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.

Prevalence and risk factors for milk allergy overdiagnosis in the BEEP trial cohort.

BACKGROUND: Cow's milk allergy (CMA) overdiagnosis in young children appears to be increasing and has not been well characterised. We used a clinical trial population to characterise CMA overdiagnosis and identify individual-level and primary care practice-level risk factors. METHODS: We analysed data from 1394 children born in England in 2014-2016 (BEEP trial, ISRCTN21528841). Participants underwent formal CMA diagnosis at ≤2 years. CMA overdiagnosis was defined in three separate ways: parent-reported milk reaction; primary care record of milk hypersensitivity symptoms; and primary care record of low-allergy formula prescription. RESULTS: CMA was formally diagnosed in 19 (1.4%) participants. CMA overdiagnosis was common: 16.1% had parent-reported cow's milk hypersensitivity, 11.3% primary care recorded milk hypersensitivity and 8.7% had low-allergy formula prescription. Symptoms attributed to cow's milk hypersensitivity in participants without CMA were commonly gastrointestinal and reported from a median age of 49 days. Low-allergy formula prescriptions in participants without CMA lasted a median of 10 months (interquartile range 1, 16); the estimated volume consumed was a median of 272 litres (26, 448). Risk factors for CMA overdiagnosis were high practice-based low-allergy formula prescribing in the previous year and maternal report of antibiotic prescription during pregnancy. Exclusive formula feeding from birth was associated with increased low-allergy formula prescription. There was no evidence that practice prescribing of paediatric adrenaline auto-injectors or anti-reflux medications, or maternal features such as anxiety, age, parity and socioeconomic status were associated with CMA overdiagnosis. CONCLUSION: CMA overdiagnosis is common in early infancy. Risk factors include high primary care practice-based low-allergy formula prescribing and maternal report of antibiotic prescription during pregnancy.

Timing of complementary feeding for early childhood allergy prevention: An overview of systematic reviews.

OBJECTIVE: To summarise and critically appraise systematic review (SR) evidence on the effects of timing of complementary feeding (CF) on the occurrence of allergic sensitisation and disease. DESIGN: Overview of SRs. AMSTAR-2 and ROBIS were used to assess methodological quality and risk of bias (RoB) of SRs. RoB 2 Tool was used to assess RoB of primary randomised controlled trials (RCTs) (or extracted). The certainty of evidence (CoE) was assessed using GRADE. Findings were synthesised narratively. DATA SOURCES: MEDLINE (via PubMed and Ovid), the Cochrane Library and Web of Science Core Collection (2010 to 27 February 2023). ELIGIBILITY CRITERIA: SRs investigating the effects of timing of CF in infants or young children (0-3 years) on risk of developing food allergy (FA), allergic sensitisation, asthma, allergic rhinitis, atopic eczema and adverse events based on RCT evidence. RESULTS: Eleven SRs were included. Only two SRs had low RoB; common issues were failure to report on funding of primary studies and failure to provide a list of excluded trials. Common limitations of included trials were lack of blinding of outcome assessment or detailed trial preregistration, and inadequate handling of high loss to follow up. Primary study overlap was very high for specific FA and slight to moderate for FA in general and other primary outcomes. Introducing specific foods (peanut, cooked egg) early probably reduces the risk of specific FA. Evidence for other allergic outcomes was mostly very uncertain and based on few primary studies. Trials varied regarding timing of CF, nature of complementary foods and population risk, which limited comparability between SRs. CONCLUSIONS: For developing guidelines to support decision-making on the timing of CF as a preventive strategy, early introduction of specific foods (i.e. egg and peanut) seems promising and safe, whereas more extensive research is required regarding other allergic outcomes and potential adverse events.

Emollients for preventing atopic eczema: Cost-effectiveness analysis of the BEEP trial.

BACKGROUND: Recent discoveries have led to the suggestion that enhancing skin barrier from birth might prevent eczema and food allergy. OBJECTIVE: To determine the cost-effectiveness of daily all-over-body application of emollient during the first year of life for preventing atopic eczema in high-risk children at 2 years from a health service perspective. We also considered a 5-year time horizon as a sensitivity analysis. METHODS: A within-trial economic evaluation using data on health resource use and quality of life captured as part of the BEEP trial alongside the trial data. Parents/carers of 1394 infants born to families at high risk of atopic disease were randomised 1:1 to the emollient group, which were advised to apply emollient (Doublebase Gel or Diprobase Cream) to their child at least once daily to the whole body during the first year of life or usual care. Both groups received advice on general skin care. The main economic outcomes were incremental cost-effectiveness ratio (ICER), defined as incremental cost per percentage decrease in risk of eczema in the primary cost-effectiveness analysis. Secondary analysis, undertaken as a cost-utility analysis, reports incremental cost per Quality-Adjusted Life Year (QALY) where child utility was elicited using the proxy CHU-9D at 2 years. RESULTS: At 2 years, the adjusted incremental cost was £87.45 (95% CI -54.31, 229.27) per participant, whilst the adjusted proportion without eczema was 0.0164 (95% CI -0.0329, 0.0656). The ICER was £5337 per percentage decrease in risk of eczema. Adjusted incremental QALYs were very slightly improved in the emollient group, 0.0010 (95% CI -0.0069, 0.0089). At 5 years, adjusted incremental costs were lower for the emollient group, -£106.89 (95% CI -354.66, 140.88) and the proportion without eczema was -0.0329 (95% CI -0.0659, 0.0002). The 5-year ICER was £3201 per percentage decrease in risk of eczema. However, when inpatient costs due to wheezing were excluded, incremental costs were lower and incremental effects greater in the usual care group. CONCLUSIONS: In line with effectiveness endpoints, advice given in the BEEP trial to apply daily emollient during infancy for eczema prevention in high-risk children does not appear cost-effective.

Early introduction of peanut reduces peanut allergy across risk groups in pooled and causal inference analyses.

BACKGROUND: The Learning Early About Peanut allergy (LEAP) study has shown the effectiveness of early peanut introduction in prevention of peanut allergy (PA). In the Enquiring About Tolerance (EAT) study, a statistically significant reduction in PA was present only in per-protocol (PP) analyses, which can be subject to bias. OBJECTIVE: The aim of this study was to combine individual-level data from the LEAP and EAT trials and provide robust evidence on the bias-corrected, causal effect of early peanut introduction. METHOD: As part of the European Union-funded iFAAM project, this pooled analysis of individual pediatric patient data combines and compares effectiveness and efficacy estimates of oral tolerance induction among different risk strata and analysis methods. RESULTS: An intention-to-treat (ITT) analysis of pooled data showed a 75% reduction in PA (p < .0001) among children randomized to consume peanut from early infancy. A protective effect was present across all eczema severity groups, irrespective of enrollment sensitization to peanut, and across different ethnicities. Earlier age of introduction was associated with improved effectiveness of the intervention. In the pooled PP analysis, peanut consumption reduced the risk of PA by 98% (p < .0001). A causal inference analysis confirmed the strong PP effect (89% average treatment effect relative risk reduction p < .0001). A multivariable causal inference analysis approach estimated a large (100%) reduction in PA in children without eczema (p = .004). CONCLUSION: We demonstrate a significant reduction in PA with early peanut introduction in a large group of pooled, randomized participants. This significant reduction was demonstrated across all risk subgroups, including children with no eczema. Furthermore, our results point to increased efficacy of the intervention with earlier age of introduction.

Emollients for prevention of atopic dermatitis: 5-year findings from the BEEP randomized trial.

BACKGROUND: The effectiveness of emollients for preventing atopic dermatitis/eczema is controversial. The Barrier Enhancement for Eczema Prevention trial evaluated the effects of daily emollients during the first year of life on atopic dermatitis and atopic conditions to age 5 years. METHODS: 1394 term infants with a family history of atopic disease were randomized (1:1) to daily emollient plus standard skin-care advice (693 emollient group) or standard skin-care advice alone (701 controls). Long-term follow-up at ages 3, 4 and 5 years was via parental questionnaires. Main outcomes were parental report of a clinical diagnosis of atopic dermatitis and food allergy. RESULTS: Parents reported more frequent moisturizer application in the emollient group through to 5 years. A clinical diagnosis of atopic dermatitis between 12 and 60 months was reported for 188/608 (31%) in the emollient group and 178/631 (28%) in the control group (adjusted relative risk 1.10, 95% confidence interval 0.93 to 1.30). Although more parents in the emollient group reported food reactions in the previous year at 3 and 4 years, cumulative incidence of doctor-diagnosed food allergy by 5 years was similar between groups (92/609 [15%] emollients and 87/632 [14%] controls, adjusted relative risk 1.11, 95% confidence interval 0.84 to 1.45). Findings were similar for cumulative incidence of asthma and hay fever. CONCLUSIONS: Daily emollient application during the first year of life does not prevent atopic dermatitis, food allergy, asthma or hay fever.

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.

National Survey of United Kingdom Paediatric Allergy Services.

BACKGROUND: Comprehensive national assessments of paediatric allergy services are rarely undertaken, and have never been undertaken in the United Kingdom. A 2006 survey estimated national capacity at 30,000 adult or paediatric new allergy appointments per year and identified 58 hospital clinics offering a paediatric allergy service. OBJECTIVE: The UK Paediatric Allergy Services Survey was the first comprehensive assessment of UK paediatric allergy service provision. METHODS: All 450 UK hospitals responded to a survey. Paediatric allergy services are provided in 154 lead hospitals with 75 further linked hospitals. All 154 lead paediatric allergy services completed a detailed questionnaire between February 2019 and May 2020. RESULTS: The 154 paediatric allergy services self-define as secondary (126/154, 82%) or tertiary (28/154, 18%) level services. The annual capacity is 85,600 new and 111,400 follow-up appointments. Fifty-eight percent (85/146) of services offer ≤10 new appointments per week (no data provided from 8 services-2 no response, 6 unknown) and 50% (70/139) of the services undertaking challenges undertake ≤2 food or drug challenges per week (no data from 3 challenge services). Intramuscular adrenaline is rarely used during challenges-median annual frequency 0 in secondary services and 2 in tertiary services. Allergen-specific immunotherapy is offered in 39% (60/154) of services, with 71% (41/58) of these centres treating ≤10 patients per annum (no data from 2 immunotherapy services). The 12 largest services see 31% of all new paediatric allergy appointments, undertake 51% of new immunotherapy patient provision and 33% of food or drug challenges. Seventy percent (97/126) of secondary and all tertiary services are part of a regional paediatric allergy network. Only nine services offer immunotherapy for any food (3 for peanut), 10 drug desensitization and 18 insect venom immunotherapy. CONCLUSIONS: There has been a fourfold increase in paediatric allergy clinics and an approximately sevenfold increase in new patient appointment numbers in the United Kingdom over the past 15 years. Most services are small, with significant regional variation in availability of specific services such as allergen immunotherapy. Our findings emphasize the need for national standards, local networks and simulation training to ensure consistent and safe service provision.

Detection and management of milk allergy: Delphi consensus study.

BACKGROUND: There is significant overdiagnosis of milk allergy in young children in some countries, leading to unnecessary use of specialized formula. This guidance, developed by experts without commercial ties to the formula industry, aims to reduce milk allergy overdiagnosis and support carers of children with suspected milk allergy. METHODS: Delphi study involving two rounds of anonymous consensus building and an open meeting between January and July 2021. Seventeen experts in general practice, nutrition, midwifery, health visiting, lactation support and relevant areas of paediatrics participated, located in Europe, North America, Middle East, Africa, Australia and Asia. Five authors of previous milk allergy guidelines and seven parents provided feedback. FINDINGS: Participants agreed on 38 essential recommendations through consensus. Recommendations highlighted the importance of reproducibility and specificity for diagnosing milk allergy in children with acute or delayed symptoms temporally related to milk protein ingestion; and distinguished between children directly consuming milk protein and exclusively breastfed infants. Consensus was reached that maternal dietary restriction is not usually necessary to manage milk allergy, and that for exclusively breastfed infants with chronic symptoms, milk allergy diagnosis should only be considered in specific, rare circumstances. Consensus was reached that milk allergy diagnosis does not need to be considered for stool changes, aversive feeding or occasional spots of blood in stool, if there is no temporal relationship with milk protein ingestion. When compared with previous guidelines, these consensus recommendations resulted in more restrictive criteria for detecting milk allergy and a more limited role for maternal dietary exclusions and specialized formula. INTERPRETATION: These new milk allergy recommendations from non-conflicted, multidisciplinary experts advise narrower criteria, more prominent support for breastfeeding and less use of specialized formula, compared with current guidelines.

Moving Complementary Feeding Forward: Report on a Workshop of the Federation of International Societies for Pediatric Gastroenterology, Hepatology and Nutrition (FISPGHAN) and the World Health Organization Regional Office for Europe.

The WHO Regional Office for Europe and the Federation of International Societies for Pediatric Gastroenterology, Hepatology, and Nutrition held a joint workshop, "Moving Complementary Feeding Forward" at the sixth World Congress Pediatric Gastroenterology, Hepatology, and Nutrition in 2021. Here we summarize workshop presentations and discussions. The workshop covered health implications of complementary feeding (CF) including allergies, challenges to meet dietary needs during the CF period, quality of commercial complementary foods (CFD) and respective marketing practices, national CF guidelines in Europe, a nutrient profiling system for CFD, and global policy perspectives on the standards and regulation of marketing for CFD. Adequate CF practices are of critical importance for short and long-term child health, prevention of nutrient deficiencies, normal growth and development, and reducing the risk of allergies. The workshop identified the need to improve feeding practices, harmonize evidence-based information and develop guidance jointly with various stakeholders, improve the composition and marketing practices of commercial CFD and their transparent labeling based on nutrient profiling. Renewed efforts for collaboration between scientists, public health experts, pediatric associations, national governments, and the WHO are necessary for advancing progress.

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.

Daily emollient during infancy for prevention of eczema: the BEEP randomised controlled trial.

BACKGROUND: Skin barrier dysfunction precedes eczema development. We tested whether daily use of emollient in the first year could prevent eczema in high-risk children. METHODS: We did a multicentre, pragmatic, parallel-group, randomised controlled trial in 12 hospitals and four primary care sites across the UK. Families were approached via antenatal or postnatal services for recruitment of term infants (at least 37 weeks' gestation) at high risk of developing eczema (ie, at least one first-degree relative with parent-reported eczema, allergic rhinitis, or asthma, diagnosed by a doctor). Term newborns with a family history of atopic disease were randomly assigned (1:1) to application of emollient daily (either Diprobase cream or DoubleBase gel) for the first year plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). The randomisation schedule was created using computer-generated code (stratified by recruiting centre and number of first-degree relatives with atopic disease) and participants were assigned to groups using an internet-based randomisation system. The primary outcome was eczema at age 2 years (defined by UK working party criteria) with analysis as randomised regardless of adherence to allocation for participants with outcome data collected, and adjusting for stratification variables. This trial is registered with ISRCTN, ISRCTN21528841. Data collection for long-term follow-up is ongoing, but the trial is closed to recruitment. FINDINGS: 1394 newborns were randomly assigned to study groups between Nov 19, 2014, and Nov 18, 2016; 693 were assigned to the emollient group and 701 to the control group. Adherence in the emollient group was 88% (466 of 532) at 3 months, 82% (427 of 519) at 6 months, and 74% (375 of 506) at 12 months in those with complete questionnaire data. At age 2 years, eczema was present in 139 (23%) of 598 infants with outcome data collected in the emollient group and 150 (25%) of 612 infants in the control group (adjusted relative risk 0·95 [95% CI 0·78 to 1·16], p=0·61; adjusted risk difference -1·2% [-5·9 to 3·6]). Other eczema definitions supported the results of the primary analysis. Mean number of skin infections per child in year 1 was 0·23 (SD 0·68) in the emollient group versus 0·15 (0·46) in the control group; adjusted incidence rate ratio 1·55 (95% CI 1·15 to 2·09). INTERPRETATION: We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children and some evidence to suggest an increased risk of skin infections. Our study shows that families with eczema, asthma, or allergic rhinitis should not use daily emollients to try and prevent eczema in their newborn. FUNDING: National Institute for Health Research Health Technology Assessment.

Adherence to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist in articles published in EAACI Journals: A bibliographic study.

Research data derived from observational studies are accumulating quickly in the field of allergy and immunology and a large amount of observational studies are published every year. The aim of the present study was to evaluate the adherence to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist by papers published in the three European Academy of Allergy and Clinical Immunology journals, during the period 2009-2018. To this end, we conducted a bibliographic study of up to eight randomly selected papers per year per Journal. Our literature search resulted in 223 papers. Amongst those, 80, 80 and 63 records were from Paediatric Allergy and Immunology, Allergy and Clinical and Translational Allergy, respectively; the latter was published only from 2011 on. Prospective, case control and cross-sectional designs were described in 88, 43 and 92 papers, respectively. Full reporting of all STROBE items was present in 47.4%, 45.6% and 41.2% for the cohort, cross-sectional and case-control studies, respectively. Generally, no time trend in adherence of reporting STROBE items was observed, apart from reporting funding, which increased from 60% in 2009/2010 to more than 90% in 2018. We identified a cluster of STROBE items with low proportions of full reporting constituted by the items on reporting study design in the title and methods, variables types along with their measurement/assessment, bias and confounding, study size, and grouping of variables. It appears that the STROBE checklist is a suitable tool in observational allergy epidemiology. However, adherence to the STROBE checklist appeared suboptimal.

Evaluating an Intervention to Increase Cereal Fiber Intake in Children: A Randomized Controlled Feasibility Trial.

BACKGROUND: Observational studies have shown that higher cereal fiber intake is associated with reduced type 2 diabetes risk. However, it remains uncertain whether this association is causal. OBJECTIVE: This study evaluated the feasibility of an intervention to increase cereal fiber intake in children using breakfast cereals. METHODS: The study was a 2-arm parallel group randomized controlled trial in 9-10-y-old children, who received free supplies of high-fiber breakfast cereals (>3.5 g/portion) or low-fiber breakfast cereals (<1.0 g/portion) to eat daily for 1 mo with behavioral support to promote adherence. Children provided baseline and 1-mo fasting blood samples, physical measurements, and 24-h dietary recalls. The primary outcome was the group difference in change in plasma total alkylresorcinol (AR) concentration; secondary outcomes were group differences in nutrient intakes and adiposity indices. Analyses (complete case and multiple imputation) were conducted by regressing the final AR concentration on baseline AR in models adjusted for sex, ethnicity, age, and school (random effect). RESULTS: Two-hundred seventy-two children were randomly assigned (137 receiving a low-fiber and 135 a high-fiber diet) and 193 (71%) provided fasting blood samples at baseline and follow-up. Among randomized participants, median (IQR) of baseline AR was 43.1 (24.6-85.5) nmol/L and of cereal fiber intake was 4.5 (2.7-6.4) g; 87% of participants reported consuming the cereal on most or all days. Compared with changes in the low-fiber group, the high-fiber group had greater increases in AR (40.7 nmol/L; 95% CI: 21.7, 59.8 nmol/L, P < 0.0001) and in reported cereal fiber intake (2.9g/d; 95% CI: 2.0, 3.7 g; P < 0.0001). There were no appreciable differences in other secondary outcomes. CONCLUSIONS: We have developed a simple and acceptable nutritional intervention that increases markers of daily cereal fiber intake in children. This intervention could be used to test whether increases in cereal fiber intake in children might reduce insulin resistance. This trial was registered at www.isrctn.com as ISRCTN33260236.

An algorithm for diagnosing IgE-mediated food allergy in study participants who do not undergo food challenge.

BACKGROUND: Food allergy diagnosis in clinical studies can be challenging. Oral food challenges (OFC) are time-consuming, carry some risk and may, therefore, not be acceptable to all study participants. OBJECTIVE: To design and evaluate an algorithm for detecting IgE-mediated food allergy in clinical study participants who do not undergo OFC. METHODS: An algorithm for trial participants in the Barrier Enhancement for Eczema Prevention (BEEP) study who were unwilling or unable to attend OFC was developed. BEEP is a pragmatic, multi-centre, randomized-controlled trial of daily emollient for the first year of life for primary prevention of eczema and food allergy in high-risk infants (ISRCTN21528841). We built on the European iFAAM consensus guidance to develop a novel food allergy diagnosis algorithm using available information on previous allergenic food ingestion, food reaction(s) and sensitization status. This was implemented by a panel of food allergy experts blind to treatment allocation and OFC outcome. We then evaluated the algorithm's performance in both BEEP and Enquiring About Tolerance (EAT) study participants who did undergo OFC. RESULTS: In 31/69 (45%) BEEP and 44/55 (80%) EAT study control group participants who had an OFC the panel felt confident enough to categorize children as "probable food allergy" or "probable no food allergy". Algorithm-derived panel decisions showed high sensitivity 94% (95%CI 68, 100) BEEP; 90% (95%CI 72, 97) EAT and moderate specificity 67% (95%CI 39, 87) BEEP; 67% (95%CI 39, 87) EAT. Sensitivity and specificity were similar when all BEEP and EAT participants with OFC outcome were included. CONCLUSION: We describe a new algorithm with high sensitivity for IgE-mediated food allergy in clinical study participants who do not undergo OFC. CLINICAL RELEVANCE: This may be a useful tool for excluding food allergy in future clinical studies where OFC is not conducted.

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.

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.).