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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

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.

Background Knowledge is limited about the relationship between clinical reactivity to foods through breastfeeding and long-term food allergy outcomes. We explored parent-perceived symptoms of food allergy via breastfeeding and the association with future tolerance. Methods Subjects identified from the Chicago Food Allergy Study (2005–2011) were categorized by parent-reported reactions to maternally ingested foods via breastfeeding (50/898 peanut-allergic, 69/620 egg-allergic, and 153/589 milk-allergic). The primary outcome was tolerance [passed oral food challenge (OFC) or consumption of previously implicated food]. Secondary outcomes included severe reactions (anaphylaxis and/or cardiovascular/respiratory symptoms) and additional concomitant food allergies. Univariate chi-square analyses were performed to assess for association between variables, followed by logistic regression models. Results Of the 50 subjects with parent-reported peanut-associated symptoms with breastfeeding, none gained tolerance. There were no significant associations between parent-reported breastfeeding symptoms and development of tolerance for egg and milk (egg: OR 0.46, 95% CI 0.21–1.01, p = 0.053; milk: OR 1.13, 95% CI 0.70–1.81, p = 0.614). All egg-allergic subjects with parent-perceived symptoms while breastfeeding also reported multiple food allergies (n = 69), but milk- and peanut-allergic subjects were not more likely to have multiple allergies (milk: OR 1.89, 95% CI 0.88–4.02, p = 0.10; peanut: OR 2.36, 95% CI 0.72–7.76, p = 0.16). There were no significant associations between parent-reported breastfeeding symptoms and subsequent reaction severity. Conclusions A significant proportion of parents perceive symptoms of food allergy attributable to indirect breastfeeding exposures. Our exploratory analysis suggests that infants with parent-perceived clinical reactivity to peanut via breastmilk may be less likely to gain tolerance. Infants with parent-reported reactivity to egg via breastmilk exposure were more likely to report multiple food allergies. Further rigorous prospective studies are needed to clarify the true prevalence of IgE-mediated food allergy symptoms attributable to indirect breastfeeding exposures and the association with development of tolerance.

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.

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.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.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.Phenotype-directed therapy with mepolizumab in urban children with exacerbation-prone eosinophilic asthma reduced the number of exacerbations.US National Institute of Allergy and Infectious Diseases and GlaxoSmithKline.

BACKGROUND AND OBJECTIVES Inpatient asthma education interventions provide benefit compared with usual care, but evaluation of the most effective educational model is needed. We compared the impact of interactive versus didactic inpatient pediatric asthma education on subsequent emergency department (ED) visits and hospitalizations. METHODS Children (aged 2‒16) with asthma admitted to a tertiary care children’s hospital with an asthma exacerbation between October 2016 and June 2017 were randomly assigned to interactive or didactic (control) asthma education. The primary outcome was asthma ED visits at 6 and 12 months; secondary outcomes included hospitalizations (6 and 12 months), inhaler technique, asthma knowledge, symptoms, quality of life, and parental management skills at baseline, discharge, and/or 12 months. RESULTS One hundred forty participants (69 interactive, 71 control) completed the study. There were no differences in ED visits at 6 or 12 months. Compared to controls, the interactive group had fewer hospitalizations (10.1% vs 22.5%; P = .04) at 6 months. Inhaler technique in the interactive group improved at discharge (mean change 4.07 [95% confidence interval (CI): 3.21–4.94]) and remained increased at 12 months (P = .03). Patient-reported asthma symptoms and quality of life were similar in both groups at baseline (19.9 vs 20.62, best possible score 8) and significantly improved in the interactive group at 12 months (least square mean change, 3.52 vs −1.75; P < .01). CONCLUSIONS There were no differences in ED visits; however, the interactive education reduced asthma hospitalizations over a 6-month period. These findings demonstrate that educational delivery methods can play a role in improving clinical outcomes for asthma.

Asthma prevalence and severity have markedly increased with urbanisation, and children in low-income urban centres have among the greatest asthma morbidity. Outdoor air pollution has been associated with adverse respiratory effects in children with asthma. However, the mechanisms by which air pollution exposure exacerbates asthma, and how these mechanisms compare with exacerbations induced by respiratory viruses, are poorly understood. We aimed to investigate the associations between regional air pollutant concentrations, respiratory illnesses, lung function, and upper airway transcriptional signatures in children with asthma, with particular focus on asthma exacerbations occurring in the absence of respiratory virus.We performed a retrospective analysis of data from the MUPPITS1 cohort and validated our findings in the ICATA cohort. The MUPPITS1 cohort recruited 208 children aged 6-17 years living in urban areas across nine US cities with exacerbation-prone asthma between Oct 7, 2015, and Oct 18, 2016, and monitored them during reported respiratory illnesses. The last MUPPITS1 study visit occurred on Jan 6, 2017. The ICATA cohort recruited 419 participants aged 6-20 years with persistent allergic asthma living in urban sites across eight US cities between Oct 23, 2006, and March 25, 2008, and the last study visit occurred on Dec 30, 2009. We included participants from the MUPPITS1 cohort who reported a respiratory illness at some point during the follow-up and participants from the ICATA cohort who had nasal samples collected during respiratory illness or at a scheduled visit. We used air quality index values and air pollutant concentrations for PMOf the 208 participants from the MUPPITS1 cohort and 419 participants from the ICATA cohort, 168 participants in the MUPPITS1 cohort (98 male participants and 70 female participants) and 189 participants in the ICATA cohort (115 male participants and 74 female participants) were included in our analysis. We identified that increased air quality index values, driven predominantly by increased PMOur findings suggest that air pollution is an important independent risk factor for asthma exacerbations in children living in urban areas and is potentially linked to exacerbations through specific inflammatory pathways in the airway. Further investigation of these potential mechanistic pathways could inform asthma prevention and management approaches.National Institutes of Health, National Institute of Allergy and Infectious Diseases.

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 β2 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.

Background In infants, distinct nasopharyngeal bacterial microbiotas differentially associate with the incidence and severity of acute respiratory tract infection and childhood asthma development. Objective We hypothesized that distinct nasal airway microbiota structures also exist in children with asthma and relate to clinical outcomes. Methods Nasal secretion samples (n = 3122) collected after randomization during the fall season from children with asthma (6-17 years, n = 413) enrolled in a trial of omalizumab (anti-IgE) underwent 16S rRNA profiling. Statistical analyses with exacerbation as the primary outcome and rhinovirus infection and respiratory illnesses as secondary outcomes were performed. Using A549 epithelial cells, we assessed nasal isolates of Moraxella, Staphylococcus, and Corynebacterium species for their capacity to induce epithelial damage and inflammatory responses. Results Six nasal airway microbiota assemblages, each dominated by Moraxella, Staphylococcus, Corynebacterium, Streptococcus, Alloiococcus, or Haemophilus species, were observed. Moraxella and Staphylococcus species–dominated microbiotas were most frequently detected and exhibited temporal stability. Nasal microbiotas dominated by Moraxella species were associated with increased exacerbation risk and eosinophil activation. Staphylococcus or Corynebacterium species–dominated microbiotas were associated with reduced respiratory illness and exacerbation events, whereas Streptococcus species–dominated assemblages increased the risk of rhinovirus infection. Nasal microbiota composition remained relatively stable despite viral infection or exacerbation; only a few taxa belonging to the dominant genera exhibited relative abundance fluctuations during these events. In vitro, Moraxella catarrhalis induced significantly greater epithelial damage and inflammatory cytokine expression (IL-33 and IL-8) compared with other dominant nasal bacterial isolates tested. Conclusion Distinct nasal airway microbiotas of children with asthma relate to the likelihood of exacerbation, rhinovirus infection, and respiratory illnesses during the fall season.

BACKGROUND Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent. METHODS We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 μg in children, 100 μg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV1. We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 μg twice daily in children and 500 μg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 μg twice daily in children, 250 μg twice daily in adolescents and adults), and 5 × ICS versus 100 μg fluticasone plus a LABA (salmeterol 50 μg twice daily). We used a genome-wide significance threshold of p

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: 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 (APIC) study recruited participants, 6 to 17 years of age, from eight US cities and classified each participant as having either DTC asthma or easy-to-control (ETC) asthma based on 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, were frozen at −20°C. The dust samples (n=265) were analyzed using qPCR to determine the concentrations of the 36 molds in the Environmental Relative Moldiness Index (ERMI). 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 (139/253) and ETC asthma (126/232). Only the average concentration of the mold Mucor was significantly (p

Background Characterization of allergic responses to cockroach (CR), a common aeroallergen associated with asthma, has focused mainly on IgE reactivity, but little is known about T cell responses, particularly in children. We conducted a functional evaluation of CR allergen‐specific T cell reactivity in a cohort of CR allergic children with asthma. Methods Peripheral blood mononuclear cells (PBMCs) were obtained from 71 children, with mild‐to‐moderate asthma who were enrolled in a CR immunotherapy (IT) clinical trial, prior to treatment initiation. PBMC were stimulated with peptide pools derived from 11 CR allergens, and CD4+ T cell responses assessed by intracellular cytokine staining. Results Highly heterogeneous responses in T cell reactivity were observed among participants, both in terms of the magnitude of cytokine response and allergen immunodominance. Reactivity against Bla g 9 and Bla g 5 was most frequent. The phenotype of the T cell response was dominated by IL‐4 production and a Th2 polarized profile in 54.9% of participants, but IFNγ production and Th1 polarization was observed in 25.3% of the participants. The numbers of regulatory CD4+ T cells were also highly variable and the magnitude of effector responses and Th2 polarization were positively correlated with serum IgE levels specific to a clinical CR extract. Conclusions Our results demonstrate that in children with mild‐to‐moderate asthma, CR‐specific T cell responses display a wide range of magnitude, allergen dominance, and polarization. These results will enable examination of whether any of the variables measured are affected by IT and/or are predictive of clinical outcomes.

Background Treatment options for peanut allergy are limited. In previous clinical trials, epicutaneous immunotherapy with a patch containing 250-μg peanut protein (Viaskin™ Peanut 250 μg [VP250]) was well tolerated and statistically superior to placebo in desensitizing peanut-allergic children. Objective To examine the safety of VP250 in children, using a study design approximating potential real-world use. Methods REALISE is a phase 3 multicenter study consisting of a 6-month, randomized, double-blind, placebo-controlled period followed by open-label active treatment. Children aged 4 to 11 years with physician diagnosis of peanut allergy received daily treatment with placebo (6 months) or VP250 (up to 36 months). Data from the 6-month, randomized, controlled phase of REALISE are reported. Results Three hundred ninety-three children were randomized 3:1 to receive VP250 (n=294) or placebo (n=99) for 6 months; 284 (72.3%) children had a history of peanut anaphylaxis. According to parent diary, all participants receiving VP250 and 83.8% receiving placebo reported at least 1 episode of local skin reaction, with frequency decreasing over time. Only 4 participants (1.4%) receiving VP250 discontinued due to adverse events. Epinephrine was administered for allergic reactions attributed to VP250 in 7 children (2.4%), of whom 5 remained in the study; none involved severe anaphylaxis. Overall adverse event rates were similar among participants with and without history of peanut anaphylaxis. Conclusions In a study designed to mirror real-world use, VP250 was observed to be well tolerated in peanut-allergic children, consistent with previous phase 2b and 3 studies.

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.

Background Evidence suggests early oral introduction of peanut prevents peanut allergy, particularly in a high risk infant population. Despite early oral introduction guidelines, there will continue to be infants and young children who develop peanut allergy. Current testing modalities utilized for evaluation of peanut allergy have poor positive predictive value, particularly when applied to patients with no history of oral exposure to peanut. The oral food challenge is a procedure conducted to confirm a food allergy diagnosis. This procedure is not without risk and has particular unique challenges in the younger patient population. Objective We sought to identify key differentially expressed genes that may distinguish peanut allergic infants among those at high risk for peanut allergy. Methods Twenty infants aged 4-11 months with egg allergy and/or severe atopic dermatitis (i.e. high risk) were prospectively recruited from a tertiary care clinic. Infants were classified as peanut allergic, peanut sensitized, but tolerant, or peanut non-allergic based on clinical history, skin prick testing, specific IgE, and/or oral food challenge. RNA was isolated from whole blood and samples underwent RNA-seq library preparation and sequencing. Differential expression analysis was performed. Results Eight genes were differentially expressed in peanut sensitized, but tolerant subjects compared to the peanut non-allergic subjects. Four genes were differentially expressed in peanut allergic versus peanut non-allergic subjects and in peanut allergic versus peanut sensitized, but tolerant subjects. Conclusion Differential gene expression in whole peripheral blood was identified between these three groups of high risk infants, however, whole blood may not be an optimal biospecimen for detection of relevant, subtle gene expression changes.

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 (

BACKGROUND: Multi-center randomized controlled trials (RCTs) for asthma management that incorporate usual care regimens could benefit from standardized application of evidence-based guidelines. OBJECTIVE: To evaluate performance of a computerized decision support tool, 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 multi-center 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, adherence estimates) were collected at visits and entered into the ACET Program. Changes in control level and treatment steps were examined during the trials. RESULTS: At screening, over half the participants were rated as not or poorly controlled. The proportion of participants who gained good control between screening and randomization increased significantly in all three trials. Between 51% and 70% were well-controlled by randomization. The proportion of well-controlled participants remained constant or improved slightly from randomization until the last post-treatment visit. Night symptoms were the most common control level determinant; there were few (

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. Respiratory infections are the principal cause of asthma exacerbations in children. Altman and colleagues use a systems approach to describe the pathways associated with asthma exacerbations in a cohort of inner-city children.

Background: As there is limited data on the sustainability of desensitization of multifood-oral immunotherapy (multifood-OIT), we conducted a multisite multifood-OIT study to compare the efficacy of successful desensitization with sustained dosing vs discontinued dosing after multifood-OIT. Methods: We enrolled 70 participants, aged 5–22 years with multiple food allergies confirmed by double-blind placebo-controlled food challenges (DBPCFCs). In the open-label phase of the study, all participants received omalizumab (weeks 1–16) and multi-OIT (2–5 allergens; weeks 8–30) and eligible participants (on maintenance dose of each allergen by weeks 28–29) were randomized 1:1:1 to 1 g, 300 mg, or 0 mg arms (blinded, weeks 30–36) and then tested by food challenge at week 36. Success was defined as passing 2 g food challenge to at least 2 foods in week 36. Findings: Most participants were able to reach a dose of 2 g or higher of each of 2, 3, 4, and 5 food allergens (as applicable to the participant's food allergens in OIT) in week 36 food challenges. Using an intent-to-treat analysis, we did not find evidence that a 300 mg dose was effectively different than a 1 g dose in maintaining desensitization, and both together were more effective than OIT discontinuation (0 mg dose) (85% vs 55%, P = 0.03). Fifty-five percent of the intent-to-treat participants and 69% of per protocol participants randomized to the 0 mg arm showed no objective reactivity after 6 weeks of discontinuation. Cross-desensitization was found between cashew/pistachio and walnut/pecan when only one of the foods was part of OIT. No statistically significant safety differences were found between the three arms. Interpretation: These results suggest that sustained desensitization after omalizumab-facilitated multi-OIT best occurs through continued maintenance OIT dosing of either 300 mg or 1 g of each food allergen as opposed to discontinuation of multi-OIT. Funding: Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Jeff and MacKenzie Bezos, NIAID AADCRC U19AI104209. Trial Registration Number: ClinicalTrials.gov number, NCT02626611. Keywords: Food allergy, Oral immunotherapy, Omalizumab, Sustained unresponsiveness, Food allergen

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; PCONCLUSIONS: 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 .).

Rationale: Rhinovirus (RV) C can cause asymptomatic infection and respiratory illnesses ranging from the common cold to severe wheezing. Objectives: To identify how age and other individual-level factors are associated with susceptibility to RV-C illnesses. Methods: Longitudinal data from the COAST (Childhood Origins of Asthma) birth cohort study were analyzed to determine relationships between age and RV-C infections. Neutralizing antibodies specific for RV-A and RV-C (three types each) were determined using a novel PCR-based assay. Data were pooled from 14 study cohorts in the United States, Finland, and Australia, and mixed-effects logistic regression was used to identify factors related to the proportion of RV-C versus RV-A detection. Measurements and Main Results: In COAST, RV-A and RV-C infections were similarly common in infancy, whereas RV-C was detected much less often than RV-A during both respiratory illnesses and scheduled surveillance visits (P

Despite major differences in health profiles and rates of health care utilization between African American and White children with food allergy (FA), the detailed phenotypic variables that can potentially impact these outcomes have not been thoroughly studied.We aimed to characterize phenotypic differences such as allergies to different foods and allergic comorbidities between African American and White children with FA enrolled in the Food Allergy Outcomes Related to White and African American Racial Differences study.Our active, prospective, multicenter cohort study is currently enrolling African American and White children aged 0 to 12 years diagnosed with FA and followed by allergy/immunology clinics at 4 urban tertiary centers in the United States. To evaluate associations between race and phenotypic variables, we used multivariable logistic regression, adjusting for important demographic and confounding factors, as well as potential household clustering.As of May 2020, there were 239 African Americans and 425 Whites with complete intake information enrolled in the study. In comparison with Whites, we found that African Americans had significantly higher adjusted odds of allergy to finfish (odds ratio [OR]: 2.54, P.01) and shellfish (OR: 3.10, P .001). African Americans also had higher adjusted odds of asthma than Whites (asthma prevalence of 60.5% in African Americans and 27.2% in Whites; OR: 2.70, P.001). In addition, shellfish allergy was associated with asthma, after controlling for race.Among a diverse cohort of children with physician-diagnosed FA, we observed that African American children had higher odds of allergy to shellfish and finfish, and higher rates of asthma. Interestingly, having asthma was independently associated with allergy to shellfish, after controlling for race.

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.

Asthma remains one of the most important challenges to pediatric public health in the US. A large majority of children with persistent and chronic asthma demonstrate aeroallergen sensitization, which remains a pivotal risk factor associated with the development of persistent, progressive asthma throughout life. In individuals with a tendency toward Type 2 inflammation, sensitization and exposure to high concentrations of offending allergens is associated with increased risk for development of, and impairment from, asthma. The cascade of biological responses to allergens is primarily mediated through IgE antibodies and their production is further stimulated by IgE responses to antigen exposure. In addition, circulating IgE impairs innate anti-viral immune responses. The latter effect could magnify the effects of another early life exposure associated with increased risk of the development of asthma – viral infections. Omalizumab binds to circulating IgE and thus ablates antigen signaling through IgE-related mechanisms. Further, it has been shown restore IFN-α response to rhinovirus and to reduce asthma exacerbations during the viral season. We therefore hypothesized that early blockade of IgE and IgE mediated responses with omalizumab would prevent the development and reduce the severity of asthma in those at high risk for developing asthma. Herein, we describe a double-blind, placebo-controlled trial of omalizumab in 2–3 year old children at high risk for development of asthma to prevent the development and reduce the severity of asthma. We describe the rationale, methods, and lessons learned in implementing this potentially transformative trial aimed at prevention of asthma.

The oral food challenge (OFC) is the criterion standard for diagnosing food allergy, but prior studies indicate many allergists may not be using OFCs for various reasons. To better understand current OFC trends, practices, and barriers, the American Academy of Allergy Asthma and Immunology (AAAAI) Adverse Reactions to Foods Committee subcommittee updated a 19-item survey (previously administered in 2009) and sent it to AAAAI and American College of Allergy, Asthma, and Immunology (ACAAI) membership. There were a total of 546 respondents who represented approximately a 10% response rate. Among the 546 respondents, compared with 2009, significantly more providers offer OFCs (95% vs 84.5%), offer10 OFCs per month (17% vs 5.6%), obtain informed consent (82.2% vs 53.6%), and performed OFCs in fellowship (71% vs 45%) (all P.001). Fellowship OFC training was limited, with 56% performing10 OFCs in fellowship and 29% performing none. Although 94% see patients12 months of age, 35.5% do not offer OFCs for early peanut introduction. Although 79% dedicate a supervising medical provider (MD, NP, PA) and 86% have a written OFC protocol, only 60% had a standardized reaction treatment protocol and 56% prepared emergency medications before OFC. Compared with 2009, there was significant worsening of perceived barriers to performing OFCs, including time (65.6% vs 55%), space (55.3% vs 27.1%), staffing (59.6% vs 44.3%), experience (16.9% vs 11.5%), and hospital proximity (10.9% vs 7.9%), though reimbursement as a barrier improved (45.9% vs 53.7%) (all P.01). Compared with 2009, although more providers offer OFCs, multiple perceived barriers to performing OFCs have worsened. Hesitancy to challenge infants and emergency preparedness issues are emerging potential concerns.

Background Compared with adults, phenotypic characterization of children with asthma is still limited and it remains difficult to predict which children with asthma are at highest risk for poor outcomes. Objective To identify latent classes in a large population of treatment-adherent children with mild to moderate asthma enrolled in clinical trials and determine whether latent class assignment predicts future lung function abnormalities and exacerbation rate. Methods Latent class analysis was performed on 2593 children with mild to moderate asthma aged 5 18 years, with 19 variables encompassing demographic characteristics, medical history, symptoms, lung function, allergic sensitization, and type 2 inflammation. Outcomes included lung function and the annualized exacerbation rate at 12 months of follow-up. Results Five latent classes were identified with differing demographic features, asthma control, sensitization, type 2 inflammatory markers, and lung function. Exacerbation rates were 1.30 ± 0.12 for class 1 (multiple sensitization with partially reversible airflow limitation), 0.90 ± 0.05 for class 2 (multiple sensitization with reversible airflow limitation), 0.87 ± 0.08 for class 3 (lesser sensitization with reversible airflow limitation), 0.87 ± 0.05 for class 4 (multiple sensitization with normal lung function), and 0.71 ± 0.06 for class 5 (lesser sensitization with normal lung function). Lung function abnormalities persisted in class 1 at 12 months. Conclusions Children with mild to moderate asthma are a heterogeneous group. Allergic sensitization and lung function may be particularly useful in identifying children at the greatest risk for future exacerbation. Additional studies are needed to determine whether latent classes correspond to meaningful phenotypes for the purpose of personalized 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.

Summary Peanut allergy can result in life-threatening reactions and is a major public health concern. Oral immunotherapy (OIT) induces desensitization to food allergens through administration of increasing amounts of allergen. To dissect peanut-specific immunoglobulin E (IgE) and IgG responses in subjects undergoing OIT, we have developed AllerScan, a method that leverages phage-display and next-generation sequencing to identify the epitope targets of peanut-specific antibodies. We observe a striking diversification and boosting of the peanut-specific IgG repertoire after OIT and a reduction in pre-existing IgE levels against individual epitopes. High-resolution epitope mapping reveals shared recognition of public epitopes in Ara h 1, 2, 3, and 7. In individual subjects, OIT-induced IgG specificities overlap extensively with IgE and exhibit strikingly similar antibody footprints, suggesting related clonal lineages or convergent evolution of peanut-specific IgE and IgG B cells. Individual differences in epitope recognition identified via AllerScan could inform safer and more effective personalized immunotherapy., Graphical abstract, Highlights • Phage immunoprecipitation sequencing simultaneously maps IgE and IgG peanut epitopes • Ara h 1, 2, 3, and 7 epitopes are highly shared among allergic individuals • High-resolution epitope mapping is achieved by saturation mutagenesis • Oral immunotherapy induces IgG specificities overlapping with pre-existing IgE, Chen et al. use a phage-display-based method to simultaneously map IgE and IgG epitopes in peanut-allergic patients undergoing oral immunotherapy (OIT). They identify shared epitopes and potentially therapeutically relevant individual differences in epitope recognition. OIT boosts and diversifies IgG responses that overlap with IgE, often with similar critical residues.

Background: Racial differences in food allergy outcomes exist. Objectives: Our aim is to characterize phenotypic differences between black and white children with food allergy (FA). Methods: We are conducting a prospective multi-center cohort study enrolling African-American (AA) or Caucasian (W) children aged 0-12 years diagnosed with …

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 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.

Background The randomized, controlled PALISADE trial demonstrated the benefit of daily oral immunotherapy with Peanut (Arachis Hypogaea) allergen powder-dnfp (PTAH, formerly AR101) in peanut-allergic children and adolescents. Objective ARC004, the open-label follow-on study to PALISADE, used 5 dosing cohorts to explore PTAH treatment beyond 1 year and alternative dosing regimens in peanut-allergic individuals. Methods Active arm (PTAH-continuing) PALISADE participants who tolerated 300-mg peanut protein at the exit double-blind placebo-controlled food challenge and placebo arm (PTAH-naive) participants could enter ARC004. PTAH-continuing participants were assigned to receive daily (cohorts 1 and 3A) or non–daily (cohorts 2, 3B, and 3C) dosing regimens; PTAH-naive participants were built up to 300 mg/d PTAH, followed by maintenance dosing. At study completion, participants underwent an exit double-blind placebo-controlled food challenge with doses up to 2000 mg peanut protein. Data were assessed using descriptive statistics. Results Overall, 358 (87.5%) eligible participants (4-17 years) entered ARC004 (PTAH-continuing, n = 256; PTAH-naive, n = 102). Among PTAH-continuing participants, exposure-adjusted adverse event rates were 12.94 to 17.54/participant-year and 25.95 to 42.49/participant-year in daily and non–daily dosing cohorts, respectively; most participants (83%) experienced mild or moderate adverse events. Daily dosing cohorts appeared to have higher desensitization rates than non–daily dosing cohorts. Of all PTAH-continuing cohorts, cohort 3A had the longest daily dosing duration and the highest desensitization rates. Changes in immune markers with PTAH continuation demonstrated ongoing immunomodulation. Outcomes in PTAH-naive participants mirrored those of the PALISADE active arm. Conclusions Continued daily PTAH treatment beyond 1 year showed sustained safety and efficacy. Ongoing immunomodulation was observed during the second year of treatment.

Background Circadian rhythms underlie many immune responses and allergic diseases. Subcutaneous immunotherapy (SCIT) can result in adverse reactions; however, it is unclear whether such reactions have a diurnal pattern. Objective To assess whether the timing of SCIT affects the rate of adverse reactions. Methods This study was a retrospective medical record review of adult patients (n = 289) who received SCIT at the Northwestern Medical Faculty Foundation, Chicago, Illinois, during a 10-year period (2004–2014). Injections were given in the outpatient setting. There were a total of 17,457 injections with 574 reactions. Covariates included age, sex, median income, asthma status, vial contents, number of injections, and previous immunotherapy reactions. Logistical regression was used to calculate the odds of having a reaction with time of SCIT administration as the primary determinate. Results Immunotherapy reactions occurred more frequently after afternoon or evening (pm) injections (328/8721 = 3.8%) vs morning (am) injections (246/8736 = 2.8%), (χ 2 = 12.26, P 2 = 0.08; P = .77). pm injections resulted in higher odds of reaction compared with am injection in a fully adjusted logistic regression model (odds ratio = 1.43; 95% confidence interval, 1.20–1.70; P P Conclusion pm injections of SCIT are associated with increased cutaneous reaction rates when compared with am injections. In patients experiencing bothersome local reactions, it may be beneficial to administer SCIT in the morning.

Background Childhood food allergy and asthma rates are increasing. The hygiene hypothesis has been proposed as an explanation for the increased incidence of allergic disease. Objective To describe the association of childhood food allergy and asthma with hygiene factors, such as the number of siblings, antibiotic use, infection history, pet exposure, child care exposure, and maternalchild factors. Methods Children ages 021 years old (N = 1359) were recruited for a cross-sectional family-based study, including children with food allergy and children without food allergy, and their siblings. We assessed the associations between childhood food allergy and asthma with hygiene factors. Results Of the 1359 children, 832 (61.2%) had food allergy, and 406 (30%) had asthma. In the adjusted analysis, the prevalence of food allergy was increased if there was a history of skin infection (prevalence ratio [RRR] 1.12 [95% confidence interval {CI}, 1.011.24]) or eczema (RRR 1.89 [95% CI, 1.702.10]). The prevalence of asthma was increased with a history of respiratory syncytial virus infection (RRR 1.60 [95% CI, 1.341.90]) or eczema (RRR 1.54 [95% CI, 1.271.86]). A greater number of siblings were associated with a decreased prevalence of food allergy (RRR 0.79 [95% CI, 0.750.84]) and asthma (RRR 0.82 [95% CI, 0.740.91]). Conclusion Our findings supported the accumulating evidence of an association between skin infections and eczema with food allergy. Because these results could be subject to recall bias, additional prospective studies are needed to substantiate these findings.

Background Children with asthma in low-income urban areas have high morbidity. Phenotypic analysis in these children is lacking, but may identify characteristics to inform successful tailored management approaches. Objective We sought to identify distinct asthma phenotypes among inner-city children receiving guidelines-based management. Methods Nine inner-city asthma consortium centers enrolled 717 children aged 6 to 17 years. Data were collected at baseline and prospectively every 2 months for 1 year. Participants' asthma and rhinitis were optimally managed by study physicians on the basis of guidelines. Cluster analysis using 50 baseline and 12 longitudinal variables was performed in 616 participants completing 4 or more follow-up visits. Results Five clusters (designated A through E) were distinguished by indicators of asthma and rhinitis severity, pulmonary physiology, allergy (sensitization and total serum IgE), and allergic inflammation. In comparison to other clusters, cluster A was distinguished by lower allergy/inflammation, minimally symptomatic asthma and rhinitis, and normal pulmonary physiology. Cluster B had highly symptomatic asthma despite high step-level treatment, lower allergy and inflammation, and mildly altered pulmonary physiology. Cluster C had minimally symptomatic asthma and rhinitis, intermediate allergy and inflammation, and mildly impaired pulmonary physiology. Clusters D and E exhibited progressively higher asthma and rhinitis symptoms and allergy/inflammation. Cluster E had the most symptomatic asthma while receiving high step-level treatment and had the highest total serum IgE level (median, 733 kU/L), blood eosinophil count (median, 400 cells/mm 3 ), and allergen sensitizations (15 of 22 tested). Conclusions Allergy distinguishes asthma phenotypes in urban children. Severe asthma often coclusters with highly allergic children. However, a symptomatic phenotype with little allergy or allergic inflammation was identified.

Background Treatment levels required to control asthma vary greatly across a population with asthma. The factors that contribute to variability in treatment requirements of inner-city children have not been fully elucidated. Objective We sought to identify the clinical characteristics that distinguish difficult-to-control asthma from easy-to-control asthma. Methods Asthmatic children aged 6 to 17 years underwent baseline assessment and bimonthly guideline-based management visits over 1 year. Difficult-to-control and easy-to-control asthma were defined as daily therapy with 500 μg of fluticasone or greater with or without a long-acting β-agonist versus 100 μg or less assigned on at least 4 visits. Forty-four baseline variables were used to compare the 2 groups by using univariate analyses and to identify the most relevant features of difficult-to-control asthma by using a variable selection algorithm. Nonlinear seasonal variation in longitudinal measures (symptoms, pulmonary physiology, and exacerbations) was examined by using generalized additive mixed-effects models. Results Among 619 recruited participants, 40.9% had difficult-to-control asthma, 37.5% had easy-to-control asthma, and 21.6% fell into neither group. At baseline, FEV 1 bronchodilator responsiveness was the most important characteristic distinguishing difficult-to-control asthma from easy-to-control asthma. Markers of rhinitis severity and atopy were among the other major discriminating features. Over time, difficult-to-control asthma was characterized by high exacerbation rates, particularly in spring and fall; greater daytime and nighttime symptoms, especially in fall and winter; and compromised pulmonary physiology despite ongoing high-dose controller therapy. Conclusions Despite good adherence, difficult-to-control asthma showed little improvement in symptoms, exacerbations, or pulmonary physiology over the year. In addition to pulmonary physiology measures, rhinitis severity and atopy were associated with high-dose asthma controller therapy requirement.

Background Pathway analyses can be used to determine how host and environmental factors contribute to asthma severity. Objective To investigate pathways explaining asthma severity in inner-city children. Methods On the basis of medical evidence in the published literature, we developed a conceptual model to describe how 8 risk-factor domains (allergen sensitization, allergic inflammation, pulmonary physiology, stress, obesity, vitamin D, environmental tobacco smoke [ETS] exposure, and rhinitis severity) are linked to asthma severity. To estimate the relative magnitude and significance of hypothesized relationships among these domains and asthma severity, we applied a causal network analysis to test our model in an Inner-City Asthma Consortium study. Participants comprised 6- to 17-year-old children (n = 561) with asthma and rhinitis from 9 US inner cities who were evaluated every 2 months for 1 year. Asthma severity was measured by a longitudinal composite assessment of day and night symptoms, exacerbations, and controller usage. Results Our conceptual model explained 53.4% of the variance in asthma severity. An allergy pathway (linking allergen sensitization, allergic inflammation, pulmonary physiology, and rhinitis severity domains to asthma severity) and the ETS exposure pathway (linking ETS exposure and pulmonary physiology domains to asthma severity) exerted significant effects on asthma severity. Among the domains, pulmonary physiology and rhinitis severity had the largest significant standardized total effects on asthma severity (−0.51 and 0.48, respectively), followed by ETS exposure (0.30) and allergic inflammation (0.22). Although vitamin D had modest but significant indirect effects on asthma severity, its total effect was insignificant (0.01). Conclusions The standardized effect sizes generated by a causal network analysis quantify the relative contributions of different domains and can be used to prioritize interventions to address asthma severity.

Serum IL-6 was associated with asthma exacerbation risk but not with symptoms or lung function in urban children; further studies to evaluate the role of IL-6 in the life course of asthma are needed.