Yamini Virkud

Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy

BACKGROUND Although peanut oral immunotherapy (OIT) has been conclusively shown to cause desensitization, it is currently unknown whether clinical protection persists after stopping therapy. OBJECTIVE Our primary objective was to determine whether peanut OIT can induce sustained unresponsiveness after withdrawal of OIT. METHODS We conducted a pilot clinical trial of peanut OIT at 2 US centers. Subjects age 1 to 16 years were recruited and treated for up to 5 years with peanut OIT. The protocol was modified over time to permit dose increases to a maximum of 4000 mg/d peanut protein. Blood was collected at multiple time points. Clinical end points were measured with 5000-mg double-blinded, placebo-controlled food challenges once specific criteria were met. RESULTS Of the 39 subjects originally enrolled, 24 completed the protocol and had evaluable outcomes. Twelve (50%) of 24 successfully passed a challenge 1 month after stopping OIT and achieved sustained unresponsiveness. Peanut was added to the diet. At baseline and the time of challenge, such subjects had smaller skin test results, as well as lower IgE levels specific for peanut, Ara h 1, and Ara h 2 and lower ratios of peanut-specific IgE/total IgE compared with subjects not passing. There were no differences in peanut IgG₄ levels or functional activity at the end of the study. CONCLUSIONS This is the first demonstration of sustained unresponsiveness after peanut OIT, occurring in half of subjects treated for up to 5 years. OIT favorably modified the peanut-specific immune response in all subjects completing the protocol. Smaller skin test results and lower allergen-specific IgE levels were predictive of successful outcome.

Familial Aggregation of Quantitative Autistic Traits in Multiplex versus Simplex Autism

Recent research has suggested that the mode of inheritance for simplex autism (SA, one individual in the family affected) may be distinct from that for multiplex autism (MA, two or more individuals affected). Since sub clinical autistic traits have been observed in “unaffected” relatives of children with autism, we explored whether the distributions of such traits in families supported differential modes of genetic transmission for SA and MA autism. We measured patterns of familial aggregation of quantitative autistic traits (QAT) in children and parents in 80 SA families and 210 MA families, using the Social Responsiveness Scale. When considering all SA and MA siblings who scored below a uniform quantitative (clinical‐level) severity threshold, MA brothers exhibited a distinct pathological shift in the distribution, compared to SA brothers (P < 0.0001). Such aggregation of QAT was also observed in fathers but not among females in MA families. Significant spousal correlations for QAT—suggestive of assortative mating—were observed in both SA and MA families, but neither group was characterized by a greater‐than‐chance level of concordant elevation among spousal pairs in this volunteer sample. Among male first degree relatives, there exist distinct patterns of QAT manifestation for simplex versus multiplex autism. These findings are consistent with the results of molecular genetic studies that have suggested differential modes of intergenerational transmission for SA and MA. Characterization of QAT and other endophenotypes among close relatives may be useful for reducing sample heterogeneity in future genetic and neurobiologic studies of autism.

Early oral immunotherapy in peanut-allergic preschool children is safe and highly effective

Background: Oral immunotherapy (OIT) is an effective experimental food allergy treatment that is limited by treatment withdrawal and the frequent reversibility of desensitization if interrupted. Newly diagnosed preschool children may have clinical and immunological characteristics more amenable to treatment. Objective: We sought to test the safety, effectiveness, and feasibility of early OIT (E‐OIT) in the treatment of peanut allergy. Methods: We enrolled 40 children aged 9 to 36 months with suspected or known peanut allergy. Qualifying subjects reacted to peanut during an entry food challenge and were block‐randomized 1:1 to receive E‐OIT at goal maintenance doses of 300 or 3000 mg/d in a double‐blinded fashion. The primary end point, sustained unresponsiveness at 4 weeks after stopping early intervention oral immunotherapy (4‐SU), was assessed by double‐blinded, placebo‐controlled food challenge either upon achieving 4 prespecified criteria, or after 3 maintenance years. Peanut‐specific immune responses were serially analyzed. Outcomes were compared with 154 matched standard‐care controls. Results: Of 40 consented subjects, 3 (7.5%) did not qualify. Overall, 29 of 37 (78%) in the intent‐to‐treat analysis achieved 4‐SU (300‐mg arm, 17 of 20 [85%]; 3000 mg, 12 of 17 [71%], P = .43) over a median of 29 months. Per‐protocol, the overall proportion achieving 4‐SU was 29 of 32 (91%). Peanut‐specific IgE levels significantly declined in E‐OIT‐treated children, who were 19 times more likely to successfully consume dietary peanut than matched standard‐care controls, in whom peanut‐specific IgE levels significantly increased (relative risk, 19.42; 95% CI, 8.7‐43.7; P < .001). Allergic side effects during E‐OIT were common but all were mild to moderate. Conclusions: At both doses tested, E‐OIT had an acceptable safety profile and was highly successful in rapidly suppressing allergic immune responses and achieving safe dietary reintroduction.

Novel baseline predictors of adverse events during oral immunotherapy in children with peanut allergy

Background: Though peanut oral immunotherapy (OIT) is a promising investigational therapy, its potential is limited by substantial adverse events (AEs), which are relatively understudied. Objective: A retrospective analysis was conducted, pooling data from 3 pediatric peanut OIT trials, comprising the largest analysis of peanut OIT safety to date. Methods: We pooled data from 104 children with peanut allergy from 3 peanut OIT studies. We catalogued AEs from parental reports, daily symptom diaries, and dose escalations. We included events that were considered likely related to OIT and identified potential baseline predictors of higher AE rates using generalized linear regression models. Results: Eighty percent of subjects experienced likely related AEs during OIT (72% during buildup and 47% during maintenance). Of these AEs, over 90% occurred while at home. Approximately 42% of subjects experienced systemic reactions, and 49% experienced gastrointestinal symptoms. Twenty percent of subjects dropped out, with half (10% of the overall group) due to persistent gastrointestinal symptoms. Baseline allergic rhinitis (AR) and peanut SPT wheal size were significant predictors of higher overall AE rates. SPT wheal size predicted increased gastrointestinal AEs, and AR predicted increased systemic reactions. Over the course of OIT, 61% of subjects received treatment for likely related AEs, 59% with antihistamines and 12% with epinephrine. Conclusions: Peanut OIT is associated with frequent AEs, with rates declining over time, and most graded mild. However, systemic reactions and intolerable gastrointestinal AEs do occur and are significantly associated with AR and peanut SPT wheal size, respectively. Further study is needed of predictive biomarkers and the overall risks and benefits of OIT.

Infant head growth in male siblings of children with and without autism spectrum disorders

Previous research has indicated that children with autism exhibit accelerated head growth (HG) in infancy, although the timing of acceleration varies between studies. We examined infant HG trajectory as a candidate autism endophenotype by studying sibling pairs. We retrospectively obtained serial head orbitofrontal circumference measurements of: a) 48 sibling pairs in which one (n = 28) or both (n = 20) sibs were affected by an autism spectrum disorder (ASD); and b) 85 control male sibling pairs. Rate of HG of ASD subjects was slightly accelerated compared to controls, but the magnitude of difference was below the limit of reliability of standard measurement methods. Sibling intra class correlation for rate of HG was highly statistically significant; the magnitude was significantly stronger among autism-affected families (ICC = .63) than among controls (ICC = .26), p < .01. Infant HG trajectory appears familial—possibly endophenotypic—but was not a reliable marker of autism risk among siblings of ASD probands in this sample.

Respiratory Support for Very Low Birth Weight Infants Receiving Dexamethasone

Objective To assess how neonatal intensive care units followed the American Academy of Pediatrics guidelines for use of dexamethasone in preterm infants by evaluating respiratory support at the time of dexamethasone administration. Study design This is an observational study of infants discharged from one of 290 neonatal intensive care units from 2003 to 2010. The cohort included very low birth weight (<1500 g birth weight) infants born at ≤32 weeks gestational age. The main outcome was respiratory support at time of exposure to dexamethasone. Significant respiratory support was defined as invasive respiratory support (conventional or high‐frequency ventilation) with a fraction of inspired oxygen (FiO2) > 0.3. Results Of 81 292 infants; 7093 (9%) received dexamethasone. At the time that dexamethasone was initiated, 4604 (65%) of infants were on significant respiratory support. Conclusions In accordance with the American Academy of Pediatrics recommendations, a majority of infants were on significant respiratory support when receiving dexamethasone, yet a substantial number of infants still received dexamethasone on less than significant respiratory support. Further research on reducing dexamethasone use in premature infants is required to decrease the risk of neurodevelopmental impairment.

Partial Least Squares Discriminant Analysis and Bayesian Networks for Metabolomic Prediction of Childhood Asthma

To explore novel methods for the analysis of metabolomics data, we compared the ability of Partial Least Squares Discriminant Analysis (PLS-DA) and Bayesian networks (BN) to build predictive plasma metabolite models of age three asthma status in 411 three year olds (n = 59 cases and 352 controls) from the Vitamin D Antenatal Asthma Reduction Trial (VDAART) study. The standard PLS-DA approach had impressive accuracy for the prediction of age three asthma with an Area Under the Curve Convex Hull (AUCCH) of 81%. However, a permutation test indicated the possibility of overfitting. In contrast, a predictive Bayesian network including 42 metabolites had a significantly higher AUCCH of 92.1% (p for difference < 0.001), with no evidence that this accuracy was due to overfitting. Both models provided biologically informative insights into asthma; in particular, a role for dysregulated arginine metabolism and several exogenous metabolites that deserve further investigation as potential causative agents. As the BN model outperformed the PLS-DA model in both accuracy and decreased risk of overfitting, it may therefore represent a viable alternative to typical analytical approaches for the investigation of metabolomics data.

Enhancing the Safety and Efficacy of Food Allergy Immunotherapy: a Review of Adjunctive Therapies

Food allergy is a potentially life-threatening condition with no approved curative therapy. A number of food allergen immunotherapies are being investigated in phase II/III trials; however, these are limited in their ability to restore immune tolerance to food allergens and often result in high rates of allergic side effects, sometimes involving anaphylaxis, that may curtail their impact. A variety of adjunctive therapies have been developed in order to enhance the efficacy and/or improve the safety of food allergen immunotherapy through either shifting the immune response from a Th2 polarized response to a Th1 and regulatory T cell dominated response or by blocking downstream effects of the allergic inflammatory response by targeting IgE or mast cell mediators. Upstream therapies that shift towards a Th1/Treg response include toll-like receptor (TLR) 4 agonists (e.g., MPL and GLA), TLR9 agonists (CpG oligonucleotides), nanoparticles encapsulating peanut allergen (with and without adjuvants, such as CpG or rapamycin), Chinese herbal medicine (food allergy herbal formula (FAHF-2)), probiotics, and interferon-gamma. In contrast, anti-IgE therapies such as omalizumab, anti-histamines like ketotifen, and leukotriene receptor antagonists all target the downstream allergic response. Anti-IgE-based therapies appear to be furthest along with probiotics, Chinese herbal medicines, and TLR-4 agonists currently in early phase clinical trials. Meanwhile, nanoparticles represent an innovative delivery vehicle for immunotherapy that could improve both efficacy and decrease allergic side effects. Furthermore, other biologic therapies directed towards the allergic immune response are on the horizon. A number of factors will need to be evaluated in comparing these treatments, including ability to decrease allergic adverse events, safety of the adjunctive therapies themselves, effect on long-term sustained unresponsiveness, and cost. Further phenotyping of food allergy patients may be necessary to determine which ones respond best to each therapy. However, with so many promising adjunctive therapies, it appears likely that clinicians will have a variety of options to optimize the administration of food allergen immunotherapy. We provided a review of these methods, their influence on allergic adverse events, and utility in improving the immunomodulatory effects of food allergen immunotherapy.

Novel eosinophilic gene expression networks associated with IgE in two distinct asthma populations

Asthma represents a significant public health burden; however, novel biological therapies targeting immunoglobulin E (IgE)‐mediated pathways have widened clinical treatment options for the disease.

An Integrative Transcriptomic and Metabolomic Study of Lung Function in Children With Asthma

Background Single omic analyses have provided some insight into the basis of lung function in children with asthma, but the underlying biologic pathways are still poorly understood. Methods Weighted gene coexpression network analysis (WGCNA) was used to identify modules of coregulated gene transcripts and metabolites in blood among 325 children with asthma from the Genetic Epidemiology of Asthma in Costa Rica study. The biology of modules associated with lung function as measured by FEV1, the FEV1/FVC ratio, bronchodilator response, and airway responsiveness to methacholine was explored. Significantly correlated gene‐metabolite module pairs were then identified, and their constituent features were analyzed for biologic pathway enrichments. Results WGCNA clustered 25,060 gene probes and 8,185 metabolite features into eight gene modules and eight metabolite modules, where four and six, respectively, were associated with lung function (P ≤ .05). The gene modules were enriched for immune, mitotic, and metabolic processes and asthma‐associated microRNA targets. The metabolite modules were enriched for lipid and amino acid metabolism. Integration of correlated gene‐metabolite modules expanded the single omic findings, linking the FEV1/FVC ratio with ORMDL3 and dysregulated lipid metabolism. This finding was replicated in an independent population. Conclusions The results of this hypothesis‐generating study suggest a mechanistic basis for multiple asthma genes, including ORMDL3, and a role for lipid metabolism. They demonstrate that integrating multiple omic technologies may provide a more informative picture of asthmatic lung function biology than single omic analyses.