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Abstract Rationale T-helper type 2 (Th2) inflammation, mediated by IL-4, IL-5, and IL-13, is considered the central molecular mechanism underlying asthma, and Th2 cytokines are emerging therapeutic targets. However, clinical studies increasingly suggest that asthma is heterogeneous. Objectives To determine whether this clinical heterogeneity reflects heterogeneity in underlying molecular mechanisms related to Th2 inflammation. Methods Using microarray and polymerase chain reaction analyses of airway epithelial brushings from 42 patients with mild-to-moderate asthma and 28 healthy control subjects, we classified subjects with asthma based on high or low expression of IL-13–inducible genes. We then validated this classification and investigated its clinical implications through analyses of cytokine expression in bronchial biopsies, markers of inflammation and remodeling, responsiveness to inhaled corticosteroids, and reproducibility on repeat examination. Measurements and Main Results Gene expression analyses identified two evenly sized and distinct subgroups, “Th2-high” and “Th2-low” asthma (the latter indistinguishable from control subjects). These subgroups differed significantly in expression of IL-5 and IL-13 in bronchial biopsies and in airway hyperresponsiveness, serum IgE, blood and airway eosinophilia, subepithelial fibrosis, and airway mucin gene expression (all P < 0.03). The lung function improvements expected with inhaled corticosteroids were restricted to Th2-high asthma, and Th2 markers were reproducible on repeat evaluation. Conclusions Asthma can be divided into at least two distinct molecular phenotypes defined by degree of Th2 inflammation. Th2 cytokines are likely to be a relevant therapeutic target in only a subset of patients with asthma. Furthermore, current models do not adequately explain non–Th2-driven asthma, which represents a significant proportion of patients and responds poorly to current therapies.

Abstract Rationale Bronchial thermoplasty (BT) is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle. Objectives To evaluate the effectiveness and safety of BT versus a sham procedure in subjects with severe asthma who remain symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting β2-agonists. Methods A total of 288 adult subjects (Intent-to-Treat [ITT]) randomized to BT or sham control underwent three bronchoscopy procedures. Primary outcome was the difference in Asthma Quality of Life Questionnaire (AQLQ) scores from baseline to average of 6, 9, and 12 months (integrated AQLQ). Adverse events and health care use were collected to assess safety. Statistical design and analysis of the primary endpoint was Bayesian. Target posterior probability of superiority (PPS) of BT over sham was 95%, except for the primary endpoint (96.4%). Measurements and Main Results The improvement from baseline in the integrated AQLQ score was superior in the BT group compared with sham (BT, 1.35 ± 1.10; sham, 1.16 ± 1.23 [PPS, 96.0% ITT and 97.9% per protocol]). Seventy-nine percent of BT and 64% of sham subjects achieved changes in AQLQ of 0.5 or greater (PPS, 99.6%). Six percent more BT subjects were hospitalized in the treatment period (up to 6 wk after BT). In the posttreatment period (6–52 wk after BT), the BT group experienced fewer severe exacerbations, emergency department (ED) visits, and days missed from work/school compared with the sham group (PPS, 95.5, 99.9, and 99.3%, respectively). Conclusions BT in subjects with severe asthma improves asthma-specific quality of life with a reduction in severe exacerbations and healthcare use in the posttreatment period. Clinical trial registered with www.clinialtrials.gov (NCT00231114).

Abstract Rationale Maternal vitamin D intake during pregnancy has been inversely associated with asthma symptoms in early childhood. However, no study has examined the relationship between measured vitamin D levels and markers of asthma severity in childhood. Objectives To determine the relationship between measured vitamin D levels and both markers of asthma severity and allergy in childhood. Methods We examined the relation between 25-hydroxyvitamin D levels (the major circulating form of vitamin D) and markers of allergy and asthma severity in a cross-sectional study of 616 Costa Rican children between the ages of 6 and 14 years. Linear, logistic, and negative binomial regressions were used for the univariate and multivariate analyses. Measurements and Main Results Of the 616 children with asthma, 175 (28%) had insufficient levels of vitamin D (<30 ng/ml). In multivariate linear regression models, vitamin D levels were significantly and inversely associated with total IgE and eosinophil count. In multivariate logistic regression models, a log10 unit increase in vitamin D levels was associated with reduced odds of any hospitalization in the previous year (odds ratio [OR], 0.05; 95% confidence interval [CI], 0.004–0.71; P = 0.03), any use of antiinflammatory medications in the previous year (OR, 0.18; 95% CI, 0.05–0.67; P = 0.01), and increased airway responsiveness (a ≤8.58-μmol provocative dose of methacholine producing a 20% fall in baseline FEV1 [OR, 0.15; 95% CI, 0.024–0.97; P = 0.05]). Conclusions Our results suggest that vitamin D insufficiency is relatively frequent in an equatorial population of children with asthma. In these children, lower vitamin D levels are associated with increased markers of allergy and asthma severity.

Abstract Rationale Virus-induced wheezing episodes in infancy often precede the development of asthma. Whether infections with specific viral pathogens confer differential future asthma risk is incompletely understood. Objectives To define the relationship between specific viral illnesses and early childhood asthma development. Methods A total of 259 children were followed prospectively from birth to 6 years of age. The etiology and timing of specific viral wheezing respiratory illnesses during early childhood were assessed using nasal lavage, culture, and multiplex reverse transcriptase–polymerase chain reaction. The relationships of these virus-specific wheezing illnesses and other risk factors to the development of asthma were analyzed. Measurements and Main Results Viral etiologies were identified in 90% of wheezing illnesses. From birth to age 3 years, wheezing with respiratory syncytial virus (RSV) (odds ratio [OR], 2.6), rhinovirus (RV) (OR, 9.8), or both RV and RSV (OR, 10) was associated with increased asthma risk at age 6 years. In Year 1, both RV wheezing (OR, 2.8) and aeroallergen sensitization (OR, 3.6) independently increased asthma risk at age 6 years. By age 3 years, wheezing with RV (OR, 25.6) was more strongly associated with asthma at age 6 years than aeroallergen sensitization (OR, 3.4). Nearly 90% (26 of 30) of children who wheezed with RV in Year 3 had asthma at 6 years of age. Conclusions Among outpatient viral wheezing illnesses in infancy and early childhood, those caused by RV infections are the most significant predictors of the subsequent development of asthma at age 6 years in a high-risk birth cohort.

Abstract Rationale Poor adherence to asthma controller medications results in poor treatment outcomes. Objectives To compare controller medication adherence and clinical outcomes in 612 adults with poorly controlled asthma randomized to one of two different treatment decision-making models or to usual care. Methods In shared decision making (SDM), nonphysician clinicians and patients negotiated a treatment regimen that accommodated patient goals and preferences. In clinician decision making, treatment was prescribed without specifically eliciting patient goals/preferences. The otherwise identical intervention protocols both provided asthma education and involved two in-person and three brief phone encounters. Measurements and Main Results Refill adherence was measured using continuous medication acquisition (CMA) indices—the total days' supply acquired per year divided by 365 days. Cumulative controller medication dose was measured in beclomethasone canister equivalents. In follow-up Year 1, compared with usual care, SDM resulted in: significantly better controller adherence (CMA, 0.67 vs. 0.46; P < 0.0001) and long-acting β-agonist adherence (CMA, 0.51 vs. 0.40; P = 0.0225); higher cumulative controller medication dose (canister equivalent, 10.9 vs. 5.2; P < 0.0001); significantly better clinical outcomes (asthma-related quality of life, health care use, rescue medication use, asthma control, and lung function). In Year 2, compared with usual care, SDM resulted in significantly lower rescue medication use, the sole clinical outcome available for that year. Compared with clinician decision making, SDM resulted in: significantly better controller adherence (CMA, 0.67 vs. 0.59; P = 0.03) and long-acting β-agonist adherence (CMA, 0.51 vs. 0.41; P = 0.0143); higher cumulative controller dose (CMA, 10.9 vs. 9.1; P = 0.005); and quantitatively, but not significantly, better outcomes on all clinical measures. Conclusions Negotiating patients' treatment decisions significantly improves adherence to asthma pharmacotherapy and clinical outcomes. Clinical trials registered with www.clinicaltrials.gov (NCT00217945 and NCT00149526).

Abstract Rationale Exhaled nitric oxide (FeNO) is a biomarker of airway inflammation in mild to moderate asthma. However, whether FeNO levels are informative regarding airway inflammation in patients with severe asthma, who are refractory to conventional treatment, is unknown. Here, we hypothesized that classification of severe asthma based on airway inflammation as defined by FeNO levels would identify a more reactive, at-risk asthma phenotype. Methods FeNO and major features of asthma, including airway inflammation, airflow limitation, hyperinflation, hyperresponsiveness, and atopy, were determined in 446 individuals with various degrees of asthma severity (175 severe, 271 nonsevere) and 49 healthy subjects enrolled in the Severe Asthma Research Program. Measurements and Main Results FeNO levels were similar among patients with severe and nonsevere asthma. The proportion of individuals with high FeNO levels (>35 ppb) was the same (40%) among groups despite greater corticosteroid therapy in severe asthma. All patients with asthma and high FeNO had more airway reactivity (maximal reversal in response to bronchodilator administration and by methacholine challenge), more evidence of allergic airway inflammation (sputum eosinophils), more evidence of atopy (positive skin tests, higher serum IgE and blood eosinophils), and more hyperinflation, but decreased awareness of their symptoms. High FeNO identified those patients with severe asthma characterized by the greatest airflow obstruction and hyperinflation and most frequent use of emergency care. Conclusions Grouping of asthma by FeNO provides an independent classification of asthma severity, and among patients with severe asthma identifies the most reactive and worrisome asthma phenotype.

Abstract Rationale Desert dust particles, including quartz, which causes inflammatory responses in the airway in animal studies, are transported to widespread regions around the globe. Epidemiologically, areas impacted by desert dust storms, such as communities in the Middle East and the Caribbean, seem to have higher incidences of asthma than might be expected. Objectives We investigated the magnitude of association between airborne mineral dust concentration and hospitalization of children for asthma exacerbation by using Light Detection And Ranging (LIDAR) with a polarization analyzer for an exposure measurement, which can distinguish mineral dust particles from other particles. Methods A case-crossover design was used. The exposure measurement was LIDAR's nonspherical extinction coefficient. The outcome measurement was hospitalization of children aged 1 to 15 years for asthma exacerbation in eight principal hospitals in Toyama, a local area in Japan bordering the Japan Sea, during February to April, 2005 to 2009. Measurements and Main Results During the study period, there were 620 admissions for asthma exacerbation, and 6 days with a heavy dust event (daily mineral dust concentration > 0.1 mg/m3). Conditional logistic regression showed a statistically significant association between asthma hospitalization and a heavy dust event. The crude odds ratio (OR) of the heavy dust event for hospitalization on the day was 1.88 (95% confidence interval [CI], 1.04–3.41; P = 0.037), and the OR of heavy dust event during the previous week was 1.83 (95% CI, 1.31–2.56; P = 0.00043). The OR adjusted by other air pollutant levels, pollen, and meteorological factors was 1.71 (95% CI, 1.18–2.48; P = 0.0050). Conclusions Heavy dust events are associated with an increased risk of hospitalizations for asthma.

Although obesity has been implicated as an asthma risk factor, there is heterogeneity in the published literature regarding its role in asthma incidence, particularly in men. To quantify the relationship between categories of body mass index (BMI) and incident asthma in adults and to evaluate the impact of sex on this relationship. Online bibliographic databases were searched for prospective studies evaluating BMI and incident asthma in adults. Independent observers extracted data regarding annualized asthma incidence from studies meeting predetermined criteria, within defined categories of normal weight (BMI < 25), overweight (BMI, 25-29.9), and obesity (BMI >or= 30). Data were analyzed by inverse-variance-weighted, random-effects meta-analysis. Stratified analysis between BMI categories and within sex was performed. Seven studies (n=333,102 subjects) met inclusion criteria. Compared with normal weight, overweight and obesity (BMI >or= 25) conferred increased odds of incident asthma, with an odds ratio (OR) of 1.51 (95% confidence interval [CI], 1.27-1.80). A dose-response effect of elevated BMI on asthma incidence was observed; the OR for incident asthma for normal-weight versus overweight subjects was 1.38 (95% CI, 1.17-1.62) and was further elevated for normal weight versus obesity (OR, 1.92; 95% CI, 1.43-2.59; p<0.0001 for the trend). A similar increase in the OR of incident asthma due to overweight and obesity was observed in men (OR, 1.46; 95% CI, 1.05-2.02) and women (OR, 1.68; 95% CI, 1.45-1.94; p=0.232 for the comparison). Overweight and obesity are associated with a dose-dependent increase in the odds of incident asthma in men and women, suggesting asthma incidence could be reduced by interventions targeting overweight and obesity.

Abstract Rationale Obesity may alter glucocorticoid response in asthma. Objectives To evaluate the relationship between body mass index (BMI, kg/m2) and glucocorticoid response in subjects with and without asthma. Methods Nonsmoking adult subjects underwent characterization of lung function, BMI, and spirometric response to prednisone. Dexamethasone (DEX, 10−6 M)-induced mitogen-activated protein kinase phosphatase-1 (MKP-1) and baseline tumor necrosis factor (TNF)-α expression were evaluated by polymerase chain reaction in peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage cells. The relationship between BMI and expression of MKP-1 and TNF-α was analyzed. Measurements and Main Results A total of 45 nonsmoking adults, 33 with asthma (mean [SD] FEV1% of 70.7 [9.8]%) and 12 without asthma were enrolled. DEX-induced PBMC MKP-1 expression was reduced in overweight/obese versus lean patients with asthma, with mean (± SEM) fold-induction of 3.11 (±0.46) versus 5.27 (±0.66), respectively (P = 0.01). In patients with asthma, regression analysis revealed a −0.16 (±0.08)-fold decrease in DEX-induced MKP-1 per unit BMI increase (P = 0.04). PBMC TNF-α expression increased as BMI increased in subjects with asthma, with a 0.27 unit increase in log (TNF-α [ng/ml]) per unit BMI increase (P = 0.01). The ratio of PBMC log (TNF-α):DEX-induced MKP-1 also increased as BMI increased in patients with asthma (+0.09 ± 0.02; P = 0.004). In bronchoalveolar lavage cells, DEX-induced MKP-1 expression was also reduced in overweight/obese versus lean patients with asthma (1.36 ± 0.09-fold vs. 1.76 ± 0.15-fold induction; P = 0.05). Similar findings were not observed in control subjects without asthma. Conclusions Elevated BMI is associated with blunted in vitro response to dexamethasone in overweight and obese patients with asthma.

Abstract Rationale Severe asthma (SA) remains poorly understood. Mast cells (MC) are implicated in asthma pathogenesis, but it remains unknown how their phenotype, location, and activation relate to asthma severity. Objectives To compare MC-related markers measured in bronchoscopically obtained samples with clinically relevant parameters between normal subjects and subjects with asthma to clarify their pathobiologic importance. Methods Endobronchial biopsies, epithelial brushings, and bronchoalveolar lavage were obtained from subjects with asthma and normal subjects from the Severe Asthma Research Program (N = 199). Tryptase, chymase, and carboxypeptidase A (CPA)3 were used to identify total MC (MCTot) and the MCTC subset (MCs positive for both tryptase and chymase) using immunostaining and quantitative real-time polymerase chain reaction. Lavage was analyzed for tryptase and prostaglandin D2 (PGD2) by ELISA. Measurements and Main Results Submucosal MCTot (tryptase-positive by immunostaining) numbers were highest in “mild asthma/no inhaled corticosteroid (ICS) therapy” subjects and decreased with greater asthma severity (P = 0.002). In contrast, MCTC (chymase-positive by immunostaining) were the predominant (MCTC/MCTot > 50%) MC phenotype in SA (overall P = 0.005). Epithelial MCTot were also highest in mild asthma/no ICS, but were not lower in SA. Instead, they persisted and were predominantly MCTC. Epithelial CPA3 and tryptase mRNA supported the immunostaining data (overall P = 0.008 and P = 0.02, respectively). Lavage PGD2 was higher in SA than in other steroid-treated groups (overall P = 0.02), whereas tryptase did not differentiate the groups. In statistical models, PGD2 and MCTC/MCTot predicted SA. Conclusions Severe asthma is associated with a predominance of MCTC in the airway submucosa and epithelium. Activation of those MCTC may contribute to the increases in PGD2 levels. The data suggest an altered and active MC population contributes to SA pathology.