Bilastine for the treatment of allergic rhinoconjunctivitis and urticaria: results from an international Delphi study.

Background: Second-generation oral H1-antihistamines, including bilastine, represent the emerging treatments of allergic rhinitis (including rhinoconjunctivitis) and chronic urticaria in both adults and children. This study analyses available evidence supporting the use of bilastine amongst second-generation antihistamines for the symptomatic treatment of allergic rhinitis and urticaria in adults and children. Methods: Consensus amongst experts from 17 countries on the ideal treatment of rhinitis and urticaria, and the specific role of bilastine was measured by means of a modified Delphi process. A total of 12 statements were voted on by the experts using a five-point Likert scale (1 = strongly disagree; 2 = disagree; 3 = undecided; 4 = agree; 5 = strongly agree). The definition of consensus was set at a minimum of 80% concordance for 4+5 scores (agree or strongly agree). Results: All proposed statements reached consensus, with a concordance of ≥98% for five statements and ≥96% for seven. Conclusions: The wide consensus obtained for the proposed statements suggests a prominent role for bilastine in the management of allergic rhinitis and urticaria.

Impaired high-density lipoprotein function and endothelial barrier stability in severe anaphylaxis.

BACKGROUND: Growing evidence demonstrates the importance of high- and low-density lipoprotein cholesterol in certain immune and allergy-mediated diseases. OBJECTIVE: This study aimed to evaluate levels of high- and low-density lipoprotein cholesterol and apolipoproteins A1 and B in sera from a cohort of patients presenting with hypersensitivity reactions. We further assessed the function of high-density lipoprotein particles as well as their involvement in the molecular mechanisms of anaphylaxis. METHODS: Lipid profile determination was performed in paired (acute and baseline) serum samples from 153 patients. Thirty-eight experienced a non-anaphylactic reaction and 115 had an anaphylactic reaction (88 moderate and 27 severe). Lecithin cholesterol acyl transferase activity was assessed in patient sera, and we also evaluated macrophage cholesterol efflux in response to the serum samples. Last, the effect of anaphylactic-derived high-density lipoprotein (HDL) particles on the endothelial barrier was studied. Detailed methods are provided in the Methods section in this article's Online Repository available at www.jacionline.org. RESULTS: Serum samples from severe anaphylactic reactions show statistically significant low levels of HDL cholesterol, low-density lipoprotein cholesterol, and apolipoproteins A1 and B, which points to their possible role as biomarkers. Specifically, HDL particles play a protective role in cardiovascular diseases. Using functional human serum cell assays, we observed impaired capacity of apolipoprotein B-depleted serum to induce macrophage cholesterol efflux in severe anaphylactic reactions. In addition, purified HDL particles from human anaphylactic sera failed to stabilize and maintain the endothelial barrier. CONCLUSION: These results encourage further research on HDL functions in severe anaphylaxis, which may lead to new diagnostic and therapeutic strategies.

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.

Circulating serum profile of small non-coding RNAs in patients with anaphylaxis beyond microRNAs.

Introduction: Anaphylaxis is the most severe manifestation of allergic disorders. Currently, an increasing number of cells, pathways and molecules involved in the etiopathogenesis of anaphylaxis are being discovered. However, there are no conclusive biomarkers to confirm its diagnosis. Small non-coding RNAs (sncRNAs) are 18-200 nucleotide molecules that can be divided into: microRNAs (miRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), transference RNA derived fragments (tRFs) and YRNA derived fragments (YRFs). These molecules participate in cell-cell communication modulating various physiological processes and have been postulated as non-invasive biomarkers of several pathologies. Therefore, in this study we characterized the serum circulating profile of other sncRNA beyond miRNAs in two populations of 5 adults and 5 children with drug- and food-mediated anaphylaxis, respectively. Methods: Samples were obtained from each patient under two different conditions: during anaphylaxis and 14 days after the reaction (control). The sncRNA analysis was carried out by Next Generation Sequencing (NGS). Results: A total of 671 sncRNAs (3 piRNAs, 74 snoRNAs, 54 snRNAs, 348 tRFs and 192 YRFs) were identified in adults with drug-induced anaphylaxis, while 612 sncRNAs (2 piRNAs, 73 snoRNAs, 52 snRNAs, 321 tRFs and 164 YRFs) were characterized in children with food-mediated anaphylaxis. However, only 33 (1 piRNA, 4 snoRNAs, 1 snRNAs, 7 tRFs and 20 YRFs) and 80 (4 snoRNAs, 6 snRNAs, 54 tRFs and 16 YRFs) of them were statistically different between both conditions, respectively. Among them, only three (Y_RNA.394, Y_RNA.781 and SCARNA2) were common to both adults and children analysis. Discussion: This study provides a differential profile of circulating serum sncRNAs beyond miRNAs in patients with anaphylaxis, postulating them as candidate biomarkers for this pathological event and as novel mediators of the reaction.

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.

Addressing common questions on food oral immunotherapy: a practical guide for paediatricians.

Food allergy has been increasing in prevalence in most westernised countries and poses a significant burden to patients and families; dietary and social limitations as well as psychosocial and economic burden affect daily activities, resulting in decreased quality of life. Food oral immunotherapy (food-OIT) has emerged as an active form of treatment, with multiple benefits such as increasing the threshold of reactivity to the allergenic food, decreasing reaction severity on accidental exposures, expanding dietary choices, reducing anxiety and generally improving quality of life. Risks associated with food immunotherapy mostly consist of allergic reactions during therapy. While the therapy is generally considered both safe and effective, patients and families must be informed of the aforementioned risks, understand them, and be willing to accept and hedge these risks as being worthwhile and outweighed by the anticipated benefits through a process of shared decision-making. Food-OIT is a good example of a preference-sensitive care paradigm, given candidates for this therapy must consider multiple trade-offs for what is considered an optional therapy for food allergy compared with avoidance. Additionally, clinicians who discuss OIT should remain increasingly aware of the growing impact of social media on medical decision-making and be prepared to counter misconceptions by providing clear evidence-based information during in-person encounters, on their website, and through printed information that families can take home and review.

Novel mediator in anaphylaxis: decreased levels of miR-375-3p in serum and within extracellular vesicles of patients.

Introduction: Anaphylaxis is among the most severe manifestations of allergic disorders, but its molecular basis remains largely unknown and reliable diagnostic markers are not currently available. MicroRNAs (miRNAs) regulate several pathophysiological processes and have been proposed as non-invasive biomarkers. Therefore, this study aims to evaluate their involvement in anaphylactic reaction and their value as biomarkers. Methods: Acute (anaphylaxis) and baseline (control) serum samples from 67 patients with anaphylaxis were studied. Among them, 35 were adults with drug-induced anaphylaxis, 13 adults with food-induced anaphylaxis and 19 children with food-induced anaphylaxis. The circulating serum miRNAs profile was characterized by next-generation sequencing (NGS). For this purpose, acute and baseline samples from 5 adults with drug-induced anaphylaxis were used. RNA was extracted, retrotranscribed, sequenced and the readings obtained were mapped to the human database miRBase_20. In addition, a system biology analysis (SBA) was performed with its target genes and revealed pathways related to anaphylactic mediators signaling. Moreover, functional and molecular endothelial permeability assays were conducted with miR-375-3p-transfected cells in response to cAMP. Results: A total of 334 miRNAs were identified, of which 21 were significant differentially expressed between both phases. Extracellular vesicles (EVs) were characterized by Western blot, electron microscopy and NanoSight. A decrease of miR-375-3p levels was determined by qPCR in both serum and EVs of patients with anaphylaxis (****p<.0001). Precisely, the decrease of miR-375-3p correlated with the increase of two inflammatory cytokines: monocyte chemoattractant protein-1 (MCP-1) and granulocyte macrophage colony-stimulating factor (GM-CSF). On the other hand, functional and molecular data obtained showed that miR-375-3p partially blocked the endothelial barrier maintenance and stabilization by disassembly of cell-cell junctions exhibiting low Rac1-Cdc42 levels. Discussion: These findings demonstrate a differential serum profile of circulating miRNAs in patients with anaphylaxis and exhibit the miR-375-3p modulation in serum and EVs during drug- and food-mediated anaphylactic reactions. Furthermore, the in silico and in vitro studies show a negative role for miR-375-3p/Rac1-Cdc42 in the endothelial barrier stability.

CHOICE international survey: Clusters of allergen immunotherapy prescription from French and Spanish cohorts.

Background: There is no description of the drivers of prescription for allergen immunotherapy (AIT) for respiratory allergic diseases. Methods: A prospective, multicentre, observational, non-interventional real-life study was performed in France and Spain for 20 months. Data were gathered using 2 different questionnaires, anonymously collected in an online platform. No names of AIT products were recorded. Multivariate analysis and unsupervised cluster analysis were performed. Results: One hundred and three physicians (50.5% from Spain and 49.5% from France) reported 1735 patients (433 in France and 1302 in Spain), 47.9% males, 64.8% adults with a mean age 26.2 years old. They suffered from allergic rhinitis (99%), allergic conjunctivitis (70.4%), allergic asthma (51.8%), atopic dermatitis (13.9%), and food allergy (9.9%). A clustering analysis based on 13 predefined relevant variables for AIT-prescription identified 5 different clusters, each of them including information regarding doctor's profile and patient demographics, baseline disease characteristics, and main AIT indication: 1) Looking at the future: focusing on asthma prevention (n = 355), 2) Efficacy after discontinuation of AIT (n = 293), 3) Fighting severe allergic disease (n = 322), 4) Looking at the present, facing current symptoms (n = 265) and 5) Doctor's own clinical experience (n = 500). Each one of these clusters have specific patients' and doctors' characteristics, representing distinctive AIT prescription drivers. Conclusion: Using data-driven analysis, we identified for the first time some reasons and patterns of AIT prescriptions in real-life clinical settings. There is no uniform indication for prescribing AIT, which varies amongst patients and doctors with multiple but specific drivers, taking into account several relevant parameters.

Food Immunotherapy: Dissecting Current Guidelines and Navigating the Gray Zone.

Food allergy is a common, chronic disease that is burdensome for patients and families, with multiple dietary and social limitations and a significant psychological impact stemming from the fear of accidental exposures and potentially severe, life-threatening reactions. Until recently, the only management option consisted of strict food avoidance. Food allergen immunotherapy (food AIT) has emerged as an alternative, active intervention to strict food avoidance, with a multitude of research studies supporting its efficacy and good safety profile. Food AIT results in a raise of allergenic threshold, which provides several benefits to food-allergic patients, including protection from accidental exposures, potentially decreased severity of allergic reactions on unintentional exposures, and improvement in quality of life. In the last few years, multiple independent reports have been published proposing strategies to implement food oral immunotherapy in U.S. clinics, although formal guidelines are currently lacking. Because food immunotherapy is gaining traction, popularity, and interest among both patients and health care providers, many physicians look for guidance on how to implement this intervention in their daily practice. In other parts of the world, use of this treatment has prompted the development of various guidelines from allergy societies. This rostrum discusses currently available guidelines on food AIT from different areas of the world, describes and comments on their similarities and differences, and highlights unmet needs in this area of therapy.

Clinical outcomes of efficacy in food allergen immunotherapy trials.

PURPOSE OF REVIEW: With food allergy affecting millions of children worldwide, the consolidation of food allergen immunotherapy represents an encouraging therapeutic option, that might expand in the next few years to reach greater number of candidates. This review aims at providing a critical overview of the efficacy outcomes employed in food allergen immunotherapy trials (AIT). RECENT FINDINGS: Understanding efficacy endpoints rely on identifying what and how these are being measured. Desensitization, as the efficacy of the therapy to increase the patient's reactivity threshold to the food during therapy, and Sustained Unresponsiveness, withholding such efficacy even if the therapy is withdrawn, are nowadays considered the main parameters of efficacy evaluation. Quality of life is a promising variable to capture food AIT impact from the patient's perspective.There is a relevant degree of heterogeneity across studies in outcomes definitions and also in oral food challenges design, the tool that is more spread to assess results, hampering study comparison. SUMMARY: Interpreting the results of a clinical trial, and comparing data from different studies is an important task, both for the researcher and the clinician, that should be done after a careful analysis of the outcomes and the evaluation tools used.

WAO consensus on DEfinition of Food Allergy SEverity (DEFASE).

Background: While several scoring systems for the severity of anaphylactic reactions have been developed, there is a lack of consensus on definition and categorisation of severity of food allergy disease as a whole. Aim: To develop an international consensus on the severity of food allergy (DEfinition of Food Allergy Severity, DEFASE) scoring system, to be used globally. Methods Phase 1: We conducted a mixed-method systematic review (SR) of 11 databases for published and unpublished literature on severity of food allergy management and set up a panel of international experts. Phase 2: Based on our findings in Phase 1, we drafted statements for a two-round modified electronic Delphi (e-Delphi) survey. A purposefully selected multidisciplinary international expert panel on food allergy (n = 60) was identified and sent a structured questionnaire, including a set of statements on different domains of food allergy severity related to symptoms, health-related quality of life, and economic impact. Participants were asked to score their agreement on each statement on a 5-point Likert scale ranging from "strongly agree" to "strongly disagree". Median scores and percentage agreements were calculated. Consensus was defined a priori as being achieved if 70% or more of panel members rated a statement as "strongly agree" to "agree" after the second round. Based on feedback, 2 additional online voting rounds were conducted. Results: We received responses from 92% of Delphi panel members in round 1 and 85% in round 2. Consensus was achieved on the overall score and in all of the 5 specific key domains as essential components of the DEFASE score. Conclusions: The DEFASE score is the first comprehensive grading of food allergy severity that considers not only the severity of a single reaction, but the whole disease spectrum. An international consensus has been achieved regarding a scoring system for food allergy disease. It offers an evaluation grid, which may help to rate the severity of food allergy. Phase 3 will involve validating the scoring system in research settings, and implementing it in clinical practice.

Criteria used by health professionals on the selection of allergen immunotherapy in real clinical practice: Methodology.

Background: Allergen immunotherapy (AIT) is today the only etiological therapy for respiratory allergic diseases, including allergic rhinitis, allergic conjunctivitis, and allergic asthma. Even though interest in real-world data has recently increased, publications mainly focus on short-term and long-term efficacy and safety of AIT. Indeed, information is still lacking regarding the "key parameters" or "drivers of prescription" used by doctors to prescribe AIT or by the patients to accept AIT as treatment for their respiratory allergic disease. Examining these factors is therefore the main goal of the CHOICE-Global Survey: "Criteria Used by Health Professionals on the Selection of Allergen Immunotherapy in Real Clinical Practice: An international academic electronic survey". Methods: We present the methodology of the CHOICE-Global Survey, an academic, prospective, multicenter, observational, transversal, web-based e-survey, conducted in real-life clinical settings designed to collect data from 31 countries representing 9 global different socio-economic and demographic regions. In the present document, we describe the survey, how it was conceived and developed, how data are stored and analyzed, and the different steps that will provide this information to the allergy community. Conclusions: The CHOICE-Global Survey will be able to provide, from an academic point of view, information on the drivers of prescription of AIT in real-life practice and improve understanding regarding the key parameters considered by doctors and patients for such therapy.

Personalized diagnostic approach and indirect quantification of extravasation in human anaphylaxis.

BACKGROUND: Anaphylaxis is the most acute and life-threatening manifestation of allergic disorders. Currently, there is a need to improve its medical management and increase the understanding of its molecular mechanisms. This study aimed to quantify the extravasation underlying human anaphylactic reactions and propose new theragnostic approaches. METHODS: Molecular determinations were performed in paired serum samples obtained during the acute phase and at baseline from patients presenting with hypersensitivity reactions. These were classified according to their severity as Grades 1, 2 and 3, the two latter being considered anaphylaxis. Tryptase levels were measured by ImmunoCAP, and serum protein concentration was quantified by Bradford assay. Human serum albumin (HSA) and haemoglobin beta subunit (HBB) levels were determined by Western blot and polyacrylamide gel electrophoresis, respectively. RESULTS: A total of 150 patients were included in the study. Of them, 112 had experienced anaphylaxis (83 and 29 with Grade 2 and 3 reactions, respectively). Tryptase diagnostic efficiency substantially improved when considering patients' baseline values (33%-54%) instead of the acute value threshold (21%). Serum protein concentration and HSA significantly decreased in anaphylaxis (p < .0001). HSA levels dropped with the severity of the reaction (6% and 15% for Grade 2 and 3 reactions, respectively). Furthermore, HBB levels increased during the acute phase of all hypersensitivity reactions (p < .0001). CONCLUSIONS: For the first time, the extravasation underlying human anaphylaxis has been evaluated based on the severity of the reaction using HSA and protein concentration measurements. Additionally, our findings propose new diagnostic and potential therapeutic approaches for this pathological event.

Children and caregiver proxy quality of life from peanut oral immunotherapy trials.

BACKGROUND: Health-related quality of life (HRQoL) is significantly and substantially reduced in individuals with peanut allergy due to many factors associated with unanticipated or potentially fatal reactions. Further insight on the impact of peanut oral immunotherapy in managing peanut allergy on HRQoL is needed. The aim of this analysis was to assess effects of peanut (Arachis hypogaea) allergen powder-dnfp (PTAH), a biologic drug for peanut oral immunotherapy, on HRQoL from three phase 3 and two follow-on trials of PTAH. METHODS: HRQoL assessments from participants aged 4-17 in the PALISADE (ARC003), ARC004 (PALISADE follow-on), ARTEMIS (ARC010), RAMSES (ARC007), and ARC011 (RAMSES follow-on) trials were included in this analysis. Responses on the Food Allergy Quality of Life Questionnaire (FAQLQ) and Food Allergy Independent Measure (FAIM) were evaluated by age group and respondent (self or caregiver proxy). Data were analyzed with descriptive statistics and Student t tests. RESULTS: Baseline FAQLQ and FAIM total scores appeared comparable between PTAH- and placebo-treated participants. Self and caregiver proxy-reported total scores on the FAQLQ for PTAH-treated participants generally improved at trial exit versus baseline; FAIM total scores improved throughout all trials. The tendency for improvement in FAQLQ total scores from baseline for PTAH appeared larger in self versus caregiver proxy-reports. Between treatment groups, PTAH was generally favored in the PALISADE and ARTEMIS trials; differences varied in the RAMSES trial based on age and respondent types. CONCLUSIONS: PTAH for the management of peanut allergy in children appeared to have a beneficial effect on HRQoL in trials. Improvements were seen despite rigors of trial participation.

Allergic diseases and immunodeficiencies in children, lessons learnt from COVID-19 pandemic by 2022: A statement from the EAACI-section on pediatrics.

By the April 12, 2022, the COVID-19 pandemic had resulted in over half a billion people being infected worldwide. There have been 6.1 million deaths directly due to the infection, but the pandemic has had many more short- and long-term pervasive effects on the physical and mental health of the population. Allergic diseases are among the most prevalent noncommunicable chronic diseases in the pediatric population, and health-care professionals and researchers were seeking answers since the beginning of pandemic. Children are at lower risk of developing severe COVID-19 or dying from infection. Allergic diseases are not associated with a higher COVID-19 severity and mortality, apart from severe/poorly controlled asthma. The pandemic disrupted routine health care, but many mitigation strategies, including but not limited to telemedicine, were successfully implemented to continue delivery of high-standard care. Although children faced a multitude of pandemic-related issues, allergic conditions were effectively treated remotely while reduction in air pollution and lack of contact with outdoor allergens resulted in improvement, particularly respiratory allergies. There is no evidence to recommend substantial changes to usual management modalities of allergic conditions in children, including allergen immunotherapy and use of biologicals. Allergic children are not at greater risk of multisystem inflammatory syndrome development, but some associations with Long COVID were reported, although the data are limited, and further research is needed. This statement of the EAACI Section on Pediatrics provides recommendations based on the lessons learnt from the pandemic, as available evidence.

Managing food allergy: GA2LEN guideline 2022.

Food allergy affects approximately 2-4% of children and adults. This guideline provides recommendations for managing food allergy from the Global Allergy and Asthma European Network (GA2LEN). A multidisciplinary international Task Force developed the guideline using the Appraisal of Guidelines for Research and Evaluation (AGREE) II framework and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. We reviewed the latest available evidence as of April 2021 (161 studies) and created recommendations by balancing benefits, harms, feasibility, and patient and clinician experiences. We suggest that people diagnosed with food allergy avoid triggering allergens (low certainty evidence). We suggest that infants with cow's milk allergy who need a breastmilk alternative use either hypoallergenic extensively hydrolyzed cow's milk formula or an amino acid-based formula (moderate certainty). For selected children with peanut allergy, we recommend oral immunotherapy (high certainty), though epicutaneous immunotherapy might be considered depending on individual preferences and availability (moderate certainty). We suggest considering oral immunotherapy for children with persistent severe hen's egg or cow's milk allergy (moderate certainty). There are significant gaps in evidence about safety and effectiveness of the various strategies. Research is needed to determine the best approaches to education, how to predict the risk of severe reactions, whether immunotherapy is cost-effective and whether biological therapies are effective alone or combined with allergen immunotherapy.