Preparing Patients for Oral Immunotherapy (PPOINT): International Delphi consensus for procedural preparation and consent.

BACKGROUND: Despite the promise of oral immunotherapy (OIT) to treat food allergies, this procedure is associated with potential risk. There is no current agreement about what elements should be included in the preparatory or consent process. OBJECTIVE: We developed consensus recommendations about the OIT process considerations and patient-specific factors that should be addressed before initiating OIT and developed a consensus OIT consent process and information form. METHODS: We convened a 36-member Preparing Patients for Oral Immunotherapy (PPOINT) panel of allergy experts to develop a consensus OIT patient preparation, informed consent process, and framework form. Consensus for themes and statements was reached using Delphi methodology, and the consent information form was developed. RESULTS: The expert panel reached consensus for 4 themes and 103 statements specific to OIT preparatory procedures, of which 76 statements reached consensus for inclusion specific to the following themes: general considerations for counseling patients about OIT; patient- and family-specific factors that should be addressed before initiating OIT and during OIT; indications for initiating OIT; and potential contraindications and precautions for OIT. The panel reached consensus on 9 OIT consent form themes: benefits, risks, outcomes, alternatives, risk mitigation, difficulties/challenges, discontinuation, office policies, and long-term management. From these themes, 219 statements were proposed, of which 189 reached consensus, and 71 were included on the consent information form. CONCLUSION: We developed consensus recommendations to prepare and counsel patients for safe and effective OIT in clinical practice with evidence-based risk mitigation. Adoption of these recommendations may help standardize clinical care and improve patient outcomes and quality of life.

Core Outcome Set for IgE-mediated food allergy clinical trials and observational studies of interventions: International Delphi consensus study 'COMFA'.

BACKGROUND: IgE-mediated food allergy (FA) is a global health concern with substantial individual and societal implications. While diverse intervention strategies have been researched, inconsistencies in reported outcomes limit evaluations of FA treatments. To streamline evaluations and promote consistent reporting, the Core Outcome Measures for Food Allergy (COMFA) initiative aimed to establish a Core Outcome Set (COS) for FA clinical trials and observational studies of interventions. METHODS: The project involved a review of published clinical trials, trial protocols and qualitative literature. Outcomes found as a result of review were categorized and classified, informing a two-round online-modified Delphi process followed by hybrid consensus meeting to finalize the COS. RESULTS: The literature review, taxonomy mapping and iterative discussions with diverse COMFA group yielded an initial list of 39 outcomes. The iterative online and in-person meetings reduced the list to 13 outcomes for voting in the formal Delphi process. One more outcome was added based on participant suggestions after the first Delphi round. A total of 778 participants from 52 countries participated, with 442 participating in both Delphi rounds. No outcome met a priori criteria for inclusion, and one was excluded as a result of the Delphi. Thirteen outcomes were brought to the hybrid consensus meeting as a result of Delphi and two outcomes, 'allergic symptoms' and 'quality of life' achieved consensus for inclusion as 'core' outcomes. CONCLUSION: In addition to the mandatory reporting of adverse events for FA clinical trials or observational studies of interventions, allergic symptoms and quality of life should be measured as core outcomes. Future work by COMFA will define how best to measure these core outcomes.

Flex-IT! Applying "Platform Trials" Methodology to Immunotherapy for Food Allergy in Research and Clinical Practice.

There is an increasing trend in the management of food allergy toward active treatment using allergen immunotherapy (AIT). Although AIT is efficacious, treatment-related adverse events are common, particularly with oral immunotherapy in those with high levels of allergen-specific IgE sensitization. In clinical practice, these adverse events inevitably create challenges: clinicians and patients routinely face decisions whether to alter the dose itself, the frequency of dosing, and the pace of escalation, or indeed discontinue AIT altogether. Flexibility is therefore needed to adapt treatment, particularly in clinical practice, so that participants are "treated-to-target." For example, this may entail a significant change in the dosing protocol or even switching from one route of administration to another in response to frequent adverse events. We refer to this approach as flexible immunotherapy. However, there is little evidence to inform clinicians as to what changes to treatment are most likely to result in treatment success. Classical clinical trials rely, by necessity, on relatively rigid updosing protocols. To provide an evidence base to optimize AIT, the food allergy community should adopt adaptive platform trials, where a "master protocol" facilitates more efficient evaluation, including longer-term outcomes of multiple interventions. Within a single clinical trial, participants are able to switch between different treatment arms; interventions can be added or dropped without compromising the integrity of the trial. Developing platform trials for food AIT may initially be costly, but they represent a significant opportunity to grow the evidence base (with respect to both treatment outcomes and biomarker discovery) at scale. In addition, they could help understand longitudinal disease trajectories that are difficult to study in clinical trials for food allergy due to the time needed to demonstrate changes in efficacy. Finally, their adoption would achieve greater collaboration and consistency in approaches to proactive management of food allergy in routine clinical practice. As a community, we need to actively pursue this with funders and established research collaborations to deliver the very best outcomes for our patients and their families.

Evaluation of clinical outcomes of efficacy in food allergen immunotherapy trials, COFAITH EAACI task force.

Food allergy is a global public health problem that until recent years lacked any aetiological treatment supported by academy, industry and regulators. Food immunotherapy (AIT) is an evolving treatment option, supported by clinical practice and industry trial data. Recent AIT meta-analyses have highlighted the difficulty in pooling safety and efficacy data from AIT trials, due to secondary heterogeneity in the study. An EAACI task force (CO-FAITH) initiated by the Paediatric Section was created to focus on AIT efficacy outcomes for milk, egg and peanut allergy rather than in trial results. A systematic search and a narrative review of AIT controlled clinical trials and large case series was conducted. A total of 63 manuscripts met inclusion criteria, corresponding to 23, 21 and 22 studies of milk, egg and peanut AIT, respectively. The most common AIT efficacy outcome was desensitization, mostly defined as tolerating a maintenance phase dose, or reaching a particular dose upon successful exit oral food challenge (OFC). However, a large degree of heterogeneity was identified regarding the dose quantity defining this outcome. Sustained unresponsiveness and patient-reported outcomes (e.g. quality of life) were explored less frequently, and to date have been most rigorously described for peanut AIT versus other allergens. Change in allergen threshold assessed by OFC remains the most common efficacy measure, but OFC methods suffer from heterogeneity and methodological disparity. This review has identified multiple heterogeneous outcomes related to measuring the efficacy of AIT. Efforts to better standardize and harmonize which outcomes, and how to measure them must be carried out to help in the clinical development of safe and efficacious food allergy treatments.

How Common Are Allergic Reactions During Commercial Flights? A Systematic Review and Meta-Analysis.

BACKGROUND: Global passenger demand for air travel has increased by over 7% annually since 2006, with a strong recovery following the coronavirus disease 2019 (COVID-19) pandemic. Prior to COVID-19, individuals with food allergies reported significant concern and anxiety over the risk of reactions when travelling by air. However, published data of in-flight medical events (IMEs) due to allergic reactions are limited. OBJECTIVE: To undertake a systematic review with meta-analysis to estimate the incidence of IMEs due to allergic reactions on commercial flights. METHODS: We searched MEDLINE, Embase, PsycINFO, and TRANSPORT databases and the Cochrane Register of Controlled Trials for relevant studies reporting IMEs of allergic etiology, published since 1980. Data were extracted in duplicate for meta-analysis, and risk of bias assessed. STUDY REGISTRATION: PROSPERO CRD42022384341. RESULTS: Seventeen studies met the inclusion criteria. At meta-analysis, a pooled estimate of 2.2% (95% confidence interval [95% CI] 1.6%-3.1%) of IMEs are coded as being due to allergic reactions. This may be higher in children (3.1%; 95% CI 1.5%-6.6%). The incidence of allergic IMEs at meta-analysis was 0.7 events per million passengers (95% CI 0.4-1.1). Reassuringly, the rate of allergic IMEs has been stable over the past 30 years, despite increasing passenger numbers and food allergy prevalence. CONCLUSIONS: Allergic reactions coded as IMEs during commercial air travel are uncommon, occurring at an incidence approximately 10 to 100 times lower than that reported for accidental allergic reactions to food occurring in the community. Despite increasing passenger numbers and food allergy prevalence, the rate of allergic IMEs has not changed over the past 3 decades.

Endpoints and Outcomes After Immunotherapy for Food Allergy: What Is Meaningful for Patients?

Multiple novel interventions for food allergy are currently at various stages of development with the goal of reducing or eliminating allergic reactions. However, the relative success of these therapeutics in achieving meaningful, long-term improvements to patients' lives is difficult to determine as there is currently very limited understanding of the degree of alignment between clinical trial efficacy endpoints and patient-centered outcomes. Furthermore, outcome measures used in clinical trials of food allergy immunotherapies vary widely, are often misinterpreted, and not necessarily consistent with what patients expect to achieve through treatment. This review aims to assist clinicians in critically interpreting outcomes reported in clinical trials and accurately communicating risks and outcomes to patients when practicing shared decision-making.

Will Oral Food Challenges Still Be Part of Allergy Care in 10 Years' Time?

Oral food challenges (OFCs) are currently the definitive diagnostic procedure in food allergy. Their design has evolved over the decades to maximize safety, optimize convenience, and address several specific clinical questions. However, they are a resource-intensive investigation that carry a risk for severe allergic reaction in which fatal outcomes, although rare, have been reported. In this review, we explore the many roles that OFC fulfil in the clinical and research settings. We also discuss progress that has been made in developing alternative diagnostic tools and how far these have reached in offering a viable replacement to OFC in clinical practice. Finally, we discuss the ongoing importance of research OFC to improve the future diagnostic capabilities of novel diagnostic tools.

Optimal dose of adrenaline auto-injector for children and young people at risk of anaphylaxis: A phase IV randomized controlled crossover study.

BACKGROUND: Guidelines recommend intramuscular injection of 500 µg adrenaline (epinephrine) for anaphylaxis in teenagers and adults; however, most autoinjectors deliver a maximum 300 µg dose. We evaluated plasma adrenaline levels and cardiovascular parameters (including cardiac output) following self-injection with 300 µg or 500 µg adrenaline in teenagers at risk of anaphylaxis. METHODS: Subjects were recruited to a randomized, single-blind two period crossover trial. Participants received all 3 injections (Emerade® 500 µg, Emerade® 300 µg, Epipen® 0.3 mg) on 2 separate visits (allocated in a randomized block design), at least 28 days apart. Intramuscular injection was confirmed by ultrasound, and heart rate/stroke volume assessed using continuous monitoring. The trial was registered at Clinicaltrials.gov (NCT03366298). RESULTS: Twelve participants (58% male, median 15.4 years) participated; all completed the study. 500 µg injection resulted in a higher and more prolonged peak concentration (p = 0.01) and greater Area-Under-Curve for plasma adrenaline (p < 0.05) compared to 300 µg, with no difference in adverse events. Adrenaline caused a significant increase in heart rate irrespective of dose and device. Unexpectedly, 300 µg adrenaline resulted in a significant increase in stroke volume when delivered with Emerade®, but a negative inotropic effect with Epipen® (p < 0.05). CONCLUSIONS: These data support a 500 µg dose of adrenaline to treat anaphylaxis in individuals >40 kg in the community. The contrasting effects on stroke volume between Epipen® and Emerade®, despite similar peak plasma adrenaline levels, are unexpected. There is an urgent need to better understand differences in pharmacodynamics following adrenaline administration by autoinjector. In the meantime, we recommend adrenaline injection by needle/syringe in the healthcare setting in individuals with anaphylaxis refractory to initial treatment.

Preventing food allergy fatalities.

Fatal anaphylaxis to food is thankfully rare, but every death is a potentially avoidable tragedy. Usually, there will be a coronial inquest to establish the 'how and why' for each death. Reviewing these food allergy-related deaths identifies a number of common themes and risk factors. While some are non-modifiable (such as age, gender and ethnicity), others are and include delayed epinephrine administration and communication difficulties in allergen avoidance. This review highlights the key messages in food allergy-related fatality prevention for healthcare professionals and patients alike, and where available, we explain the evidence behind such recommendations. We describe the data behind the good practice points to facilitate their adoption in routine practice without generating additional anxiety for what is a comparatively rare event. We also propose an information leaflet for patients and carers, developed with patients and endorsed by two major allergy charities, to facilitate dissemination of the recommendations in this review.

Impact of using less objective symptoms to define tolerated dose during food challenges: A data-driven approach.

BACKGROUND: Food challenges (FCs) form the basis for assessing efficacy outcomes in interventional studies of food allergy; however, different studies have used a variety of similar but not identical criteria to define a challenge reaction, including subjective (nonobjective) symptoms occurring in a single-organ system as dose limiting. OBJECTIVE: Our aim was to undertake a secondary analysis of 4 interventional studies to assess the impact of using less objective criteria to determine challenge-stop on reaction thresholds and their reproducibility. METHODS: We analyzed individual participant data, including individual participant data meta-analysis, by using 3 different published challenge-stop criteria: (1) PRACTALL consesus criteria; (2) Consortium for Food Allergy Research version 3 (CoFAR v3) with at least 1 moderate- or severe-grade symptom; or (3) CoFAR v3 with at least 2 mild symptoms occurring in different organ systems. Reproducibility of challenge threshold was also assessed in participants undergoing subsequent repeat FCs. RESULTS: Four studies, with detailed challenge data from a total of 592 participants, were included. Applying CoFAR v3 definitions for dose-limiting symptoms resulted in an underestimate of reaction thresholds compared with those in PRACTALL (P < .001) that is equivalent to almost a single dosing increment when using a semi-log dosing regimen. Reproducibility was also reduced when applying CoFAR v3 (P < .001 [n = 223]). Using the least conservative interpretation of CoFAR v3 (≥2 mild symptoms occurring in different systems) resulted in a significant overestimate of 15% when assessing oral immunotherapy efficacy. Applying a data-driven minor modification to CoFAR v3 resulted in a new set of challenge-stop criteria with validity similar to that of PRACTALL but one that is simpler to implement and in which significant gastrointestinal discomfort with observable decreased activity remains a dose-limiting symptom. CONCLUSION: The use of less objective symptoms to define challenge-stop compromises the reproducibility of the FC as a tool to assess efficacy outcomes in interventional studies, and potentially overestimates the efficacy of the intervention tested.

Reproducibility of food challenge to cow's milk: Systematic review with individual participant data meta-analysis.

BACKGROUND: Cow's milk (CM) is an increasingly common cause of severe allergic reactions, but there is uncertainty with respect to severity of reactions at low-level CM exposure, as well as the reproducibility of reaction thresholds. OBJECTIVE: We undertook an individual participant data (IPD) meta-analysis of studies reporting double-blind, placebo-controlled food challenges in CM to determine the rate of anaphylaxis to low-level exposures and the reproducibility of reaction thresholds. METHODS: We performed a systematic review and IPD meta-analysis of studies reporting relevant data. Authors were contacted to provide additional data and/or clarification as needed. Risk of bias was assessed using the National Institute for Clinical Excellence methodologic checklists. RESULTS: Thirty-four studies were included, representing data from over 1000 participants. The cumulative ED01 and ED05 (cumulative doses causing objective symptoms in 1% and 5% of the at-risk allergic population) were 0.3 (95% confidence interval [CI], 0.2-0.5) and 2.9 (95% CI, 1.6-5.4) mg, respectively. At meta-analysis, 4.8% (95% CI, 2.0-10.9) and 4.8% (95% CI, 0.7-27.1) of individuals reacting to ≤5 mg and ≤0.5 mg of CM protein had anaphylaxis (minimal heterogeneity, I2 = 0%). Then 110 individuals underwent repeat double-blind, placebo-controlled food challenges; the intraindividual variation in reaction threshold was limited to a ½-log change in 80% (95% CI, 65-89) of participants. Two individuals initially tolerated 5 mg CM protein but then reacted to this dose at a subsequent challenge, although neither had anaphylaxis. CONCLUSIONS: About 5% of CM-allergic individuals reacting to ED01 or ED05 exposure might have anaphylaxis to that dose. This equates to 5 and 24 anaphylaxis events per 10,000 patients exposed to an ED01 or ED05 dose, respectively, in the broader CM-allergic population. Most of these anaphylactic reactions would be mild and respond to a single dose of epinephrine.

Risk factors for severe reactions in food allergy: Rapid evidence review with meta-analysis.

This rapid review summarizes the most up to date evidence about the risk factors for severe food-induced allergic reactions. We searched three bibliographic databases for studies published between January 2010 and August 2021. We included 88 studies and synthesized the evidence narratively, undertaking meta-analysis where appropriate. Significant uncertainties remain with respect to the prediction of severe reactions, both anaphylaxis and/or severe anaphylaxis refractory to treatment. Prior anaphylaxis, an asthma diagnosis, IgE sensitization or basophil activation tests are not good predictors. Some molecular allergology markers may be helpful. Hospital presentations for anaphylaxis are highest in young children, yet this age group appears at lower risk of severe outcomes. Risk of severe outcomes is greatest in adolescence and young adulthood, but the contribution of risk taking behaviour in contributing to severe outcomes is unclear. Evidence for an impact of cofactors on severity is lacking, although food-dependent exercise-induced anaphylaxis may be an exception. Some medications such as beta-blockers or ACE inhibitors may increase severity, but appear less important than age as a factor in life-threatening reactions. The relationship between dose of exposure and severity is unclear. Delays in symptom recognition and anaphylaxis treatment have been associated with more severe outcomes. An absence of prior anaphylaxis does not exclude its future risk.

Oral immunotherapy for food allergy in children: is it worth it?

INTRODUCTION: Oral immunotherapy (OIT) is effective at inducing desensitization in food-allergic individuals, and is a valid therapeutic option for those allergic to peanut, cow's milk and egg. However, there is a high rate of dose-related adverse events, and at least one fatality to OIT has been reported. AREAS COVERED: We provide an update on the broader framework of issues which will impact on the availability and uptake of OIT. EXPERT OPINION: The need for standardized products remains controversial. A licensed product exists for peanut-OIT, but OIT can also be safely achieved using peanut-containing foods at much lower cost. For other allergens, OIT can only be done with non-pharma products - something which has been done safely for over 2 decades. There is a need to develop personalized protocols for OIT, particularly for the 20% of patients unable to tolerate standard OIT. Cost-effectiveness is dependent on improved quality of life, but evidence for this is currently lacking, and is a key evidence gap. OIT is likely to be cost-effective, particularly if noncommercial products are used. There may be a trade-off: in patients with lower reaction thresholds, a commercial product may be needed for initial updosing, until a level of desensitization is achieved when they can be switched to natural food products.

Peanut Can Be Used as a Reference Allergen for Hazard Characterization in Food Allergen Risk Management: A Rapid Evidence Assessment and Meta-Analysis.

Regional and national legislation mandates the disclosure of "priority" allergens when present as an ingredient in foods, but this does not extend to the unintended presence of allergens due to shared production facilities. This has resulted in a proliferation of precautionary allergen ("may contain") labels (PAL) that are frequently ignored by food-allergic consumers. Attempts have been made to improve allergen risk management to better inform the use of PAL, but a lack of consensus has led to variety of regulatory approaches and nonuniformity in the use of PAL by food businesses. One potential solution would be to establish internationally agreed "reference doses," below which no PAL would be needed. However, if reference doses are to be used to inform the need for PAL, then it is essential to characterize the hazard associated with these low-level exposures. For peanut, there are now published data relating to over 3000 double-blind, placebo-controlled challenges in allergic individuals, but a similar level of evidence is lacking for other priority allergens. We present the results of a rapid evidence assessment and meta-analysis for the risk of anaphylaxis to a low-level allergen exposure for priority allergens. On the basis of this analysis, we propose that peanut can and should be considered an exemplar allergen for the hazard characterization at a low-level allergen exposure.

Food immunotherapy practice: Nation differences across Europe, the FIND project.

BACKGROUND: Food allergen immunotherapy (FA-AIT) practice is known to vary globally. This project aims to identify and characterize European centres performing FA-AIT. METHODS: An EAACI task force conducted an online survey to gather relevant information regarding FA-AIT practice and setting-specific resources after reviewing the published literature and congress abstracts throughout Europe. RESULTS: We identified 102 FA-AIT centres in 18 countries; only Spain (n = 39) and France (n = 16) had ≥10 such centres. Overall, most facilities were hospital-based (77.5%), publicly funded (80.4%) and delivered FA-AIT as routine clinical care (80.4%). On average, departments had 3 allergists/paediatric allergists and 2 nurses. Surveyed centres had provided FA-AIT for a median of 9 years [1-24] to a median of 105 [5-2415] patients. The estimated total number of treated patients was 24875, of whom 41.3% received AIT for milk, 34.2% egg, 12.8% peanut and 11.7% other foods. Anaphylaxis to AIT doses requiring over 4-6 h of observation was reported by 70.6% of centres, ICU admissions by 10.8% and eosinophilic esophagitis by 45.1%. Quality of life and sustained unresponsiveness were evaluated in 20.6% and 54.9% of centres, respectively. The main contraindications for food AIT were severe asthma (57%-63%), eosinophilic esophagitis (56%-48%) and age below 5 years (47%-41%). CONCLUSIONS: In Europe, FA-AIT is provided mostly in clinical practice. Significant variation is seen in the number of centres per country, facility characteristics and inclusion/exclusion criteria, and in certain aspects of protocols. Potential inequality in access to AIT has been identified as well as the need for education and guidance for treatment standardization.

Global patterns in anaphylaxis due to specific foods: A systematic review.

BACKGROUND: There are increasing global data relating to prevalence of food allergy and food-induced anaphylaxis; however, this is often based on surrogate measures of sensitization rather than objective symptoms at food challenge. In terms of protecting food-allergic consumers from reactions, to our knowledge, there has been no global survey assessing geographic differences in the proportion of anaphylaxis triggered by specific foods. OBJECTIVE: We sought to identify common triggers for food-induced anaphylaxis and how these vary from country to country. METHODS: Systematic review of relevant reports published between January 2010 and November 2020. Results were reported following PRISMA guidelines. Publications were screened and data extracted by 2 independent reviewers, and the risk of bias was assessed. RESULTS: Sixty-five studies (encompassing 41 countries and all 6 regions as defined by the Food and Agriculture Organization of the United Nations) were included. Significant regional variations in the most common triggers of food anaphylaxis were seen; however, in general, there was good agreement between local legislative requirements for allergen disclosure and the most common allergens for each region or nation. CONCLUSIONS: Local legislation for allergen disclosure generally reflects those allergens commonly responsible for food anaphylaxis. Cow's milk and crustaceans appear to cause a higher proportion of anaphylaxis compared to peanut in some regions.