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.

Clinical characteristics and management of pediatric egg-induced anaphylaxis: A cross-sectional study.

BACKGROUND: Egg is the third most common food allergy in children; however, data on pediatric egg-induced anaphylaxis are sparse. OBJECTIVE: To describe the clinical characteristics, management, and outcomes of pediatric egg-induced anaphylaxis. METHODS: Children presenting with anaphylaxis were recruited from 13 emergency departments as part of the Cross-Canada Anaphylaxis Registry, from which data on anaphylaxis triggered by egg were extracted. Multivariate logistic regression was used to determine factors associated with prehospital epinephrine autoinjector (EAI) use and to compare anaphylaxis triggered by egg with other triggers of food-induced anaphylaxis (FIA). RESULTS: We recruited 302 children with egg-induced anaphylaxis. The mean age was 2.6 years (SD = 3.6), and 55.3% were male. Only 39.4% had previously been diagnosed with an egg allergy. Prehospital EAI use was 32.1%, but this was not significantly lower than in other triggers of FIA (P = .26). Only 1.4% of patients required hospital admission. Relative to other triggers of FIA, patients with egg-induced anaphylaxis were significantly younger (P < .001) and exhibited more vomiting (P = .0053) and less throat tightness (P = .0015) and angioedema (P < .001). CONCLUSION: To the best of our knowledge, this is the largest published cohort of pediatric egg-induced anaphylaxis. In this cohort, prehospital EAI use was very low. In addition, we identified certain symptoms that distinguish egg-induced from other triggers of FIA. Taken together, high suspicion is crucial in identifying egg-induced anaphylaxis, given the younger patient demographic and frequent lack of FIA history.

Degree of hydrolysis is a poor predictor of the sensitizing capacity of whey- and casein-based hydrolysates in a Brown Norway rat model of cow's milk allergy.

The use of infant formulas (IFs) based on hydrolyzed cow's milk proteins to prevent cow's milk allergy (CMA) is highly debated. The risk of sensitization to milk proteins induced by IFs may be affected by the degree of hydrolysis (DH) as well as other physicochemical properties of the cow's milk-based protein hydrolysates within the IFs. The immunogenicity (specific IgG1 induction) and sensitizing capacity (specific IgE induction) of 30 whey- or casein-based hydrolysates with different physicochemical characteristics were compared using an intraperitoneal model of CMA in Brown Norway rats. In general, the whey-based hydrolysates demonstrated higher immunogenicity than casein-based hydrolysates, inducing higher levels of hydrolysate-specific and intact-specific IgG1. The immunogenicity of the hydrolysates was influenced by DH, peptide size distribution profile, peptide aggregation, nano-sized particle formation, and surface hydrophobicity. Yet, only the surface hydrophobicity was found to affect the sensitizing capacity of hydrolysates, as high hydrophobicity was associated with higher levels of specific IgE. The whey- and casein-based hydrolysates exhibited distinct immunological properties with highly diverse molecular composition and physicochemical properties which are not accounted for by measuring DH, which was a poor predictor of sensitizing capacity. Thus, future studies should consider and account for physicochemical characteristics when assessing the sensitizing capacity of cow's milk-based protein hydrolysates.

Disproportionate Rates of COVID-19 Among Black Canadian Communities: Lessons from a Cross-Sectional Study in the First Year of the Pandemic.

BACKGROUND: Racialized communities, including Black Canadians, have disproportionately higher COVID-19 cases. We examined the extent to which SARS-CoV-2 infection has affected the Black Canadian community and the factors associated with the infection. METHODS: We conducted a cross-sectional survey in an area of Ontario (northwest Toronto/Peel Region) with a high proportion of Black residents along with 2 areas that have lower proportions of Black residents (Oakville and London, Ontario). SARS-CoV-2 IgG antibodies were determined using the EUROIMMUN assay. The study was conducted between August 15, 2020, and December 15, 2020. RESULTS: Among 387 evaluable subjects, the majority, 273 (70.5%), were enrolled from northwest Toronto and adjoining suburban areas of Peel, Ontario. The seropositivity values for Oakville and London were comparable (3.3% (2/60; 95% CI 0.4-11.5) and 3.9% (2/51; 95% CI 0.5-13.5), respectively). Relative to these areas, the seropositivity was higher for the northwest Toronto/Peel area at 12.1% (33/273), relative risk (RR) 3.35 (1.22-9.25). Persons 19 years of age or less had the highest seropositivity (10/50; 20.0%, 95% CI 10.3-33.7%), RR 2.27 (1.23-3.59). There was a trend for an interaction effect between race and location of residence as this relates to the relative risk of seropositivity. INTERPRETATION: During the early phases of the pandemic, the seropositivity within a COVID-19 high-prevalence zone was threefold greater than lower prevalence areas of Ontario. Black individuals were among those with the highest seroprevalence of SARS-CoV-2.

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.

Baked milk and egg diets revisited.

Most children with milk and egg allergy are nonreactive to modified forms of milk and egg in bakery products such as muffins because of conformational changes in proteins. These baked milk (BM) and baked egg (BE) diets have become commonplace in the management of milk and egg allergy, respectively. Current laboratory- and skin test-based diagnostic approaches remain limited in their ability to predict BM/BE tolerance, resulting in various approaches to introduce these foods. One approach to introduce BM/BE is to offer a medically supervised oral food challenge and then advise dietary introduction of baked products for children who have tolerance. Another approach is adapted from a home-based protocol of graded ingestion of BM or BE originally intended for non-IgE mediated allergy, often referred to as a "ladder." The ladder advises home ingestion of increasing amounts of BM or BE. For children who have allergy to BM or BE, the ladder is essentially oral immunotherapy, although not always labeled or recognized as such. Risk assessment and education of patients suitable for home introduction are essential. A home approach that may be called a ladder can also be used to escalate diets after demonstrated tolerance of baked forms by introducing lesser cooked forms of milk or egg after tolerating BM or BE. A randomized controlled trial provided clear evidence that baked diets can hasten the resolution of IgE-mediated milk allergy. Moreover, BM/BE foods have an emerging role in the treatment of non-IgE-mediated allergy. There is tangential evidence for BM and BE diets in the prevention of IgE-mediated allergy.

Milk-induced anaphylaxis among children presenting to Canadian emergency departments.

BACKGROUND: Cow's milk is one of the most common and burdensome allergens in pediatrics, and it can induce severe anaphylactic reactions in children. However, data on cow's milk-induced anaphylaxis are sparse. OBJECTIVE: To describe the epidemiology of pediatric cow's milk-induced anaphylaxis and to determine risk factors for repeat emergency department (ED) epinephrine administration. METHODS: Between April 2011 and May 2023, data were collected on children with anaphylaxis presenting to 10 Canadian EDs. A standardized form documenting symptoms, triggers, treatment, and outcome was used. Multivariate logistic regression was used. RESULTS: Of 3118 anaphylactic reactions, 319 milk-induced anaphylaxis cases were identified (10%). In the prehospital setting, 54% of patients with milk-induced anaphylaxis received intramuscular epinephrine. In those with milk-induced anaphylaxis, receiving epinephrine before presenting to the ED was associated with a reduced risk of requiring 2 or more epinephrine doses in the ED (adjusted odds ratio, 0.95 [95% CI, 0.90-0.99]). Children younger than 5 years of age were more likely to experience a mild reaction compared with that in older children, who experienced a moderate reaction more often (P < .0001). Compared with other forms of food-induced anaphylaxis, children presenting with milk-induced anaphylaxis were younger; a greater proportion experienced wheezing and vomiting, and less experienced angioedema. CONCLUSION: Prehospital epinephrine in pediatric milk-induced anaphylaxis is underused; however, it may decrease risk of requiring 2 ED epinephrine doses. Milk-induced anaphylaxis in children younger than 5 years of age may be less severe than in older children. Wheezing and vomiting are more prevalent in milk-induced anaphylaxis compared with that of other foods.

Managing anaphylaxis: Epinephrine, antihistamines, and corticosteroids: More than 10 years of Cross-Canada Anaphylaxis REgistry data.

BACKGROUND: Epinephrine is the first-line treatment for anaphylaxis but is often replaced with antihistamines or corticosteroids. Delayed epinephrine administration is a risk factor for fatal anaphylaxis. Convincing data on the role of antihistamines and corticosteroids in anaphylaxis management are sparse. OBJECTIVE: To establish the impact of prehospital treatment with epinephrine, antihistamines, and/or corticosteroids on anaphylaxis management. METHODS: Patients presenting with anaphylaxis were recruited prospectively and retrospectively in 10 Canadian and 1 Israeli emergency departments (EDs) between April 2011 and August 2022, as part of the Cross-Canada Anaphylaxis REgistry. Data on anaphylaxis cases were collected using a standardized form. Primary outcomes were uncontrolled reactions (>2 doses of epinephrine in ED), no prehospital epinephrine use, use of intravenous fluids in ED, and hospital admission. Multivariate regression was used to identify factors associated with primary outcomes. RESULTS: Among 5364 reactions recorded, median age was 8.8 years (IQR, 3.78-16.9); 54.9% of the patients were males, and 52.5% had a known food allergy. In the prehospital setting, 37.9% received epinephrine; 44.3% received antihistamines, and 3.15% received corticosteroids. Uncontrolled reactions happened in 250 reactions. Patients treated with prehospital epinephrine were less likely to have uncontrolled reactions (adjusted odds ratio [aOR], 0.955 [95% CI, 0.943-0.967]), receive intravenous fluids in ED (aOR, 0.976 [95% CI, 0.959-0.992]), and to be admitted after the reaction (aOR, 0.964 [95% CI, 0.949-0.980]). Patients treated with prehospital antihistamines were less likely to have uncontrolled reactions (aOR, 0.978 [95% CI, 0.967-0.989]) and to be admitted after the reaction (aOR, 0.963 [95% CI, 0.949-0.977]). Patients who received prehospital corticosteroids were more likely to require intravenous fluids in ED (aOR, 1.059 [95% CI, 1.013-1.107]) and be admitted (aOR, 1.232 [95% CI, 1.181-1.286]). CONCLUSION: Our findings in this predominantly pediatric population support the early use of epinephrine and suggest a beneficial effect of antihistamines. Corticosteroid use in anaphylaxis should be revisited.

Food Allergy Education and Management in Early Learning and Childcare Centres: A Scoping Review on Current Practices and Gaps.

Anaphylaxis has occurred in preschools/schools yet there are no consistent food allergy (FA) management practices in early learning and childcare centres (ELCC) across jurisdictions. Presently, there are no reviews that have synthesized FA-related knowledge and management practices within ELCC. We aimed to perform a scoping review of FA management in ELCC, and report on perceived gaps or barriers. A PRISMA-ScR-guided search was conducted for North American, European and Australian articles in English/French in the OVID-MedLine, Scopus, and PsycInfo databases. Two independent reviewers screened the titles/abstracts of 2010 articles and full-text screened 77 articles; 15 of which were specifically related to ELCC. If the two reviewers could not agree to the relevance of a given study, a third reviewer provided guidance. This third reviewer also screened French articles. Thematic and descriptive reports of the studies were presented. We reported solely on pre-Coronavirus Disease pandemic ELCC studies. We included ten articles in this review, which provide evidence that ELCC staff have variable baseline knowledge, comprehension, experience, and practices in place to manage FA. ELCC staff also have limited FA-related training and experience regarding administration of epinephrine auto-injectors (EAI). Emergency Anaphylaxis Plans (EAP) were described in four studies. One study reported the parental influence on the site's food purchasing and FA management. Three studies provided educational interventions, which demonstrated increased and sustained FA-related knowledge and confidence post-intervention. Participants deemed the training beneficial and desired annual training and more FA resources to be available. Across jurisdictions, ELCC staff have provided care and administered EAI in emergencies, but training remained variable. Communication and care planning amongst ELCC staff, and parents, is crucial. Annual education, available EAI and EAPs are tools necessary for effectively managing emergencies.

Safety and immunogenicity of the live-attenuated varicella vaccine in pediatric solid organ transplant recipients: A systematic review and meta-analysis.

This study aimed to synthesize the available evidence on the immunogenicity, safety, and effectiveness of live-attenuated varicella vaccine in solid organ transplant recipients. Medline and EMBASE were searched using predefined search terms to identify relevant studies. The included articles reported varicella vaccine administration in the posttransplant period in children and adults. A pooled proportion of transplant recipients who seroconverted and who developed vaccine-strain varicella and varicella disease was generated. Eighteen articles (14 observational studies and 4 case reports) were included, reporting on 711 transplant recipients who received the varicella vaccine. The pooled proportion was 88.2% (95% confidence interval 78.0%-96.0%, 13 studies) for vaccinees who seroconverted, 0% (0%-1.2%, 13 studies) for vaccine-strain varicella, and 0.8% (0%-4.9%, 9 studies) for varicella disease. Most studies followed clinical guidelines for administering live-attenuated vaccines, with criteria that could include being at least 1 year posttransplant, 2 months postrejection episode, and on low-dose immunosuppressive medications. Varicella vaccination in transplant recipients was overall safe in the included studies, with few cases of vaccine-strain-induced varicella or vaccine failure, and although it was immunogenic, the proportion of recipients who seroconverted was lower than that seen in the general population. Our data support varicella vaccination in select pediatric solid organ transplant recipients.

When Supplemental Formula Is Essential: Overcoming Barriers to Hypoallergenic Formula Access for Patients With Food Allergies.

For food-allergic patients, hypoallergenic formulas (HFs) are medically indicated, often a primary component of the diet and essential for patient safety, health, nutrition, and overall well-being. Yet, food allergy is not included among the conditions mandated for coverage under federal health programs and private health insurance. The 2022 infant formula crisis has affected many North American families and has particularly influenced patients with food allergies who rely on a limited number of safe HF brands to safely meet their nutritional needs for growth and development. The current formula shortage further highlights the longstanding difficulties faced by families with food allergies in accessing HF. Within this context, this article focuses on chronic barriers faced by patients with food allergies in accessing HF and proposes potential solutions. Legislation is desperately needed to address HF affordability through changes in insurance reimbursement and disparities in access to HF among individuals with food allergy.

Baked Milk and Baked Egg Survey: A Work Group Report of the AAAAI Adverse Reactions to Foods Committee.

Most milk- and egg-allergic children can tolerate milk and egg in baked forms. Some allergists have extended the use of baked milk (BM) and baked egg (BE) to advocating for the stepwise introduction of small amounts of BM and BE to children who are reactive to larger amounts of BM and BE. Little is known about the practice of introducing BM and BE and existing barriers to this approach. The purpose of this study was to gather a current assessment of the implementation of BM and BE oral food challenges and diets for milk- and egg-allergic children. We conducted an electronic survey of North American Academy of Allergy, Asthma & Immunology members offering BM and BE introduction in 2021. The response rate was 10.1% of distributed surveys (72 of 711). Surveyed allergists had a similar approach to both BM and BE introduction. Demographic features of time in practice and region of practice were significantly associated with the odds of introducing BM and BE. A wide variety of tests and clinical features guided decisions. Some allergists determined BM and BE to be appropriate for home introduction and offered this for BM and BE more often than other foods. The use of BM and BE as a food for oral immunotherapy was endorsed by almost half of respondents. Less time in practice was the most significant factor associated with offering this approach. Published recipes were used and written information was widely provided to patients by most allergists. The wide practice variabilities reveal a need for more structured guidance about oral food challenges, in-office versus home procedures, and patient education.

An update on recent developments and highlights in food allergy.

While both the incidence and general awareness of food allergies is increasing, the variety and clinical availability of therapeutics remain limited. Therefore, investigations into the potential factors contributing to the development of food allergy (FA) and the mechanisms of natural tolerance or induced desensitization are required. In addition, a detailed understanding of the pathophysiology of food allergies is needed to generate compelling, enduring, and safe treatment options. New findings regarding the contribution of barrier function, the effect of emollient interventions, mechanisms of allergen recognition, and the contributions of specific immune cell subsets through rodent models and human clinical studies provide novel insights. With the first approved treatment for peanut allergy, the clinical management of FA is evolving toward less intensive, alternative approaches involving fixed doses, lower maintenance dose targets, coadministration of biologicals, adjuvants, and tolerance-inducing formulations. The ultimate goal is to improve immunotherapy and develop precision-based medicine via risk phenotyping allowing optimal treatment for each food-allergic patient.

Nutrition and immunity: perspectives on key issues and next steps.

In January 2022, a group of experts came together to discuss current perspectives and future directions in nutritional immunology as part of a symposium organized by the Canadian Nutrition Society. Objectives included (1) creating an understanding of the complex interplay between diet and the immune system from infants through to older adults, (2) illustrating the role of micronutrients that are vital to the immune system, (3) learning about current research comparing the impact of various dietary patterns and novel approaches to reduce inflammation, autoimmune conditions, allergies, and infections, and (4) discussing select dietary recommendations aimed at improving disease-specific immune function. The aims of this review are to summarize the symposium and to identify key areas of research that require additional exploration to better understand the dynamic relationship between nutrition and immune function.