Biomarkers of peanut allergy in children over time
Background: Various biomarkers are used to define peanut allergy (PA). We aimed to observe changes in PA resolution and persistence over time comparing biomarkers in PA and peanut sensitised but tolerant (PS) children in a population-based cohort. Methods: Participants were recruited from the EAT and EAT-On studies, conducted across England and Wales, and were exclusively breastfeed babies recruited at 3 months old and followed up until 7-12 years old. Clinical characteristics, skin prick test (SPT), sIgE to peanut and peanut components and mast cell activation tests (MAT) were assessed at 12 months, 36 months and 7-12 years. PA status was determined at the 7-12 year time point. Results: The prevalence of PA was 2.1% at 7-12 years. Between 3 and 7-12 year, two children developed PA and one outgrew PA. PA children had larger SPT, higher peanut-sIgE, Ara h 2-sIgE and MAT (all p < .001) compared to PS children from 12 months onwards. SPT, peanut-sIgE, Ara h 2-sIgE and MAT between children with persistent PA, new PA, outgrown PA and PS were statistically significant from 12 months onwards (p < .001). Those with persistent PA had SPT, peanut-sIgE and Ara h 2-sIgE that increased over time and MAT which was highest at 36 months. New PA children had increased SPT and peanut-sIgE from 36 months to 7-12 years, but MAT remained low. PS children had low biomarkers across time. Conclusions: In this cohort, few children outgrow or develop new PA between 36 months and 7-12 years. Children with persistent PA have raised SPT, peanut-sIgE, Ara h 2-sIgE and MAT evident from infancy that consistently increase over time. https://doi.org/10.1111/all.16193
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.
https://doi.org/10.1111/all.15905
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.
https://doi.org/10.1111/all.15939
Phase 1 trial supports safety and mechanism of action of peptide immunotherapy for peanut allergy
Background: Food allergy is a leading cause of anaphylaxis worldwide. Allergen-specific immunotherapy is the only treatment shown to modify the natural history of allergic disease, but application to food allergy has been hindered by risk of severe allergic reactions and short-lived efficacy. Allergen-derived peptides could provide a solution. PVX108 comprises seven short peptides representing immunodominant T-cell epitopes of major peanut allergens for treatment of peanut allergy. Methods: Pre-clinical safety of PVX108 was assessed using ex vivo basophil activation tests (n = 185). Clinical safety and tolerability of single and repeat PVX108 doses were evaluated in a first-in-human, randomized, double-blind, placebo-controlled trial in peanut-allergic adults (46 active, 21 placebo). The repeat-dose cohort received six doses over 16 weeks with safety monitored to 21 weeks. Exploratory immunological analyses were performed at pre-dose, Week 21 and Month 18 after treatment. Results: PVX108 induced negligible activation of peanut-sensitised basophils. PVX108 was safe and well tolerated in peanut-allergic adults. There were no treatment-related hypersensitivity events or AEs of clinical concern. The only events occurring more frequently in active than placebo were mild injection site reactions. Exploratory immunological analyses revealed a decrease in the ratio of ST2+ Th2A:CCR6+ Th17-like cells within the peanut-reactive Th pool which strengthened following treatment. Conclusion: This study supports the concept that PVX108 could provide a safe alternative to whole peanut immunotherapies and provides evidence of durable peanut-specific T-cell modulation. Translation of these findings to clinical efficacy in ongoing Phase 2 trials would provide important proof-of-concept for using peptides to treat food allergy.
https://doi.org/10.1111/all.15966
EAACI guidelines on the diagnosis of IgE-mediated food allergy
This European Academy of Allergy and Clinical Immunology guideline provides recommendations for diagnosing IgE-mediated food allergy and was developed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Food allergy diagnosis starts with an allergy-focused clinical history followed by tests to determine IgE sensitization, such as serum allergen-specific IgE (sIgE) and skin prick test (SPT), and the basophil activation test (BAT), if available. Evidence for IgE sensitization should be sought for any suspected foods. The diagnosis of allergy to some foods, such as peanut and cashew nut, is well supported by SPT and serum sIgE, whereas there are less data and the performance of these tests is poorer for other foods, such as wheat and soya. The measurement of sIgE to allergen components such as Ara h 2 from peanut, Cor a 14 from hazelnut and Ana o 3 from cashew can be useful to further support the diagnosis, especially in pollen-sensitized individuals. BAT to peanut and sesame can be used additionally. The reference standard for food allergy diagnosis is the oral food challenge (OFC). OFC should be performed in equivocal cases. For practical reasons, open challenges are suitable in most cases. Reassessment of food allergic children with allergy tests and/or OFCs periodically over time will enable reintroduction of food into the diet in the case of spontaneous acquisition of oral tolerance.
https://doi.org/10.1111/all.15902
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.
https://doi.org/10.1111/all.15905
Early introduction of peanut reduces peanut allergy across risk groups in pooled and causal inference analyses.
Background: The LEAP study has shown the effectiveness of early peanut introduction in prevention of peanut allergy (PA). In the EAT study, a statistically significant reduction in PA was present only in per-protocol (PP) analyses, which can be subject to bias. Objective: To combine individual-level data from the LEAP and EAT trials and provide robust evidence on the bias-corrected, causal effect of early peanut introduction. Method: As part of the European Union-funded iFAAM project, this pooled analysis of individual paediatric patient data combines and compares effectiveness and efficacy estimates of oral tolerance induction among different risk strata and analysis methods. Results: An intention-to-treat (ITT) analysis of pooled data showed a 75% reduction in PA (p<0.0001) among children randomized to consume peanut from early infancy. A protective effect was present across all eczema severity groups, irrespective of enrolment sensitization to peanut, and across different ethnicities. Earlier age of introduction was associated with improved effectiveness of the intervention. In the pooled PP analysis, peanut consumption reduced the risk of PA by 98% (p<0.0001). A causal inference analysis confirmed the strong PP effect (89% average treatment effect relative risk reduction p<0.0001). A multivariable causal inference analysis approach estimated a large (100%) reduction in PA in children without eczema (p=0.004). Conclusion: We demonstrate a significant reduction in PA with early peanut introduction in a large group of pooled, randomized participants. This significant reduction was demonstrated across all risk subgroups, including children with no eczema. Furthermore, our results point to increased efficacy of the intervention with earlier age of introduction. https://doi.org/10.1111/all.15597
Efficacy and safety of food allergy oral immunotherapy in adults.
Background: Oral immunotherapy (OIT) is an emerging method for treating food allergy in children. However, data regarding adults undergoing this process are lacking. Methods: We retrospectively analyzed the medical records of patients with food allergy aged ≥17 years who completed OIT treatment between April 2010 and December 2020 at Shamir Medical Center. Data were compared with that of children aged 4 to <11 years and adolescents aged ≥11 to 17 treated during the same time period. Results: A total of 96 adults at a median age of 22.3 years who underwent OIT for milk (n = 53), peanut (n = 18), sesame (n = 7), egg (n = 5), and tree nuts (n = 13) were analyzed and compared with 1299 children and 309 adolescents. Adults experienced more adverse reactions requiring injectable epinephrine, both during in-clinic up-dosing (49% vs. 15.9% and 26.5% for children and adolescents, respectively, p < 0.0001) and during home treatment (22.9% vs. 12.4%, p = 0.007 for children, and 17.5%, p = 0.23 for adolescents). Most adults (61.5%) were fully desensitized, but the rates of full desensitization were significantly lower than children (73.4%, p = 0.013). Significantly more adults (28.3%) undergoing milk OIT failed treatment than children (14.3%, p = 0.015) and adolescents (14.1%, p = 0.022), while failure rates in adults undergoing OIT for other foods were low (9.3%) and comparable with children and adolescents. Conclusions: OIT is successful in desensitizing most adults with IgE-mediated food allergy. Adults undergoing milk OIT are at increased risk for severe reactions and for OIT failure while failure rates in adults undergoing OIT for other foods are low. https://doi.org/10.1111/all.15537
Remission of peanut allergy is associated with rewiring of allergen-driven T helper 2-related gene networks
Background: The immunological changes underpinning acquisition of remission (also called sustained unresponsiveness) following food immunotherapy remain poorly defined. Limited access to effective therapies and biosamples from treatment responders has prevented progress. Probiotic peanut oral immunotherapy is highly effective at inducing remission, providing an opportunity to investigate immune changes. Methods: Using a systems biology approach, we examined gene co-expression network patterns in peanut-specific CD4+ T cell responses before and after probiotic and peanut oral immunotherapy in subjects enrolled in the PPOIT-001 randomized trial: Responders who attained remission (n = 16), placebo-treated who remained allergic (n = 16). Results: Acquisition of remission was associated with rewiring of gene network patterns, which was characterized by integration of T helper 2 and interferon signalling modules, markedly reduced T helper 2 gene connectivity, and shutdown in co-expression activity between T helper 2 effectors and cell cycle regulators. Conclusion: The immunological changes underlying remission following peanut oral immunotherapy are mediated by reprogramming of T helper 2-associated gene networks in the CD4+ T cell compartment. Findings provide insight into immune mechanisms driving the acquisition of remission following oral immunotherapy, paving the way for the development of improved approaches to induce remission/sustained unresponsiveness in patients with food allergy. doi.org/10.1111/all.15324.
Cashew Oral Immunotherapy for Desensitizing Cashew-Pistachio Allergy (Nut CRACKER Study)
Background: Oral immunotherapy (OIT) is a treatment option for patients with milk, egg and peanut allergy, but data on the efficacy and safety of cashew OIT is limited. Methods: A cohort of 50 cashew-allergic patients aged ≥4 years, who were consecutively enrolled into cashew OIT (target dose 4000 mg protein) between 4/2016-12/2019. Fifteen cashew-allergic patients who continued cashew elimination served as observational controls. Co-allergy to pistachio and walnut was determined. Full desensitization rate and associated immunological changes in both groups were compared. Patients fully desensitized to cashew were instructed to consume a dose of 1200 mg protein cashew for 6 months and were then challenged to a full dose. Patients with co-allergy to pistachio or walnut were challenged to the respective nut. Results: 44 of 50 OIT-treated patients (88%) compared to 0% in controls, tolerated a dose of 4000 mg cashew protein at the end of the study (odds ratio 8.3, 95% CI 3.9 - 17.7, p<0.001). An additional 3 patients were desensitized to 1200 mg cashew protein and 3 patients stopped treatment. Three patients (6%) were treated with injectable epinephrine for home reactions. Desensitized patients had decreased SPT, sIgE, basophil reactivity and increased sIgG4, following treatment. Following cashew desensitization, all pistachio (n=35) and 4 of 8 walnut co-allergic patients were cross-desensitized to the respective nut. All (n=44) patients consuming a low cashew dose for ≥6 months following desensitization, passed a full dose cashew OFC. Conclusions: Cashew OIT desensitizes most cashew allergic patients and cross-desensitizes to pistachio. Safety is similar to OIT for other foods. https://doi.org/10.1111/all.15212