Developing a Prediction Model for Determination of Peanut Allergy Status in the Learning Early About Peanut Allergy (LEAP) Studies.

BACKGROUND: The Learning Early About Peanut Allergy (LEAP) study team developed a protocol-specific algorithm using dietary history, peanut-specific IgE, and skin prick test (SPT) to determine peanut allergy status if the oral food challenge (OFC) could not be administered or did not provide a determinant result. OBJECTIVE: To investigate how well the algorithm determined allergy status in LEAP; to develop a new prediction model to determine peanut allergy status when OFC results are not available in LEAP Trio, a follow-up study of LEAP participants and their families; and to compare the new prediction model with the algorithm. METHODS: The algorithm was developed for the LEAP protocol before the analysis of the primary outcome. Subsequently, a prediction model was developed using logistic regression. RESULTS: Using the protocol-specified algorithm, 73% (453/617) of allergy determinations matched the OFC, 0.6% (4/617) were mismatched, and 26% (160/617) participants were nonevaluable. The prediction model included SPT, peanut-specific IgE, Ara h 1, Ara h 2, and Ara h 3. The model inaccurately predicted 1 of 266 participants as allergic who were not allergic by OFC and 8 of 57 participants as not allergic who were allergic by OFC. The overall error rate was 9 of 323 (2.8%) with an area under the curve of 0.99. The prediction model additionally performed well in an external validation cohort. CONCLUSION: The prediction model performed with high sensitivity and accuracy, eliminated the problem of nonevaluable outcomes, and can be used to estimate peanut allergy status in the LEAP Trio study when OFC is not available.

Incorporating genetics in identifying peanut allergy risk and tailoring allergen immunotherapy: A perspective on the genetic findings from the LEAP trial.

Examining the genetics of peanut allergy (PA) in the context of clinical trial interventions and outcomes provides an opportunity to not only understand gene-environment interactions for PA risk but to also understand the benefit of allergen immunotherapy. A consistent theme in the genetics of food allergy is that in keeping with the dual allergen exposure hypothesis, barrier- and immune-related genes are most commonly implicated in food allergy and tolerance. With a focus on PA, we review how genetic risk factors across 3 genes (FLG, MALT1, and HLA-DQA1) have helped delineate distinct allergic characteristics and outcomes in the context of environmental interventions in the Learning Early about Peanut Allergy (LEAP) study and other clinical trials. We specifically consider and present a framework for genetic risk prediction for the development of PA and discuss how genetics, age, and oral consumption intertwine to predict PA outcome. Although there is some promise in this proposed framework, a better understanding of the mechanistic pathways by which PA develops and persists is needed to develop targeted therapeutics for established disease. Only by understanding the mechanisms by which PA develops, persists, and resolves can we identify adjuvants to oral immunotherapy to make older children and adults immunologically similar to their younger, more malleable counterparts and thus more likely to achieve long-term tolerance.

Epidermal differentiation complex genetic variation in atopic dermatitis and peanut allergy.

BACKGROUND: Deleterious variation in the epidermal differentiation complex (EDC) on chromosome 1 is a well-known genetic determinant of atopic dermatitis (AD) and has been associated with risk of peanut allergy (PA) in population-based studies. OBJECTIVE: Our aim was to determine the effect of genetic variation in the EDC on AD trajectory and risk of PA in early life. METHODS: Genome sequencing was used to measure genetic variation in the EDC in the Learning Early about Peanut Allergy (LEAP) study participants. Association tests were done to identify gene- and variant-level predicted deleterious variation associated with AD severity by using the Scoring Atopic Dermatitis (SCORAD) tool (n = 559) at baseline and each follow-up visit, as well as PA and food allergy in peanut avoiders (n = 275). Predicted deleterious variants included missense variants that were frameshift insertions, frameshift deletions, stop-gain mutations, or stop-loss mutations. Associations between variant load, SCORAD score, and PA were tested by using linear and generalized linear regression models. RESULTS: The genes FLG, FLG2, HRNR, and TCHH1 harbored the most predicted deleterious variation (30, 6, 3, and 1 variant, respectively). FLG variants were associated with SCORAD score at all time points; 4 variants (R1798X, R501X, S126X, and S761fs) drove the association with SCORAD score at each time point, and higher variant load was associated with greater AD severity over time. There was an association between these variants and PA, which remained significant independent of baseline AD severity (odds ratio = 2.63 [95% CI = 1.11-6.01] [P = .02]). CONCLUSIONS: Variation in FLG predicted to be deleterious is associated with AD severity at baseline and longitudinally and has an association with PA independent of baseline severity.

HLA-associated outcomes in peanut oral immunotherapy trials identify mechanistic and clinical determinants of therapeutic success.

Rationale: Previous studies identified an interaction between HLA and oral peanut exposure. HLA-DQA1*01:02 had a protective role with the induction of Ara h 2 epitope-specific IgG4 associated with peanut consumption during the LEAP clinical trial for prevention of peanut allergy, while it was a risk allele for peanut allergy in the peanut avoidance group. We have now evaluated this gene-environment interaction in two subsequent peanut oral immunotherapy (OIT) trials - IMPACT and POISED - to better understand the potential for the HLA-DQA1*01:02 allele as an indicator of higher likelihood of desensitization, sustained unresponsiveness, and peanut allergy remission. Methods: We determined HLA-DQA1*01:02 carrier status using genome sequencing from POISED (N=118, age: 7-55yr) and IMPACT (N=126, age: 12-<48mo). We tested for association with remission, sustained unresponsiveness (SU), and desensitization in the OIT groups, as well as peanut component specific IgG4 (psIgG4) using generalized linear models and adjusting for relevant covariates and ancestry. Results: While not quite statistically significant, a higher proportion of HLA-DQA1*01:02 carriers receiving OIT in IMPACT were desensitized (93%) compared to non-carriers (78%); odds ratio (OR)=5.74 (p=0.06). In this sample we also observed that a higher proportion of carriers achieved remission (35%) compared to non-carriers (22%); OR=1.26 (p=0.80). In POISED, carriers more frequently attained continued desensitization (80% versus 61% among non-carriers; OR=1.28, p=0.86) and achieved SU (52% versus 31%; OR=2.32, p=0.19). psIgG4 associations with HLA-DQA1*01:02 in the OIT arm of IMPACT which included younger study subjects recapitulated patterns noted in LEAP, but no associations of note were observed in the older POISED study subjects. Conclusions: Findings across three clinical trials show a pattern of a gene environment interaction between HLA and oral peanut exposure. Age, and prior sensitization contribute additional determinants of outcomes, consistent with a mechanism of restricted antigen recognition fundamental to driving protective immune responses to OIT.

Biomarkers and mechanisms of tolerance induction in food allergic patients drive new therapeutic approaches.

Immunotherapy for food-allergic patients has been effective in inducing desensitization in some populations, but long-term tolerance has remained an elusive target. A challenge facing our field is how to differentiate immune markers that are impacted by immunotherapy from those that are critical biomarkers of tolerance. Data from recent clinical trials have identified several biomarkers and mechanisms for achieving tolerance. These biomarkers include younger age, lower food-specific IgE, lower food component-specific IgE, specific linear epitope profiles, and subsets of food-specific CD4+ T cells. Additional biomarkers under investigation for their relevance in tolerance induction include TCR repertoires, gastrointestinal and skin microbiome, and local tissue immunity. This mini-review highlights recent advances in understanding biomarkers and mechanisms of tolerance induction in food immunotherapy and how these are influencing clinical trial development.

Approaches to Establishing Tolerance in Immune Mediated Diseases.

The development of rational approaches to restore immune tolerance requires an iterative approach that builds on past success and utilizes new mechanistic insights into immune-mediated pathologies. This article will review concepts that have evolved from the clinical trial experience of the Immune Tolerance Network, with an emphasis on lessons learned from the innovative mechanistic studies conducted for these trials and new strategies under development for induction of tolerance.

Case series of sebelipase alfa hypersensitivity reactions and successful sebelipase alfa rapid desensitization.

Allergic immune-mediated hypersensitivity reactions are known potential complications of enzyme replacement therapy. Sebelipase alfa, recombinant lysosomal acid lipase (LAL), is a potentially life-altering treatment for patients with LAL deficiency. There is very little information on the diagnosis and management of immediate hypersensitivity reactions to this drug. Here we present three unique cases of hypersensitivity reactions to sebelipase alfa, spanning a broad age spectrum from infancy to adulthood, each managed with successful rapid desensitization.

Passive Nocturnal Physiologic Monitoring Enables Early Detection of Exacerbations in Children with Asthma. A Proof-of-Concept Study.

RATIONALE: Asthma management depends on prompt identification of symptoms, which challenges both patients and providers. In asthma, a misapprehension of health between exacerbations can compromise compliance. Thus, there is a need for a tool that permits objective longitudinal monitoring without increasing the burden of patient compliance. OBJECTIVES: We sought to determine whether changes in nocturnal physiology are associated with asthma symptoms in pediatric patients. METHODS: Using a contactless bed sensor, nocturnal heart rate (HR), respiratory rate, relative stroke volume, and movement in children with asthma 5-18 years of age (n = 16) were recorded. Asthma symptoms and asthma control test (ACT) score were reported every 2 weeks. Random forest model was used to identify physiologic parameters associated with asthma symptoms. Elastic net regression was used to identify variables associated with ACT score. MEASUREMENTS AND MAIN RESULTS: The model on the full cohort performed with sensitivity of 47.2%, specificity of 96.3%, and accuracy of 87.4%; HR and respiratory parameters were the most important variables in this model. The model predicted asthma symptoms 35% of the time on the day before perception of symptoms, and 100% of the time for a select subject for which the model performed with greater sensitivity. Multivariable and bivariable analyses demonstrated significant association between HR and respiratory rate parameters and ACT score. CONCLUSIONS: Nocturnal physiologic changes correlate with asthma symptoms, supporting the notion that nocturnal physiologic monitoring represents an objective diagnostic tool capable of longitudinally assessing disease control and predicting asthma exacerbations in children with asthma at home.

Impact of school peanut-free policies on epinephrine administration.

BACKGROUND: Children with food allergies spend a large proportion of time in school but characteristics of allergic reactions in schools are not well studied. Some schools self-designate as peanut-free or have peanut-free areas, but the impact of policies on clinical outcomes has not been evaluated. OBJECTIVE: We sought to determine the effect of peanut-free policies on rates of epinephrine administration for allergic reactions in Massachusetts public schools. METHODS: In this retrospective study, we analyzed (1) rates of epinephrine administration in all Massachusetts public schools and (2) Massachusetts public school nurse survey reports of school peanut-free policies from 2006 to 2011 and whether schools self-designated as "peanut-free" based on policies. Rates of epinephrine administration were compared for schools with or without peanut-restrictive policies. RESULTS: The percentage of schools with peanut-restrictive policies did not change significantly in the study time frame. There was variability in policies used by schools self-designated as peanut-free. No policy was associated with complete absence of allergic reactions. Both self-designated peanut-free schools and schools banning peanuts from being served in school or brought from home reported allergic reactions to nuts. Policies restricting peanuts from home, served in schools, or having peanut-free classrooms did not affect epinephrine administration rates. Schools with peanut-free tables, compared to without, had lower rates of epinephrine administration (incidence rate per 10,000 students 0.2 and 0.6, respectively, P = .009). CONCLUSIONS: These data provide a basis for evidence-based school policies for children with food allergies. Further studies are required before decisions can be made regarding peanut-free policies in schools.

School Environmental Intervention to Reduce Particulate Pollutant Exposures for Children with Asthma.

BACKGROUND: Home-based interventions to improve indoor air quality have demonstrated benefits for asthma morbidity, yet little is known about the effect of environmental interventions in the school setting. OBJECTIVE: We piloted the feasibility and effectiveness of a classroom-based air cleaner intervention to reduce particulate pollutants in classrooms of children with asthma. METHODS: In this pilot randomized controlled trial, we assessed the effect of air cleaners on indoor air particulate pollutant concentrations in 18 classrooms (9 control, 9 intervention) in 3 urban elementary schools. We enrolled 25 children with asthma (13 control, 12 intervention) aged 6 to 10 years. Classroom air pollutant measurements and spirometry were completed once before and twice after randomization. Asthma symptoms were surveyed every 3 months. RESULTS: Baseline classroom levels of fine particulate matter (particulate matter with diameter of <2.5 µm [PM2.5]) and black carbon (BC) were 6.3 and 0.41 µg/m3, respectively. When comparing the intervention to the control group, classroom PM2.5 levels were reduced by 49% and 42% and BC levels were reduced by 58% and 55% in the first and second follow-up periods, respectively (P < .05 for all comparisons). When comparing the children randomized to intervention and control classrooms, there was a modest improvement in peak flow, but no significant changes in forced expiratory volume in 1 second (FEV1) and asthma symptoms. CONCLUSIONS: In this pilot study, a classroom-based air cleaner intervention led to significant reductions in PM2.5 and BC. Future large-scale studies should comprehensively evaluate the effect of school-based environmental interventions on pediatric asthma morbidity.