Saliva antibody profiles are associated with reaction threshold and severity of peanut allergic reactions
Background: Reaction threshold and severity in food allergy are difficult to predict, and there is a lack of non-invasive predictors. Objectives: We sought to determine the relationships between pre-challenge levels of peanut (PN)-specific antibodies in saliva and reaction threshold, severity, and organ-specific symptoms during peanut allergic reactions. Methods: We measured PN-specific antibody levels in saliva collected from 127 children with suspected peanut allergy prior to double-blind, placebo-controlled peanut challenges where reaction threshold, severity, and symptoms were rigorously characterized. Low-threshold peanut allergy was defined as reaction to <300mg of peanut protein cumulatively consumed. A consensus severity grading system was used to grade severity. We analyzed associations between antibody levels and reaction threshold, severity, and organ-specific symptoms. Results: Among the 127 children, those with high pre-challenge saliva PN IgE had higher odds of low-threshold peanut allergy (OR 3.9, 95%CI 1.6-9.5), while those with high saliva PN IgA: PN IgE or PN IgG4:PN IgE had lower odds of low-threshold peanut allergy (OR 0.3, 95%CI 0.1-0.8, and OR 0.4, 95%CI 0.2-0.9, respectively). Children with high pre-challenge saliva PN IgG4 had lower odds of severe peanut reactions (OR 0.4, 95%CI 0.2-0.9). Those with high saliva PN IgE had higher odds of respiratory symptoms (OR 8.0, 95%CI 2.2-26.8). Saliva PN IgE modestly correlated with serum PN IgE levels (Pearson r=0.31, P=0.0004). High and low saliva PN IgE levels further distinguished reaction threshold and severity in participants stratified by serum PN IgE, suggesting endotypes. Conclusion: Saliva PN antibodies could aid in non-invasive risk stratification of peanut allergy threshold, severity, and organ-specific symptoms. https://doi.org/10.1016/j.jaci.2024.05.020
Follow-up to Adolescence after Early Peanut Introduction for Allergy Prevention
Background: A randomized trial demonstrated consumption of peanut from infancy to age 5 years prevented the development of peanut allergy. An extension of that trial demonstrated the effect persisted after 1 year of peanut avoidance. This follow-up trial examined the durability of peanut tolerance at age 144 months after years of ad libitum peanut consumption. Methods: Participants from a randomized peanut consumption trial were assessed for peanut allergy following an extended period of eating or avoiding peanuts as desired. The primary end point was the rate of peanut allergy at age 144 months. Results: We enrolled 508 of the original 640 participants (79.4%); 497 had complete primary end point data. At age 144 months, peanut allergy remained significantly more prevalent in participants in the original peanut avoidance group than in the original peanut consumption group (15.4% [38 of 246 participants] vs. 4.4% [11 of 251 participants]; P<0.001). Participants in both groups reported avoiding peanuts for prolonged periods of time between 72 and 144 months. Participants at 144 months in the peanut consumption group had levels of Ara h2-specific immunoglobulin E (a peanut allergen associated with anaphylaxis) of 0.03 ± 3.42 kU/l and levels of peanut-specific immunoglobulin G4 of 535.5 ± 4.98 μg/l, whereas participants in the peanut avoidance group had levels of Ara h2-specific immunoglobulin E of 0.06 ± 11.21 kU/l and levels of peanut-specific immunoglobulin G4 of 209.3 ± 3.84 μg/l. Adverse events were uncommon, and the majority were related to the food challenge. Conclusions: Peanut consumption, starting in infancy and continuing to age 5 years, provided lasting tolerance to peanut into adolescence irrespective of subsequent peanut consumption, demonstrating that long-term prevention and tolerance can be achieved in food allergy. (Funded by the National Institute of Allergy and Infectious Diseases and others; ITN070AD, ClinicalTrials.gov number, NCT03546413.). https://doi.org/10.1056/EVIDoa2300311
Prediction of pediatric peanut oral food challenge outcomes using machine learning
Background: Clinical testing, including food-specific skin and serum IgE level tests, provides limited accuracy to predict food allergy. Confirmatory oral food challenges (OFCs) are often required, but the associated risks, cost, and logistic difficulties comprise a barrier to proper diagnosis. Objective: We sought to utilize advanced machine learning methodologies to integrate clinical variables associated with peanut allergy to create a predictive model for OFCs to improve predictive performance over that of purely statistical methods. Methods: Machine learning was applied to the Learning Early about Peanut Allergy (LEAP) study of 463 peanut OFCs and associated clinical variables. Patient-wise cross-validation was used to create ensemble models that were evaluated on holdout test sets. These models were further evaluated by using 2 additional peanut allergy OFC cohorts: the IMPACT study cohort and a local University of Michigan cohort. Results: In the LEAP data set, the ensemble models achieved a maximum mean area under the curve of 0.997, with a sensitivity and specificity of 0.994 and 1.00, respectively. In the combined validation data sets, the top ensemble model achieved a maximum area under the curve of 0.871, with a sensitivity and specificity of 0.763 and 0.980, respectively. Conclusions: Machine learning models for predicting peanut OFC results have the potential to accurately predict OFC outcomes, potentially minimizing the need for OFCs while increasing confidence in food allergy diagnoses.
https://doi.org/10.1016/j.jacig.2024.100252
Effects of enzymatic hydrolysis combined with pressured heating on tree nut allergenicity
Hazelnut, pistachio and cashew are tree nuts with health benefits but also with allergenic properties being prevalent food allergens in Europe. The allergic characteristics of these tree nuts after processing combining heat, pressure and enzymatic digestion were analyzed through in vitro (Western blot and ELISA) and in vivo test (Prick-Prick). In the analyzed population, the patients sensitized to Cor a 8 (nsLTP) were predominant over those sensitized against hazelnut seed storage proteins (Sprot, Cor a 9 and 14), which displayed higher IgE reactivity. The protease E5 effectively hydrolyzed proteins from hazelnut and pistachio, while E7 was efficient for cashew protein hydrolysis. When combined with pressured heating (autoclave and Controlled Instantaneous Depressurization (DIC)), these proteases notably reduced the allergenic reactivity. The combination of DIC treatment before enzymatic digestion resulted in the most effective methodology to drastically reduce or indeed eliminate the allergenic capacity of tree nuts.
https://doi.org/10.1016/j.foodchem.2024.139433
Identification of New Allergens in Macadamia Nut and Cross-Reactivity with Other Tree Nuts in a Spanish Cohort
The consumption of macadamia nuts has increased due to their cardioprotective and antioxidant properties. However, this rise is consistent with an increase in the cases of macadamia nut allergy, leading to severe reactions. Although two Macadamia integrifolia allergens (Mac i 1 and Mac i 2) have been identified in Australian and Japanese patients, the allergenic sensitization patterns in Western European populations, particularly in Spain, remain unclear. For this purpose, seven patients with macadamia nut allergy were recruited in Spain. Macadamia nut protein extracts were prepared and, together with hazelnut and walnut extracts, were used in Western blot and inhibition assays. IgE-reactive proteins were identified using MALDI-TOF/TOF mass spectrometry (MS). Immunoblotting assays revealed various IgE-binding proteins in macadamia nut extracts. Mass spectrometry identified three new allergens: an oleosin, a pectin acetylesterase, and an aspartyl protease. Cross-reactivity studies showed that hazelnut extract but not walnut extract inhibited macadamia nut oleosin-specific IgE binding. This suggests that oleosin could be used as marker for macadamia–hazelnut cross-reactivity. The results show an allergenic profile in the Spanish cohort different from that previously detected in Australian and Japanese populations. The distinct sensitization profiles observed highlight the potential influence of dietary habits and environmental factors exposure on allergenicity.
https://doi.org/10.3390/nu16070947
Current options in the management of tree nut allergy: A systematic review and narrative synthesis
Tree nut allergy is a lifelong and potentially life-threatening condition. The standard of care is strictly avoiding the culprit nut and treating accidental reactions symptomatically. To evaluate potential therapeutic options for desensitizing patients with IgE-mediated tree nut allergy, we systematically searched three bibliographic databases for studies published until January 2024. We looked for active treatments of IgE-mediated allergy to tree nuts (walnut, hazelnut, pistachio, cashew, almond, pecan, macadamia nut, and brazil nut). We focused on allergen-specific immunotherapy (AIT) using oral (OIT), sublingual (SLIT), epicutaneous (EPIT), or subcutaneous (SCIT) delivery, or other disease-modifying treatments. We found 19 studies that met our criteria: 3 studies investigated sublingual immunotherapy, 5 studied oral immunotherapy to a single tree nut, and 6 used multi-food oral immunotherapy with or without omalizumab. The remaining studies investigated the effectiveness of monoclonal antibodies or IgE-immunoadsorption in multi-food allergic patients, including patients with tree nut allergy. The heterogeneity of the studies prevented pooling and meta-analysis. Oral immunotherapy, single or multi-nut, with or without omalizumab, was the most studied approach and appears effective in conferring protection from accidental exposures. Omalizumab monotherapy is the only approved alternative management for reducing allergic reactions that may occur with accidental exposure.
https://doi.org/10.1111/pai.14132
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.
https://doi.org/10.1111/pai.14115
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. https://doi.org/10.1016/j.jaip.2024.02.012
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. https://doi.org/10.1016/j.jaci.2023.11.406
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. https://doi.org/10.1016/j.jaci.2023.11.876