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Children 4 to 11 months of age who were at high risk for development of peanut allergy were assigned to consumption or avoidance of peanuts until 60 months of age. Peanut allergy was more than five times as likely to develop in children assigned to peanut avoidance. The prevalence of peanut allergy among children in Western countries has doubled in the past 10 years, reaching rates of 1.4 to 3.0%, 1 – 3 and peanut allergy is becoming apparent in Africa and Asia. 4 , 5 This allergy is the leading cause of anaphylaxis and death due to food allergy and imposes substantial psychosocial and economic burdens on patients and their families. 6 Peanut allergy develops early in life and is rarely outgrown. 7 – 9 Clinical practice guidelines from the United Kingdom in 1998 9 and from the United States in 2000 10 recommended the exclusion of allergenic foods from the diets of infants at . . .

Six foods commonly associated with food allergy were introduced in the diets of children at 3 months or 6 months of age. Intention-to-treat analysis showed no benefit of early introduction with respect to the prevalence of food allergy; a per-protocol analysis showed a difference. The World Health Organization recommends exclusive breast-feeding of infants for their first 6 months of life. 1 Two national guidelines that had previously recommended the delayed introduction of allergenic foods have been withdrawn (see the Introduction section in the Supplementary Appendix, available with the full text of this article at NEJM.org). In the 2010 United Kingdom Infant Feeding Survey, 45% of the mothers of infants 8 to 10 months of age reported avoiding giving their infant a particular food: 48% avoided nuts, 14% eggs, 10% dairy, and 6% fish. 2 Fear of allergy was the most common reason for avoiding foods, followed by . . .

For young children with peanut allergy, dietary avoidance is the current standard of care. We aimed to assess whether peanut oral immunotherapy can induce desensitisation (an increased allergic reaction threshold while on therapy) or remission (a state of non-responsiveness after discontinuation of immunotherapy) in this population. We did a randomised, double-blind, placebo-controlled study in five US academic medical centres. Eligible participants were children aged 12 to younger than 48 months who were reactive to 500 mg or less of peanut protein during a double-blind, placebo-controlled food challenge (DBPCFC). Participants were randomly assigned by use of a computer, in a 2:1 allocation ratio, to receive peanut oral immunotherapy or placebo for 134 weeks (2000 mg peanut protein per day) followed by 26 weeks of avoidance, with participants and study staff and investigators masked to group treatment assignment. The primary outcome was desensitisation at the end of treatment (week 134), and remission after avoidance (week 160), as the key secondary outcome, were assessed by DBPCFC to 5000 mg in the intention-to-treat population. Safety and immunological parameters were assessed in the same population. This trial is registered on ClinicalTrials.gov, NCT03345160. Between Aug 13, 2013, and Oct 1, 2015, 146 children, with a median age of 39·3 months (IQR 30·8–44·7), were randomly assigned to receive peanut oral immunotherapy (96 participants) or placebo (50 participants). At week 134, 68 (71%, 95% CI 61–80) of 96 participants who received peanut oral immunotherapy compared with one (2%, 0·05–11) of 50 who received placebo met the primary outcome of desensitisation (risk difference [RD] 69%, 95% CI 59–79; p<0·0001). The median cumulative tolerated dose during the week 134 DBPCFC was 5005 mg (IQR 3755–5005) for peanut oral immunotherapy versus 5 mg (0–105) for placebo (p<0·0001). After avoidance, 20 (21%, 95% CI 13–30) of 96 participants receiving peanut oral immunotherapy compared with one (2%, 0·05–11) of 50 receiving placebo met remission criteria (RD 19%, 95% CI 10–28; p=0·0021). The median cumulative tolerated dose during the week 160 DBPCFC was 755 mg (IQR 0–2755) for peanut oral immunotherapy and 0 mg (0–55) for placebo (p<0·0001). A significant proportion of participants receiving peanut oral immunotherapy who passed the 5000 mg DBPCFC at week 134 could no longer tolerate 5000 mg at week 160 (p<0·001). The participant receiving placebo who was desensitised at week 134 also achieved remission at week 160. Compared with placebo, peanut oral immunotherapy decreased peanut-specific and Ara h2-specific IgE, skin prick test, and basophil activation, and increased peanut-specific and Ara h2-specific IgG4 at weeks 134 and 160. By use of multivariable regression analysis of participants receiving peanut oral immunotherapy, younger age and lower baseline peanut-specific IgE was predictive of remission. Most participants (98% with peanut oral immunotherapy vs 80% with placebo) had at least one oral immunotherapy dosing reaction, predominantly mild to moderate and occurring more frequently in participants receiving peanut oral immunotherapy. 35 oral immunotherapy dosing events with moderate symptoms were treated with epinephrine in 21 participants receiving peanut oral immunotherapy. In children with a peanut allergy, initiation of peanut oral immunotherapy before age 4 years was associated with an increase in both desensitisation and remission. Development of remission correlated with immunological biomarkers. The outcomes suggest a window of opportunity at a young age for intervention to induce remission of peanut allergy. National Institute of Allergy and Infectious Disease, Immune Tolerance Network.

A previous trial showed that early consumption of peanuts resulted in fewer cases of allergy than did avoidance. In a follow-up study, all participants avoided peanuts from 5 to 6 years of age; those who had eaten peanuts in early life retained the ability to do so. Peanut allergy is a common and potentially life-threatening food allergy for which prevention and treatment strategies are required. 1 – 5 The Learning Early about Peanut Allergy (LEAP) trial showed that among infants at high risk for allergy, the sustained consumption of peanut, beginning in the first 11 months of life, resulted in an 81% lower rate of peanut allergy at 60 months of age than the rate among children who avoided peanuts. 6 , 7 In a study of oral immunotherapy to hen’s egg white, although children achieved unresponsiveness to an oral food challenge with egg, the majority had a reversion to egg . . .

Small studies suggest peanut oral immunotherapy (OIT) might be effective in the treatment of peanut allergy. We aimed to establish the efficacy of OIT for the desensitisation of children with allergy to peanuts. We did a randomised controlled crossover trial to compare the efficacy of active OIT (using characterised peanut flour; protein doses of 2–800 mg/day) with control (peanut avoidance, the present standard of care) at the NIHR/Wellcome Trust Cambridge Clinical Research Facility (Cambridge, UK). Randomisation (1:1) was by use of an audited online system; group allocation was not masked. Eligible participants were aged 7–16 years with an immediate hypersensitivity reaction after peanut ingestion, positive skin prick test to peanuts, and positive by double-blind placebo-controlled food challenge (DBPCFC). We excluded participants if they had a major chronic illness, if the care provider or a present household member had suspected or diagnosed allergy to peanuts, or if there was an unwillingness or inability to comply with study procedures. Our primary outcome was desensitisation, defined as negative peanut challenge (1400 mg protein in DBPCFC) at 6 months (first phase). Control participants underwent OIT during the second phase, with subsequent DBPCFC. Immunological parameters and disease-specific quality-of-life scores were measured. Analysis was by intention to treat. Fisher's exact test was used to compare the proportion of those with desensitisation to peanut after 6 months between the active and control group at the end of the first phase. This trial is registered with Current Controlled Trials, number ISRCTN62416244. The primary outcome, desensitisation, was recorded for 62% (24 of 39 participants; 95% CI 45–78) in the active group and none of the control group after the first phase (0 of 46; 95% CI 0–9; p<0·001). 84% (95% CI 70–93) of the active group tolerated daily ingestion of 800 mg protein (equivalent to roughly five peanuts). Median increase in peanut threshold after OIT was 1345 mg (range 45–1400; p<0·001) or 25·5 times (range 1·82–280; p<0·001). After the second phase, 54% (95% CI 35–72) tolerated 1400 mg challenge (equivalent to roughly ten peanuts) and 91% (79–98) tolerated daily ingestion of 800 mg protein. Quality-of-life scores improved (decreased) after OIT (median change −1·61; p<0·001). Side-effects were mild in most participants. Gastrointestinal symptoms were, collectively, most common (31 participants with nausea, 31 with vomiting, and one with diarrhoea), then oral pruritus after 6·3% of doses (76 participants) and wheeze after 0·41% of doses (21 participants). Intramuscular adrenaline was used after 0·01% of doses (one participant). OIT successfully induced desensitisation in most children within the study population with peanut allergy of any severity, with a clinically meaningful increase in peanut threshold. Quality of life improved after intervention and there was a good safety profile. Immunological changes corresponded with clinical desensitisation. Further studies in wider populations are recommended; peanut OIT should not be done in non-specialist settings, but it is effective and well tolerated in the studied age group. MRC-NIHR partnership.

IntroductionThe predisposition to food allergy development and the induction of allergen-specific immune responses appears to be initiated early in infancy. Early exposure to food allergens, such as peanut and cashew nut, via human milk is likely important in initiating oral tolerance and reducing risk of food allergy development. This trial aims to determine if the risk of developing peanut and cashew nut allergy during infancy can be reduced by a high peanut and cashew nut maternal diet during lactation.Methods and analysisThis is a multisite, parallel, two-arm (1:1 allocation), single-blinded (outcome assessors, statistical analyst and investigators), randomised controlled trial. Target sample size is 4412 participants (2206 per group). Women (aged 18–50 years) with a singleton pregnancy, who are planning to breastfeed and do not have peanut and/or cashew nut allergies are eligible to participate. After obtaining written informed consent, participants are randomised to either a high peanut and cashew nut diet (at least 60 peanuts and 40 cashew nuts per week) or a low peanut and cashew nut diet (no more than 20 peanuts and 12 cashew nuts per week). Participants are asked to follow their allocated diet from birth to 6 months postnatal. Individual lactation consultant advice and support is provided as required. The study’s primary outcome is food challenge proven IgE-mediated peanut and/or cashew nut allergy during infancy (0–18 months). Key secondary outcomes include infant sensitisation to peanut and/or cashew nut. Analyses will be performed on an intention-to-treat basis according to a prespecified statistical analysis plan.Ethics and disseminationEthical approval has been granted from the Western Australian Child and Adolescent Health Service Human Research Ethics Committee (approval number RGS0000006685). Trial results will be presented at scientific conferences and published in peer-reviewed journals.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN ACTRN12624000134527)

In this issue of the Journal , Greenhawt and colleagues report the findings of the EPITOPE (Epicutaneous Immunotherapy in Toddlers with Peanut Allergy) trial, a phase 3, multinational, double-blind, randomized, placebo-controlled trial of Viaskin Peanut 250 μg, a patch that delivers peanut protein to the skin to desensitize young children with peanut allergy. 1 The trial, which involved toddlers 1 to 3 years of age, met its clinical end points, and the product, if approved, could eventually be used in this population. The primary finding is that after receiving treatment with the peanut patch for a year, 67.0% of the toddlers in . . .

Food allergy results from failure in oral tolerance that usually occurs in infancy or early childhood. Exposure to peanut and hen’s egg via the inflamed and disrupted epithelial barrier in children with severe atopic dermatitis is a risk factor for the development of allergy to these foods and supports the hypothesis that epicutaneous exposure in the absence of oral feeding is an important pathway of allergic IgE sensitization in infants. In recent years, the collective evidence has pointed toward the protective effect of an early feeding with peanut and egg in children with eczema, taking advantage of the pathways underlying oral tolerance to counteract epicutaneous exposure. An addendum to the NIAID food allergy guidelines recommends introduction of peanut into the diet of 4-to 6-month-old infants with severe eczema or egg allergy as an effective strategy to prevent peanut allergy. Strategies aimed at restoring the skin barrier are currently explored as an alternative approach of prevention of eczema and allergic sensitization. Manipulation of the diet via supplementation with probiotics and prebiotics to restore the healthy gut microbiota represents another potential pathway to induction of tolerance in the gut. Oral, epicutaneous, and sublingual routes of food immunotherapy are promising and induce desensitization in the majority of the treated subjects with food allergy but are not proven to restore permanent oral tolerance. Rigorous multicenter randomized clinical trials are necessary to elucidate the optimal timing, dose, duration, as well as the preventive and therapeutic effects of these diverse approaches.

IntroductionFood allergy is a major public health challenge in Australia. Despite widespread uptake of infant feeding and allergy prevention guidelines the incidence of peanut allergy in infants has not fallen, and prevalence of peanut allergy in school-aged children continues to rise. Therefore, effective and accessible treatments for peanut allergy are required. There is high-quality evidence for efficacy of oral immunotherapy in children aged 4–17 years old; however, few randomised trials have investigated peanut oral immunotherapy (OIT) in young children. Furthermore, the use of food products for OIT with doses prepared and administered by parents without requiring pharmacy compounding has the potential to reduce costs associated with the OIT product.Methods and AnalysisEarly Peanut Immunotherapy in Children is an open-label randomised controlled trial of peanut OIT compared with standard care (avoidance) to induce desensitisation in children aged 1–4 years old with peanut allergy. n=50 participants will be randomised 1:1 to intervention (daily peanut OIT for 12 months) or control (peanut avoidance). The primary outcome is the proportion of children in each group with a peanut eliciting dose >600 mg peanut protein as assessed by open peanut challenge after 12 months, analysed by intention to treat. Secondary outcomes include safety as assessed by frequency and severity of treatment-related adverse events, quality of life measured using age-appropriate food allergy-specific questionnaires and immunological changes during OIT.EthicsThe trial is approved by the Child and Adolescent Health Service Human Research Ethics Committee and prospectively registered with the Australia and New Zealand Clinical Trials Registry.DisseminationTrial outcomes will be published in a peer-review journal and presented and local and national scientific meetings.Trial registration numberACTRN12621001001886.

Management of food allergy includes recognition of anaphylaxis, availability of epinephrine, avoidance of food allergens, and education about safe foods. Early introduction of peanuts in the first year of life significantly reduces the risk of peanut allergy.