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Based on productive translational research programs conducted over the last 20 years, the clinical landscape of peanut allergy is now rapidly changing. In this review, we review data from recent trials of investigational peanut oral and epicutaneous immunotherapies, explore the pipeline of novel therapies in early development, and identify future research needs and priorities.

Background The randomized, controlled PALISADE trial demonstrated the benefit of daily oral immunotherapy with Peanut (Arachis Hypogaea) allergen powder-dnfp (PTAH, formerly AR101) in peanut-allergic children and adolescents. Objective ARC004, the open-label follow-on study to PALISADE, used 5 dosing cohorts to explore PTAH treatment beyond 1 year and alternative dosing regimens in peanut-allergic individuals. Methods Active arm (PTAH-continuing) PALISADE participants who tolerated 300-mg peanut protein at the exit double-blind placebo-controlled food challenge and placebo arm (PTAH-naive) participants could enter ARC004. PTAH-continuing participants were assigned to receive daily (cohorts 1 and 3A) or non–daily (cohorts 2, 3B, and 3C) dosing regimens; PTAH-naive participants were built up to 300 mg/d PTAH, followed by maintenance dosing. At study completion, participants underwent an exit double-blind placebo-controlled food challenge with doses up to 2000 mg peanut protein. Data were assessed using descriptive statistics. Results Overall, 358 (87.5%) eligible participants (4-17 years) entered ARC004 (PTAH-continuing, n = 256; PTAH-naive, n = 102). Among PTAH-continuing participants, exposure-adjusted adverse event rates were 12.94 to 17.54/participant-year and 25.95 to 42.49/participant-year in daily and non–daily dosing cohorts, respectively; most participants (83%) experienced mild or moderate adverse events. Daily dosing cohorts appeared to have higher desensitization rates than non–daily dosing cohorts. Of all PTAH-continuing cohorts, cohort 3A had the longest daily dosing duration and the highest desensitization rates. Changes in immune markers with PTAH continuation demonstrated ongoing immunomodulation. Outcomes in PTAH-naive participants mirrored those of the PALISADE active arm. Conclusions Continued daily PTAH treatment beyond 1 year showed sustained safety and efficacy. Ongoing immunomodulation was observed during the second year of treatment.

Background Food protein–induced allergic proctocolitis (FPIAP) is an early and common manifestation of food allergy, yet its epidemiology and relationship to other allergic diseases remain unclear. Objective To prospectively define the incidence of FPIAP as it is being diagnosed clinically in the community and to identify factors associated with its development. Methods A total of 1003 of 1162 eligible serial healthy newborn infants recruited from a single suburban pediatrics practice were followed prospectively for the diagnosis of FPIAP. Investigators reviewed each case to confirm prespecified inclusion criteria, including documented gross or occult blood in the stool. Results A total of 903 infants were analyzed (46% females, 89% term, 32% caesarian-section, 9% neonatal antibiotics); 153 cases met inclusion criteria, a cumulative incidence of 17%, while 63 (7%) had gross blood. Infants initially fed both breast milk and formula were 61% less likely to develop FPIAP compared with those exclusively formula-fed (hazard ratio, 0.39; P = .005). Breast milk and formula at any point during the first 4 months were also associated with lower risk compared with exclusive formula or exclusive breast milk (hazard ratio, 0.44; P = .005; hazard ratio, 0.62; P = .0497). Eczema (odds ratio, 1.5; 95% confidence interval, 1.1- 2.2; P = .02) or a first-degree relative with food allergies (odds ratio, 1.9; 95% confidence interval, 1.2-2.8; P = .005) were among risk factors for FPIAP development. Conclusions The prospectively defined incidence of FPIAP when diagnosed clinically by community pediatricians without challenge is markedly higher than published estimates. Combination feeding of formula and breast milk is associated with the lowest rate of FPIAP in this population.

Eosinophilic esophagitis (EoE) is an emergent disease with unclear environmental causes. In the few studies of the epidemiology of EoE, male sex and white race have been identified as risk factors. A recent report suggested that cesarean section and early life antibiotic use may increase the risk of EoE, but other studies have not specifically looked at these factors, nor have they examined associations between early life gastrointestinal symptoms and EoE. The aim of this study was to investigate associations between EoE and dietary, environmental, and medical exposures during infancy. Subjects and controls ages 1-5 years old were recruited from the pediatric clinics at the Massachusetts General Hospital. EoE cases were identified by a systematic review of pediatric gastroenterology and allergy clinic visits (by International Classification of Diseases, Ninth Revision codes) between March 2011 and May 2012, and a review of all age-eligible endoscopy procedure visits between January 2008 and May 2012. A diagnosis of EoE was based on endoscopy findings of 15 eosinophils in any high-powered field on esophageal biopsy specimens while the subject was on adequate proton-pump inhibitor therapy ( 1 mg/kg/d for 6 weeks). Subjects were excluded if they had known eosinophilic gastroenteritis, inflammatory bowel disease, or any systemic hypereosinophilic syndromes. Control subjects were recruited from the Pediatric Ambulatory Care Clinic well-child and followup visits. This clinic has a comparable demographic profile to the specialty clinics, with a similar percentage of patients covered by state-assisted health insurance. Control subjects were excluded if they had symptoms suggestive of undiagnosed EoE, including feeding difficulty, frequent vomiting, frequent chest and/or abdominal pain, or dysphagia. Frequency matching of controls was performed for a family history of atopy and for sex. Approval for this study was given by the Massachusetts General Hospital Institutional Review Board. The parent of each subject completed a questionnaire at the time of a clinic visit or via electronic mail. The screening and study questionnaire included questions extracted from the International Study of Asthma and Allergies in Childhood study questionnaires. Study data were collected and managed by using REDCap electronic data capture tools hosted at Massachusetts General Hospital. Characteristics of subjects and controls were compared by the Fisher exact test for dichotomous variables and by the Mann-Whitney 2-sample statistic for continuous variables. Odds ratios (OR) were calculated by logistic regression. The only significant demographic difference between the groups was age; therefore, analyses were adjusted for age, and for the frequency matching variables (atopic family history and sex). To explore mediators of associations found, additional analyses of timing of dietary introduction were adjusted for history of formula intolerance, and analyses of mode of delivery and early life antibiotic use were adjusted for personal history of atopy. Calculations were done with STATA SE 11.2 (College Station, Texas). Twenty-five subjects with EoE and 74 controls were enrolled; 14 subjects were excluded because of symptoms that could be suggestive of undiagnosed EoE. Questionnaires were completed by 89% and 85% of approached subjects and controls, respectively. As seen in Table I, demographic characteristics of subjects and controls were similar, except that the subjects were younger (median 41 vs 51 months). The subjects with EoE were more frequently born by cesarean section than were the controls (60% vs 34%; P 1⁄4 .03) and had a significantly higher rate of antibiotic use in the first year of life (67% vs 33%; P 1⁄4 .004), differences that were significant when adjusting for age, family history of atopy, and sex. (Tables I and II). After also adjusting for a personal history of atopy, the subjects still had increased odds of antibiotic use in the first year of life (OR 3.61 [95% CI, 1.11e11.74]; P 1⁄4 .03), although the relationship with mode of delivery was no longer statistically significant (OR 2.69 [95% CI, 0.93e7.83]; P 1⁄4 .07). Patients with EoE reported a significantly higher frequency of signs and symptoms of gastrointestinal allergy early in life. Unexpectedly, lower gastrointestinal tract disease manifestations also were significantly associated with EoE. Specifically, the subjects with EoE had substantially higher rates of hematochezia (22% vs 4%; P 1⁄4 .02) and mucous in the stool (35% vs 7%; P 1⁄4 .002) during the first year of life, although the difference in hematochezia was no longer significant when adjusting for age, a family history of atopy, and sex (P 1⁄4 .07) (Table I). No significant differences were seen between groups on measures of breastfeeding; timing of first solid food introduction; or timing of introduction of dairy, concentrated egg, wheat, meats, corn, or peanuts. Small significant differences in timing of foods typically introduced later in infancy, including baked egg products, tree nuts, shellfish, and fish generally did not persist after adjusting for the use of hypoallergenic formula, although age of introduction of baked egg products and fish remained higher in the subjects than with the controls (see Tables E1 and E2 in this article’s Online Repository at www.jaci-inpractice.org). The aim of this study was to investigate the association between early life exposures with the later development of EoE. We found that cesarean delivery and antibiotic exposure in the first year of life were significantly associated with the development of EoE. The findings with regard to cesarean section and antibiotic use are of similar magnitude to another case-control study of EoE in children up to age 17 years old, despite the differences in ages. The mode of delivery has not otherwise been linked to EoE