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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 Airway eosinophilia is typical of asthma, and many controller treatments target eosinophilic disease. Asthma is clinically heterogeneous, however, and a subgroup of people with asthma do not have airway eosinophilia. The size of this subgroup is uncertain because prior studies have not examined repeated measures of sputum cytology to determine when people with asthma have intermittent versus persistent sputum eosinophila and when they are persistently noneosinophilic. Objectives To determine the prevalence and clinical characteristics of the noneosinophilic asthma phenotype. Methods We analyzed sputum cytology data from 995 subjects with asthma enrolled in clinical trials in the Asthma Clinical Research Network where they had undergone sputum induction and measures of sputum cytology, often repeatedly, and assessment of responses to standardized asthma treatments. Measurements and Main Results In cross-sectional analyses, sputum eosinophilia (≥2% eosinophils) was found in only 36% of subjects with asthma not taking an inhaled corticosteroid (ICS) and 17% of ICS-treated subjects with asthma; an absence of eosinophilia was noted frequently, even in subjects with asthma whose disease was suboptimally controlled. In repeated measures analyses of people with asthma not taking an ICS, 22% of subjects had sputum eosinophilia on every occasion (persistent eosinophilia); 31% had eosinophilia on at least one occasion (intermittent eosinophilia); and 47% had no eosinophilia on every occasion (persistently noneosinophilic). Two weeks of combined antiinflammatory therapy caused significant improvements in airflow obstruction in eosinophilic asthma, but not in persistently noneosinophilic asthma. In contrast, bronchodilator responses to albuterol were similar in eosinophilic and noneosinophilic asthma. Conclusions Approximately half of patients with mild-to-moderate asthma have persistently noneosinophilic disease, a disease phenotype that responds poorly to currently available antiinflammatory therapy.

Abstract Rationale The role of airway microbiome in corticosteroid response in asthma is unknown. Objectives To examine airway microbiome composition in patients with corticosteroid-resistant (CR) asthma and compare it with patients with corticosteroid-sensitive (CS) asthma and normal control subjects and explore whether bacteria in the airways of subjects with asthma may direct alterations in cellular responses to corticosteroids. Methods 16S rRNA gene sequencing was performed on bronchoalveolar lavage (BAL) samples of 39 subjects with asthma and 12 healthy control subjects. In subjects with asthma, corticosteroid responsiveness was characterized, BAL macrophages were stimulated with pathogenic versus commensal microorganisms, and analyzed by real-time polymerase chain reaction for the expression of corticosteroid-regulated genes and cellular p38 mitogen-activated protein kinase (MAPK) activation. Measurements and Main Results Of the 39 subjects with asthma, 29 were CR and 10 were CS. BAL microbiome from subjects with CR and CS asthma did not differ in richness, evenness, diversity, and community composition at the phylum level, but did differ at the genus level, with distinct genus expansions in 14 subjects with CR asthma. Preincubation of asthmatic airway macrophages with Haemophilus parainfluenzae, a uniquely expanded potential pathogen found only in CR asthma airways, resulted in p38 MAPK activation, increased IL-8 (P < 0.01), mitogen-activated kinase phosphatase 1 mRNA (P < 0.01) expression, and inhibition of corticosteroid responses (P < 0.05). This was not observed after exposure to commensal bacterium Prevotella melaninogenica. Inhibition of transforming growth factor-β–associated kinase-1 (TAK1), upstream activator of MAPK, but not p38 MAPK restored cellular sensitivity to corticosteroids. Conclusions A subset of subjects with CR asthma demonstrates airway expansion of specific gram-negative bacteria, which trigger TAK1/MAPK activation and induce corticosteroid resistance. TAK1 inhibition restored cellular sensitivity to corticosteroids.

Dupilumab, a fully human anti-interleukin-4 receptor α monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling, key drivers of type-2-mediated inflammation. Adults with uncontrolled persistent asthma who are receiving medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist require additional treatment options as add-on therapy. We aimed to assess the efficacy and safety of dupilumab as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist, irrespective of baseline eosinophil count. We did this randomised, double-blind, placebo-controlled, parallel-group, pivotal phase 2b clinical trial at 174 study sites across 16 countries or regions. Adults (aged ≥18 years) with an asthma diagnosis for 12 months or more based on the Global Initiative for Asthma 2009 Guidelines receiving treatment with medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist were eligible for participation. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous dupilumab 200 mg or 300 mg every 2 weeks or every 4 weeks, or placebo, over a 24-week period. The primary endpoint was change from baseline at week 12 in forced expiratory volume in 1 s (FEV1 in L) in patients with baseline blood eosinophil counts of at least 300 eosinophils per μL assessed in the intention-to-treat population. Safety outcomes were assessed in all patients that received at least one dose or part of a dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT01854047, and with the EU Clinical Trials Register, EudraCT number 2013-000856-16. 769 patients (158 in the placebo group and 611 in the dupilumab groups) received at least one dose of study drug. In the subgroup with at least 300 eosinophils per μL, the greatest increases (200 mg every 2 weeks, p=0·0008; 300 mg every 2 weeks, p=0·0063) in FEV1 compared with placebo were observed at week 12 with doses every 2 weeks in the 300 mg group (mean change 0·39 L [SE 0·05]; mean difference 0·21 [95% CI 0·06–0·36; p=0·0063]) and in the 200 mg group (mean change 0·43 L [SE 0·05]; mean difference 0·26 [0·11–0·40; p=0·0008]) compared with placebo (0·18 L [SE 0·05]). Similar significant increases were observed in the overall population and in the fewer than 300 eosinophils per μL subgroup (overall population: 200 mg every 2 weeks, p<0·0001; 300 mg every 2 weeks, p<0·0001; <300 eosinophils per μL: 200 mg every 2 weeks, p=0·0034; 300 mg every 2 weeks, p=0·0086), and were maintained to week 24. Likewise, dupilumab every 2 weeks produced the greatest reductions in annualised rates of exacerbation in the overall population (70–70·5%), the subgroup with at least 300 eosinophils per μL (71·2–80·7%), and the subgroup with fewer than 300 eosinophils per μL (59·9–67·6%). The most common adverse events with dupilumab compared with placebo were upper respiratory tract infections (33–41% vs 35%) and injection-site reactions (13–26% vs 13%). Dupilumab increased lung function and reduced severe exacerbations in patients with uncontrolled persistent asthma irrespective of baseline eosinophil count and had a favourable safety profile, and hence in addition to inhaled corticosteroids plus long-acting β2-agonist therapy could improve the lives of patients with uncontrolled persistent asthma compared with standard therapy alone. Sanofi-Genzyme and Regeneron Pharmaceuticals.

Abstract Asthma and obesity are prevalent disorders, each with a significant public health impact, and a large and growing body of literature suggests an association between the two. The systemic inflammatory milieu in obesity leads to metabolic and cardiovascular complications, but whether this environment alters asthma risk or phenotype is not yet known. Animal experiments have evaluated the effects of leptin and obesity on airway inflammation in response to both allergic and nonallergic exposures and suggest that airway inflammatory response is enhanced by both endogenous and exogenous leptin. Cross-sectional and prospective cohort studies of humans have shown a modest overall increase in asthma incidence and prevalence in the obese, although body mass index does not appear be a significant modifier of asthma severity. Studying the obesity–asthma relationship in large cohorts, in which self-reports are frequently used to ascertain the diagnosis of asthma, has been complicated by alterations in pulmonary physiology caused by obesity, which may lead to dyspnea or other respiratory symptoms but do not fulfill accepted physiologic criteria for asthma. Recent investigations toward elucidating a shared genetic basis for these two disorders have identified polymorphisms in specific regions of chromosomes 5q, 6p, 11q13, and 12q, each of which contains one or more genes encoding receptors relevant to asthma, inflammation, and metabolic disorders, including the β2-adrenergic receptor gene ADRB2 and the glucocorticoid receptor gene NR3C1. Further research is warranted to synthesize these disparate observations into a cohesive understanding of the relationship between obesity and asthma.

Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with dupilumab, a fully-human monoclonal antibody that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments. In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (≥16 at baseline) and inadequate response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned (1:1:1:1:1:1), stratified by severity (moderate or severe, as assessed by Investigator's Global Assessment) and region (Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study drug. This trial is registered with ClinicalTrials.gov, number NCT01859988. Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week [n=63], 300 mg every 2 weeks [n=64], 200 mg every 2 weeks [n=61], 300 mg every 4 weeks [n=65], 100 mg every 4 weeks [n=65]; placebo [n=61]). EASI score improvements favoured all dupilumab regimens versus placebo (p<0·0001): 300 mg once a week (−74% [SE 5·16]), 300 mg every 2 weeks (−68% [5·12]), 200 mg every 2 weeks (−65% [5·19]), 300 mg every 4 weeks (−64% [4·94]), 100 mg every 4 weeks (−45% [4·99]); placebo (−18% [5·20]). 258 (81%) of 318 patients given dupilumab and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events; nasopharyngitis was the most frequent (28% and 26%, respectively). Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns. Our findings show that IL-4 and IL-13 are key drivers of atopic dermatitis. Sanofi and Regeneron Pharmaceuticals.

Abstract Rationale An antagonist (MK-7123) of the cytokine receptor CXCR2 reduces neutrophil chemotaxis and thus may alleviate airway inflammation in chronic obstructive pulmonary disease (COPD). Objectives To assess the efficacy, safety, and tolerability of three dose levels of MK-7123, compared with placebo, in patients with moderate to severe COPD. Methods This 6-month, double-blind study randomized patients with moderate to severe COPD (already on standard therapy) to daily MK-7123 at 10, 30, or 50 mg or placebo. The primary endpoint was change from baseline in post-bronchodilator FEV1. Measurements and Main Results A total of 616 patients (71% male; mean age, 63 yr; 45% current smokers; baseline FEV1 [SD], 1.43 L [0.45]; mean FEV1 percent predicted, 43.9%) were randomized. Only MK-7123 50 mg led to significant improvement in FEV1 over placebo (mean difference [SE], 67 ml [32]). Reduced sputum neutrophil count was observed among the 122 patients examined; P = 0.003 (3 mo) and P = 0.092 (6 mo) (MK-7123 50 mg vs. placebo). The stratum of current smokers, but not that of nonsmokers, showed significant improvement versus placebo in FEV1 (168 ml) and time-to-first exacerbation, and showed numerical improvement in St. George’s Respiratory Questionnaire for COPD score. MK-7123 caused a dose-dependent decrease in absolute neutrophil count (ANC) and reduced inflammatory biomarkers matrix metallopeptidase-9 and myeloperoxidase in plasma and sputum; ANC lower than 1.5 × 109/L led to discontinuations with higher doses of MK-7123 (18% in the MK-7123 50-mg group vs. 1% in placebo). Plasma C-reactive protein and fibrinogen increased with MK-7123 treatment. Rates of infections at 6 months were similar in all groups. Conclusions Treatment with MK-7123 50 mg versus placebo led to significant improvement in FEV1 in patients with COPD, suggesting clinically important antiinflammatory effects with CXCR2 antagonism, although dose-related discontinuations were observed because of ANC decreases with MK-7123. Greater response was observed in smokers versus ex-smokers. Clinical trial registered with www.clinicaltrials.gov (NCT 01006616).

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.

Asthma is a heterogeneous disease with variability among patients in characteristics such as lung function, symptoms and control, body weight, markers of inflammation, and responsiveness to glucocorticoids (GC). Cluster analysis of well-characterized cohorts can advance understanding of disease subgroups in asthma and point to unsuspected disease mechanisms. We utilized an hypothesis-free cluster analytical approach to define the contribution of obesity and related variables to asthma phenotype. In a cohort of clinical trial participants (n = 250), minimum-variance hierarchical clustering was used to identify clinical and inflammatory biomarkers important in determining disease cluster membership in mild and moderate persistent asthmatics. In a subset of participants, GC sensitivity was assessed via expression of GC receptor alpha (GCRα) and induction of MAP kinase phosphatase-1 (MKP-1) expression by dexamethasone. Four asthma clusters were identified, with body mass index (BMI, kg/m(2)) and severity of asthma symptoms (AEQ score) the most significant determinants of cluster membership (F = 57.1, p<0.0001 and F = 44.8, p<0.0001, respectively). Two clusters were composed of predominantly obese individuals; these two obese asthma clusters differed from one another with regard to age of asthma onset, measures of asthma symptoms (AEQ) and control (ACQ), exhaled nitric oxide concentration (F(E)NO) and airway hyperresponsiveness (methacholine PC(20)) but were similar with regard to measures of lung function (FEV(1) (%) and FEV(1)/FVC), airway eosinophilia, IgE, leptin, adiponectin and C-reactive protein (hsCRP). Members of obese clusters demonstrated evidence of reduced expression of GCRα, a finding which was correlated with a reduced induction of MKP-1 expression by dexamethasone Obesity is an important determinant of asthma phenotype in adults. There is heterogeneity in expression of clinical and inflammatory biomarkers of asthma across obese individuals. Reduced expression of the dominant functional isoform of the GCR may mediate GC insensitivity in obese asthmatics.

Abstract Rationale Severe asthma is characterized by airway inflammatory responses associated with aberrant metabolism of arachidonic acid. Lipoxins (LX) are arachidonate-derived pro-resolving mediators that are decreased in severe asthma, yet mechanisms for defective LX biosynthesis and a means to increase LXs in severe asthma remain to be established. Objectives To determine if oxidative stress and soluble epoxide hydrolase (sEH) activity are linked to decreased LX biosynthesis in severe asthma. Methods Aliquots of blood, sputum, and bronchoalveolar lavage fluid were obtained from asthma subjects for mediator determination. Select samples were exposed to t-butyl-hydroperoxide or sEH inhibitor (sEHI) before activation. Peripheral blood leukocyte–platelet aggregates were monitored by flow cytometry, and bronchial contraction was determined with cytokine-treated human lung sections. Measurements and Main Results 8-Isoprostane levels in sputum supernatants were inversely related to LXA4 in severe asthma (r = −0.55; P = 0.03) and t-butyl-hydroperoxide decreased LXA4 and 15-epi-LXA4 biosynthesis by peripheral blood leukocytes. LXA4 and 15-epi-LXA4 levels were inversely related to sEH activity in sputum supernatants and sEHIs significantly increased 14,15-epoxy-eicosatrienoic acid and 15-epi-LXA4 generation by severe asthma whole blood and bronchoalveolar lavage fluid cells. The abundance of peripheral blood leukocyte–platelet aggregates was related to asthma severity. In a concentration-dependent manner, LXs significantly inhibited platelet-activating factor–induced increases in leukocyte–platelet aggregates (70.8% inhibition [LXA4 100 nM], 78.3% inhibition [15-epi-LXA4 100 nM]) and 15-epi-LXA4 markedly inhibited tumor necrosis factor-α–induced increases in bronchial contraction. Conclusions LX levels were decreased by oxidative stress and sEH activity. Inhibitors of sEH increased LXs that mediated antiphlogistic actions, suggesting a new therapeutic approach for severe asthma. Clinical trial registered with www.clinicaltrials.gov (NCT 00595114).