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Objective Food protein-induced enterocolitis syndrome (FPIES) is typically diagnosed based on a characteristic clinical history; however, an oral food challenge (OFC) may be necessary to confirm the diagnosis or evaluate for the development of tolerance. FPIES OFC methods vary globally, and there is no universally agreed upon protocol. The objective of this review is to summarize reported FPIES OFC approaches and consider unmet needs in diagnosing and managing FPIES. Data Sources PubMed database was searched using the keywords food protein-induced enterocolitis syndrome, oral food challenge, cow milk allergy, food allergy, non-immunoglobulin E–mediated food allergy and FPIES. Study Selections Primary and review articles were selected based on relevance to the diagnosis of FPIES and the FPIES OFC. Results We reviewed the history of FPIES and the evolution and variations in the FPIES OFC. A summary of current literature suggests that most patients with FPIES will react with 25% to 33% of a standard serving of the challenged food, there is little benefit to offering a divided dose challenge unless there is suspicion of specific immunoglobulin E to the food being challenged, reactions typically appear within 1 to 4 hours of ingestion, and reactions during OFC rarely result in emergency department or intensive care unit admission. Conclusion International standardization in the FPIES OFC approach is necessary with particular attention to specific dose administration across challenged foods, timing between the patient’s reaction and offered OFC to verify tolerance, patient safety considerations before the OFC, and identification of characteristics that would indicate home reintroduction is appropriate.

Deleterious variation in the epidermal differentiation complex (EDC) on chromosome 1 is a well-known genetic determinant of atopic dermatitis (AD) and has been associated with risk of peanut allergy (PA) in population-based studies.Our aim was to determine the effect of genetic variation in the EDC on AD trajectory and risk of PA in early life.Genome sequencing was used to measure genetic variation in the EDC in the Learning Early about Peanut Allergy (LEAP) study participants. Association tests were done to identify gene- and variant-level predicted deleterious variation associated with AD severity by using the Scoring Atopic Dermatitis (SCORAD) tool (n = 559) at baseline and each follow-up visit, as well as PA and food allergy in peanut avoiders (n = 275). Predicted deleterious variants included missense variants that were frameshift insertions, frameshift deletions, stop-gain mutations, or stop-loss mutations. Associations between variant load, SCORAD score, and PA were tested by using linear and generalized linear regression models.The genes FLG, FLG2, HRNR, and TCHH1 harbored the most predicted deleterious variation (30, 6, 3, and 1 variant, respectively). FLG variants were associated with SCORAD score at all time points; 4 variants (R1798X, R501X, S126X, and S761fs) drove the association with SCORAD score at each time point, and higher variant load was associated with greater AD severity over time. There was an association between these variants and PA, which remained significant independent of baseline AD severity (odds ratio = 2.63 [95% CI = 1.11-6.01] [P = .02]).Variation in FLG predicted to be deleterious is associated with AD severity at baseline and longitudinally and has an association with PA independent of baseline severity.

Background Peanut allergy is the leading cause of food-related anaphylaxis. Current management options can negatively affect food allergy-related quality of life. We aimed to investigate the efficacy of an investigational oral biologic drug (AR101). Methods The AR101 Trial in Europe Measuring Oral Immunotherapy Success in peanut-allergic children (ARTEMIS) trial was a multicentre, double-blind, randomised, placebo-controlled phase 3 trial done at 18 hospitals in Ireland, France, Germany, Italy, Spain, Sweden, and the UK. Children and adolescents with peanut allergy, aged 4–17 years, who developed dose-limiting symptoms to 300 mg or less peanut protein (equivalent to approximately one peanut kernel) during a double-blind placebo-controlled food challenge test at study entry were enrolled. Participants were randomly assigned (3:1) to receive daily doses of either AR101 oral immunotherapy (AR101 group) or a taste-masked placebo (placebo group). All participants, investigators, and care providers were masked to treatment allocation until the study was completed. Doses were increased every 2 weeks over 6 months until a dose of 300 mg was reached and maintained for 3 months. The primary endpoint was the proportion of participants in the intention-to-treat or safety population (defined as those participants who had been randomly assigned and had received at least one dose of the assigned drug) who could consume a single dose of 1000 mg (cumulative dose 2043 mg) peanut protein without developing dose-limiting allergic symptoms at an exit double-blind placebo-controlled food challenge after 9 months of treatment. Additional endpoints included safety (ie, the frequency and severity of adverse events) and changes in food allergy-related quality of life, assessed by use of age-appropriate Food Allergy Quality of Life Questionnaires (FAQLQs) and the Food Allergy Independent Measure (FAIM). The study is registered with ClinicalTrials.gov, NCT03201003, and is completed. Findings Between June 12, 2017, and Feb 15, 2018, 227 patients were screened, of whom 175 were randomly assigned to the AR101 group (n=132) and the placebo group (n=43). All primary and secondary endpoints were met. 77 (58%) of 132 participants in the AR101 group tolerated 1000 mg peanut protein at the exit food challenge versus one (2%) of 43 participants in the placebo group (AR101–placebo treatment difference 56·0% [95% CI 44·1–65·2], p

Objective To highlight challenges associated with this novel preventive strategy. Data Sources The Learning Early About Peanuts (LEAP) and Enquiring About Tolerance (EAT) Studies, with reference to other oral tolerance induction studies. Study Selections Randomized clinial trials seeking to prevent food allergy through allergen introduction in infancy. Results Oral tolerance induction programs that use a regimen of consumption of 2 g/week of protein are effective in preventing peanut and egg allergy. LEAP findings suggest oral tolerance induction is allergen specific. Adding peanut and other common food allergens (egg, fish, sesame, milk) to the infant diet has no adverse nutritional or growth effects and does not increase rates of food allergy. Breastfeeding rates are not adversely affected by these interventions. In the Western world, nonwhite children have the highest risk of food allergy, but their families are the least likely to participate in oral tolerance induction programs. Conclusion Many challenges must be overcome to implement successful food allergy prevention strategies. Allergy testing of high-risk infants (those with moderate to severe eczema and/or egg allergy) before commencing oral tolerance induction is desirable, but access is not universal. Dietary interventions would ideally be implemented in infancy before allergic sensitization and allergy occur, using a program that provides protection against multiple common allergens. Further research and consensus with regard to food preparations, target populations, dosing regimens, and preparations and clearly defined adherence are now required.

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 Live attenuated influenza vaccine (LAIV) is an intranasal vaccine recently incorporated into the United Kingdom immunization schedule. However, it contains egg protein and, in the absence of safety data, is contraindicated in patients with egg allergy. Furthermore, North American guidelines recommend against its use in asthmatic children. Objective We sought to assess the safety of LAIV in children with egg allergy. Methods We performed a prospective, multicenter, open-label, phase IV intervention study involving 11 secondary/tertiary centers in the United Kingdom. Children with egg allergy (defined as a convincing clinical reaction to egg within the past 12 months and/or >95% likelihood of clinical egg allergy as per published criteria) were recruited. LAIV was administered under medical supervision, with observation for 1 hour and telephone follow-up 72 hours later. Results Four hundred thirty-three doses were administered to 282 children with egg allergy (median, 4.9 years; range, 2-17 years); 115 (41%) had experienced prior anaphylaxis to egg. A physician's diagnosis of asthma/recurrent wheezing was noted in 67%, and 51% were receiving regular preventer therapy. There were no systemic allergic reactions (upper 95% CI for population, 1.3%). Eight children experienced mild self-limiting symptoms, which might have been due an IgE-mediated allergic reaction. Twenty-six (9.4%; 95% CI for population, 6.2% to 13.4%) children experienced lower respiratory tract symptoms within 72 hours, including 13 with parent-reported wheeze. None of these episodes required medical intervention beyond routine treatment. Conclusions In contrast to current recommendations, LAIV appears to be safe for use in children with egg allergy. Furthermore, the vaccine appears to be well tolerated in children with a diagnosis of asthma or recurrent wheeze.

Background:Most of the peanut-sensitized children do not have clinical peanut allergy. In equivocal cases, oral food challenges (OFCs) are required. However, OFCs are laborious and not without risk; thus, a test that could accurately diagnose peanut allergy and reduce the need for OFCs is desirable.Objective:To assess the performance of basophil activation test (BAT) as a diagnostic marker for peanut allergy.Methods:Peanut-allergic (n = 43), peanut-sensitized but tolerant (n = 36) and non–peanut-sensitized nonallergic (n = 25) children underwent skin prick test (SPT) and specific IgE (sIgE) to peanut and its components. BAT was performed using flow cytometry, and its diagnostic performance was evaluated in relation to allergy versus tolerance to peanut and validated in an independent population (n = 65).Results:BAT in peanut-allergic children showed a peanut dose-dependent upregulation of CD63 and CD203c while there was no significant response to peanut in peanut-sensitized but tolerant (P < .001) and non–peanut-sensitized nonallergic children (P < .001). BAT optimal diagnostic cutoffs showed 97% accuracy, 95% positive predictive value, and 98% negative predictive value. BAT allowed reducing the number of required OFCs by two-thirds. BAT proved particularly useful in cases in which specialists could not accurately diagnose peanut allergy with SPT and sIgE to peanut and to Arah2. Using a 2-step diagnostic approach in which BAT was performed only after equivocal SPT or Arah2-sIgE, BAT had a major effect (97% reduction) on the number of OFCs required.ConclusionsBAT proved to be superior to other diagnostic tests in discriminating between peanut allergy and tolerance, particularly in difficult cases, and reduced the need for OFCs.

Although urticaria is not a life-threatening disease, its impact on quality of life in children should not be overlooked. A systematic search of online databases, including Medline, was performed to inform a review aiming to equip clinicians with an evidence-based approach to all aspects of pediatric urticaria. This review hinges on an illustrative case and includes a summary table of studies pertaining to disease management in children. The multiple issues faced by patients, their families, and treating clinicians are highlighted, and the current literature on the presentation, natural history, investigation, and management of this poorly understood condition is assessed.

Background Most children with peanut allergy (PA) react on first known oral exposure to peanut. Recent data suggest cutaneous exposure as a route of sensitization. Objectives This study aimed to establish the relevant route of peanut exposure in the development of allergy. Methods Questionnaires were administered to children with PA and to high-risk controls (with egg allergy) and controls without allergy. Questionnaires were completed before subjects were aware of their PA status, avoiding recall bias. Questionnaires recorded maternal peanut consumption during pregnancy, breast-feeding, and the first year of life. Peanut consumption was determined among all household members, allowing quantification of environmental household exposure (household peanut). Results Median weekly household peanut in the 133 PA cases was significantly elevated (18.8 g) compared with 150 controls without allergy (6.9 g) and 160 high-risk controls (1.9 g). There were no differences in infant peanut consumption between groups. Differences in maternal peanut consumption during pregnancy (and lactation) were significant but become nonsignificant after adjusting for household peanut. A dose-response relationship was observed between environmental (nonoral) peanut exposure and the development of PA, which was strongest for peanut butter. Early oral exposure to peanut in infants with high environmental peanut exposure may have had a protective effect against the development of PA. Conclusions High levels of environmental exposure to peanut during infancy appear to promote sensitization, whereas low levels may be protective in atopic children. No effect of maternal peanut consumption during pregnancy or lactation is observed, supporting the hypothesis that peanut sensitization occurs as a result of environmental exposure.

Oral food challenges (OFC) are the gold standard for the diagnosis of food allergy. They are also the method of choice to assess the resolution of food allergies. In clinical practice, most centers use open OFC for diagnostic purposes. In the research setting, double-blind placebo-controlled food challenges (DBPCFC) are required to ensure an unbiased outcome. In therapeutic trials for food allergy, DBPCFC are performed in patients known to be allergic and a positive outcome is expected, with potentially severe symptoms that can be life-threatening. Furthermore, patients with food allergy entering clinical research studies often have to be submitted to repeat DBPCFC to assess response to treatment. In studies where OFC are performed to diagnose food allergy, the rate of severe reactions that require the use of epinephrine is usually low, which varies between 1.6% and 11%. In this issue of the journal, Noone et al reported a higher proportion (39.2%) of patients being treated with epinephrine in 74 positive DBPCFC performed as part of 2 therapeutic trials carried out at one center with extensive expertise in the field. Treatment with epinephrine was associated with prior need for epinephrine for allergic reactions and with the absence of asthma, but not with the previous history of anaphylaxis, food challenged, threshold dose, skin prick test, or specific IgE results.

Background Peanut allergy (PA) is rare in countries in which peanuts are introduced early into infants' diets. Learning Early About Peanut Allergy (LEAP) is an interventional study aiming to assess whether PA can be prevented by oral tolerance induction. Objective We sought to characterize a population screened for the risk of PA. Methods Subjects screened for the LEAP interventional trial comprise the LEAP screening study cohort. Infants were aged 4 to 10 months and passed a prescreening questionnaire. Results This analysis includes 834 infants (mean age, 7.8 months). They were split into the following: group I, patients with mild eczema and no egg allergy (n = 118); group II, patients with severe eczema, egg allergy, or both but 0-mm peanut skin prick test (SPT) wheal responses (n = 542); group III, patients with severe eczema, egg allergy, or both and 1- to 4-mm peanut wheal responses (n = 98); and group IV, patients with greater than 4-mm peanut wheal responses (n = 76). Unexpectedly, many (17%) in group II had peanut-specific IgE sensitization (≥0.35 kU/L); 56% of group III were similarly sensitized. In contrast, none of the patients in group I and 91% of those in group IV had peanut-specific IgE sensitization. Sensitization on skin testing to peanut (SPT response of 1-4 mm vs 0 mm) was associated with egg allergy and severe eczema (odds ratio [OR], 2.31 [95% CI, 1.39-3.86] and 2.47 [95% CI, 1.14-5.34], respectively). Similar associations were observed with specific IgE sensitization. Black race was associated with a significantly higher risk of peanut-specific IgE sensitization (OR, 5.30 [95% CI, 2.85-9.86]). Paradoxically, for a given specific IgE level, black race was protective against cutaneous sensitization (OR, 0.15 [95% CI, 0.04-0.61]). Conclusion Egg allergy, severe eczema, or both appear to be useful criteria for identifying high-risk infants with an intermediate level of peanut sensitization for entry into a PA prevention study. The relationship between specific IgE level and SPT sensitization needs to be considered within the context of race.