Antigen-specific IgG2 and IgG3 are rarely measured in food allergy clinical trials despite known function in preventing mast cell and basophil activation. Our objective was to determine whether measuring peanut-specific IgG2 and IgG3 levels would correlate with peanut allergy status. Peanut-specific IgG subclasses were measured via ELISA assays in Learning Early About Peanut allergy (LEAP) trial participants at 5 years of age and were correlated with peanut allergy vs peanut sensitization vs non-peanut allergic and peanut consumption vs peanut avoidance. Peanut-specific IgG1, IgG2, IgG3, and IgG4 levels were significantly different between participants with peanut allergy vs peanut sensitization vs non-peanut allergic, and a multivariate logistic regression model and stepwise selection found that IgG1 most closely associated with peanut allergy status. Similarly, all subclasses differentiated those consuming vs those avoiding peanut, but subsequent modeling found that IgG4 most closely associated with consumption status. Amongst the peanut-specific IgG subclasses, IgG1 was the best biomarker for peanut allergy, while IgG4 was the best biomarker for peanut antigen exposure in this highly atopic cohort. Our study did not find added value from evaluating peanut-specific IgG 2 and 3 as biomarkers of peanut allergy, although they did correlate with peanut allergy. Subsequent studies should assess the value of adding IgG subclasses to multivariate models predicting peanut allergy status.

(1) Peanut allergy is associated with high risk of anaphylaxis which could be prevented by oral immunotherapy. Patients eligible for immunotherapy are selected on the basis of a food challenge, although currently the assessment of antibodies against main peanut molecules (Ara h 1, 2, 3 and 6) is thought to be another option. (2) The current study assessed the relationship between the mentioned antibodies, challenge outcomes, skin tests and some other parameters in peanut-sensitized children. It involved 74 children, divided into two groups, based on their response to a food challenge. (3) Both groups differed in results of skin tests, levels of component-specific antibodies and peanut exposure history. The antibody levels were then used to calculate thresholds for prediction of challenge results or symptom severity. While the antibody-based challenge prediction revealed statistical significance, it failed in cases of severe symptoms. Furthermore, no significant correlation was observed between antibody levels, symptom-eliciting doses and the risk of severe anaphylaxis. Although in some patients it could result from interference with IgG4, the latter would not be a universal explanation of this phenomenon. (4) Despite some limitations, antibody-based screening may be an alternative to the food challenge, although its clinical relevance still requires further studies.

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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.
CONCLUSIONS: Application of this intervention has the potential to inform the development of strategies to speed implementation of PPA guidelines.

BACKGROUND: The prevalence of peanut allergy is about 2% and mostly lifelong. Studies of oral immunotherapy (OIT) with peanut (the daily oral intake of an initially low and then increasing dose of peanut) often show problematic side effects, but there are indications of better safety and effect in younger children compared with older children and adults.
OBJECTIVE: To determine the safety and effectiveness of peanut OIT with a slow up-dosing strategy and low maintenance dose in children aged 1 to 3 years who were allergic to peanut, through a 1-year interim analysis.
METHODS: In a randomized controlled trial (2:1 ratio), 75 children, median age 31 months (interquartile range [IQR], 23-40 months) were assigned to receive peanut OIT (n = 50) or peanut avoidance (n = 25).
RESULTS: In the OIT and avoidance groups, 43 of 50 and 20 of 25 children, respectively, performed the 1-year open oral peanut challenge. A cumulative dose of 750 mg peanut protein after 1 year was tolerated by 72% (36 of 50 children) in the OIT group compared with 4% (1 of 25) in the avoidance group (P < .001). Median tolerated cumulative dose was 2,750 mg (IQR, 275-5,000 mg) peanut protein in the OIT group compared with 2.8 mg (IQR, 0.3-27.8 mg) in the avoidance group (P < .001). Of the doses administered at home during the first year of OIT, 1.4% resulted in adverse events and 79% were mild, and three doses of epinephrine were given at home to two individuals.
CONCLUSIONS: In children aged 1 to 3 years, peanut OIT with the combination of slow up-dosing and low maintenance dose seems safe and effective after 1 year.

BACKGROUND: Reaction thresholds in peanut allergy are highly variable. Elucidating causal relationships between molecular and cellular processes associated with variable thresholds could point to therapeutic pathways for raising thresholds.
OBJECTIVE: The aim of this study was to characterize molecular and cellular systemic processes associated with reaction threshold in peanut allergy and causal relationships between them.
METHODS: A total of 105 children aged 4 to 14 years with suspected peanut allergy underwent double-blind, placebo-controlled food challenge to peanut. The cumulative peanut protein quantity eliciting allergic symptoms was considered the reaction threshold for each child. Peripheral blood samples collected at 0, 2, and 4 hours after challenge start were used for RNA sequencing, whole blood staining, and cytometry. Statistical and network analyses were performed to identify associations and causal mediation between the molecular and cellular profiles and peanut reaction threshold.
RESULTS: Within the cohort (N = 105), 81 children (77%) experienced allergic reactions after ingesting varying quantities of peanut, ranging from 43 to 9043 mg of cumulative peanut protein. Peripheral blood expression of transcripts (eg, IGF1R [false discovery rate (FDR) = 5.4e-5] and PADI4 [FDR = 5.4e-5]) and neutrophil abundance (FDR = 9.5e-4) were associated with peanut threshold. Coexpression network analyses revealed that the threshold-associated transcripts were enriched in modules for FcγR-mediated phagocytosis (FDR = 3.2e-3) and Toll-like receptor (FDR = 1.4e-3) signaling. Bayesian network, key driver, and causal mediation analyses identified key drivers (AP5B1, KLHL21, VASP, TPD52L2, and IGF2R) within these modules that are involved in bidirectional causal mediation relationships with neutrophil abundance.
CONCLUSIONS: Key driver transcripts in FcγR-mediated phagocytosis and Toll-like receptor signaling interact bidirectionally with neutrophils in peripheral blood and are associated with reaction threshold in peanut allergy.

BACKGROUND: Data suggest that food allergies greatly impact a child\'s health and growth due to inadequate nutrient intake. Our study aimed to establish the long-term outcome of children with food allergies compared to a control group.
METHODS: This study was a retrospective cohort study with longitudinal follow-up with a mean period of 4.85 years from the diagnosis to the last study visit. The patients\' nutritional intake was assessed using a three-day food diary and analysed by a dietitian. Patients (61 boys and 33 girls, mean age 6.9 years) had a single food allergy including 21 patients with cow\'s milk, 34 with egg, and 39 with peanut allergies. The control group included 36 children (19 boys and 17 girls, mean age 8.03 years). Blood analysis was performed on all participants.
RESULTS: Data from our study showed that patients with cow\'s milk, egg or peanut allergies had normal growth and achieved catch-up growth from the diagnosis until the last study visit. In the cow\'s milk allergy group, the allergy was shown to affect calcium intake (p < 0.05), while egg and peanut allergies did not impact the dietary intake of nutrients. None of the investigated food allergies affected blood results (p < 0.05).
CONCLUSIONS: In the present study, we showed that single food allergies do not compromise growth in children if they are provided with appropriate support and that the affected children reach catch-up growth from the diagnosis.

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.
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.
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.
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.

To compared the cost-effectiveness of coadministration of a probiotic adjuvant with peanut oral immunotherapy (PPOIT) with placebo (no treatment) in children with peanut allergy.
Prospectively planned cost-effectiveness analysis alongside a randomised control trial.
The Royal Children\'s Hospital, Melbourne, Australia.
56 children with peanut allergy aged 1-10 years at recruitment.
A daily dose of probiotic Lactobacillus rhamnosus CGMCC 1.3724 (NCC4007) and peanut oral immunotherapy administered for 1.5 years.
Costs were considered from a healthcare system perspective and included costs of treatment delivery and adverse events. Effectiveness outcomes included rate of sustained unresponsiveness (SU) and quality-adjusted life years (QALYs). The cost-effectiveness of PPOIT versus placebo was analysed using patient-level data. Time horizon was 10 years from commencement of PPOIT treatment, comprising 1.5 years of treatment (actual data), 4 years of post-treatment follow-up (actual data), and 4.5 years of extrapolation thereafter (modelling).
Healthcare cost per patient over 10 years was higher for PPOIT compared with placebo ($A9355 vs $A1031, p<0.001). Over half of the per patient healthcare cost (53%) in the PPOIT group was attributable to treatment delivery, while the remaining cost was attributable to adverse events. Both measures of effectiveness were superior in the PPOIT group: the average SU rate over 10 years was 54% for PPOIT versus 6% for placebo (p<0.001); QALYs over 10 years were 9.05 for PPOIT versus 8.63 for placebo (p<0.001). Overall, cost per year of SU achieved was $A1694 (range $A1678, $A1709) for PPOIT compared with placebo, and cost per additional QALY gained was $A19 386 (range $A19 024, $A19 774).
Cost per QALY gained using PPOIT compared with no treatment is approximately $A20 000 (£10 000) and is well below the conventional value judgement threshold of $A50 000 (£25 000) per QALY gained, thus deemed good value for money ($A1= £0.5 approximately).
Australian New Zealand Clinical Trials Registry ACTRN12608000594325; Post-results.

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