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Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. COPD, however, is a heterogeneous collection of diseases with differing causes, pathogenic mechanisms, and physiological effects. Therefore a comprehensive approach to COPD prevention will need to address the complexity of COPD. Advances in the understanding of the natural history of COPD and the development of strategies to assess COPD in its early stages make prevention a reasonable, if ambitious, goal.

An antagonist (MK-7123) of the cytokine receptor CXCR2 reduces neutrophil chemotaxis and thus may alleviate airway inflammation in chronic obstructive pulmonary disease (COPD). To assess the efficacy, safety, and tolerability of three dose levels of MK-7123, compared with placebo, in patients with moderate to severe COPD. 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. 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 × 10(9)/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. 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).

In patients with chronic obstructive pulmonary disease (COPD), lung function decreases rapidly. Analysis of data from a large observational study of COPD showed that the rate of such loss is highly variable, and current smoking was associated with a rapid loss. Since the seminal studY by Fletcher et al. in the 1970s, 1 , 2 it has been widely accepted that chronic obstructive pulmonary disease (COPD) is characterized by an accelerated decline in forced expiratory volume in 1 second (FEV 1 ). However, surprisingly few longitudinal studies of patient cohorts have provided detailed data regarding the rate of decline in FEV 1 , 3 – 8 and none of these studies have related changes in FEV 1 to specific subgroups of patients with COPD or to levels of systemic biomarkers. We used data from a large, observational, 3-year study that included detailed assessments of patients . . .

BackgroundCigarette smoking is the strongest risk factor for COPD. Smoking burden is frequently measured in pack-years, but the relative contribution of cigarettes smoked per day versus duration towards the development of structural lung disease, airflow obstruction and functional outcomes is not known.MethodsWe analysed cross-sectional data from a large multicentre cohort (COPDGene) of current and former smokers. Primary outcome was airflow obstruction (FEV1/FVC); secondary outcomes included five additional measures of disease: FEV1, CT emphysema, CT gas trapping, functional capacity (6 min walk distance, 6MWD) and respiratory morbidity (St George’s Respiratory Questionnaire, SGRQ). Generalised linear models were estimated to compare the relative contribution of each smoking variable with the outcomes, after adjustment for age, race, sex, body mass index, CT scanner, centre, age of smoking onset and current smoking status. We also estimated adjusted means of each outcome by categories of pack-years and combined groups of categorised smoking duration and cigarettes/day, and estimated linear trends of adjusted means for each outcome by categorised cigarettes/day, smoking duration and pack-years.Results10 187 subjects were included. For FEV1/FVC, standardised beta coefficient for smoking duration was greater than for cigarettes/day and pack-years (P<0.001). After categorisation, there was a linear increase in adjusted means FEV1/FVC with increase in pack-years (regression coefficient β=−0.023±SE0.003; P=0.003) and duration over all ranges of smoking cigarettes/day (β=−0.041±0.004; P<0.001) but a relatively flat slope for cigarettes/day across all ranges of smoking duration (β=−0.009±0.0.009; P=0.34). Strength of association of duration was similarly greater than pack-years for emphysema, gas trapping, FEV1, 6MWD and SGRQ.ConclusionSmoking duration alone provides stronger risk estimates of COPD than the composite index of pack-years.Trial registration numberPost-results; NCT00608764.

Background Cachexia is associated with increased mortality risk among chronic obstructive pulmonary disease (COPD) patients. However, low body mass index (BMI) as opposed to cachexia is often used, particularly when calculating the BODE (BMI, Obstruction, Dyspnea and Exercise) index. For this reason, we examined mortality using a consensus definition and a weight-loss definition of cachexia among COPD cases and compared two new COPD severity indices with BODE. Methods In the current report, the consensus definition for cachexia incorporated weight-loss > 5% in 12-months or low BMI in addition to 3/5 of decreased muscle strength, fatigue, anorexia, low FFMI and inflammation. The weight-loss definition incorporated weight-loss > 5% or weight-loss > 2% (if low BMI) in 12-months. The low BMI component in BODE was replaced with the consensus definition to create the CODE (Consensus cachexia, Obstruction, Dyspnea and Exercise) index and the weight-loss definition to create the WODE (Weight loss, Obstruction, Dyspnea and Exercise) index. Mortality was assessed using Kaplan-Meier survival and Cox Regression. Performance of models was compared using C-statistics. Results Among 1483 COPD cases, the prevalences of cachexia by the consensus and weight-loss definitions were 4.7 and 10.4%, respectively. Cachectic patients had a greater than three-fold increased mortality by either the consensus or the weight-loss definition of cachexia independent of BMI and lung function. The CODE index predicted mortality slightly more accurately than the BODE and WODE indices. Conclusions Cachexia is associated with increased mortality among COPD patients. Monitoring cachexia using weight-loss criteria is relatively simple and predictive of mortality among COPD cases who may be missed if only low BMI is used.

Depression is prevalent in patients with chronic obstructive pulmonary disease (COPD); however, its etiology and relationship to the clinical features of COPD are not well understood. Using data from a large cohort, we explored prevalence and determinants of depression in subjects with COPD. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study is an observational 3-year multicenter study that enrolled smokers with and without COPD and nonsmoker controls. At baseline, several patient-reported outcomes were measured including the Center for Epidemiologic Studies of Depression Scale. For the purposes of this analysis, depression was defined as a score of 16 and higher on this scale, which reflects a high load of depressive symptoms and has a good correspondence with a clinical diagnosis of major depression. The study cohort consisted of 2,118 subjects with COPD; 335 smokers without COPD (smokers); and 243 nonsmokers without COPD (nonsmokers). A total of 26%, 12%, and 7% of COPD, smokers, and nonsmokers, respectively, suffered from depression. In subjects with COPD, higher depression prevalence was seen in females, current smokers, and those with severe disease (Global Initiative for Obstructive Lung Disease [GOLD]-defined). Multivariate modeling of depression determinants in subjects with COPD revealed that increased fatigue, higher St. George's Respiratory Questionnaire for COPD patients score, younger age, female sex, history of cardiovascular disease, and current smoking status were all significantly associated with depression; physiologic and biologic measures were weak or nonsignificant descriptors. Depression is more prevalent in subjects with COPD compared with smokers and nonsmokers without COPD. Clinical and biologic measures were less important determinants of depression in COPD than disease symptoms and quality-of-life. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).

Background Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease (COPD) that are greater than those derived from either treatment alone. The efficacy and safety of a fixed-dose combination (FDC) of aclidinium bromide, a long-acting muscarinic antagonist, and formoterol fumarate, a long-acting β 2 -agonist, in patients with moderate to severe COPD are presented. Methods In this 24-week double-blind study, 1692 patients with stable COPD were equally randomized to twice-daily treatment with FDC aclidinium 400μg/formoterol 12μg (ACL400/FOR12 FDC), FDC aclidinium 400μg/formoterol 6μg (ACL400/FOR6 FDC), aclidinium 400μg, formoterol 12μg, or placebo administered by a multidose dry powder inhaler (Genuair ® /Pressair ® )*. Coprimary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV 1 (FDCs versus aclidinium) and change from baseline to week 24 in morning predose (trough) FEV 1 (FDCs versus formoterol). Secondary endpoints were change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score and improvement in Transition Dyspnea Index (TDI) focal score at week 24. Safety and tolerability were also assessed. Results At study end, improvements from baseline in 1-hour postdose FEV 1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium (108 mL and 87 mL, respectively; p < 0.0001). Improvements in trough FEV 1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol (45 mL; p = 0.0102), a numerical improvement of 26 mL in trough FEV 1 over formoterol was observed with ACL400/FOR6 FDC. Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end (p < 0.0001), with differences over placebo exceeding the minimal clinically important difference of ≥4 points and ≥1 unit, respectively. All treatments were well tolerated, with safety profiles of the FDCs similar to those of the monotherapies. Conclusions Treatment with twice-daily aclidinium 400μg/formoterol 12μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy; clinically significant improvements in dyspnea and health status were evident compared with placebo. Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD. Trial registration Clinicaltrials.gov NCT01437397 . *Registered trademarks of Almirall S.A., Barcelona, Spain; for use within the US as Pressair ® and Genuair ® within all other licensed territories.

Background As chronic obstructive pulmonary disease (COPD) is a heterogeneous disease it is unlikely that all patients will benefit equally from a given therapy. Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, has been shown to improve lung function in moderate and severe COPD but its effect on exacerbations in unselected populations was inconclusive. This led to the question of whether a responsive subset existed that could be investigated further. Methods The datasets of two previous replicate, randomized, double-blind, placebo-controlled, parallel-group studies (oral roflumilast 500 μg or placebo once daily for 52 weeks) that were inconclusive regarding exacerbations were combined in a post-hoc, pooled analysis to determine whether roflumilast reduced exacerbations in a more precisely defined patient subset. Results The pooled analysis included 2686 randomized patients. Roflumilast significantly decreased exacerbations by 14.3% compared with placebo (p = 0.026). Features associated with this reduction were: presence of chronic bronchitis with or without emphysema (26.2% decrease, p = 0.001), presence of cough (20.9% decrease, p = 0.006), presence of sputum (17.8% decrease, p = 0.03), and concurrent use of inhaled corticosteroids (ICS; 18.8% decrease, p = 0.014). The incidence of adverse events was similar with roflumilast and placebo (81.5% vs 80.1%), but more patients in the roflumilast group had events assessed as likely or definitely related to the study drug (21.5% vs 8.3%). Conclusions This post-hoc, pooled analysis showed that roflumilast reduced exacerbation frequency in a subset of COPD patients whose characteristics included chronic bronchitis with/without concurrent ICS. These observations aided the design of subsequent phase 3 studies that prospectively confirmed the reduction in exacerbations with roflumilast treatment. Trials registration ClinicalTrials.gov identifiers: NCT00076089 and NCT00430729 .

There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of alpha(1)-antitrypsin, which is present in 1-2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the alpha-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48 x 10(-10), (rs8034191) and 5.74 x 10(-10) (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer.

Background Chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging and is associated with comorbid conditions including osteoporosis and sarcopenia. These extrapulmonary conditions are highly prevalent yet frequently underdiagnosed and overlooked by pulmonologists in COPD treatment and management. There is evidence supporting a role for bone-muscle crosstalk which may compound osteoporosis and sarcopenia risk in COPD. Chest CT is commonly utilized in COPD management, and we evaluated its utility to identify low bone mineral density (BMD) and reduced pectoralis muscle area (PMA) as surrogates for osteoporosis and sarcopenia. We then tested whether BMD and PMA were associated with morbidity and mortality in COPD. Methods BMD and PMA were analyzed from chest CT scans of 8468 COPDGene participants with COPD and controls (smoking and non-smoking). Multivariable regression models tested the relationship of BMD and PMA with measures of function (6-min walk distance (6MWD), handgrip strength) and disease severity (percent emphysema and lung function). Multivariable Cox proportional hazards models were used to evaluate the relationship between sex-specific quartiles of BMD and/or PMA derived from non-smoking controls with all-cause mortality. Results COPD subjects had significantly lower BMD and PMA compared with controls. Higher BMD and PMA were associated with increased physical function and less disease severity. Participants with the highest BMD and PMA quartiles had a significantly reduced mortality risk (36% and 46%) compared to the lowest quartiles. Conclusions These findings highlight the potential for CT-derived BMD and PMA to characterize osteoporosis and sarcopenia using equipment available in the pulmonary setting.