Optimising the management of peanut allergy by targeting immune plasticity.

Randomised controlled trials investigating the efficacy of oral tolerance induction to peanut have enabled detailed comparison of their clinical and immunological success. They have demonstrated that the regular consumption of peanut for at least 2 years by babies who are not allergic enables protection from developing peanut allergy. The LEAP study intervention tested the impact of regular peanut consumption for 4 years and demonstrated a sustained protection against the development of peanut allergy even after 12 months of peanut avoidance from 5 to 6 years of age. The PreventADALL trial introduced multiple allergens into babies' diets from early infancy and reduced the prevalence of food allergy at 3 years, especially by protecting against peanut allergy. Immunological studies from the LEAP cohort demonstrated that regular peanut consumption was associated with a prompt induction of peanut-specific IgG4 and reduced manufacture of peanut and Ara h 2-specific IgE. Even after stopping peanut consumption for 5 years, there continued to be a significant fall in peanut-specific Ara h 2 IgE in the consumption group from 5 to 6 years of age (p < .01). Children who developed peanut allergy by 5 years started to develop increasing sensitisation to linear sequential peanut epitopes from 2.5 years of age, suggesting that putative disease-modifying interventions should commence before 3 years. Data comparing clinical outcomes between children undergoing peanut immunotherapy from infancy suggest that younger children can consume higher portions of peanut without reaction on challenge whilst taking immunotherapy, have fewer side effects and are more likely to enjoy remission of PA. Peanut oral immunotherapy modulates T-cell populations in order to bring about hypo-responsiveness of allergy effector cells. Studies are now needed to characterise and compare different states of immunological tolerance. This will accelerate the design of interventions which can promote primary, secondary and tertiary levels of PA prevention across a range of age groups.

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.

Pros and cons: Is faecal microbiota transplantation a safe and efficient treatment option for gut dysbiosis?

Faecal Microbiota Transplantation (FMT) is well established as an effective treatment for Clostridioides difficile infection (CDI), restoring gut microbiome diversity and function. The utility of FMT is currently being explored in relation to other immune-mediated pathologies, such as allergic disease, inflammatory bowel diseases and autoimmune diseases. Clinical trials in these areas are ongoing, and the altered gut microbiota (dysbiosis) that is often observed in these pathologies provides a rationale for the application of FMT to restore the microbiome. However, there is controversy on the risk-benefit ratio as it relates to the use of FMTs in pathologies other than CDI. In this Pro and Con article, we present the arguments for and against the use of FMT in immune-mediated pathologies, such as allergic disease. We further identify research gaps and recommend how these may be addressed in future studies.

Early Gluten Introduction and Celiac Disease in the EAT Study: A Prespecified Analysis of the EAT Randomized Clinical Trial.

Importance: There are no strategies for the prevention of celiac disease (CD). Current guidelines stating that the age at gluten introduction does not affect the prevalence of CD are based on the results from several randomized clinical trials, but the doses of gluten and timing of its introduction varied. Objective: To determine whether early introduction of high-dose gluten lowers the prevalence of CD at age 3 years. Design, Setting, and Participants: The Enquiring About Tolerance (EAT) Study was an open-label randomized clinical trial. A total of 1303 children from the general population in England and Wales were recruited and followed up from November 2, 2009, to July 30, 2012. For the present study, samples were collected from November 1, 2012, to March 31, 2015, and data were analyzed from April 25, 2017, to September 17, 2018. Interventions: Infants were randomized to consume 6 allergenic foods (peanut, sesame, hen's egg, cow's milk, cod fish, and wheat) in addition to breast milk from age 4 months (early introduction group [EIG]) or to avoid allergenic foods and follow UK infant feeding recommendations of exclusive breastfeeding until approximately age 6 months (standard introduction group [SIG]). Main Outcomes and Measures: Evaluation of CD was an a priori secondary end point of the EAT Study, and at age 3 years, all children with available serum samples were tested for antitransglutaminase type 2 antibodies. Children with antibody levels greater than 20 IU/L were referred to independent gastroenterologists for further investigation. Results: Of the 1004 infants included in the analysis, 514 were male (51.2%). The mean (SD) quantity of gluten consumed between ages 4 and 6 months was 0.49 (1.40) g/wk in the SIG and 2.66 (1.85) g/wk in the EIG (P < .001). Mean (SD) weekly gluten consumption ranged from 0.08 (1.00) g/wk at age 4 months to 0.9 (2.05) g/wk at age 6 months in the SIG vs 1.3 (1.54) g/wk at age 4 months to 4.03 (2.40) g/wk at age 6 months in the EIG. Seven of 516 children from the SIG (1.4%) had a diagnosis of CD confirmed vs none of the 488 children in the EIG (P = .02, risk difference between the groups using the bootstrap, 1.4%; 95% CI, 0.6%-2.6%). Conclusions and Relevance: In this analysis of infants in the EAT Study, the introduction of gluten from age 4 months was associated with reduced CD prevalence. These results suggest that early high-dose consumption of gluten should be considered as a strategy to prevent CD in future studies. Trial Registration: isrctn.org Identifier: ISRCTN14254740.

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.

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.

Association of Early Introduction of Solids With Infant Sleep: A Secondary Analysis of a Randomized Clinical Trial.

Importance: The World Health Organization recommends exclusive breastfeeding for 6 months. However, 75% of British mothers introduce solids before 5 months and 26% report infant waking at night as influencing this decision. Objective: To determine whether early introduction of solids influences infant sleep. Design, Setting, and Participants: The Enquiring About Tolerance study was a population-based randomized clinical trial conducted from January 15, 2008, to August 31, 2015, that included 1303 exclusively breastfed 3-month-old infants from England and Wales. Clinical visits took place at St Thomas' Hospital, London, England, and the trial studied the early introduction of solids into the infant diet from age 3 months. Interventions: The early introduction group (EIG) continued to breastfeed while nonallergenic and then 6 allergenic foods were introduced. The standard introduction group (SIG) followed British infant feeding guidelines (ie, exclusive breastfeeding to around age 6 months and to avoid any food consumption during this period). Main Outcomes and Measures: Secondary analysis of an a priori secondary outcome of the effect of early food introduction on infant sleep using the standardized Brief Infant Sleep Questionnaire. Results: Of the 1303 infants who were enrolled in the Enquiring About Tolerance study, 1225 participants (94%) completed the final 3-year questionnaire (618 SIG [95%] and 607 EIG [93%]). Randomization was effective and there were no significant baseline differences between the 2 groups. Following the early introduction of solids, infants in the EIG slept significantly longer and woke significantly less frequently than infants in the SIG. Differences between the 2 groups peaked at age 6 months. At this point, in the intention-to-treat analysis infants in the EIG slept for 16.6 (95% CI, 7.8-25.4) minutes longer per night and their night waking frequency had decreased from 2.01 to 1.74 wakings per night. Most clinically important, very serious sleep problems, which were significantly associated with maternal quality of life, were reported significantly more frequently in the SIG than in the EIG (odds ratio, 1.8; 95% CI, 1.22-2.61). Conclusions and Relevance: In a randomized clinical trial, the early introduction of solids into the infant's diet was associated with longer sleep duration, less frequent waking at night, and a reduction in reported very serious sleep problems. Trial Registration: isrctn.org Identifier: ISRCTN14254740.

Demystifying Dysbiosis: Can the Gut Microbiome Promote Oral Tolerance Over IgE-mediated Food Allergy?

The growing burden of food allergy is being driven by environmental exposures and the potential role of gut micro-organisms (or 'microbiota') is hotly debated. Early culture-based studies outlined that imbalances between commensal gut constituents ('dysbiosis') early in life may raise the risk of developing allergic disease. A number of studies using animal models describe mechanisms by which specific bacterial taxa within the gut microbiota, their diversity and dietary substrates such as fibre may promote oral tolerance. Next-generation sequencing now allows the detailed characterization of the microbiota in relation to epidemiological exposures and clinical food allergy status in humans. Faecal samples from one birth cohort characterized for food allergy status have been sequenced and showed less gut microbiota richness amongst three month infants who later developed food sensitization at one year. A large cross-sectional survey of young children with milk allergy showed that greater gut microbiota diversity and enrichment of Clostridia and Firmicutes phyla during early infancy is associated with greater likelihood of out-growing milk allergy by eight years of age. Case control studies are limited to selecting participants from amongst hospital patients and have only allowed comparison of heterogeneous groups. To assess whether infants' gut microbiota may predispose towards the development of food allergy, cohort studies must be undertaken to evaluate gut microbiota development from early in infancy and prospectively characterise patterns according to whether challenge proven food allergy later develops, whilst adjusting for atopic dermatitis, dietary and antibiotic exposures.

Immune mechanisms of food allergy and its prevention by early intervention.

The environmental factors driving the increase in food allergies are unclear and possibly involve dual exposure to allergens, microbiome-driven effects or other mechanisms. Until they can be better understood, early intervention aiming at establishing oral tolerance provides an effective way to decrease the window-of-risk when children may develop allergic sensitisation to foods due to the absence of a protective immune response. Thus, the recent LEAP (Learning Early About Peanut allergy) and LEAP-On studies achieved a high level of peanut allergy prevention by early introduction of peanuts in the infants diet and conveyed more information regarding the evolution of IgE and IgG4 antibody responses to food antigens over time.

Association between domestic water hardness, chlorine, and atopic dermatitis risk in early life: A population-based cross-sectional study.

BACKGROUND: Domestic water hardness and chlorine have been suggested as important risk factors for atopic dermatitis (AD). OBJECTIVE: We sought to examine the link between domestic water calcium carbonate (CaCO3) and chlorine concentrations, skin barrier dysfunction (increased transepidermal water loss), and AD in infancy. METHODS: We recruited 1303 three-month-old infants from the general population and gathered data on domestic water CaCO3 (in milligrams per liter) and chlorine (Cl2; in milligrams per liter) concentrations from local water suppliers. At enrollment, infants were examined for AD and screened for filaggrin (FLG) skin barrier gene mutation status. Transepidermal water loss was measured on unaffected forearm skin. RESULTS: CaCO3 and chlorine levels were strongly correlated. A hybrid variable of greater than and less than median levels of CaCO3 and total chlorine was constructed: a baseline group of low CaCO3/low total chlorine (CaL/ClL), high CaCO3/low total chlorine (CaH/ClL), low CaCO3/high total chlorine (CaL/ClH) and high CaCO3/high total chlorine (CaH/ClH). Visible AD was more common in all 3 groups versus the baseline group: adjusted odds ratio (AOR) of 1.87 (95% CI, 1.25-2.80; P = .002) for the CaH/ClL group, AOR of 1.46 (95% CI, 0.97-2.21; P = .07) for the CaL/ClH, and AOR of 1.61 (95% CI, 1.09-2.38; P = .02) for the CaH/ClH group. The effect estimates were greater in children carrying FLG mutations, but formal interaction testing between water quality groups and filaggrin status was not statistically significant. CONCLUSIONS: High domestic water CaCO3 levels are associated with an increased risk of AD in infancy. The influence of increased total chlorine levels remains uncertain. An intervention trial is required to see whether installation of a domestic device to decrease CaCO3 levels around the time of birth can reduce this risk.

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.).