TreEAT trial: Protocol for a randomized controlled trial investigating the efficacy and safety of early introduction of tree nuts for the prevention of tree nut allergy in infants with peanut allergy.

INTRODUCTION: Children with peanut allergy are at increased risk of developing tree nut allergies, which can be severe and for most lifelong. Introduction of peanut in the first year of life can reduce the risk of peanut allergy; however, prevention strategies for tree nut allergies have not been established. We aimed to test the efficacy and safety of a novel strategy, a supervised multi-nut oral food challenge (OFC) compared with standard care for tree nut allergy prevention in infants at high risk of developing tree nut allergy, TreEAT. METHODS AND ANALYSIS: TreEAT is a 2-armed, open-label, randomized, controlled trial (RCT). Infants (n = 212) aged 4-11 months with peanut allergy will be randomized 1:1 at peanut allergy diagnosis to either a hospital-based multi-tree nut (almond, cashew, hazelnut, and walnut) OFC using multi-nut butter or standard care (home introduction of individual tree nuts). All infants will be assessed at age 18 months, with questionnaires and SPT to peanut and tree nuts. Peanut and tree nut OFCs will be performed as required to determine the allergy status for each nut. The primary outcome is tree nut allergy at age 18 months. Secondary outcomes include peanut allergy resolution, proportion, and severity of adverse events related to tree nut ingestion, number and frequency of tree nuts ingested, quality of life and parental anxiety, and allergy-related healthcare visits from randomization to 18 months of age. Analyses will be performed on an intention-to-treat basis. ETHICS AND DISSEMINATION: TreEAT was approved by the Royal Children's Hospital Human Research Ethics Committee (#70489). Outcomes will be presented at scientific conferences and disseminated through publication. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov ID: NCT04801823.

An International First: Stakeholder Consensus Statement for Food Allergen Management in Packaged Foods and Food Service for Australia and New Zealand.

Food-allergic consumers encounter inadequate, confusing, and ambiguous allergen information for packaged and unpackaged foods. Key Australian and New Zealand allergy organizations convened multiple forums to facilitate discussions among consumers, food manufacturers, food retailers, regulatory bodies, researchers, and health professionals to develop a unified approach to improving food allergen management. The following stakeholder consensus statement provides a foundation for advocacy for improved food allergen management and safety. It is the responsibility of consumers to: 1. declare their food allergies and read food labels (including ingredient lists and allergen declaration statements), and 2. ultimately make their own judgment about the foods they choose to consume. We consider that to enable consumers to make informed decisions about their safety, It is the responsibility of packaged food manufacturers to: 1. follow robust allergen management practices including quantitative risk assessment, and 2. use clear, consistent labeling to inform consumers about that food's allergen content, including the possible presence of unintended allergens. It is the responsibility of food service establishments and providers to: 1. follow robust allergen management practices, and 2. ensure that staff understand and can inform consumers about the allergen content of the food they provide, including the possible presence of unintended allergens.

Altered immune cell profiles and impaired CD4 T-cell activation in single and multi-food allergic adolescents.

BACKGROUND: Approximately 5% of adolescents have a food allergy, with peanut and tree nut allergies the most common. Having two or more food allergies in adolescence also doubles the risk of any adverse food reaction, and is associated with increased dietary and social burden. Investigations of immune function in persistently food allergic children are rare. OBJECTIVE: In the present study, we aimed to investigate the immune mechanisms that underlie food allergy in adolescence. METHODS: We used high-dimensional flow cytometry, unsupervised computational analysis and functional studies to comprehensively phenotype a range of non-antigen-specific immune parameters in a group of well-characterized adolescents with clinically defined single peanut allergy, multi-food allergy and aged-matched non-food allergic controls. RESULTS: We show that food allergic adolescents have higher circulating proportions of dendritic cells (p = .0084, FDR-adjusted p = .087, median in no FA: 0.63% live cells, in FA: 0.93%), and higher frequency of activated, memory-like Tregs relative to non-food allergic adolescents (p = .011, FDR-adjusted p = .087, median in no FA: 0.49% live cells, in FA: 0.65%). Cytokine profiling revealed that CD3/CD28 stimulated naïve CD4 T cells from food allergic adolescents produced less IL-6 (p = .0020, FDR-adjusted p = .018, median log2 fold change [stimulated/unstimulated] in no FA: 3.03, in FA: 1.92) and TNFα (p = .0044, FDR-adjusted p = .020, median in no FA: 9.16, in FA: 8.64) and may secrete less IFNγ (p = .035, FDR-adjusted p = .11, median in no FA: 6.29, in FA: 5.67) than naïve CD4 T cells from non-food allergic controls. No differences between clinical groups were observed for LPS-stimulated monocyte secretion of cytokines. CONCLUSIONS: These results have important implications for understanding the evolution of the immune response in food allergy throughout childhood, revealing that dendritic cell and T-cell signatures previously identified in early life may persist through to adolescence.

The Interplay Between Eczema and Breastfeeding Practices May Hide Breastfeeding's Protective Effect on Childhood Asthma.

BACKGROUND: Longer duration of breastfeeding may be protective against asthma. However, early manifestations of allergic disease, such as eczema, are risk factors for asthma and can influence the duration of breastfeeding, and hence, may bias observable associations. OBJECTIVE: To examine the relationship between breastfeeding ever and duration and the development of asthma and allergic asthma phenotypes, stratified by a diagnosis of eczema during or after the breastfeeding period. METHODS: A total of 3663 children participated in the 6-year-old follow-up of the HealthNuts study, a population-based, longitudinal study of allergic diseases in Australia. At age 1 year, breastfeeding and eczema data were collected and at age 6 years, information on wheeze, medication use, and parental report of doctor-diagnosed asthma were obtained, both via questionnaire. Skin prick test responses to food and aeroallergens at age 6 years further distinguished asthmatic children into allergic and nonallergic phenotypes. RESULTS: Breastfeeding initiation was not associated with current asthma at age 6 years (adjusted odds ratio, 0.76; 95% CI, 0.45-1.29) when compared with never breastfeeding. Results were similar for length of exclusiveness and overall duration of breastfeeding, and allergic and nonallergic asthma phenotypes. However, increased duration of breastfeeding among children without eczema in infancy was associated with reduced odds of asthma (per month increase, adjusted odds ratio, 0.98; 95% CI, 0.95-1.0; P = .05), which equates to 0.86 (95% CI, 0.74-1.0) reduced odds of asthma for a 6-month increase in breastfeeding. This association was not apparent in children who were diagnosed with eczema during breastfeeding (adjusted odds ratio, 1.03; 95% CI, 0.98-1.08; P = .3). CONCLUSIONS: Longer duration of breastfeeding was associated with a reduced odds of asthma among children without eczema in the first year of life; this association was masked before stratification by eczema in infancy. Future studies examining breastfeeding practices and the risk of allergic outcomes in later childhood need to consider the presence of early-life allergic manifestations impacting on breastfeeding behavior.

Community-Based Adverse Food Reactions and Anaphylaxis in Children with IgE-Mediated Food Allergy at Age 6 Years: A Population-Based Study.

BACKGROUND: Few studies have investigated adverse food reactions among food-allergic children in a population-based sample, which is critical for the development of evidence-based management strategies. OBJECTIVE: We aimed to evaluate the frequency, characteristics, and risk factors for adverse food reactions, including anaphylaxis, among food-allergic 6-year-old-children using the population-based HealthNuts study. METHODS: The HealthNuts study of 5276 infants (1-year-old) followed them up at age 6 years (84.4% participated). A total of 260 children with IgE-mediated food allergy who completed a questionnaire detailing recent adverse food reactions were included in this analysis. RESULTS: Among food-allergic children, 44.6% (95% CI, 38.6%-50.8%) reported an adverse food reaction in the last 12 months and 10.8% (95% CI, 7.5%-15.2%) reported an anaphylactic reaction, although only half of these were recognized as anaphylaxis by parents. Adrenaline autoinjectors were used in 25% (4 of 16) of recognized anaphylaxis episodes. Nut allergy was associated with a reduced risk of having an adverse reaction (adjusted odds ratio, 0.3; 95% CI, 0.1-0.7). There were trends that adverse reactions were more likely in children with at least 1 parent born in Asia compared with both parents born in Australia (adjusted odds ratio, 1.9; 95% CI, 0.9-3.9), and in children with 3 or more food allergies compared with children with a single food allergy (adjusted odds ratio, 1.8; 95% CI, 0.9-3.5). CONCLUSIONS: Adverse food reactions occurred in almost half of all food-allergic 6-year-old children and anaphylaxis occurred in 1 in 10 children over a 12-month period. Anaphylaxis was poorly recognized and adrenaline autoinjectors were not used appropriately. Improved regular education on the prevention, recognition, and management of adverse food reactions is urgently needed.

Prevalence and natural history of tree nut allergy.

OBJECTIVE: Tree nuts are common causes of food-related allergic reactions and anaphylaxis. Resolution of tree nut allergy is thought to be low, yet studies of the natural history of tree nut allergy are limited. This review summarizes the available literature regarding tree nut allergy prevalence and natural history and discusses emerging diagnostic and prognostic developments that will inform clinical management of tree nut allergy. DATA SOURCES: A comprehensive literature search using PubMed was performed. STUDY SELECTIONS: Peer-reviewed publications relating to tree nut allergy prevalence, resolution, and diagnosis were selected, and findings were summarized using a narrative approach. RESULTS: Tree nut allergy prevalence varies by age, region, and food allergy definition, and ranges from less than 1% to approximately 3% worldwide. Reports on the natural history of tree nut allergy data are limited to retrospective clinical data or cross-sectional survey data of self-reported food allergy, with reported resolution ranging from 9% to 14%. Component-resolved diagnostics and basophil activation testing offer the potential to improve the diagnostic accuracy and predicted prognosis of specific tree nut allergy, but studies are limited. CONCLUSION: Tree nut allergy remains an understudied area of food allergy research with limited region-specific studies based on robust food allergy measures in population cohorts with longitudinal follow-up. This currently limits our understanding of tree nut allergy prognosis.

Early Exposure to Cow's Milk Protein Is Associated with a Reduced Risk of Cow's Milk Allergic Outcomes.

BACKGROUND: Overall early exposure to allergenic foods in the infant's diet is a new strategy for preventing food allergy to that allergen, but the optimal timing of exposure for different allergens is not known. OBJECTIVES: We aimed to examine the relationship between exposure to cow's milk protein in the first 3 months of life and risk of cow's milk allergy at age 12 months. METHODS: HealthNuts is a longitudinal population-based food allergy study that recruited 5,276 twelve-month-old infants. Skin prick testing to cow's milk was conducted on the second half of the cohort (n = 2,715) and sensitization defined as a wheal ≥2 mm. Cow's milk allergy was defined as a parent-reported reaction to cow's milk consistent with IgE-mediated allergy together with evidence of sensitization. Early exposure to cow's milk protein was captured through parental questionnaire administered at 1 year of age and defined as consumption of cow's milk-based infant formula during the first 3 months of life. RESULTS: Forty-two percent of infants were exposed to cow's milk in the first 3 months of life (n= 1,977/4,712) and 87% of these infants were also breastfed. Early exposure to cow's milk protein was associated with a reduced risk of cow's milk sensitization (adjusted odds ratio [aOR] 0.44, 95% confidence interval [CI] 0.23-0.83), parent-reported reactions to cow's milk (aOR 0.44, 95% CI 0.29-0.67), and cow's milk allergy (aOR 0.31, 95% CI 0.10-0.91) at age 12 months. Age at exposure to cow's milk protein was not associated with the risk of other food allergies. CONCLUSIONS: Exposure to cow's milk protein in the first 3 months of life was associated with a reduced risk of cow's milk allergy. These findings are from an observational study and clinical trials are warranted to further assess this association before any recommendations to infant feeding guidelines can be made.

Self-reported adverse food reactions and anaphylaxis in the SchoolNuts study: A population-based study of adolescents.

BACKGROUND: Adolescents are at the highest risk of death from anaphylaxis, yet few population-based studies have described the frequencies and risk factors for allergic reactions caused by accidental allergen ingestion in this group. METHODS: We describe the prevalence, frequency, and associated risk factors for recent adverse food reactions in 10- to 14-year-olds in Melbourne, Australia, recruited from a stratified, random, population-based sample of schools (SchoolNuts, n = 9663; 48% response rate). Self-reported food allergy and adverse reaction details, including anaphylaxis, were identified by using a student questionnaire over the past year. RESULTS: Of 547 students with possible IgE-mediated food allergy, 243 (44.4%; 95% CI, 40.3% to 48.7%) reported a reaction to a food. Fifty-three (9.7%; 95% CI, 7.2% to 12.2%) students reported 93 anaphylaxis episodes. Peanut and tree nuts were the most common food triggers. Among students with current IgE-mediated food allergy, those with resolved or current asthma (adjusted odds ratio [aOR], 1.9 [95% CI, 1.1-1.3] and 1.7 [95% CI, 1.1-2.6]) and those with more than 2 food allergies (aOR, 1.9 [95% CI, 1.1-3.1]) were at greatest risk of any adverse food reaction, and those with nut allergy were most at risk of severe reactions (aOR, 2.9 [95% CI, 1.1-4.4]). Resolved or current asthma was not associated with increased risk of severe reactions (aOR, 0.8 [95% CI, 0.3-2.2] and 1.6 [95% CI, 0.7-3.7]). CONCLUSIONS: Adolescents with food allergy are frequently exposed to food allergens. Those with asthma and more than 2 food allergies were at the greatest risk for adverse food reactions. Those with nut allergies were most at risk of severe reactions.