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1 | Domain | Outcome | Preliminary Description | Mirjana Turkalj | Carmen Riggioni | Eva Stylianou | Paul Turner | Mimi Tang | Melanie Lloyd | Pablo Rodríguez del Río | Reviewer | Reviewer | Reviewer | Reviewer | Reviewer | Reviewer | Reviewer | Reviewer | Reviewer | Reviewer | Reviewer | Reviewer | Reviewer | ||||
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4 | 1. | Physiological/clinical | Desensitisation | "Temporary state that allows a person to consume more of the food allergen than they could prior to an intervention, but the underlying food allergy is still present so patients must still continue with strict allergen avoidance in daily life. Desensitisation requires the food allergen to be consumed regularly, without stopping, to maintain protection. Importantly, the level of protection is unstable so patients can react to their daily desensitisation treatment." This should be confirmed by oral food challenge (a medical procedure in which a food is eaten slowly, in gradually increasing amounts, under medical supervision, to accurately diagnose or rule out a true food allergy). | desensitisation | The statement " so patients still need to continue allergen avoidance in not correct as this is not a real life scenario to people who undergo a food desensitization process. Most of this patients are able to tolerate diverse abount of the allergen on a daily basis and incorporate it to their routine. | This definition goes beyond what desensitisation is. Underlying FA is still present, but the rest of that sentence (as flagged by Carmen) is not true. For example, those with allergy to milk/egg, but who tolerate baked CM/egg... or sesame allergic patients who tolerate sesame seeds on buns etc. You shouldn't mix up the defintiion with then a proposed management strategy (especially when that strategy is not appropriate for many many individuals with FA). I'm not quite sure as to the point of the 2nd sentence: "the level of protection is unstable so patients can react to their daily desensitisation treatment" - do you mean that people may be desensitised, but then react to their maintenance dose? In which case why don't you specifically say that: "the level of desensitisation is unstable, so treated individuals can react to dose they have previously eaten within reaction". Protection implies protection from what? So not a good word to use. WHAT "should be confirmed by oral food challenge"? Suggest you are more specific over this - I assume you mean "desensitisation" rather than "level of protection being unstable" which is how the current wording could be interpreted. While I am personally keen on challenges, it is possible to realise some of the benefit of desensitisation without FC... for example, if maintenance dose is 5 peanuts, for example, then when that dose is tolerated every day, it is clear that there is desensitisation to 5 peanuts even without FC... | "This should be confirmed by oral food challenge...." is a vague and should be more specific eg "The amount of food the desensitised individual is able to comsume should be confirmed by oral food challenge...." or "Desensitisation should be confirmed by oral food challenge (....) performed both before and during/after therapy". I would like to include the sentence regarding avoiding allergen other than the daily dosing amount to maintain desensitisation ( that others are suggesting to remove ) - it might well be that some clinicians are recommending patients can stop avoiding but this is fraught with problems as there has to be a limit to the amount taken. Perhaps a compromise would be to say patients should only consume up to their threshold amount in a given day. | May need to specify that even if the level of desensitisation is relatively stable, it is related to the dose regularly consumed. For example, if only desensitised to 300mg peanut likely only protected against trace exposures or cross contamination. Clarify that "consumed regularly" refers to a strict daily dose schedule NOT free consumption of the allergen. | .- I agree on the relevance of this outcome .- I think we should try to make a more simple definition, this is too complex. .- I think we should also try to give more granularity to the definition to make it operational across studies, by adding some limits: doses, time on therapy, long term efficacy and some other parameters that are very relevant .- To me, there is the definition of desensitization: “the result of an increase in the reactivity threshold after an intervention” (or any other wording we come up with), and then, the conditions and particularities associated to this state: ie: regular intake, cofactors, measuring method (challenge vs other), transiency .- I would recommend to adapt already existing definitions, instead of starting from scratch: EAACI guidelines 2018, or GALEN 2022 | |||||||||||||||||
5 | 2. | Physiological/clinical | Maximum tolerated amount of allergenic food Consider renaming to "Change in maximum tolerated dose" | Change in the tolerated (associated with the absence of symptoms) dose of food from the beginning to the end of the study, confirmed by oral food challenge (a medical procedure in which a food is eaten slowly, in gradually increasing amounts, under medical supervision, to accurately diagnose or rule out a true food allergy). | maximmum tolerated dose | Maximum tolerated dose is better | Change in Maximun tolerated dose is better | You've ignored the MASSIVE elephant in the room here - which is what "tolerated" means. Someone who gets 20mins abdo pain to a dose arguably does not tolerate that dose, but wouldn't in general trigger "dose not tolerated" under current challenge-stop definitions. Who should decide is something is tolerated? Us as HCPs? The food allergic person themselves? Or some combination of the two? | Isn't the relevance of the maximum dose linked to some dietary criteria (e.g. 2 peanuts)? I would think that for patients it is more important to know what they can and can't safely eat, rather than their personal increase in tolerated dose. THerefore I favour "Maximum tolerated amount" over "change in maximum". | .- As mentioned by Paul, the definition used for “tolerated” is very blurred. In fact, pure toleration is infrequently used, I would suggest to go for the most frequently used definition that is no reactivity or only symptoms not requiring treatment, to encompass our definitions to what has already been published and aligned with what seems to be the regulatory bodies recommendations .- Again, I see this definition too long. There´s no need to explain on it what is a food challenge | |||||||||||||||||
6 | 3. | Physiological/clinical | Sustained unresponsiveness Consider renaming to "Remission" | Ability of a person with food allergy to consume a larger amount of food than they could tolerate before an intervention without having an allergic reaction, after having paused treatment for a period of, at least, several weeks. Typically, the person with food allergy is able to tolerate a standard standard serving or pass a diagnostic oral food challenge (a medical procedure in which a food is eaten slowly, in gradually increasing amounts, under medical supervision, to accurately diagnose or rule out a true food allergy) weeks after treatment discontinuation. | permanent remission | Several weeks is too vague. Sustained unresponsiveness for me is a better term BUT remission is more easily understood. The work PERMANENT remission cant be used. There are patients who have an allergic reaction after years of being in remission so we cant guarantee this is a permanent condition | Sustained uresponsiveness is better for me | The term "remission" was proposed by a limited number of authors in 2018 (https://doi.org/10.1016/j.jaci.2017.11.005) as the word is commonly used to describe autoimmune disease, so why not allergy... Personally, I prefer SU rather than remission. I see others do too... so perhaps there should be a vote as to whether to go with one phrase or the other, or indeed both. Several weeks is vague - ideally need to specifiy this, and this should form part of the definition e.g. 4 week-SU, 8 week-SU. Some studies now pushing out to 6+months. SO time interval really needs to be specified. There are many ways to prove/disprove SU - tolerance of serving portion is just one "cut-off"... again, this needs to be defined. How do you define tolerance? Many people still have low grade symptoms, eg. itchy mouth. Does that mean they don't tolerate a dose?? Who decides what is toelrated or not? A better description might be: Ability of a person with food allergy to consume a larger amount of food than they could tolerate before an intervention without having an allergic reaction, having paused treatment for a STATED period of TIME... | I like remission as it is more accessible to all stakeholder groups - patients, clinicians, policy makers **Strongly disagree with "Ability .... to consume a larger amount.... than they could tolerate before an intervention..." = this is describing desensitisation. THe disctinction should be that there is "an absence of clinical reactivity" ie the patient should pass a standard diagnostic challenge to confirm that at this time there is no evidence of clinical allergy. Persistence of an increased threshold after a period of withdrawal should be referred to as "sustained desensitisation", which has been shown with Viaskin Peanut. I will add this as a new outcome term. Disagree with "after having Paused treatment for a period of..." - this presumes patient will continue on therapy which is not necessarily the case. More accurate to say "after having withdrawn treatment for a period of..." Would prefer to find agreement on a minimum duration of elimination that can identify remission; however i suspect this will be difficult, in which case I agree with the suggestion to specify the elimination period applied when testing for SU eg 4 week-SU, 8 week-SU. Don't agree with Paul's point that in remission "underlying food allergy is still present" - we dont know that this is the case. Our data shows that although sIgE may still be detectiable, levels are significnatly reduced compared to baseline and more importantly, gene connections have been rewired from allergic to regulatory model. Also there is no evidence of clinical allergy ( 4g or 5g peanut challenge) off therapy for 4 or 8 weeks (after desensitisation effects on mast cells/basophils should have dissipated) - might be that sIgE levels are detectable because of half life and not from new production. | Agree with Mimi. Key feature of remission is that there is no need for a rigid dosing regime, and that free consumption in daily life is essential. | .- I also prefer SU, although remission has been used .- as happens with desensitization, we might need to be more detailed on relevant parameters as to what dose, the period off therapy .- Some other difficulties in this proposed definition is that some explanations might limit a greater agreement on it in the future: “without having an allergic reaction” (previously commented), “standard serving” (not all SU aim for an standard serving, what is an “standard” serving of peanuts?) | ||||||||||||||||
7 | 4. | Physiological/clinical | Symptoms Consider renaming to "Allergy-specific symptoms" | Occurrence and frequency of allergy-specific symptoms (e.g. tingling or itching; a raised, itchy red rash (hives); swelling of the face, mouth (angioedema), throat or other areas of the body; difficulty swallowing; wheezing or shortness of breath; feeling dizzy and lightheaded; feeling sick (nausea) or vomiting; abdominal pain or diarrhoea; anaphylaxis; hay fever-like symptoms, such as sneezing or itchy eyes (allergic conjunctivitis) due to an intervention, accidental exposure to the same allergen, or by accidental exposure to a different allergen. | allergy specific symptoms | Allergy-spsesific symptoms | I don't understand why you need the wording in blue. The description is about allergic symptoms, not the specific trigger. Or are you trying to mix the two? ie. rather than "allergic symptoms", you mean specific symptoms to a specific trigger... in which case make that clear | Suggest remove "feeling sick (nausea) since this is such a soft symptom ubiquitous to many conditions and if there are GI symptoms there would be vomiting (immediate reaction) or abdo pain (EoE). Could replace "feeling dizzy or lighheaded" with "fainting" - former is also a bit of a 'soft' symptom. ** Hoarse voice is missing from the list of symptoms - suggest include. | Just curious as to how these will be differentiated between a food-related symptom and other allergic comorbidities? Eg. hay-fever like symptoms due to seasonal rhinitis. Will there be an attempt to link to food consumption? Or just frequency of any of these symptoms regardless of cause? | With symptoms you mean adverse events during the treatment? I guess so, as you state “due to an intervention”. I would be more clear on this and say if you mean adverse events in the course of a treatment (either due to therapy or accidental exposures). I think this is a relevant outcome, but it needs a lot more of granularity in order to really become an outcome that can be compared from study to study. Different scales have been used, a lot of debate open around the concept of anaphylaxis from a clinician vs regulatory point of view | |||||||||||||||||
8 | 5. | Physiological/clinical | Immune response Consider renaming to "Biological markers" | Measurement of biological markers (e.g. IgE, IgG4, and IgA antibody levels to food protein, BAT test, MCAS test) or allergy tests (e.g. SPT), gut microbiome assessment. | biological markers | biomarkers or biological markers is better as not alll of them will necessarily be immunological | Biological markers | Immune response is not the same as biomarker. Which one are you intending to describe here? | Suggest "levels of specific IgE, IgG4, and IgA to food protein..." Delete "Allergy Tests" and just go with "Skin Prick Test" because sIgE is also an allergy test and there are no other valid clinical tests for food allergy (at this time) that could be included here (eg patch test is not really utilised as a standalone for food allergy) Dont agree with including microbiome assessment - this is not a validated "biomarker" and it is not technically speaking "Immune response" either. If you decide to include microbiome then should also include gene expression, epigentics, metabolomics, proteomics etc etc etc .... suggest remove. | As happened with symptoms, this is a too huge field as to just state “immune response”. There are great experts in the field in within the group, and I think that biomarkers solely should need for several proposals | |||||||||||||||||
9 | 6. | Physiological/clinical | Allergic comorbidities | Occurrence of new cases of other allergic comorbidities (e.g. eosinophilic esophagitis, eczema, asthma, allergic rhintitis etc.), the change of severity of previously existing comorbidities or remission. | ok | ok | Hang on... why new co-morbidities. A co-morbidity is a co-morbidity. Whether it is existing or new is a different concept. | Not limited to just "new cases", and if it is a new case then it is not a comorbidity yet... suggest replace the entire first sentence with "Occureence of new cases of other allergic disorders and exacerbations of existing allergic comorbidities, such as EoE, eczema, asthma, allergic rhinitis etc). " I would replace the phrase ".... the change of severity of previously existing comorbidities or remission" with a separate sentence "For existing allergic comorbidities, frequency and severity of exacerbations may increase, decrease or remain the same." - This adds a change in frequency of exacerbations (as well as severity). I have not included "remission" because we are not proposing to challenge with allergen chamber / patch test etc to determine if the comorbidity has gone into remission vs improved control. Also since exacerbations may increase, decrease or remain the same, i dont think we need to select improvement specifically. | If onset of new allergic diseases associated (potentially of confirmed) to the therapy, it should be included in “Symptoms” or better named as adverse events. If new diseases apparently not associated to the therapy, still would represent some kind of Pharmacovigilance or “phase IV” evaluation of the therapy. Worsening of previously diseases (ie asthma), might be due to natural evolution or interaction. Overall, I don´t see this one as a good outcome. It is in the grey zone, and overlaps with safety outcomes | ||||||||||||||||||
10 | 7. | Functioning | Satisfaction with intervention | The degree to which intervention/services fulfilled the expectations of the person with food allergy and/or their carers | ok | ok | OK | I like the concept, but I don´t know if it has been really used so far. It can be meaningful for patients and regulators and relevant for the decision-making process. As far as I know there are no validated tools, and definitively nothing really developed specifically for food AIT. Another concept that might be considered is Burden of the treatment (the other side of the same coin), which HAS been measured, but again, only in very small number of trials | |||||||||||||||||||
11 | 8. | Functioning | Meet initial expectations from an intervention | The degree to which the expectation (anticipation or the belief) about what is to be encountered in an intervention or in the healthcare system will be met. | ok | ok | This is really unclear and confusing. The outcome "meet intiial expectations from an intervention" doesnt align with the desscription? It's unclear to me what we are trying to measure here. If it is to assess the patient /family expectation BEFORE treatment of what their treatmetn will offer then I would suggest the outcome should be "Treatment goals of the patient and family" and refine the description to more clearly articulate the outcome. | Or are you trying to differentiate between the treatment experience (ie. how well the patient was prepared for going through an immunotherapy regime) vs. how well the eventual outcome was aligned with their goals? | This is too overlapping with satisfaction with the intervention. I would suggest to merge Satisfaction with meeting initial expectations as satisfaction is heavily influence by meeting initial expectations. I find it easier to measure satisfaction than meeting expectations | ||||||||||||||||||
12 | 9. | Functioning | Food-related psychological impact | Anxiety (including phobias), distress or worries related to food social impairments associated with food avoidance or consumption, and symptoms caused by intervention and accidental exposures. | ok | ok | What about self-efficacy (ie row 16) - ability to self-manage the condition? That is different from anxiety/distress etc, but also impacts on psychological wellbeing | Why limit to "... food social impairments..." . Shouldnt this include anxiety from any source related to the presence of food allergy with 'social impairments' being only one possible cause? Several other sources of anxiety are not listed - eg upredictability of reactions, lack of control in social settings, peer pressure, etc etc There are other psychological impacts other than anxiety and I'm not sure we should group phobia with anxiety...suggest we keep it broad and include anxiety, pscyhological distress or phobia etc etc. | I'm not sure social/lifestyle impairments and psychological impairment are the same thing, even though they are interrelated. The first refers to the practical limitations placed on an individual / family, and the second relates to mental health. It is possible for only one of these to be impaired. Maybe separate them out? | A CHANGE in food related psychological impact could be measured and could be considered a relevant outcome. | |||||||||||||||||
13 | 10. | Functioning | Food allergy-related quality of life | The effects of a food allergy and its consequent therapy upon a person with food allergy and their carers, as perceived by food allergic individual/carer (to add domains as examples) | ok | ok | Could clarify that this measure is a combined measure that includes some assessment of anxiety and emotional distress | Can probably get a standardized definition of health-related quality of life from the literature. Are you planning to differentiate quality of life from health utility? | Probably this is the best outcome to measure also the previous one. Food related psychological impact is a mixture of several areas of psychological impact of the therapy, of food allergy, and the patient´s background itself. I would bet for this one, as there is also relevant work on the topic with validated tools on the field. | ||||||||||||||||||
14 | 11. | Functioning | Adherence | The extent to which a person's behaviour (e.g. taking medication, following a diet, and/or executing lifestyle changes) corresponds with agreed recommendations from a health care provider. | ok | ok | this overlaps a bit with item 15 - to delineate this item, could stipulate this item as "adhreance to management" and #15 to "Confidence and competence in seeking cooperation from others to assist with food allergy management" | As per Mimi. | Interesting, difficult to measure outside the clinical trial setting and data coming from clinical trial will probably not mirror real life adherence | ||||||||||||||||||
15 | 12. | Functioning | Social role-functioning and relationship problems | Food allergy impact on connecting with others, including family members and friends, maintaining and creating new friendships and personal/romantic relationship and social activities. | ok | ok | This overlaps with Item 9. Maybe take the social and lifestyle limitations out of 9? | ||||||||||||||||||||
16 | 13. | Functioning | Impact on work, studies or extracurricular activities | Impact of food allergy on work, study, attendance, engagement/ participation in extracurricular activities | ok | ok | As for 12. | Associated, not the same, but close to all the QoL questions. I´m worried on potential overlapping of these concepts Also, it should be clarified that it should be measured the impact of the therapy on Social role-functioning… as this might be also affected by food allergy itself, and as we´re evaluating outcomes for food AIT therapies, a way to understand the part of impairment/improvement due to the therapy has to be elucidated. For the rest of Functioning outcomes, all are interesting. In order to propose them (eventually) as core outcomes, we have to consider to which extent these can be meassured independently or better be meassured as a whole in a condensed QoL evaluation. In my humble opinion, the degree of interaction between all these functioning evaluations is very high and aiming at measuring them independently might represent a bias. In my opinion, and I´m not an expert in QoL, an overall measurement of QoL integrating all these aspects will balance their interactions and will be a more fair evaluation of functioning aspects | |||||||||||||||||||
17 | 14. | Functioning | Stigma | Fear or experiences of being discriminated against, bullied, excluded from activities, ignored, including by employer/school/nursery/university, medical professionals, social groups, family/friends/neighbours, or others | ok | ok | OK | ||||||||||||||||||||
18 | 15. | Functioning | Food allergy management behaviour Consider renaming to "Self- or caregiver food allergy management behaviour" | Degree to which confidence, competence and motivation exists to manage food allergy (e.g. being able to communicate about allergies at restaurants, carrying and using auto-injectors and other medicines (e.g. antihistamines, inhaled steroids). | food allergy management behavior | agree | Also called "self-efficacy" in the literature. | ||||||||||||||||||||
19 | 16. | Resource use | Impact on the household | The way in which food allergy impacts people living with a person with food allergy. | ok | ok | I think you need to be specific about the Impacts you are referring to here. It should only be things that are not captured in the items above where you refer to caregiver QOL / functioning / psychological wellbeing etc. By "Resource Use" I'm assuming you are referring to ability to work? | ||||||||||||||||||||
20 | 17. | Resource use | Economic impact | Financial impact resulting from the costs of medications, food, and non-health related costs due to food allergy. Frequency of seeing healthcare professionals (e.g., doctor, psychotherapist, psychologist), taking rescue medications, returning to the hospital or emergency care, including complementary/alternative medicine (e.g., acupuncturists, naturopaths); indirect costs (time loss, lost productivity and opportunity costs due to food allergy); the costs to the healthcare system. | ok | ok | This is very broad and will have overlap between costs related to therapy as well as costs related to disease all mixed together. Suggest we try to separate out - costs of FA when taking an immunotherapy; costs of FA when avoiding the allergen; etc. I would suggest adding a separate outcome for COST effectiveness of treatment - that is both during intervention and then long-term cost effectiveness in the real world. | I don't agree with Mimi here - I think it is important to get the list of cost items clear, and then the timing of when these are measured will depend on the research question. I think you've got most of the common costs that are considered in economic evaluations, only one I would potentially add is travel time for appointments, and emergency transport (ambulance). Will also be important to differentiate between type of health professional (not just frequency). | |||||||||||||||||||
21 | Comment from Kate: Should we consider adding 'TOLERANCE' and 'Adverse events' as outcome measures? | Comment from Carmen: Tolerance cant be added because you have desesnitizationand sustained unresponsiveness (remission) which are diferent degrees of tolerance. A way to add this will be to degranulate the definitios more but it can be complicated to explain in layman termns. | I agree to be added "adverse events" | Adverse events should be added | |||||||||||||||||||||||
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23 | Suggested additional outcomes (Mimi) | Long-term outcomes - remission, DS, reactions, cost impact | This could be separated out into individual items and described accordingly | ||||||||||||||||||||||||
24 | Sustained Desensitisation | Ability of a person with food allergy to consume a larger amount of food than they could tolerate before an intervention without having an allergic reaction, after having paused treatment for a period of, at least, several weeks. The person remains food allergic and will react to larger amounts of food that exceed their reaction threshold amount. Sustained desensitisation should be confirmed by performing a food challenge (a medical procedure in which a food is eaten slowly, in gradually increasing amounts, under medical supervision, to accurately diagnose or rule out a true food allergy) weeks after treatment discontinuation. | |||||||||||||||||||||||||
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