Design of the Intervention to Reduce Early Peanut Allergy in Children (iREACH): A practice-based clinical trial

Background: Introducing peanut products early can prevent peanut allergy (PA). The "Addendum guidelines for the prevention of PA in the United States" (PPA guidelines) recommend early introduction of peanut products to low and moderate risk infants and evaluation prior to starting peanut products for infants at high risk for PA (those with severe eczema and/or egg allergy). Rapid adoption of guidelines could aid in lowering the prevalence of PA. The Intervention to Reduce Early (Peanut) Allergy in Children (iREACH) trial was designed to promote PPA guideline adherence by pediatric clinicians. Methods: A two-arm, cluster-randomized, controlled clinical trial was designed to measure the effectiveness of an intervention that included clinician education and accompanying clinical decision support tools integrated in electronic health records (EHR) versus standard care. Randomization was at the practice level (n = 30). Primary aims evaluated over an 18-month trial period assess adherence to the PPA guidelines using EHR documentation at 4- and 6-month well-child care visits aided by natural language processing. A secondary aim will evaluate the effectiveness in decreasing the incidence of PA by age 2.5 years using EHR documentation and caregiver surveys. The unit of observation for evaluations are individual children with clustering at the practice level. Conclusion: Application of this intervention has the potential to inform the development of strategies to speed implementation of PPA guidelines.


Validation of the NUT CRACKER diagnostic algorithm and prediction for cashew and pistachio co-allergy

Background: Due to the high cross sensitization among tree nuts, the NUT CRACKER study proposed a diagnostic algorithm to minimize the number of required oral food challenges (OFC). Objective: The objective of this study was to validate the algorithm for cashew and pistachio allergy and determine markers for allergic severity. Methods: Patients (n=125) aged 7.9 (5.9-11.2) years (median (IQR)) with suspected tree nut allergy were evaluated prospectively with decision tree points based on skin prick test (SPT), basophil activation test (BAT) and knowledge of the coincidence of allergies. Validation of allergic status was determined by OFC. Markers of clinical severity were evaluated using the combined original and prospective cohort (n=187) in relationship to SPT, BAT and Ana o 3-sIgE. Results: Reactivity to cashew in SPT, BAT and Ana o 3-sIgE and the incidence of abdominal pain upon challenge were significantly higher in dual-allergic cashew/pistachio patients (n=82) vs single cashew allergy (n=18) (p=0.001). All three diagnostic tests showed significant inverse correlation with log10 reaction doses for positive cashew OFC. The algorithm reduced overall the total number of OFCs by 72.0% with a PPV and NPV of 93.0% and 99.0%, respectively. Cashew false positives were observed primarily in hazelnut allergic patients (p=0.026). In this population, Ana o 3-sIgE could diagnose cashew allergy with a sensitivity over 90%, and a specificity over 95%. Conclusion: The NUT CRACKER diagnostic algorithm was validated and reduced the number of diagnostic OFCs required. Markers for severity phenotypes may guide oral immunotherapy protocols, improving the risk/benefit ratio for patients.


Long-term Safety Results of Epicutaneous Immunotherapy (EPIT) with Viaskin Peanut in Peanut-Allergic Children Aged 4-11 Years in the Phase 3 PEOPLE Study

Rationale: Previously reported interim results from PEOPLE (PEPITES Open-Label Extension) demonstrated Viaskin Peanut 250 μg (VP250) led to continued treatment response and was well-tolerated out to 3 years. Here we report PEOPLE end-of-study safety results. Methods: In PEPITES, 356 peanut-allergic participants (aged 4-11 years) were randomized to placebo or VP250. In PEOPLE, 298 participants were treated with open-label VP250 for up to 48 (placebo+VP250) or 60 (VP250+VP250) months. Safety outcomes included duration and severity of treatment-emergent adverse events (TEAEs) and serious TEAEs. Results: 87/298 (29.2%) participants continued treatment in the PEOPLE extension period (Years 4 and 5); mean (range) age was 11.1 (8-16) years. During the Extension Period, there were no discontinuations due to TEAEs, or treatment-related serious TEAEs; 1 (1.1%) participant experienced a treatment-related severe TEAE. Treatment-related TEAEs decreased over time: 63/87 (72.4%) in Year 1 to 9/59 (15.3%) in Year 5. Subjects reporting TEAEs leading to systemic or inhaled corticosteroid use decreased from 20/87 (23.0%) in Year 1 to 1/59 (1.7%) in Year 5. Treatment-related anaphylaxis occurred in 2/87 (2.3%) (Years 1 and 2 only). Treatment-related TEAEs leading to epinephrine use occurred in 1/87 (1.1%) participants (Year 1 only). Overall mean treatment compliance remained high out to 5 years (93%). Conclusions: VP250 treatment over 5 years in PEOPLE showed decreasing frequency and severity of TEAEs, no new safety signals, and high treatment compliance. These data suggest long-term VP250 treatment in peanut-allergic children may have a favorable safety and tolerability profile, which may facilitate its use over multiple years of treatment.


An Unintentional Randomized Trial of Early Environmental Exposure to Peanut: The Younger Siblings of LEAP Participants

Rationale: The Dual Allergen Exposure Hypothesis proposes that food allergy develops due to cutaneous exposure in the absence of oral consumption. Evaluation of the younger siblings of the Learning Early About Peanut (LEAP) participants provides an opportunity to understand the impact of environmental exposure to peanut during infancy and early childhood on the development of peanut sensitization and allergy through a prospective randomized trial of high environmental versus low environmental peanut exposure. Methods: LEAP-Trio evaluated the allergic status of younger siblings who resided in the home of LEAP participants at any time during the LEAP intervention. The primary endpoint was sensitization (defined as skin prick test ≥ 3 mm, peanut specific-IgE ≥ 0.35 kU/L, or Ara h2 ≥ 0.1 kU/L). Results: 144 younger siblings of LEAP avoiders and 154 younger siblings of LEAP consumers participated. Younger siblings of consumers had a higher rate of sensitization than younger siblings of avoiders, 30.4% (41/135) versus 20.0% (26/130) P=0.055, and a higher rate of allergy, 10.0% (15/150) versus 5.0% (7/140) P=0.116. Among younger siblings of LEAP consumers, younger siblings that introduced peanut in the first year of life had a significantly lower rate of sensitization than younger siblings that did not introduce peanut, 18.3% (13/71) versus 44.4% (28/63) (P=0.002). No differences were found in egg or milk sensitization between groups. Conclusions: There was a trend toward increased sensitization and allergy in younger siblings of LEAP consumers, an effect that was greatly reduced if the younger sibling introduced peanut early.


Omalizumab for the Treatment of Multiple Food Allergies

BACKGROUND: Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. METHODS: In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension. RESULTS: Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 67% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group. CONCLUSIONS: In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; number, NCT03881696. opens in new tab.)



Prevalence of tree nut allergy in Europe: A systematic review and meta-analysis

In 2014, the European Academy of Allergy and Clinical Immunology (EAACI) published the first systematic review that summarized the prevalence of food allergy (FA) and food sensitization in Europe for studies published 2000-2012. However, only summary estimates for tree nut allergy (TNA) were feasible in that work. In the current update of that systematic review, we summarized the prevalence of tree nut allergy/sensitization to individual tree nuts. Six databases were searched for relevant papers published 2012-2021 and 17 eligible studies were added to the 15 studies already identified between 2000 and 2012, giving a total of 32 studies. Of the investigated tree nuts, meta-analysis was possible for hazelnut, walnut, almond, and in few cases, for cashew, and Brazil nut. The lifetime self-reported prevalence was 0.8% (95% CI 0.5-1.1) for hazelnut and 0.4% (0.2-0.9) for walnut. The point self-reported prevalence was 4.0% (2.9-5.2) for hazelnut, 3.4% (2.0-4.9) for Brazil nut, 2.0% (1.1-2.9) for almond, and 1.8% (1.1-2.5) for walnut. Point prevalence of food challenge-confirmed TNA was 0.04% (0.0-0.1) for hazelnut and 0.02% (0.01-0.1) for walnut. Due to paucity of data, we could not identify any meaningful and consistent differences across age groups and European regions.


Systematic review and meta-analyses on the accuracy of diagnostic tests for IgE-mediated food allergy

The European Academy of Allergy and Clinical Immunology (EAACI) is updating the Guidelines on Food Allergy Diagnosis. We aimed to undertake a systematic review of the literature with meta-analyses to assess the accuracy of diagnostic tests for IgE-mediated food allergy. We searched three databases (Cochrane CENTRAL (Trials), MEDLINE (OVID) and Embase (OVID)) for diagnostic test accuracy studies published between 1 October 2012 and 30 June 2021 according to a previously published protocol (CRD42021259186). We independently screened abstracts, extracted data from full texts and assessed risk of bias with QUADRAS 2 tool in duplicate. Meta-analyses were undertaken for food-test combinations for which three or more studies were available. A total of 149 studies comprising 24,489 patients met the inclusion criteria and they were generally heterogeneous. 60.4% of studies were in children ≤12 years of age, 54.3% were undertaken in Europe, ≥95% were conducted in a specialized paediatric or allergy clinical setting and all included oral food challenge in at least a percentage of enrolled patients, in 21.5% double-blind placebo-controlled food challenges. Skin prick test (SPT) with fresh cow's milk and raw egg had high sensitivity (90% and 94%) for milk and cooked egg allergies. Specific IgE (sIgE) to individual components had high specificity: Ara h 2-sIgE had 92%, Cor a 14-sIgE 95%, Ana o 3-sIgE 94%, casein-sIgE 93%, ovomucoid-sIgE 92/91% for the diagnosis of peanut, hazelnut, cashew, cow's milk and raw/cooked egg allergies, respectively. The basophil activation test (BAT) was highly specific for the diagnosis of peanut (90%) and sesame (93%) allergies. In conclusion, SPT and specific IgE to extracts had high sensitivity whereas specific IgE to components and BAT had high specificity to support the diagnosis of individual food allergies.

CD23+IgG1+ memory B cells are poised to switch to pathogenic IgE production in food allergy

Food allergy is caused by allergen-specific immunoglobulin E (IgE) antibodies, but little is known about the B cell memory of persistent IgE responses. Here, we describe, in human pediatric peanut allergy, a population of CD23+IgG1+ memory B cells arising in type 2 immune responses that contain high-affinity peanut-specific clones and generate IgE-producing cells upon activation. The frequency of CD23+IgG1+ memory B cells correlated with circulating concentrations of IgE in children with peanut allergy. A corresponding population of "type 2-marked" IgG1+ memory B cells was identified in single-cell RNA sequencing experiments. These cells differentially expressed interleukin-4 (IL-4)- and IL-13-regulated genes, such as FCER2/CD23+, IL4R, and germline IGHE, and carried highly mutated B cell receptors (BCRs). In children with high concentrations of serum peanut-specific IgE, high-affinity B cells that bind the main peanut allergen Ara h 2 mapped to the population of "type 2-marked" IgG1+ memory B cells and included clones with convergent BCRs across different individuals. Our findings indicate that CD23+IgG1+ memory B cells transcribing germline IGHE are a unique memory population containing precursors of high-affinity pathogenic IgE-producing cells that are likely to be involved in the long-term persistence of peanut allergy.

Pediatric oral food challenges in the outpatient setting: A single-center experience

Background: Oral food challenge (OFC) is the criterion standard for diagnosing food allergy (FA). It is important to have parameters to aid in selecting ideal OFC candidates. Objective: We sought to characterize outcomes and predictors of OFCs for common food allergens. Methods: We completed a retrospective chart review of all OFCs for IgE-mediated FA performed at Duke University pediatric allergy clinics from June 2017 through May 2022. Patients were deemed eligible for milk, egg, and nut OFC if testing revealed a specific IgE level not exceeding 2 kU/L and a skin prick test (SPT) resulting in a wheal size not exceeding 5 mm. Different parameters were followed for selecting candidates for baked challenge. Results: A total of 663 OFCs were conducted on 510 patients (59% male). The most common foods challenged were peanut (26%), plain egg (23%), baked egg (8%), and milk (8%), with pass rates of 84%, 88%, 62%, and 84%, respectively. Of the patients who failed OFC, 84% had objective symptoms, 23% had multisystemic reactions, and 15% required epinephrine. Although the presence of a personal or family history of atopy or prior failed OFC was not associated with outcomes, a history of anaphylaxis (regardless of the trigger) was associated with increased risk of failure. Conclusion: Although there are no established consensus guidelines, our study provides a benchmark illustrating that cutoffs of a specific IgE level not exceeding 2 kU/L and SPT finding not exceeding 5 mm result in a failure rate of approximately 13% for nonbaked milk, nonbaked egg, and nuts. The high rate of failed baked egg OFCs is likely related to selection bias, but our results illustrate the low negative predictive value of ovomucoid.

Screening of probiotic Lactobacillus to reduce peanut allergy and with potential anti-allergic activity

Background: Peanut is a significant source of nutrition and a valuable oilseed crop. It is also a serious allergy source, which poses a threat to 1.1% of the population. This study aimed to screen lactic acid bacteria (LAB) with the capacity to alleviate peanut allergenicity and exhibit anti-allergic properties. Result: The results show that LAB can make use of substances in peanuts to reduce the pH of peanut milk from 6.603 to 3.593-4.500 by acid production and that it can utilize the protein in peanuts to reduce the allergenic content (especially Ara h 1) and improve biological activity in peanut pulp. The content of Ara h 1 peanut-sensitizing protein was reduced by 74.65% after fermentation. The protein extracted from fermented peanut pulp is more readily digestible by gastrointestinal juices. The inhibitory activity assay of hyaluronidase (an enzyme with strong correlation to allergy) increased from 46.65% to a maximum of 90.57% to reveal that LAB fermentation of peanut pulp exhibited a robust anti-allergic response. Conclusion: The strains identified in this study exhibited the ability to mitigate peanut allergenicity partially and to possess potential anti-allergic properties. Lactobacillus plantarum P1 and Lactobacillus salivarius C24 were identified as the most promising strains and were selected for further research. © 2023 Society of Chemical Industry.