fiber formula, particularly the enrichment of SCFA-producing bacteria, might be associated with the alleviation of both GI and non-GI symptoms such as anxiety and palpitations”
• Wang Y, Wu G, Zhao L, Wang W. Nutritional Modulation of Gut Microbiota Alleviates Severe Gastrointestinal Symptoms in a Patient with Post-Acute COVID-19 Syndrome. mBio. 2022 Apr 26;13(2):e0380121

Nutritional modulation of the gut microbiota to treat post acute COVID-19

• Study of one patient with COVID-19 with severe GI symptom
• 2 months of expanded access high fiber formula
• Her symptoms loss of appetite , palpitations, anxiety , nausea, diarrhea, abd pain
• Significant improvement in symptoms by the end of intervention
• Also improved : lipid profile, insulin level, leptin level compared to baseline
• Significant structural changes of the patients gut microbiota and reduced microbial fermentation activity in the small intestine

High fiber study cont

• Diet was pre cooked mixture of 12 component material from whole grains, TCM foods which contain fiber from- ablay, oat, white beans, big jujube, yellow corn, red bean, soy bean, yam, peanut, lotus seed, wolf berry prepared into a gruel
• Aimed at increasing SCFA produced by gut bacteria
• 100g contains 59 carb, 15 g protein, 6 g. fiber
• Slowly increased her dose ( could not find what the dose was)

Fiber study cont

Significant structural changes of the patient’s gut microbiota

Reduced microbial fermentation activity in the small intestine

Considered SIBO as the cause of her long lasting nausea and anorexia

Her breath hydrogen test improved

Probiotics

• Promising strains for potential management of SARS-CoV-2 infection related to induction of strange anti inflammatory response
• Lactobacillus rhamnosus CRL 1505
• Lactobacillus gasseri SBT 2055
• Lactobacillus casei DK128
• Some strains of bifidobacterium difidum
• Probiotics reference Todorov, S. et al “could probiotics and postbiotics function as a silver bullet in the Post COVID 19 era. Probioitcs and antimicrobials 13, 1499-1507 (2021)

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Treatment of fatigue

• Mitochondrial function and the electron transport chain
• Detox pathways in the liver
• Both are impacted by nutritional deficiencies

critical minerals

i.e. iron, magnesium, zinc, copper

critical vitamins

i.e. riboflavin, B12, vitamin C,

Improving energy production

• Ketogenic diet can positively impact on mitochondrial bioenergetics, mitochondrial ROS/redox metabolism and mitochondrial dynamics. 
• Changbo Qu, Jaap Keijer, Merel J.W. Adjobo-Hermans, Melissa van de Wal, Tom Schirris, Clara van Karnebeek, Yihang Pan, Werner J.H. Koopman, The ketogenic diet as a therapeutic intervention strategy in mitochondrial disease, The International Journal of Biochemistry & Cell Biology, Volume 138, 2021, 106050, ISSN 1357-2725
• Julie Milder, Manisha Patel, Modulation of oxidative stress and mitochondrial function by the ketogenic diet, Epilepsy Research, Volume 100, Issue 3, 2012, Pages 295-303, ISSN 0920-1211

Other supportive lifestyle measures

• Help for anosmia
• Help for fatigue and lack of stamina
• Improvement of psychological symptoms
• Improvement of sleep disorders
• Improvement of dyspnea?

Scent training for anosmia

• Floral: fresh flowers, plants, floral perfume, floral tea leaves or bags, and lavender, rose, chamomile, or jasmine essential oils
• Fruity: lemon, lime, orange, grapefruit, lemongrass, and bergamot
• Spicy: kitchen spices or oils such as clove, ginger, cinnamon, nutmeg, cardamom, or allspice
• Resinous: coffee grounds, black pepper, and oils such as myrrh, benzoin, and frankincense

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Anosmia cont

• Smell the four items for 20 seconds each, at least twice a day.

Take short, light sniffs, and concentrate on the scent you are smelling. It may take several weeks

track your progress and note any changes in your ability, no matter how small. Another way to track your progress may be how you feel about smelling items, since smell and mood are closely linked.

• May constantly experience an unpleasant smell or the scent of burning rubber, you may have parosmia. This is a natural step in the healing process for olfactory nerves, but it may take weeks to go away.

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Breath- vagal tone/ modulation of parasympathetic tone

Slow deep breaths

• Build up of carbon dioxide with slower, longer exhalation allows more circulation of oxygen
• improves sensitivity of vagal nerve which modulates neuro chemicals
• Recommended practices:
• Box breathing
• 3:7:8 breathing
• Resources:
• Calm.com
• Wim Hof
• Breath by James Nestor

Help for low cortisol

• RELAX
• Mediation
• Sleep hygiene
• Avoid strenuous exercise (limit cardio)🡪 yoga, tai chi
• Breathe
• L-carnitine
• Avoid stimulants: caffeine, sugar, alcohol
• Adaptagenic herbs: Ashwagandha, licorice root, holy basil

A word on exercise

• Many post-COVID patients report low stamina and dyspnea, muscle pain, joint pain, etc
• Think about the mitochondria-> energy production
• Autonomic conditioning therapy has been shown to reduce fatigue, improve global functioning
• Begins with supine range of motion and gradually incorporates CVP therapy
• Post-Acute Covid-19 Exercise and Rehabilitation (PACER) Project
• increase practitioner proficiency in cardiovascular and pulmonary (CVP) physical therapy, including critical illness sequelae

CASE REPORT

Case 1

• 65 yo female with a history of gastric bypass and lymphoma
• Typically worked up to 60 hours per week as CNA and EMT, enjoyed hiking, Zumba, gardening, dancing
• Symptomatic COVID infection in June 2020 and again January 2021
• CNA in local long term care facility, vaccinated 12/ 2020
• Presented with fatigue, SOB, lack of stamina, productive cough, anosmia, diffuse arthralgia, oxygen desaturations with exertion to 70%

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Work up

• Jan 2021 – after 2^nd COVID infection
• CBC nml but with hi monocytes, CMP OK but with new high glucose of 137, pBNP- nml, Mag- 1.7, CRP-0.80, Chol- 186, TG-95, HDL-54, LDL-113, B12- 463
• AM cortisol low- 2.9, PM cortisol nml-4.9; TSH high- 17.9, high TPO, FT4- 1.08 on 75 mcg levothyroxine

Case- My assessment:�

• New pulmonary symptoms- concerning for fibrosis or other developing condition
• Baseline inflammation from ongoing stressors and probable high oxidative state
• Also inflammation from SAD foods, too much activity, lack of rest

Case - Initial recommendations: �

• Plant-based diet- modified Mediterranean style
• curcumin 1000 mg daily, zinc 45 mg daily , vitamin D3 5000 IU, Vitamin C 2000 mg daily, melatonin 30 mg daily, 4 cups of green tea (for ECGC) and Resveratrol 150 mg BID
• She wanted to push herself to exercise- told to stop all exercise and rest
• gentle application of sniffing exercises for anosmia, vagal tone

Case - Referred to Pulmonary service PASC clinic�

• CT of thorax- mild emphysematous changes, May 2021
• Initially had normal 6 minute walk test May 2021
• PFT, July 2021:

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Diagnosed with bronchiectasis, referred for chest PT

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Case -3 months later

• Thyroid dose had been increased
• TSH- 3.9, FT4- 1.38, TPO- nml
• Referred for PACER PT to build stamina
• initially could ride recumbent bike for 1 min before O2 Saturation dropped
• Complaint of back pain/ hip pain became more acute
• Laboratory testing to rule out new autoimmune disease
• ESR high at 24
• CRP, RF, ANA all normal
• referred to PT for more targeted therapy for these concerns

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Case- 5 months later

• Exposed to respiratory illness- COVID, influenza and RSV neg but sick with cough, fever, malaise for 5 days
• Lab- CBC- nml, BMP- nml, ESR- <17, CRP- nml
• Complained of worsened fatigue
• I prescribed a diet focused on energy production and nutrients specific to mitochondrial recovery
• anti-inflammatory, low-glycemic, gluten-free, low-grain, high-quality fats approach to eating. The plan focuses on supporting healthy mitochondria through the use of therapeutic foods that improve energy production. This is a ketogenic diet

Case – 10 months later

• Improved dyspnea
• Able to walk 0.5-0.75 miles on flat surface outdoors
• Will still drop O2 saturations to as low as 85% if pushing wheelchair
• Working 32 hours per week- cannot work more than 2 days in a row or will develop severe fatigue
• PT improved her back and hip pain significantly- using yoga to continue her progress
• Joint pains managed with curcumin + black pepper, anti-inflammatory diet
• Anosmia now resolved with sniffing exercises

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REFERENCES

• Functional medicine: focusing on imbalances in core metabolic processes FA Orlando, KL Chang, IM Estores Journal of Fam Prac 2021;70(10):482-8
• Beyerstedt S, Casaro EB, Rangel ÉB. COVID-19: angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection. Eur J Clin Microbiol Infect Dis. 2021 May;40(5):905-919.
• Bansal R, Gubbi S, Muniyappa R. Metabolic Syndrome and COVID 19: Endocrine-Immune-Vascular Interactions Shapes Clinical Course. Endocrinology. 2020 Oct 1;161(10):bqaa112.

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• Iddir M, Brito A, Dingeo G, Fernandez Del Campo SS, Samouda H, La Frano MR, Bohn T. Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis. Nutrients. 2020 May 27;12(6):1562.
• Zabetakis I, Lordan R, Norton C, Tsoupras A. COVID-19: The Inflammation Link and the Role of Nutrition in Potential Mitigation. Nutrients. 2020 May 19;12(5):1466.
• Azkur AK, Akdis M, Azkur D, Sokolowska M, van de Veen W, Brüggen MC, O'Mahony L, Gao Y, Nadeau K, Akdis CA. Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy. 2020 Jul;75(7):1564-1581.
• Song P, Li W, Xie J, Hou Y, You C. Cytokine storm induced by SARS-CoV-2. Clin Chim Acta. 2020 Oct;509:280-287.

• Sisó-Almirall A, Brito-Zerón P, Conangla Ferrín L, Kostov B, Moragas Moreno A, Mestres J, Sellarès J, Galindo G, Morera R, Basora J, Trilla A, Ramos-Casals M, On Behalf Of The CAMFiC Long Covid-Study Group. Long Covid-19: Proposed Primary Care Clinical Guidelines for Diagnosis and Disease Management. Int J Environ Res Public Health. 2021 Apr 20;18(8):4350.
• Donati Zeppa S, Agostini D, Piccoli G, Stocchi V, Sestili P. Gut Microbiota Status in COVID-19: An Unrecognized Player? Front Cell Infect Microbiol. 2020 Nov 26;10:576551.
• Zuo T, Wu X, Wen W, Lan P. Gut Microbiome Alterations in COVID-19. Genomics Proteomics Bioinformatics. 2021 Oct;19(5):679-688.
• Zuo T, Zhan H, Zhang F, Liu Q, Tso EYK, Lui GCY, Chen N, Li A, Lu W, Chan FKL, Chan PKS, Ng SC. Alterations in Fecal Fungal Microbiome of Patients With COVID-19 During Time of Hospitalization until Discharge. Gastroenterology. 2020 Oct;159(4):1302-1310.e5.

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• The Lifetime Risk of Adult-Onset Rheumatoid Arthritis and Other Inflammatory Autoimmune Rheumatic Diseases Cynthia S. Crowson, Eric L. Matteson, Elena Myasoedova, Clement J. Michet, Floranne C. Ernste, Kenneth J. Warrington, John M. Davis, III, Gene G. Hunder, Terry M. Therneau, Sherine E. Gabriel Arthritis Rheum. Author manuscript; available in PMC 2012 Mar 1.Published in final edited form as: Arthritis Rheum. 2011 Mar; 63(3): 633–639.

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• The Prevalence of Autoimmune Disorders in Women: A Narrative Review Fariha Angum, Tahir Khan, Jasndeep Kaler, Lena Siddiqui, Azhar Hussain Cureus. 2020 May; 12(5): e8094.
• Huang C. et al. 6 month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet 2021. Jan 16;397(10270):220-232.
• Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19 Maximilian Ackermann, Stijn E. Verleden, Mark Kuehnel, Axel Haverich, Tobias Welte, Florian Laenger, Arno Vanstapel, Christopher Werlein, Helge Stark, Alexandar Tzankov, William W. Li, Vincent W. Li, Steven J. Mentzer, Danny Jonigk N Engl J Med. Author manuscript; available in PMC 2021 Jan 9.Published in final edited form as: N Engl J Med. 2020 Jul 9; 383(2): 120–128.

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• Characterization of cardiac autonomic function in COVID-19 using heart rate variability: a hospital based preliminary observational study. Kaliyaperumal D, Rk K, Alagesan M, Ramalingam S J Basic Clin Physiol Pharmacol. 2021 Mar 12; 32(3):247-253.
• Testing cardiovascular autonomic function in the COVID-19 era: lessons from Bologna's Autonomic Unit. Guaraldi P, Barletta G, Baschieri F, Calandra-Buonaura G, Provini F, Cortelli P Clin Auton Res. 2020 Aug; 30(4):325-330

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• Martinez-Proveda (2019) The Mediterranean Diet, a Rich Source of Angiopreventive Compounds in Cancer Beatriz Martínez-Poveda, José Antonio Torres-Vargas, María del Carmen Ocaña, Melissa García-Caballero, Miguel Ángel Medina, Ana R. Quesada Nutrients. 2019 Sep; 11(9): 2036.
• Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential Dharambir Kashyap, Vivek Kumar Garg, Hardeep Singh Tuli, Mukerrem Betul Yerer, Katrin Sak, Anil Kumar Sharma, Manoj Kumar, Vaishali Aggarwal, Sardul Singh Sandhu Biomolecules. 2019 May; 9(5): 174.

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• Zuo, T. et al (2020) Alternations in gut microbiota of patients with covid-19 during time of hospitalization. Gastroenterology 159, 944-955 e8
• Zeppa, D. et al. (2020) Gut microbiota status in COVID-19 : an unrecognized player?Front. Cel; Infect. Microbiol. 10, 576551.
• Bradley, K. et al. (2019) Microbiota driven tonic interferon signals in lung stromal cells protect from influenza virus infection. Cell rep. 28, 245-256.
• Brisdelli F, D’Andrea G, Bozzi A. Resveratrol: a natural polyphenol with multiple chemopreventive properties. Curr Drug Metab. 2009;10(6):530-546.
• Lin SC, Ho CT, Chuo WH, Li S, Wang TT, Lin CC. Effective inhibition of MERS-CoV infection by resveratrol. BMC Infect Dis. 2017;17(1):144

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• Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study; Aranka V Ballering, Sander K R van Zon, Tim C olde Hartman, Judith G M Rosmalen, for the Lifelines Corona Research Initiative* Lancet 2022; 400: 452–61
• Distinguishing features of Long COVID identified through immune profiling; Jon Klein, Jamie Wood, Jillian Jaycox, Peiwen Lu, Rahul M. Dhodapkar, Jeff R. Gehlhausen, Alexandra Tabachnikova, Laura Tabacof, Amyn A. Malik, Kathy Kamath, Kerrie Greene, Valter Silva Monteiro, Mario Peña-Hernandez, Tianyang Mao, Bornali Bhattacharjee, Takehiro Takahashi, Carolina Lucas, Julio Silva, Dayna Mccarthy, Erica Breyman, Jenna Tosto-Mancuso, Yile Dai, Emily Perotti, Koray Akduman, Tiffany J. Tzeng, Lan Xu, Inci Yildirim, Harlan M. Krumholz, John Shon, Ruslan Medzhitov, Saad B. Omer, David van Dijk, Aaron M. Ring, David Putrino, Akiko Iwasaki medRxiv 2022.08.09.22278592; doi: https://doi.org/10.1101/2022.08.09.22278592

• Multiple early factors anticipate post-acute COVID-19 sequelae; Su, Yapeng et al. Cell, Volume 185, Issue 5, 881 - 895.
• Xie, Y., Bowe, B. & Al-Aly, Z. Burdens of post-acute sequelae of COVID-19 by severity of acute infection, demographics and health status. Nat Commun 12, 6571 (2021).
• Perciavalle, V., Blandini, M., Fecarotta, P. et al. The role of deep breathing on stress. Neurol Sci 38, 451–458 (2017).
• Nolen, L.T., Mukerji, S.S. & Mejia, N.I. Post-acute neurological consequences of COVID-19: an unequal burden. Nat Med 28, 20–23 (2022).

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• Tabacof L, Tosto-Mancuso J, Wood J, Cortes M, Kontorovich A, McCarthy D, Rizk D, Rozanski G, Breyman E, Nasr L, Kellner C, Herrera JE, Putrino D. Post-acute COVID-19 Syndrome Negatively Impacts Physical Function, Cognitive Function, Health-Related Quality of Life, and Participation. Am J Phys Med Rehabil. 2022 Jan 1;101(1):48-52.

Reference for microbiome

• Wang, Y. et al. Nutritional modulation of gut microbiota alleviates severe gastrointestinal symptoms in a patient with post acute COVID-19 syndrome. ASM jornals, vol 13, no 2 , 7 march 2022
• Zhao L, Zhang F, Ding X, Wu G, Lam YY, Wang X, Fu H, Xue X, Lu C, Ma J, Yu L, Xu C, Ren Z, Xu Y, Xu S, Shen H, Zhu X, Shi Y, Shen Q, Dong W, Liu R, Ling Y, Zeng Y, Wang X, Zhang Q, Wang J, Wang L, Wu Y, Zeng B, Wei H, Zhang M, Peng Y, Zhang C. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science. 2018 Mar 9;359(6380):1151-1156.

anosmia

• Zilstorff, K. (1966). Parosmia. The Journal of Laryngology & Otology, 80(11), 1102-1104. doi:10.1017/S0022215100066457
• Aïn, S. A., Poupon, D., Hétu, S., Mercier, N., Steffener, J., & Frasnelli, J. (2019). Smell training improves olfactory function and alters brain structure. NeuroImage, 189, 45-54. doi:10.1016/j.neuroimage.2019.01.008