Basophil activation test as predictor of severity and threshold of allergic reactions to egg.

BACKGROUND: Identifying patients at risk of severe allergic reactions and/or low threshold of reactivity is very important, particularly for staple foods like egg. METHODS: One hundred and fifty children underwent double-blind placebo-controlled food challenge (DBPCFC) to baked egg (BE), skin prick testing and blood collection for serology and basophil activation test (BAT). Patients who passed BE DBPCFC underwent loosely cooked egg (LCE) DBPCFC. Severity of allergic reactions was classified following Practall guidelines and threshold dose was determined during DBPCFC. RESULTS: Sixty out of 150 (40%) children reacted to BE and 16 out of 77 (21%) to LCE on DBPCFC. Considering DBPCFC to BE, 23 children (38%) had severe reactions and 33 (55%) reacted to 0.13 g or less of egg protein (low threshold group). Two children (2 out of 16 = 12%) had severe reactions to LCE. Demographic, clinical and most immunological features were not significantly different between severe/non-severe BE reactors or low/high threshold groups. Severe BE reactors had higher ovomucoid-sIgE (p = .009) and higher BAT to BE (p = .001). Patients with lower threshold to BE had higher IgE-specific activity (p = .027) and BAT to egg (p = .007) but lower severity score (p = .008). Optimal cut-offs for ovomucoid-sIgE had 100% sensitivity, 35% specificity and 60% accuracy and for BAT 76% sensitivity, 74% specificity and 75% accuracy to identify BE severe reactors. Optimal cut-offs for specific activity had 70% sensitivity, 68% specificity and 69% accuracy and for BAT 70% sensitivity, 72% specificity and 71% accuracy to identify low threshold patients. CONCLUSIONS: BAT was the best biomarker to predict severity and threshold of allergic reactions to BE and can be useful when making decisions about management of egg allergy.

Biomarkers of peanut allergy in children over time.

BACKGROUND: Various biomarkers are used to define peanut allergy (PA). We aimed to observe changes in PA resolution and persistence over time comparing biomarkers in PA and peanut sensitised but tolerant (PS) children in a population-based cohort. METHODS: Participants were recruited from the EAT and EAT-On studies, conducted across England and Wales, and were exclusively breastfeed babies recruited at 3 months old and followed up until 7-12 years old. Clinical characteristics, skin prick test (SPT), sIgE to peanut and peanut components and mast cell activation tests (MAT) were assessed at 12 months, 36 months and 7-12 years. PA status was determined at the 7-12 year time point. RESULTS: The prevalence of PA was 2.1% at 7-12 years. Between 3 and 7-12 year, two children developed PA and one outgrew PA. PA children had larger SPT, higher peanut-sIgE, Ara h 2-sIgE and MAT (all p < .001) compared to PS children from 12 months onwards. SPT, peanut-sIgE, Ara h 2-sIgE and MAT between children with persistent PA, new PA, outgrown PA and PS were statistically significant from 12 months onwards (p < .001). Those with persistent PA had SPT, peanut-sIgE and Ara h 2-sIgE that increased over time and MAT which was highest at 36 months. New PA children had increased SPT and peanut-sIgE from 36 months to 7-12 years, but MAT remained low. PS children had low biomarkers across time. CONCLUSIONS: In this cohort, few children outgrow or develop new PA between 36 months and 7-12 years. Children with persistent PA have raised SPT, peanut-sIgE, Ara h 2-sIgE and MAT evident from infancy that consistently increase over time.

Skin as the target for allergy prevention and treatment.

The fact that genetic and environmental factors could trigger disruption of the epithelial barrier and subsequently initiate a TH2 inflammatory cascade conversely proposes that protecting the same barrier and promoting adequate interactions with other organs, such as the gut, may be crucial for lowering the risk and preventing atopic diseases, particularly, food allergies. In this review, we provide an overview of structural characteristics that support the epithelial barrier hypothesis in patients with atopic dermatitis, including the most relevant filaggrin gene mutations, the recent discovery of the role of the transient receptor potential vanilloid 1, and the role involvement of the microbiome in healthy and damaged skin. We present experimental and human studies that support the mechanisms of allergen penetration, particularly the dual allergen exposure and the outside-in, inside-out, and outside-inside-outside hypotheses. We discuss classic skin-targeted therapies for food allergy prevention, including moisturizers, steroids, and topical calcineurin inhibitors, along with pioneering trials proposed to change their current use (Prevention of Allergy via Cutaneous Intervention and Stopping Eczema and ALlergy). We provide an overview of the novel therapies that enhance the skin barrier, such as probiotics and prebiotics topical application, read-through drugs, direct and indirect FLG replacement, and interleukin and janus kinases inhibitors. Last, we discuss the newer strategies for preventing and treating food allergies in the form of epicutaneous immunotherapy and the experimental use of single-dose of adeno-associated virus vector gene immunotherapy.

Diagnostic utility of allergy tests to predict baked egg and lightly cooked egg allergies compared to double-blind placebo-controlled food challenges.

BACKGROUND: Double-blind placebo-controlled food challenges (DBPCFC) are the gold-standard to diagnose food allergy. However, they can cause allergic reactions of unpredictable severity. We assessed accuracy of current and new diagnostic tests compared to DBPCFC to baked egg (BE) and to lightly cooked egg (LCE). METHODS: Children aged 6 months to 15 years were assessed for possible egg allergy as part of the BAT2 study (NCT03309488). They underwent clinical assessment, skin prick test (SPT), specific IgE (sIgE) and basophil activation test (BAT). The results of the tests were compared with DBPCFC outcomes to both BE and LCE. RESULTS: A total of 150 children underwent DBPCFC to BE, 60 (40%) reacted to and 85 (57%) tolerated BE and 5 (3%) had inconclusive oral food challenges (OFC). Seventy-seven children tolerant to BE had DBPCFC to LCE and 16 reacted. The test within each modality with the best diagnostic performance for BE allergy was as follows: SPT to egg white (EW) (AUC = 0.726), sIgE to EW (AUC = 0.776) and BAT to egg (AUC = 0.783). BAT (AUC = 0.867) was the best test in the younger than 2 years age group. Applying 100% sensitivity and 100% specificity cut-offs, followed by OFC, resulted in 100% diagnostic accuracy. BAT enabled the greatest reduction in OFC (41%). Using sIgE followed by BAT allowed to reduce the number of BATs performed by about 30% without significantly increasing the number of OFC. CONCLUSIONS: The best diagnostic test was BAT to egg in terms of diagnostic accuracy and reduction in number of OFC. Using sIgE to EW followed by BAT required fewer BATs with sustained OFC reduction and diagnostic accuracy.

Frequency of guideline-defined cow's milk allergy symptoms in infants: Secondary analysis of EAT trial data.

BACKGROUND: Non-IgE-mediated Cow's Milk Allergy (CMA) has a prevalence of less than 1% in children. Guidelines developed to help non-specialists diagnose CMA may lead to misattribution of normal symptoms and contribute to overdiagnosis of CMA. We sought to establish the frequency of symptoms during infancy associated with non-IgE-mediated CMA, using the international Milk Allergy in Primary Care (iMAP) guideline as representative of CMA guidelines more generally. METHOD: Secondary analysis of the Enquiring About Tolerance (EAT) randomized controlled trial (ISRCTN 14254740; 1303 exclusively breastfed 3-month-old healthy infants). Key outcomes were ≥2 iMAP symptoms associated with 'mild-moderate' and 'severe' non-IgE-mediated CMA. RESULTS: Whilst breastfeeding and parental atopy rates were higher than the general population, participants were otherwise similar to the population of England and Wales. Two or more non-IgE CMA symptoms were reported by 25% families for mild-moderate and 1.4% for severe symptoms each month between ages 3 and 12 months, peaking at 38% with ≥2 mild-moderate and 4.3% ≥2 severe symptoms at three months, when participants were not directly consuming cow's milk. 74% of participants reported ≥2 mild-moderate symptoms and 9% ≥2 severe symptoms in at least one month during this period. At six months there was no evidence of difference in the proportion of children with ≥2 symptoms between those consuming (29.5% mild-moderate, 1.8% severe) and not consuming cow's milk (35.3% mild-moderate, 2.2% severe). Mean monthly reporting of ≥2 symptoms was also no different between those with (15.8% mild-moderate, 1.1% severe) or without eczema at baseline (16.7% mild-moderate, 1.3% severe). CONCLUSIONS: Guideline-defined symptoms of non-IgE-mediated CMA are very common in infants. Guidelines may promote milk allergy overdiagnosis by labelling normal infant symptoms as possible milk allergy.

Association of frequent moisturizer use in early infancy with the development of food allergy.

BACKGROUND: Food allergy is thought to develop through transcutaneous sensitization, especially in the presence of skin barrier impairment and inflammation. Regular moisturizer application to infant skin could potentially promote transcutaneous sensitization and the development of food allergy. OBJECTIVES: We tested this hypothesis in the Enquiring About Tolerance (EAT) study population. METHODS: The EAT study was a population-based randomized clinical trial conducted from January 15, 2008, to August 31, 2015, and recruited 1303 exclusively breastfed 3-month-old infants and their families from England and Wales. At enrollment at 3 months, families completed a questionnaire that included questions about frequency and type of moisturizer applied, use of corticosteroid creams, and parental report of dry skin or eczema. Infants were examined for visible eczema at the enrollment visit. RESULTS: A statistically significant dose-response relationship was observed between parent-reported moisturization frequency at 3 months of age and the subsequent development of food allergy. Each additional moisturization per week was associated with an adjusted odds ratio of 1.20 (95% CI, 1.13-1.27; P < .0005) for developing food allergy. For infants with no visible eczema at the enrollment visit, the corresponding adjusted odds ratio was 1.18 (95% CI, 1.07-1.30; P = .001) and for those with eczema at the enrollment visit, 1.20 (95% CI, 1.11-1.31; P < .0005). Moisturizer frequency showed similar dose-response relationships with the development of both food and aeroallergen sensitization at 36 months. CONCLUSIONS: These findings support the notion that regular application of moisturizers to the skin of young infants may promote the development of food allergy through transcutaneous sensitization.

Gut microbiota development during infancy: Impact of introducing allergenic foods.

BACKGROUND: The gut microbiota potentially plays an important role in the immunologic education of the host during early infancy. OBJECTIVE: We sought to determine how the infant gut microbiota evolve during infancy, particularly in relation to hygiene-related environmental factors, atopic disorders, and a randomized introduction of allergenic solids. METHODS: A total of 1303 exclusively breast-fed infants were enrolled in a dietary randomized controlled trial (Enquiring About Tolerance study) from 3 months of age. In this nested longitudinal study, fecal samples were collected at baseline, with additional sampling of selected cases and controls at 6 and 12 months to study the evolution of their gut microbiota, using 16S ribosomal RNA gene-targeted amplicon sequencing. RESULTS: In the 288 baseline samples from exclusively breast-fed infant at 3 months, the gut microbiota was highly heterogeneous, forming 3 distinct clusters: Bifidobacterium-rich, Bacteroides-rich, and Escherichia/Shigella-rich. Mode of delivery was the major discriminating factor. Increased Clostridium sensu stricto relative abundance at 3 months was associated with presence of atopic dermatitis on examination at age 3 and 12 months. From the selected cases and controls with longitudinal samples (n = 70), transition to Bacteroides-rich communities and influx of adult-specific microbes were observed during the first year of life. The introduction of allergenic solids promoted a significant increase in Shannon diversity and representation of specific microbes, such as genera belonging to Prevotellaceae and Proteobacteria (eg, Escherichia/Shigella), as compared with infants recommended to exclusively breast-feed. CONCLUSIONS: Specific gut microbiota characteristics of samples from 3-month-old breast-fed infants were associated with cesarean birth, and greater Clostridium sensu stricto abundance was associated with atopic dermatitis. The randomized introduction of allergenic solids from age 3 months alongside breast-feeding was associated with differential dynamics of maturation of the gut microbial communities.

Ara h 2 is the dominant peanut allergen despite similarities with Ara h 6.

BACKGROUND: Arachis hypogaea 2 (Ara h 2)-specific IgE is to date the best serologic marker to diagnose peanut allergy. Ara h 6 shares approximately 60% sequence identity and multiple epitopes with Ara h 2. OBJECTIVE: Our aim was to assess the diagnostic utility and relative importance of Ara h 2 and Ara h 6 in peanut allergy. METHODS: A cohort 100 of children was studied. The cohort included chidren who had peanut allergy, children who were sensitized to but tolerant of peanut, and children who were neither sensitized nor allergic to peanut. Levels of specific IgE to peanut and individual allergens were quantified by using ImmunoCAP. ImmunoCAP inhibition experiments and mast cell activation tests in response to both Ara h 2 and Ara h 6 were performed. Statistical analyses were done using SPSS version 14 and Prism version 7 software. RESULTS: Ara h 2-specific IgE and Ara h 6-specific IgE showed the greatest diagnostic accuracy for peanut allergy when compared with specific IgE to peanut and other peanut allergens. Most patients with peanut allergy were sensitized to both Ara h 2 and Ara h 6. Ara h 2 reduced Ara h 2-specific IgE binding more than Ara h 6 did (P < .001), whereas Ara h 6-specific IgE binding was inhibited to a similar degree by Ara h 2 and Ara h 6 (P = .432). In the mast cell activation test, Ara h 2 induced significantly greater maximal reactivity (P = .001) and a lower half maximal effective concentration (P = .002) than did Ara h 6 when testing cosensitized individuals. CONCLUSIONS: Ara h 2-specific IgE and Ara h 6-specific IgE provide the greatest accuracy to diagnose peanut allergy. Ara h 2 is the dominant conglutin in peanut allergy in the United Kingdom, despite a degree of cross-reactivity with Ara h 6.

Biomarkers of severity and threshold of allergic reactions during oral peanut challenges.

BACKGROUND: Oral food challenge (OFC) is the criterion standard to assess peanut allergy (PA), but it involves a risk of allergic reactions of unpredictable severity. OBJECTIVE: Our aim was to identify biomarkers for risk of severe reactions or low dose threshold during OFC to peanut. METHODS: We assessed Learning Early about Peanut Allergy study, Persistance of Oral Tolerance to Peanut study, and Peanut Allergy Sensitization study participants by administering the basophil activation test (BAT) and the skin prick test (SPT) and measuring the levels of peanut-specific IgE, Arachis hypogaea 2-specific IgE, and peanut-specific IgG4, and we analyzed the utility of the different biomarkers in relation to PA status, severity, and threshold dose of allergic reactions to peanut during OFC. RESULTS: When a previously defined optimal cutoff was used, the BAT diagnosed PA with 98% specificity and 75% sensitivity. The BAT identified severe reactions with 97% specificity and 100% sensitivity. The SPT, level of Arachis hypogaea 2-specific IgE, level of peanut-specific IgE, and IgG4/IgE ratio also had 100% sensitivity but slightly lower specificity (92%, 93%, 90%, and 88%, respectively) to predict severity. Participants with lower thresholds of reactivity had higher basophil activation to peanut in vitro. The SPT and the BAT were the best individual predictors of threshold. Multivariate models were superior to individual biomarkers and were used to generate nomograms to calculate the probability of serious adverse events during OFC for individual patients. CONCLUSIONS: The BAT diagnosed PA with high specificity and identified severe reactors and low threshold with high specificity and high sensitivity. The BAT was the best biomarker for severity, surpassed only by the SPT in predicting threshold. Nomograms can help estimate the likelihood of severe reactions and reactions to a low dose of allergen in individual patients with PA.

Defining challenge-proven coexistent nut and sesame seed allergy: A prospective multicenter European study.

BACKGROUND: Peanut, tree nut, and sesame allergies are responsible for most life-threatening food-induced allergic reactions. Rates of coexistent allergy between these foods have been from mostly retrospective studies that include only a limited number of tree nuts or were not based on oral food challenges. OBJECTIVE: The Pronuts study is a multicenter European study (London, Geneva, and Valencia) assessing the challenge-proven rate of coexistent peanut, tree nut, and/or sesame seed allergy. METHODS: Children aged 0 to 16 years with at least 1 confirmed nut or sesame seed allergy underwent sequential diagnostic food challenges to all other nuts and sesame seed. RESULTS: Overall, the rate of coexistent peanut, tree nut, and sesame seed allergy was 60.7% (n = 74/122; 95% CI, 51.4% to 69.4%). Peanut allergy was more common in London, cashew and pistachio nut allergies were more common in Geneva, and walnut and pecan allergies were more common in Valencia. Strong correlations were found between cashew-pistachio, walnut-pecan, and walnut-pecan-hazelnut-macadamia clusters. Age (>36 months) and center (Valencia > Geneva > London) were associated with an increased odds of multiple nut allergies. By pursuing the diagnostic protocol to demonstrate tolerance to other nuts, participants were able to introduce a median of 9 nuts. CONCLUSION: We found a higher rate of coexistent nut and sesame seed allergies than previously reported. Performing sequential food challenges was labor intensive and could result in severe allergic reactions; however, it reduced dietary restrictions. Age was a significant predictor of multiple nut allergies, and thus the secondary spread of nut allergies occurred in older children.

Factors influencing adherence in a trial of early introduction of allergenic food.

BACKGROUND: The Enquiring About Tolerance (EAT) study examined whether the early introduction of 6 allergenic foods from 3 months of age in exclusively breastfed infants prevented the development of food allergy. The intervention was effective in the per-protocol analysis for allergy to 1 or more foods and for egg and peanut individually, but only 42% of early introduction group (EIG) children met the per-protocol criteria. OBJECTIVE: We sought to identify which factors were responsible for nonadherence in the EAT study. METHODS: Factors influencing adherence within the key early introduction period in the EIG (up to 6 months of age) were divided into enrollment and postenrollment factors, and their association with nonadherence was explored. RESULTS: In an adjusted analysis, at enrollment, increased maternal age, nonwhite ethnicity, and lower maternal quality of life were independently and significantly associated with overall nonadherence in the EIG. Enrollment eczema and enrollment serum allergen-specific IgE sensitization to 1 or more foods (≥0.1 kU/L) were not related to overall nonadherence. After enrollment, 2 factors were significantly related to EIG overall nonadherence: parent-reported IgE-type symptoms with infant allergenic food consumption by 6 months of age and reported feeding difficulties by 4 months of age. CONCLUSION: If early introduction of allergenic foods were to be considered a strategy to prevent food allergy, families of nonwhite ethnicity, those with older mothers, and those with infants with reported feeding difficulties or early-onset eczema would benefit from support to promote early and sustained consumption.

Efficacy of the Enquiring About Tolerance (EAT) study among infants at high risk of developing food allergy.

BACKGROUND: The Enquiring About Tolerance (EAT) study was a randomized trial of the early introduction of allergenic solids into the infant diet from 3 months of age. The intervention effect did not reach statistical significance in the intention-to-treat analysis of the primary outcome. OBJECTIVE: We sought to determine whether infants at high risk of developing a food allergy benefited from early introduction. METHODS: A secondary intention-to-treat analysis was performed of 3 groups: nonwhite infants; infants with visible eczema at enrollment, with severity determined by SCORAD; and infants with enrollment food sensitization (specific IgE ≥0.1 kU/L). RESULTS: Among infants with sensitization to 1 or more foods at enrollment (≥0.1 kU/L), early introduction group (EIG) infants developed significantly less food allergy to 1 or more foods than standard introduction group (SIG) infants (SIG, 34.2%; EIG, 19.2%; P = .03), and among infants with sensitization to egg at enrollment, EIG infants developed less egg allergy (SIG, 48.6%; EIG, 20.0%; P = .01). Similarly, among infants with moderate SCORAD (15-<40) at enrollment, EIG infants developed significantly less food allergy to 1 or more foods (SIG, 46.7%; EIG, 22.6%; P = .048) and less egg allergy (SIG, 43.3%; EIG, 16.1%; P = .02). CONCLUSION: Early introduction was effective in preventing the development of food allergy in specific groups of infants at high risk of developing food allergy: those sensitized to egg or to any food at enrollment and those with eczema of increasing severity at enrollment. This efficacy occurred despite low adherence to the early introduction regimen. This has significant implications for the new national infant feeding recommendations that are emerging around the world.

Challenges experienced with early introduction and sustained consumption of allergenic foods in the Enquiring About Tolerance (EAT) study: A qualitative analysis.

BACKGROUND: The early introduction group participants of the Enquiring About Tolerance study were asked to undertake a proscriptive regimen of early introduction and sustained consumption of 6 allergenic foods. It was envisaged that this might be challenging, and early introduction group families were presented with an open-text question to express any problems they were experiencing with the regimen in recurring online questionnaires. OBJECTIVE: We sought to analyze these open-text questionnaire responses with the aim of identifying challenges associated with the introduction and regular consumption of allergenic foods. METHODS: Three combinations of interim questionnaire responses were selected for analysis, representing the early period (4, 5, and 6 months), middle period (8 and 12 months), and late period (24 and 36 months) of participation in the Enquiring About Tolerance study. Responses were assigned a code to describe their content and subsequently grouped into themes to portray key messages. A thematic content analysis allowed for conversion of qualitative codes into quantitative summaries. RESULTS: Three main challenges to allergenic food consumption were identified. First, some children refused the allergenic food, causing a sense of defeat among caregivers. Second, caregivers were concerned that allergenic foods might be causing a reaction, triggering a need for reassurance. Third, practical problems associated with the regimen compromised caregivers' capacity to persist. CONCLUSION: Understanding the challenges experienced with allergenic food introduction and sustained consumption is the necessary precursor to developing specific communication and support strategies that could be used by caregivers, practitioners, policymakers, and key stakeholders to address these problems.

Association of Staphylococcus aureus colonization with food allergy occurs independently of eczema severity.

BACKGROUND: Staphylococcus aureus has been implicated in the pathophysiology of eczema, allergic rhinitis, asthma, and food allergy. S aureus is a marker of more severe eczema, which is a risk factor for food sensitization/allergy. Therefore it might be that the association between S aureus and food allergy in eczematous patients is related to eczema severity. OBJECTIVE: We sought to investigate the association of S aureus colonization with specific IgE (sIgE) production to common food allergens and allergies in early childhood independent of eczema severity. We additionally determined the association of S aureus colonization with eczema severity and persistence. METHODS: In Learning Early About Peanut Allergy (LEAP) study participants eczema severity was assessed, and skin/nasal swabs were cultured for S aureus. Sensitization was identified by measuring sIgE levels. Peanut allergy was primarily determined by means of oral food challenge, and persistent egg allergy was primarily determined by using skin prick tests. RESULTS: Skin S aureus colonization was significantly associated with eczema severity across the LEAP study, whereas at 12 and 60 months of age, it was related to subsequent eczema deterioration. Skin S aureus colonization at any time point was associated with increased levels of hen's egg white and peanut sIgE independent of eczema severity. Participants with S aureus were more likely to have persistent egg allergy and peanut allergy at 60 and 72 months of age independent of eczema severity. All but one of the 9 LEAP study consumers with peanut allergy (9/312) were colonized at least once with S aureus. CONCLUSION: S aureus, independent of eczema severity, is associated with food sensitization and allergy and can impair tolerance to foods. This could be an important consideration in future interventions aimed at inducing and maintaining tolerance to food allergens in eczematous infants.

Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants.

BACKGROUND: The age at which allergenic foods should be introduced into the diet of breast-fed infants is uncertain. We evaluated whether the early introduction of allergenic foods in the diet of breast-fed infants would protect against the development of food allergy. METHODS: We recruited, from the general population, 1303 exclusively breast-fed infants who were 3 months of age and randomly assigned them to the early introduction of six allergenic foods (peanut, cooked egg, cow's milk, sesame, whitefish, and wheat; early-introduction group) or to the current practice recommended in the United Kingdom of exclusive breast-feeding to approximately 6 months of age (standard-introduction group). The primary outcome was food allergy to one or more of the six foods between 1 year and 3 years of age. RESULTS: In the intention-to-treat analysis, food allergy to one or more of the six intervention foods developed in 7.1% of the participants in the standard-introduction group (42 of 595 participants) and in 5.6% of those in the early-introduction group (32 of 567) (P=0.32). In the per-protocol analysis, the prevalence of any food allergy was significantly lower in the early-introduction group than in the standard-introduction group (2.4% vs. 7.3%, P=0.01), as was the prevalence of peanut allergy (0% vs. 2.5%, P=0.003) and egg allergy (1.4% vs. 5.5%, P=0.009); there were no significant effects with respect to milk, sesame, fish, or wheat. The consumption of 2 g per week of peanut or egg-white protein was associated with a significantly lower prevalence of these respective allergies than was less consumption. The early introduction of all six foods was not easily achieved but was safe. CONCLUSIONS: The trial did not show the efficacy of early introduction of allergenic foods in an intention-to-treat analysis. Further analysis raised the question of whether the prevention of food allergy by means of early introduction of multiple allergenic foods was dose-dependent. (Funded by the Food Standards Agency and others; EAT Current Controlled Trials number, ISRCTN14254740.).

Effect of Avoidance on Peanut Allergy after Early Peanut Consumption.

BACKGROUND: In a randomized trial, the early introduction of peanuts in infants at high risk for allergy was shown to prevent peanut allergy. In this follow-up study, we investigated whether the rate of peanut allergy remained low after 12 months of peanut avoidance among participants who had consumed peanuts during the primary trial (peanut-consumption group), as compared with those who had avoided peanuts (peanut-avoidance group). METHODS: At the end of the primary trial, we instructed all the participants to avoid peanuts for 12 months. The primary outcome was the percentage of participants with peanut allergy at the end of the 12-month period, when the participants were 72 months of age. RESULTS: We enrolled 556 of 628 eligible participants (88.5%) from the primary trial; 550 participants (98.9%) had complete primary-outcome data. The rate of adherence to avoidance in the follow-up study was high (90.4% in the peanut-avoidance group and 69.3% in the peanut-consumption group). Peanut allergy at 72 months was significantly more prevalent among participants in the peanut-avoidance group than among those in the peanut-consumption group (18.6% [52 of 280 participants] vs. 4.8% [13 of 270], P<0.001). Three new cases of allergy developed in each group, but after 12 months of avoidance there was no significant increase in the prevalence of allergy among participants in the consumption group (3.6% [10 of 274 participants] at 60 months and 4.8% [13 of 270] at 72 months, P=0.25). Fewer participants in the peanut-consumption group than in the peanut-avoidance group had high levels of Ara h2 (a component of peanut protein)-specific IgE and peanut-specific IgE; in addition, participants in the peanut-consumption group continued to have a higher level of peanut-specific IgG4 and a higher peanut-specific IgG4:IgE ratio. CONCLUSIONS: Among children at high risk for allergy in whom peanuts had been introduced in the first year of life and continued until 5 years of age, a 12-month period of peanut avoidance was not associated with an increase in the prevalence of peanut allergy. Longer-term effects are not known. (Funded by the National Institute of Allergy and Infectious Diseases and others; LEAP-On ClinicalTrials.gov number, NCT01366846.).

Dog ownership at three months of age is associated with protection against food allergy.

BACKGROUND: The prevention of food allergy is a key priority for reducing the burden of allergic disease. Environmental exposures modulate the risk of developing food allergy and some of this may be mediated by the infants' developing microbiome. However, the role of potentially protective environmental exposures, such as pet ownership, is largely uninvestigated with respect to food allergy. METHODS: We performed a secondary cohort analysis in the Enquiring About Tolerance (EAT) study, which enrolled 1303 three-month infants onto a randomized trial to prevent food allergy. A survey elicited domestic animal ownership and participants were examined for atopic dermatitis (AD) at enrolment. Sensitization to foods and aeroallergens were elicited by skin and serum testing at 3, 12 and 36 months. Food allergy status was determined by double-blind placebo-controlled food challenges between 1 and 3 years. RESULTS: Food allergy was diagnosed amongst 6.1% (68/1124) of participants with complete data. No significant relationships were demonstrated between food allergy and caesarean delivery, infections or antibiotic exposure in early life. After adjusting for familial atopic disease, maternal dog/cat sensitization and participant AD, living with dogs was associated with a 90% reduction in the odds of infants developing food allergy (adjusted odds ratio (aOR) 0.10 (confidence interval (CI) 0.01-0.71), P = 0.02). None of the 49 infants living with at least two dogs developed food allergy, suggesting a dose-response relationship (each dog owned aOR 0.12 (CI 0.02-0.81), P = 0.03). No relationship was demonstrated between owning dogs or cats and the development of AD. CONCLUSION: Dog ownership in infancy may prevent food allergy.

Allergen specificity of early peanut consumption and effect on development of allergic disease in the Learning Early About Peanut Allergy study cohort.

BACKGROUND: Early introduction of dietary peanut in high-risk infants with severe eczema, egg allergy, or both prevented peanut allergy at 5 years of age in the Learning Early About Peanut Allergy (LEAP) study. The protective effect persisted after 12 months of avoiding peanuts in the 12-month extension of the LEAP study (LEAP-On). It is unclear whether this benefit is allergen and allergic disease specific. OBJECTIVE: We sought to assess the effect of early introduction of peanut on the development of allergic disease, food sensitization, and aeroallergen sensitization. METHODS: Asthma, eczema, and rhinoconjunctivitis were diagnosed based on clinical assessment. Reported allergic reactions and consumption of tree nuts and sesame were recorded by questionnaire. Sensitization to food allergens and aeroallergens was determined by means of skin prick testing and specific IgE measurement. RESULTS: A high and increasing burden of food allergen and aeroallergen sensitization and allergic disease was noted across study time points; 76% of LEAP participants had at least 1 allergic disease at 60 months of age. There were no differences in allergic disease between LEAP groups. There were small differences in sensitization and reported allergic reactions for select tree nuts, with levels being higher in the LEAP consumption group. Significant resolution of eczema and sensitization to egg and milk occurred in LEAP participants and was not affected by peanut consumption. CONCLUSION: Early consumption of peanut in infants at high risk of peanut allergy is allergen specific and does not prevent the development of other allergic disease, sensitization to other food allergens and aeroallergens, or reported allergic reactions to tree nuts and sesame. Furthermore, peanut consumption does not hasten the resolution of eczema or egg allergy.

Randomized trial of peanut consumption in infants at risk for peanut allergy.

BACKGROUND: The prevalence of peanut allergy among children in Western countries has doubled in the past 10 years, and peanut allergy is becoming apparent in Africa and Asia. We evaluated strategies of peanut consumption and avoidance to determine which strategy is most effective in preventing the development of peanut allergy in infants at high risk for the allergy. METHODS: We randomly assigned 640 infants with severe eczema, egg allergy, or both to consume or avoid peanuts until 60 months of age. Participants, who were at least 4 months but younger than 11 months of age at randomization, were assigned to separate study cohorts on the basis of preexisting sensitivity to peanut extract, which was determined with the use of a skin-prick test--one consisting of participants with no measurable wheal after testing and the other consisting of those with a wheal measuring 1 to 4 mm in diameter. The primary outcome, which was assessed independently in each cohort, was the proportion of participants with peanut allergy at 60 months of age. RESULTS: Among the 530 infants in the intention-to-treat population who initially had negative results on the skin-prick test, the prevalence of peanut allergy at 60 months of age was 13.7% in the avoidance group and 1.9% in the consumption group (P<0.001). Among the 98 participants in the intention-to-treat population who initially had positive test results, the prevalence of peanut allergy was 35.3% in the avoidance group and 10.6% in the consumption group (P=0.004). There was no significant between-group difference in the incidence of serious adverse events. Increases in levels of peanut-specific IgG4 antibody occurred predominantly in the consumption group; a greater percentage of participants in the avoidance group had elevated titers of peanut-specific IgE antibody. A larger wheal on the skin-prick test and a lower ratio of peanut-specific IgG4:IgE were associated with peanut allergy. CONCLUSIONS: The early introduction of peanuts significantly decreased the frequency of the development of peanut allergy among children at high risk for this allergy and modulated immune responses to peanuts. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00329784.).

Enquiring About Tolerance (EAT) study: Feasibility of an early allergenic food introduction regimen.

BACKGROUND: The influence of early exposure to allergenic foods on the subsequent development of food allergy remains uncertain. OBJECTIVE: We sought to determine the feasibility of the early introduction of multiple allergenic foods to exclusively breast-fed infants from 3 months of age and the effect on breastfeeding performance. METHODS: We performed a randomized controlled trial. The early introduction group (EIG) continued breastfeeding with sequential introduction of 6 allergenic foods: cow's milk, peanut, hard-boiled hen's egg, sesame, whitefish (cod), and wheat; the standard introduction group followed the UK infant feeding recommendations of exclusive breastfeeding for around 6 months with no introduction of allergenic foods before 6 months of age. RESULTS: One thousand three hundred three infants were enrolled. By 5 months of age, the median frequency of consumption of all 6 foods was 2 to 3 times per week for every food in the EIG and no consumption for every food in the standard introduction group (P < .001 for every comparison). By 6 months of age, nonintroduction of the allergenic foods in the EIG was less than 5% for each of the 6 foods. Achievement of the stringent per-protocol consumption target for the EIG proved more difficult (42% of evaluable EIG participants). Breastfeeding rates in both groups significantly exceeded UK government data for equivalent mothers (P < .001 at 6 and at 9 months of age). CONCLUSION: Early introduction, before 6 months of age, of at least some amount of multiple allergenic foods appears achievable and did not affect breastfeeding. This has important implications for the evaluation of food allergy prevention strategies.