Sex-specific Leukocyte Responses to Peanut Allergen: Uncovering Potential Links to the Molecular Circadian Clock
Food allergies, particularly peanut allergies, are on the rise, affecting ∼10% of the U.S. population and 17% of adults. We explored sex-based differences in inflammatory responses to peanut allergens using a mouse model. Female mice exhibited severe allergic symptoms and a greater drop in body temperature than males when challenged with peanut extract and cholera toxin. Females showed higher levels of interstitial macrophages and neutrophils, while males showed increased eosinophil and lymphocyte influx. Elevated cytokines (IL-4, IL-5, IL-9) in females correlate with increased IgE and histamine, indicating heightened mast cell activation. Reduced expression of the circadian gene Rev-erbα in female intestines post-challenge suggests a link between inflammatory responses and circadian disruption. IgE/mast cell and IgG/neutrophil-mediated pathways appeared to be involved in female responses. These findings suggest that hormonal and circadian influences may play critical roles in sex-based differences in peanut allergen, with further investigation needed to elucidate the underlying mechanisms.
https://doi.org/10.1093/jleuko/qiaf097
Infant diet recommendations reduce IgE-mediated egg, peanut and cow's milk allergies
Background: Meta-analyses of randomized controlled trials have found that introducing eggs and peanuts earlier during infancy reduced egg and peanut allergy risk. Hence, infant feeding advice has dramatically changed from previous recommendations of avoidance to current recommendations of inclusion of common food allergens in infant diets. Objective: To compare the prevalence of IgE-mediated food allergies at 1-year of age between two cohorts, before and after infant feeding and allergy prevention guidelines changed. Methods: In cohort 1 (506 infants born 2006-2014), no infant feeding advice was provided to participants. In cohort 2 (566 infants born 2016-2022), when the infants were 6 months of age, all families were provided with updated infant feeding and allergy prevention guidelines. All infants had a first-degree relative with a history of allergic disease. At 1-year of age, infant food allergen sensitization and IgE-mediated food allergy were assessed. Results: Peanut, egg and cow's milk were introduced earlier in cohort 2 compared to cohort 1 (all p<0.001). Combined prevalence of IgE-mediated peanut, egg and/or cow's milk allergies was 4.1% in cohort 2 compared to 12.6% in cohort 1, adjusted odd ratio (aOR) 0.28, 95% CI 0.16-0.48, p<0.001). Specifically, peanut allergy 1.1% vs 5.8% (aOR 0.24, 95% CI 0.08-0.76, p=0.015), egg allergy 2.8% vs 11.7% (aOR 0.23, 95% CI 0.12-0.45, p<0.001), and cow's milk allergy 0.5% vs 2.4% (aOR 0.14, 95% CI 0.04-0.55, p=0.005). Conclusion: Direct provision of updated food allergy prevention guidelines to families facilitated earlier introduction and reduced prevalence of IgE-mediated peanut, egg and cow's milk allergies.
https://doi.org/10.1016/j.jaip.2025.06.012
The kinetics of epitope-specific IgE and IgG4 in early peanut allergy development and resolution
Background: The development and resolution of peanut allergy (PA) was evaluated in children enrolled or screened for the LEAP intervention trial. The development of epitope-specific-immunoglobulin(es-Ig)E and es-IgG4 antibodies was evaluated in a subset of these children to determine whether their PA status could be predicted at 4-11 months of age. Methods: Sera from 386children enrolled or screened as part of the LEAP trial were assayed at 4-11 months (baseline) and 60 months of age, and final allergy status was established by OFC at 60 months. Es-IgE and es-IgG4 to 64 informative peanut epitopes were analyzed using linear mixed-effect models and Machine Learning (ML) was used to develop a predictive algorithm. Results: Children were categorized in four groups: 37 developed PA early that persisted (EP), 17 developed PA early but resolved (ER), 33 developed PA later in childhood (by 60 months of age, LA), and 298 never developed PA (NA). Differences among groups in es-IgE and es-IgG4 were detectable at baseline. ER showed lower levels of Ara h 2_008 es-IgE and higher es-IgG4 levels to several epitopes compared to the EP group. Both EP and ER groups had greater levels of several baseline es-IgE antibodies compared to the LA. By 60 months, all three groups had significant increases in both the levels and diversity of es-IgG4 antibodies, while es-IgE antibodies increased only in EP and LA groups and decreased in ER group. ML models were predictive of persistent allergy by 60 months of age with an average AUC in testing of 0.75. Conclusions: These results suggest that baseline es-IgE in children sensitized in the first year of life can predict likely persistent peanut allergy. Clinical implications: Evaluation of es-IgE antibodies in the first year of life is useful for identifying infants who will develop persistent peanut allergy and in whom early treatment should be prioritized.
https://doi.org/10.1016/j.jaci.2025.06.022
The kinetics of early peanut allergy development and resolution in the EAT, LEAP, and PAS cohorts
Background: Little is known about the development and resolution of early peanut allergy (PA). We examined the natural history and biomarkers of PA longitudinally in three cohorts. Methods: PA development was examined in the EAT, LEAP and PAS cohorts. Early PA was defined by skin prick test (SPT) >4mm by 12-months or oral food challenge (OFC) at study entry. PA was confirmed by OFC at study endpoint (36-months for EAT, 60-months for LEAP/PAS). Four groups were defined: early PA development with persistence (EP); early PA development with resolution (ER); late PA development (LA); never peanut allergic (NA). Clinical characteristics and biomarkers were compared between the groups. Results: 56.3% of peanut allergic children developed PA by 12-months; 32.1% had early PA resolution by study endpoint. The rate of early PA resolution was 54.2% in EAT, 41.4% in LEAP and 18.6% in PAS cohorts. Median SPTs for EP, ER and LA were: 6mm, 2mm, 0mm at baseline and 10mm, 0mm, 9mm at study endpoint. Median peanut-sIgE levels for EP, ER and LA were 5.9kUA/L, 0.4kUA/L, 0.3kUA/L (p<0.001) at baseline; 4.7kUA/l, 1.3kUA/L, 0.9kUA/L (p<0.001) at 12-months; and 20.1kUA/L, 0.2kUA/L, 5.1kUA/L (p<0.001) at study endpoint. LA had slower component expansion (number of components Ara h 1-sIgE, Ara h 2-sIgE, Ara h 3-sIgE >0.1kUA/L) compared to EP. ER showed component expansion from baseline to 12-months but component retraction by study endpoint. Absence of eczema and egg allergy, low peanut-sIgE or SPT were predictive of PA resolution. Conclusion: A significant proportion of PA resolves in early childhood. Different phenotypes of PA display different biomarkers trajectories.
https://doi.org/10.1016/j.jaci.2024.10.042
Exploring quality of life and related clinical factors in children with tree nut allergies
Background: In Türkiye, tree nut allergy (TNA) is the most common form of food allergy, characterized by persistence and the potential for life-threatening reactions. This study aimed to evaluate the quality of life (QoL) of Turkish children aged 0-12 years with IgE-mediated TNA and explore influential factors, including parental anxiety. Materials and methods: Primary caregiver-parents of children diagnosed with TNA completed the Food Allergy Quality of Life Questionnaire-Parent Form (FAQLQ-PF) and State-Trait Anxiety Inventory (STAI) to assess QoL and parental anxiety, respectively. Results: Of 120 eligible patients diagnosed with TNA, 88 were included in the study. Questionnaires were completed by mothers in 79 cases (90%) and fathers in 9 cases (10%). Parents reported significantly higher FAQLQ-PF scores for children with hazelnut allergy, a history of anaphylaxis, and those who had to use an adrenaline auto-injector. There was significant but weak correlations between FAQLQ-PF and anxiety (STAI) domains. The multivariate linear regression analysis revealed that having a hazelnut allergy, a history of anaphylaxis, and higher parental state anxiety were all associated with higher FAQLQ-PF scores, but fathers tended to report better level of QoL. Conclusion: QoL for children with TNA is influenced by several factors such as adverse life experiences, local and situational factors, and parental anxiety. Understanding these diverse factors is crucial for enhancing the well-being of children with TNA.
https://doi.org/10.24953/turkjpediatr.2025.5293
The safety and efficacy of oral immunotherapy compared to epicutaneous immunotherapy in peanut allergen desensitisation amongst the paediatric cohort-a narrative review
Peanut allergies result from a type 1 hypersensitivity reaction, with a prevalence of approximately 1% in children under 5 years of age. The allergens that instigate this reaction are the peanut proteins (Ara h 1-Ara h 8) for which IgE antibodies are specifically produced. Allergen immunotherapy (AIT), despite the uncertainty regarding its mode of action, has been increasingly utilised with the aim of desensitisation against these allergens. AIT encompasses various modes of administration, including epicutaneous immunotherapy (EPIT) and oral immunotherapy (OIT). The review adheres to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, with a comprehensive literature search conducted using databases including MEDLINE®, Embase™, PubMed®, and Google Scholar™. Search terms targeted OIT and EPIT in the desensitisation and management of peanut allergy in children, with studies spanning the past 20 years included based on predefined eligibility criteria. The extent of the immunotherapies' efficacy and safety in children is yet to be thoroughly established; however, OIT demonstrated increased desensitisation rates amongst children when compared to EPIT. The long-term efficacy has not been fully established, with sustained unresponsiveness not reported within most studies. Both modes of administration had a high proportion of participants experiencing adverse effects (AEs), with gastrointestinal symptoms more common with OIT and cutaneous reactions with EPIT. Serious AEs were observed less frequently, however, systemic reactions such as anaphylaxis were more apparent with OIT. Future research should focus on peanut EPIT, as the literature was relatively scarce. Furthermore, research studies should assess sustained unresponsiveness to fully gauge the long-term effects of AIT in children.
https://doi.org/10.3389/falgy.2025.1613237
HLA variation associated with peanut allergy and anaphylaxis among non-Hispanic Black individuals
Background: Peanut is a major cause of food allergy. HLA genes have been consistently associated with peanut allergy in association studies. To date, however, there have been very few genetic studies of peanut allergy in non-Hispanic Black (Black) individuals, a group disproportionately affected by food allergy. Objective: Our aim was to study the relationship between HLA alleles and peanut allergy among Black individuals. Methods: The analysis consisted of Black participants from the Study of Asthma-Related Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE), a large cohort of individuals from metropolitan Detroit. At the time of enrollment, participants provided detailed food allergy histories, including symptoms. Four-digit resolution HLA allele calls were made using whole genome sequence data. Results: The cases consisted of 119 individuals with reported peanut allergy and 59 individuals with peanut-related anaphylaxis; the comparison group consisted of 2640 individuals without reported food allergy. HLA-DRB1∗13:02 was the most significant allele associated with peanut allergy (adjusted odds ratio = 1.94 [95% CI = 1.28-2.93]), and HLA-DQA1∗01:02 was the top association with peanut-related anaphylaxis (aOR = 1.67 [95% CI = 1.14-2.44]). Amino acid polymorphisms at position 71 in the binding groove of HLA-DRB1 were associated with peanut allergy and estimated to affect peanut allergen binding affinity. Conclusions: In a cohort of Black individuals, this study independently identified the same associations of peanut allergy and HLA that were previously observed in non-Hispanic White individuals. Our findings suggest that specific HLA binding groove amino acid polymorphisms may confer similar peanut allergy risk across population groups and HLA alleles.
https://doi.org/10.1016/j.jacig.2025.100485
Walnut threshold dose distribution and safe dose in allergic patients (Nut CRACKER Study)
Background: Walnut is a significant global food allergen, but data relating to population reaction thresholds are limited. This hampers the ability of industry and regulators to undertake allergen risk assessment, increases use of allergen labeling, and impairs patient quality of life. Objective: To describe reaction eliciting doses in a large walnut-allergic population METHODS: Retrospective cohort study including all reactive walnut oral food challenges (OFCs) performed between July 2014 and May 2023 at Shamir Medical Center. OFCs were performed for either diagnostic reasons or at the beginning of oral immunotherapy (OIT). Objective signs were used as stopping criteria. Confirmatory safe-dose OFCs with dose intervals of ≥90 minutes were also analyzed. Results: Overall, 415 walnut OFCs were analyzed, with no left or right censored data. Corresponding estimated ED01 and ED05 (amount of protein eliciting an objective reaction in 1% and 5% of the walnut-allergic population, respectively) were 0.8 mg (range 0.3-24) and 3.8 mg (range 1.1-96.4) for discrete, and 1.2 mg (range 0.4-29.4) and 5.9 mg (range 1.7-140.5) for cumulative dosing. Doses ≤1 mg elicited subjective reactions (in 12.5% of patients), but no objective reactions during the 295 safe-dose OFCs performed. Factors associated with a lower reaction threshold to walnut included a younger age, OIT-OFC protocol, and co-allergy to pecan (p<0.001 for all). Conclusions: This is the largest published dataset to inform eliciting doses to walnut, with greater certainty of eliciting dose with the inclusion of safe dose-OFCs. These data address an evidence-gap in the global Codex efforts to improve evidence-based allergen risk assessment for walnut.
https://doi.org/10.1016/j.jaip.2025.05.041
Open access online calculator predicts peanut allergic reactions with high accuracy
Background: The Peanut Allergy Prediction Web Tool is a newly developed online aid, which calculates the probability of an individual's allergic reaction based on their SPT, Ara h 2-specific IgE (Ara h 2-sIgE) and/or basophil activation test (BAT) results. Objective: To validate the diagnostic performance of the online tool and assess its ability to discriminate between peanut-allergic (PA) and peanut-sensitised tolerant (PST) cases. Methods: Demographical data, clinical history, results for SPT, Ara h 2-sIgE, BAT and oral food challenge (OFC) outcomes were collected for paediatric cases with a confirmed peanut allergy status (PA or PST). Receiver operating characteristic (ROC) curve analysis, area under the curve (AUC) and sensitivity (S), specificity (Sp) positive and negative predictive values (PPV and NPV) were determined to assess the diagnostic performance of the tool using variations of one, two or three test results. Results: AUC value for all test results combinations exhibited excellent degrees of discriminative performance between PA and PST individuals. The BAT was the greatest single test performer (AUC=0.945; S=85%; Sp=97%; PPV=99%; NPV=71%). The two-test combination of Ara h 2-sIgE and BAT, (AUC=0.959; S=87%; Sp=97%; PPV=99%; NPV=74%) and the three-test combination (AUC=0.949; S=88%; Sp=89%; PPV=96%; NPV=74%) demonstrated the highest discriminatory ability and diagnostic accuracy. Conclusion: The Peanut Allergy Prediction Web Tool's diagnostic performance proves highly accurate using several different combinations of test results when classifying PA and PST cases. Future validation is needed to assess the tool's performance in predicting PA severity in comparison to OFC outcomes.
https://doi.org/10.1016/j.jaip.2025.05.016
Clinical and laboratory characteristics of cashew nut allergy in Korean children: Findings from a tertiary hospital
Objective: Cashew nut (CN) allergy is becoming increasingly prevalent and represents a major cause of tree nut-induced anaphylaxis in Korean children. This study investigated the clinical characteristics and laboratory findings of CN allergy in Korean children. Patients and methods: Sixty-four children with a history of CN ingestion, who underwent serum CN-specific immunoglobulin E (CN-sIgE) measurements from January 2013 to February 2023, were enrolled through a retrospective medical record review. The demographic characteristics, clinical profiles, and laboratory findings were evaluated. Result: Thirty-five patients had immediate-type reactions after exposure to CN (CN-allergic group), whereas 29 showed no symptoms after ingesting CN (CN-tolerant group). Over 60% of patients in the CN-allergic group were allergic to ≥ 1 other tree nuts and 17.1% had peanut allergies. In the CN-allergic group, cutaneous symptoms were most common (94.1%), followed by respiratory (35.3%), gastrointestinal (32.4%), and cardiovascular (2.9%) symptoms. Anaphylaxis due to CN exposure was observed in 51.4% of patients in the CN-allergic group. The median CN-sIgE level of the CN-allergic group was significantly higher than that of the CN-tolerant group (5.5 kUA/L vs. 0.06 kUA/L, P < 0.001). The optimal cutoff level for distinguishing the CN-allergic group from the CN-tolerant group was 0.55 kUA/L (sensitivity 94.29%, specificity 93.10%). Conclusion: Co-allergies to other tree nuts were common in children with CN allergy and more than 50% of patients with CN allergy experienced anaphylaxis. The optimal cutoff level for distinguishing between the CN-allergic and CN-tolerant groups was 0.55 kUA/L.
https://doi.org/10.15586/aei.v53i3.1289