Transcriptome networks identify mechanisms of viral and nonviral asthma exacerbations in children.

Respiratory infections are common precursors to asthma exacerbations in children, but molecular immune responses that determine whether and how an infection causes an exacerbation are poorly understood. By using systems-scale network analysis, we identify repertoires of cellular transcriptional pathways that lead to and underlie distinct patterns of asthma exacerbation. Specifically, in both virus-associated and nonviral exacerbations, we demonstrate a set of core exacerbation modules, among which epithelial-associated SMAD3 signaling is upregulated and lymphocyte response pathways are downregulated early in exacerbation, followed by later upregulation of effector pathways including epidermal growth factor receptor signaling, extracellular matrix production, mucus hypersecretion, and eosinophil activation. We show an additional set of multiple inflammatory cell pathways involved in virus-associated exacerbations, in contrast to squamous cell pathways associated with nonviral exacerbations. Our work introduces an in vivo molecular platform to investigate, in a clinical setting, both the mechanisms of disease pathogenesis and therapeutic targets to modify exacerbations.

Phase 3 Trial of Epicutaneous Immunotherapy in Toddlers with Peanut Allergy.

BACKGROUND: No approved treatment for peanut allergy exists for children younger than 4 years of age, and the efficacy and safety of epicutaneous immunotherapy with a peanut patch in toddlers with peanut allergy are unknown. METHODS: We conducted this phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving children 1 to 3 years of age with peanut allergy confirmed by a double-blind, placebo-controlled food challenge. Patients who had an eliciting dose (the dose necessary to elicit an allergic reaction) of 300 mg or less of peanut protein were assigned in a 2:1 ratio to receive epicutaneous immunotherapy delivered by means of a peanut patch (intervention group) or to receive placebo administered daily for 12 months. The primary end point was a treatment response as measured by the eliciting dose of peanut protein at 12 months. Safety was assessed according to the occurrence of adverse events during the use of the peanut patch or placebo. RESULTS: Of the 362 patients who underwent randomization, 84.8% completed the trial. The primary efficacy end point result was observed in 67.0% of children in the intervention group as compared with 33.5% of those in the placebo group (risk difference, 33.4 percentage points; 95% confidence interval, 22.4 to 44.5; P<0.001). Adverse events that occurred during the use of the intervention or placebo, irrespective of relatedness, were observed in 100% of the patients in the intervention group and 99.2% in the placebo group. Serious adverse events occurred in 8.6% of the patients in the intervention group and 2.5% of those in the placebo group; anaphylaxis occurred in 7.8% and 3.4%, respectively. Serious treatment-related adverse events occurred in 0.4% of patients in the intervention group and none in the placebo group. Treatment-related anaphylaxis occurred in 1.6% in the intervention group and none in the placebo group. CONCLUSIONS: In this trial involving children 1 to 3 years of age with peanut allergy, epicutaneous immunotherapy for 12 months was superior to placebo in desensitizing children to peanuts and increasing the peanut dose that triggered allergic symptoms. (Funded by DBV Technologies; EPITOPE ClinicalTrials.gov number, NCT03211247.).

Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the USA (MUPPITS-2): a randomised, double-blind, placebo-controlled, parallel-group trial.

BACKGROUND: Black and Hispanic children living in urban environments in the USA have an excess burden of morbidity and mortality from asthma. Therapies directed at the eosinophilic phenotype reduce asthma exacerbations in adults, but few data are available in children and diverse populations. Furthermore, the molecular mechanisms that underlie exacerbations either being prevented by, or persisting despite, immune-based therapies are not well understood. We aimed to determine whether mepolizumab, added to guidelines-based care, reduced the number of asthma exacerbations during a 52-week period compared with guidelines-based care alone. METHODS: This is a randomised, double-blind, placebo-controlled, parallel-group trial done at nine urban medical centres in the USA. Children and adolescents aged 6-17 years, who lived in socioeconomically disadvantaged neighbourhoods and had exacerbation-prone asthma (defined as ≥two exacerbations in the previous year) and blood eosinophils of at least 150 cells per µL were randomly assigned 1:1 to mepolizumab (6-11 years: 40 mg; 12-17 years: 100 mg) or placebo injections once every 4 weeks, plus guideline-based care, for 52 weeks. Randomisation was done using a validated automated system. Participants, investigators, and the research staff who collected outcome measures remained masked to group assignments. The primary outcome was the number of asthma exacerbations that were treated with systemic corticosteroids during 52 weeks in the intention-to-treat population. The mechanisms of treatment response were assessed by study investigators using nasal transcriptomic modular analysis. Safety was assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03292588. FINDINGS: Between Nov 1, 2017, and Mar 12, 2020, we recruited 585 children and adolescents. We screened 390 individuals, of whom 335 met the inclusion criteria and were enrolled. 290 met the randomisation criteria, were randomly assigned to mepolizumab (n=146) or placebo (n=144), and were included in the intention-to-treat analysis. 248 completed the study. The mean number of asthma exacerbations within the 52-week study period was 0·96 (95% CI 0·78-1·17) with mepolizumab and 1·30 (1·08-1·57) with placebo (rate ratio 0·73; 0·56-0·96; p=0·027). Treatment-emergent adverse events occurred in 42 (29%) of 146 participants in the mepolizumab group versus 16 (11%) of 144 participants in the placebo group. No deaths were attributed to mepolizumab. INTERPRETATION: Phenotype-directed therapy with mepolizumab in urban children with exacerbation-prone eosinophilic asthma reduced the number of exacerbations. FUNDING: US National Institute of Allergy and Infectious Diseases and GlaxoSmithKline.

Association of mold levels in urban children's homes with difficult-to-control asthma.

BACKGROUND: Mold sensitization and exposure are associated with asthma severity, but the specific species that contribute to difficult-to-control (DTC) asthma are unknown. OBJECTIVE: We sought to determine the association between overall and specific mold levels in the homes of urban children and DTC asthma. METHODS: The Asthma Phenotypes in the Inner-City study recruited participants, aged 6 to 17 years, from 8 US cities and classified each participant as having either DTC asthma or easy-to-control (ETC) asthma on the basis of treatment step level. Dust samples had been collected in each participant's home (n = 485), and any dust remaining (n = 265 samples), after other analyses, was frozen at -20oC. The dust samples (n = 265) were analyzed using quantitative PCR to determine the concentrations of the 36 molds in the Environmental Relative Moldiness Index. Logistic regression was performed to discriminate specific mold content of dust from homes of children with DTC versus ETC asthma. RESULTS: Frozen-dust samples were available from 54% of homes of children with DTC (139 of 253) and ETC asthma (126 of 232). Only the average concentration of the mold Mucor was significantly (P < .001) greater in homes of children with DTC asthma. In homes with window air-conditioning units, the Mucor concentration contributed about a 22% increase (1.6 odds ratio; 95% CI, 1.2-2.2) in the ability to discriminate between cases of DTC and ETC asthma. CONCLUSIONS: Mucor levels in the homes of urban youth were a predictor of DTC asthma, and these higher Mucor levels were more likely in homes with a window air-conditioner.

Seasonal airway microbiome and transcriptome interactions promote childhood asthma exacerbations.

BACKGROUND: Seasonal variation in respiratory illnesses and exacerbations in pediatric populations with asthma is well described, though whether upper airway microbes play season-specific roles in these events is unknown. OBJECTIVE: We hypothesized that nasal microbiota composition is seasonally dynamic and that discrete microbe-host interactions modify risk of asthma exacerbation in a season-specific manner. METHODS: Repeated nasal samples from children with exacerbation-prone asthma collected during periods of respiratory health (baseline; n = 181 samples) or first captured respiratory illness (n = 97) across all seasons, underwent bacterial (16S ribosomal RNA gene) and fungal (internal transcribed spacer region 2) biomarker sequencing. Virus detection was performed by multiplex PCR. Paired nasal transcriptome data were examined for seasonal dynamics and integrative analyses. RESULTS: Upper airway bacterial and fungal microbiota and rhinovirus detection exhibited significant seasonal dynamics. In seasonally adjusted analysis, variation in both baseline and respiratory illness microbiota related to subsequent exacerbation. Specifically, in the fall, when respiratory illness and exacerbation events were most frequent, several Moraxella and Haemophilus members were enriched both in virus-positive respiratory illnesses and those that progressed to exacerbations. The abundance of 2 discrete bacterial networks, characteristically comprising either Streptococcus or Staphylococcus, exhibited opposing interactions with an exacerbation-associated SMAD3 nasal epithelial transcriptional module to significantly increase the odds of subsequent exacerbation (odds ratio = 14.7, 95% confidence interval = 1.50-144, P = .02; odds ratio = 39.17, 95% confidence interval = 2.44-626, P = .008, respectively). CONCLUSIONS: Upper airway microbiomes covary with season and with seasonal trends in respiratory illnesses and asthma exacerbations. Seasonally adjusted analyses reveal specific bacteria-host interactions that significantly increase risk of asthma exacerbation in these children.

Mometasone or Tiotropium in Mild Asthma with a Low Sputum Eosinophil Level.

BACKGROUND: In many patients with mild, persistent asthma, the percentage of eosinophils in sputum is less than 2% (low eosinophil level). The appropriate treatment for these patients is unknown. METHODS: In this 42-week, double-blind, crossover trial, we assigned 295 patients who were at least 12 years of age and who had mild, persistent asthma to receive mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist), or placebo. The patients were categorized according to the sputum eosinophil level (<2% or ≥2%). The primary outcome was the response to mometasone as compared with placebo and to tiotropium as compared with placebo among patients with a low sputum eosinophil level who had a prespecified differential response to one of the trial agents. The response was determined according to a hierarchical composite outcome that incorporated treatment failure, asthma control days, and the forced expiratory volume in 1 second; a two-sided P value of less than 0.025 denoted statistical significance. A secondary outcome was a comparison of results in patients with a high sputum eosinophil level and those with a low level. RESULTS: A total of 73% of the patients had a low eosinophil level; of these patients, 59% had a differential response to a trial agent. However, there was no significant difference in the response to mometasone or tiotropium, as compared with placebo. Among the patients with a low eosinophil level who had a differential treatment response, 57% (95% confidence interval [CI], 48 to 66) had a better response to mometasone, and 43% (95% CI, 34 to 52) had a better response to placebo (P = 0.14). In contrast 60% (95% CI, 51 to 68) had a better response to tiotropium, whereas 40% (95% CI, 32 to 49) had a better response to placebo (P = 0.029). Among patients with a high eosinophil level, the response to mometasone was significantly better than the response to placebo (74% vs. 26%) but the response to tiotropium was not (57% vs. 43%). CONCLUSIONS: The majority of patients with mild, persistent asthma had a low sputum eosinophil level and had no significant difference in their response to either mometasone or tiotropium as compared with placebo. These data provide equipoise for a clinically directive trial to compare an inhaled glucocorticoid with other treatments in patients with a low eosinophil level. (Funded by the National Heart, Lung, and Blood Institute; SIENA ClinicalTrials.gov number, NCT02066298.).

Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma.

BACKGROUND: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients. METHODS: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry. RESULTS: When quintupling the dose of fluticasone (to 250 µg twice a day) was compared with adding salmeterol (50 µg twice a day) and doubling the fluticasone (to 100 µg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age. CONCLUSIONS: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.).

Real world use of peanut component testing among children in the Chicago metropolitan area.

Background: Peanut component tests (PCT) have become important in the evaluation of peanut allergy. There remains a paucity of research across the United States in investigating the utility of PCT in clinical practice in conjunction with current standards of care. Objective: The primary aims were to evaluate the performance and sensitization patterns of PCT in clinical practice when first available at our institution. Methods: We performed a retrospective chart review of 184 children with PCT and oral food challenge (OFC) results between 2012 and 2017. Simple logistic regression models assessed the associations between PCT and OFC outcomes. Receiver operator characteristic curves were constructed, and a predicted probability curve was derived for Ara h2. Results: The median (interquartile range [IQR]) age at OFC was 4 years (2-7 years), and 111 patients (60%) were boys. Ara h 2 was the most commonly sensitized PCT. Sixty-one patients (33%) reacted at OFC. Ara h 2 specific immunoglobulin E (sIgE) ≥ 0.35 kUA/L was associated with increased odds of reacting at OFC (odds ratio 5.91 95% confidence interval, 2.93-11.89; p < 0.001); however, 19 patients (37%) positive for Ara h 2 did not react. Ara h 2 sIgE of 0.49 kUA/L and 4.58 kUA/L were associated with 50% and 90% probability, respectively, of reacting at OFC. Among those sensitized only to Ara h 8 or 9 (n = 21), 86% had no reaction. There was no statistically significant association with polysensitization to Ara h 1, 2, and 3, and peanut OFC outcome. Conclusion: Although the Ara h 2 sIgE value was associated with clinical reactivity, a significant proportion of the patients sensitized to Ara h 2 tolerated peanut. OFC remains an important tool in the evaluation of peanut allergy.

Inducible expression quantitative trait locus analysis of the MUC5AC gene in asthma in urban populations of children.

BACKGROUND: Mucus plugging can worsen asthma control, lead to reduced lung function and fatal exacerbations. MUC5AC is the secretory mucin implicated in mucus plugging, and MUC5AC gene expression has been associated with development of airway obstruction and asthma exacerbations in urban children with asthma. However, the genetic determinants of MUC5AC expression are not established. OBJECTIVES: This study sought to assess single-nucleotide polymorphisms (SNPs) that influence MUC5AC expression and relate to pulmonary functions in childhood asthma. METHODS: This study used RNA-sequencing data from upper airway samples and performed cis-expression quantitative trait loci (eQTL) and allele-specific expression analyses in 2 cohorts of predominantly Black and Hispanic urban children, a high asthma-risk birth cohort, and an exacerbation-prone asthma cohort. Inducible MUC5AC eQTLs were further investigated during incipient asthma exacerbations. Significant eQTLs SNPs were tested for associations with lung function measurements and their functional consequences were investigated in DNA regulatory databases. RESULTS: Two independent groups of SNPs in the MUC5AC gene that were significantly associated with MUC5AC expression were identified. Moreover, these SNPs showed stronger eQTL associations with MUC5AC expression during asthma exacerbations, which is consistent with inducible expression. SNPs in 1 group also showed significant association with decreased pulmonary functions. These SNPs included multiple EGR1 transcription factor binding sites, suggesting a mechanism of effect. CONCLUSIONS: These findings demonstrate the applicability of organ-specific RNA-sequencing data to determine genetic factors contributing to a key disease pathway. Specifically, they suggest important genetic variations that may underlie propensity to mucus plugging in asthma and could be important in targeted asthma phenotyping and disease management strategies.

AR101 Oral Immunotherapy for Peanut Allergy.

BACKGROUND: Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions. METHODS: In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms. RESULTS: Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). During the exit food challenge, the maximum severity of symptoms was moderate in 25% of the participants in the active-drug group and 59% of those in the placebo group and severe in 5% and 11%, respectively. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. Efficacy was not shown in the participants 18 years of age or older. CONCLUSIONS: In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .).

Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations.

BACKGROUND: Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited. METHODS: We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 µg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 µg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids. RESULTS: The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06). CONCLUSIONS: In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129 .).

Coconut allergy: Characteristics of reactions and diagnostic predictors in a pediatric tertiary care center.

BACKGROUND: Little is known on the clinical manifestations of coconut allergy. Our knowledge to date is mainly based on case reports. OBJECTIVE: To characterize the allergic reactions to coconut and suggest diagnostic cutoffs for specific immunoglobulin E (sIgE) and skin prick testing (SPT) to predict clinically reactive coconut allergy. METHODS: Methods include retrospective chart review at an urban tertiary care center of patients with positive testing result for coconut. Probability curves were computed by logistic regression for SPT and coconut sIgE. RESULTS: Of 275 records reviewed, 69 patients reported coconut reactions and 206 were sensitized only or nonallergic. The reactions occurred with breastfeeding (n = 2), contact (n = 10), or oral ingestion (n = 57). Approximately 50% of oral ingestion reactions were associated with mild/moderate anaphylaxis. Clinical reactivity vs sensitization was more common in topical coconut users (2-fold) (P = .02). Although not statistically significant, there was a trend toward more coconut allergy vs sensitization in Asian and African American patients. The probability of allergy with positive SPT result was approximately 50% and with sIgE was approximately 60%. At an SPT of 9 mm wheal or sIgE of 58 kU of allergen/L, there is a 95% probability of reaction. Cosensitization with tree nuts, legumes, and seeds was common. Macadamia nut had the strongest correlation with coconut (r = 0.81, P < .001, n = 101). CONCLUSION: Although the rate of reactivity to coconut in sensitized individuals is low, half of the reactions from consumption met the criteria for anaphylaxis. Clinicians should be aware of the spectrum of reactions and diagnostic use of sIgE and SPT.

Food allergy-related bullying and associated peer dynamics among Black and White children in the FORWARD study.

BACKGROUND: The experiences of Black children with food allergy (FA) are not well characterized, particularly with respect to bullying victimization and other psychosocial outcomes. OBJECTIVE: To evaluate bullying experiences of Black and White children with FA, including associations with peer relationships, anxiety, and school policies. METHODS: Surveys were administered to parents of 252 children with physician-diagnosed FA enrolled in the multisite FORWARD cohort. The surveys assessed demographics, atopic disease, bullying victimization, and school FA management practices and policies. Descriptive statistics of bullying by race were compared by χ2 tests. Multiple logistic regression analyses adjusting for race, age, parental education, household income, child sex, and multi-FA compared adjusted probabilities of bullying victimization by school policies. RESULTS: Nearly 20% of school-aged children were bullied for FA with no substantial racial differences overall, though for children ages 11 years and up, White children reported higher rates of bullying. However, Black children experienced non-FA-related bullying twice as frequently as White children (38.6% vs 17.7%; P = .002). Most of the caregivers (85.7%) who intervened in their child's bullying reported that it was helpful. Among parents, 17.3% reported that they were teased or bullied owing to their child's FA. More than half of the respondents (54.8%) reported that some allergens are banned from their child's school, most typically peanut. In schools banning peanuts, FA-related bullying was less frequently reported by all students who have food allergy. CONCLUSION: Bullying owing to FA is common, and caregivers, medical professionals, and school administrators can help reduce bullying by screening for bullying and supporting and educating school policies.

Long-term, open-label extension study of the efficacy and safety of epicutaneous immunotherapy for peanut allergy in children: PEOPLE 3-year results.

BACKGROUND: The PEPITES (Peanut EPIT Efficacy and Safety) trial, a 12-month randomized controlled study of children with peanut allergy and 4 to 11 years old, previously reported the safety and efficacy of epicutaneous immunotherapy (EPIT) for peanut allergy (250 µg, daily epicutaneous peanut protein; DBV712 250 µg). OBJECTIVE: We sought to assess interim safety and efficacy of an additional 2 years of EPIT from the ongoing (5-year treatment) PEOPLE (PEPITES Open-Label Extension) study. METHODS: Subjects who completed PEPITES were offered enrollment in PEOPLE. Following an additional 2 years of daily DBV712 250 µg, subjects who had received DBV712 250 µg in PEPITES underwent month-36 double-blind, placebo-controlled food challenge with an optional month-38 sustained unresponsiveness assessment. RESULTS: Of 213 eligible subjects who had received DBV712 250 µg in PEPITES, 198 (93%) entered PEOPLE, of whom 141 (71%) had assessable double-blind, placebo-controlled food challenge at month 36. At month 36, 51.8% of subjects (73 of 141) reached an eliciting dose of ≥1000 mg, compared with 40.4% (57 of 141) at month 12; 75.9% (107 of 141) demonstrated increased eliciting dose compared with baseline; and 13.5% (19 of 141) tolerated the full double-blind, placebo-controlled food challenge of 5444 mg. Median cumulative reactive dose increased from 144 to 944 mg. Eighteen subjects underwent an optional sustained unresponsiveness assessment; 14 of those (77.8%) maintained an eliciting dose of ≥1000 mg at month 38. Local patch-site skin reactions were common but decreased over time. There was no treatment-related epinephrine use in years 2 or 3. Compliance was high (96.9%), and withdrawals due to treatment-related adverse events were low (1%). CONCLUSIONS: These results demonstrate that daily EPIT treatment for peanut allergy beyond 1 year leads to continued response from a well-tolerated, simple-to-use regimen.

Multicenter, randomized, double-blind, placebo-controlled clinical trial of vital wheat gluten oral immunotherapy.

BACKGROUND: Wheat is a common food allergen that can cause anaphylaxis. OBJECTIVE: We sought to determine the efficacy and safety of vital wheat gluten (VWG) oral immunotherapy (OIT). METHODS: After baseline double-blind, placebo-controlled food challenge (DBPCFC), 46 patients with wheat allergy (median age, 8.7 years; range, 4.2-22.3 years) were randomized 1:1 to low-dose VWG OIT or placebo, with biweekly escalation to 1445 mg of wheat protein (WP). After a year 1 DBPCFC, active subjects continued low-dose VWG OIT for another year and underwent a year 2 DBPCFC and, if passed, a subsequent off-therapy DBPCFC. Placebo-treated subjects crossed over to high-dose VWG OIT (maximum, 2748 mg of WP). RESULTS: The median baseline successfully consumed dose (SCD) was 43 mg of WP in both groups. At year 1, 12 (52.2%) of 23 low-dose VWG OIT-treated and 0 (0%) of 23 placebo-treated subjects achieved the primary end point of an SCD of 4443 mg of WP or greater (P < .0001); median SCDs were 4443 and 143 mg, respectively. At year 2, 7 (30.4%) of 23 low-dose VWG OIT-treated subjects were desensitized to an SCD of 7443 mg of WP; 3 (13%) achieved sustained unresponsiveness 8 to 10 weeks off therapy. Among placebo-treated subjects who crossed over to high-dose VWG OIT, 12 (57.1%) of 21 were desensitized after 1 year (median SCD, 7443 mg of WP; nonsignificant vs low-dose VWG OIT). At year 1, skin prick test responses and wheat- and omega-5 gliadin-specific IgE levels did not differ between groups; the low-dose VWG OIT median specific IgG4 level was greater than placebo (wheat, P = .0005; omega-5 gliadin, P = .0001). Year 1 SCDs correlated with wheat-specific (rho = 0.55, P = .0003) and omega-5 gliadin-specific (rho = 0.51, P = .001) IgG4 levels in all subjects. Among 7822 low-dose VWG OIT doses in year 1, 15.4% were associated with adverse reactions: 0.04% were severe, and 0.08% subjects received epinephrine. Among 7921 placebo doses, 5.8% were associated with adverse reactions; none were severe. CONCLUSIONS: Low- and high-dose VWG OIT induced desensitization in about one half of the subjects after 1 year of treatment. Two years of low-dose VWG OIT resulted in 30% desensitization, and 13% had sustained unresponsiveness.

A computerized decision support tool to implement asthma guidelines for children and adolescents.

BACKGROUND: Multicenter randomized controlled trials (RCTs) for asthma management that incorporate usual-care regimens could benefit from standardized application of evidence-based guidelines. OBJECTIVE: We sought to evaluate performance of a computerized decision support tool, the Asthma Control Evaluation and Treatment (ACET) Program, to standardize usual-care regimens for asthma management in RCTs. METHODS: Children and adolescents with persistent uncontrolled asthma living in urban census tracts were recruited into 3 multicenter RCTs (each with a usual-care arm) between 2004 and 2014. A computerized decision support tool scored asthma control and assigned an appropriate treatment step based on published guidelines. Control-level determinants (symptoms, rescue medication use, pulmonary function measure, and adherence estimates) were collected at visits and entered into the ACET Program. Changes in control levels and treatment steps were examined during the trials. RESULTS: At screening, more than half of the participants were rated as having symptoms that were not controlled or poorly controlled. The proportion of participants who gained good control between screening and randomization increased significantly in all 3 trials. Between 51% and 70% had symptoms that were well controlled by randomization. The proportion of well-controlled participants remained constant or improved slightly from randomization until the last posttreatment visit. Nighttime symptoms were the most common control-level determinant; there were few (<1%) instances of complete overlap of factors. FEV1 was the driver of control-level assignment in 30% of determinations. CONCLUSION: The ACET Program decision support tool facilitated standardized asthma assessment and treatment in multicenter RCTs and was associated with attaining and maintaining good asthma control in most participants.

Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma.

BACKGROUND: Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking. METHODS: In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial. RESULTS: Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events. CONCLUSIONS: Among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA ClinicalTrials.gov number, NCT01606319.).

Hereditary and acquired angioedema.

Hereditary angioedema (HAE) is an autosomal dominant disorder defined by a deficiency of functional C1 esterase inhibitor (C1-INH). Acquired angioedema is due to either consumption (type 1) or inactivation (type 2) of CI-INH. Both HAE and acquired angioedema can be life-threatening. Of the three types of HAE, type 1 is most common, occurring in approximately 85% of patients and characterized by decreased production of C1-INH, which results in reduced functional activity to 5-40% of normal. Type 2 occurs in 15% of cases; C1-INH is detectable in normal or elevated quantities but is dysfunctional. Also, HAE with normal CI-INH (previously called type 3 HAE) is rare and characterized by normal complement studies. Specific genetic mutations have been linked to factor XII, angiopoietin-1, and plasminogen gene. Patients with unknown mutations are classified as unknown. The screening test for types 1 and 2 is complement component C4, which is low to absent at times of angioedema and during quiescent periods. A useful test to differentiate HAE from acquired angioedema is C1q protein, which is normal in HAE and low in acquired angioedema. The management of HAE has been transformed with the advent of disease-specific therapies. On-demand therapy options include plasma and recombinant C1-INH for intravenous infusion; ecallantide, an inhibitor of kallikrein; and icatibant, a bradykinin ß2 receptor antagonist, both administered subcutaneously. For long-term prophylaxis, intravenous or subcutaneous C1-INH enzyme replacement and lanadelumab, a monoclonal antibody against kallikrein that is administered subcutaneously, are effective agents.

Food allergy: Diagnosis and treatment.

Immunoglobulin E-mediated food reactions usually develop within minutes of food ingestion. Although most reactions are not life-threatening, fatalities do occur. Risk factors for fatal food-induced anaphylaxis include the presence of asthma (a risk factor for anaphylaxis in general), failure to use epinephrine autoinjectors promptly, a history of severe reactions, known food allergy, denial of symptoms, and adolescent and young adult age. The most commonly implicated foods are cow's milk, egg, peanut, soy, tree nuts, fish, shellfish, and wheat. Peanut, tree nuts, and seafood are the most common food allergens in adults, whereas cow's milk, peanut, egg, soy, and wheat are more common in children. The major food allergens are glycoproteins, which are generally water soluble and stable to the effects of heat, proteases, and acids. Recent studies showed that natural tolerance can be acquired at a later age than previously thought, even during adolescence. Allergies to peanut, tree nuts, and seafood are frequently life-long. Patients and their caregivers should be taught when and how to administer injectable epinephrine. In terms of primary prevention, there is evidence that early introduction, followed by ongoing regular consumption of peanut has a protective effect on the development of peanut allergy.

Obstruction phenotype as a predictor of asthma severity and instability in children.

BACKGROUND: Small-airways instability resulting in premature airway closure has been recognized as a risk for asthma severity and poor control. Although spirometry has limited sensitivity for detecting small-airways dysfunction, a focus on the air-trapping component of obstruction might identify a risk factor for asthma instability. OBJECTIVE: We sought to use spirometric measurements to identify patterns of airway obstruction in children and define obstruction phenotypes that relate to asthma instability. METHODS: Prebronchodilation and postbronchodilation spirometric data were obtained from 560 children in the Asthma Phenotypes in the Inner City study. An air-trapping obstruction phenotype (A Trpg) was defined as a forced vital capacity (FVC) z score of less than -1.64 or an increase in FVC of 10% of predicted value or greater with bronchodilation. The airflow limitation phenotype (A Limit) had an FEV1/FVC z score of less than -1.64 but not A Trpg. The no airflow limitation or air-trapping criteria (None) phenotype had neither A Trpg nor A Limit. The 3 obstruction phenotypes were assessed as predictors of number of exacerbations, asthma severity, and airway lability. RESULTS: Patients with the A Trpg phenotype (14% of the cohort) had more exacerbations during the 12-month study compared with those with the A Limit (P < .03) and None (P < .001) phenotypes. Patients with the A Trpg phenotype also had the highest Composite Asthma Severity Index score, the highest asthma treatment step, the greatest variability in FEV1 over time, and the greatest sensitivity to methacholine challenge. CONCLUSIONS: A Trpg and A Limit patterns of obstruction, as defined by using routine spirometric measurements, can identify obstruction phenotypes that are indicators of risk for asthma severity and instability.