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Rationale: The new Global Initiative for Obstructive Lung Disease (GOLD) stratification of chronic obstructive pulmonary disease (COPD) into categories A, B, C, and D is based on symptoms, level of lung function, and history of exacerbations. Objectives: To investigate the abilities of this stratification to predict the clinical course of COPD. Methods: Two similar population studies were performed in an area of Copenhagen including 6,628 individuals with COPD. Measurements and Main Results: The patients were monitored for an average period of 4.3 years regarding COPD exacerbations, hospital admissions, and mortality. The percentages of individuals experiencing a COPD exacerbation during the first year of observation were 2.2% in group A, 5.8% in group B, 25.1% in group C, and 28.6% in group D. One- and 3-year mortality rates were 0.6 and 3.8%, respectively, in group A, 3.0 and 10.6% in group B, 0.7 and 8.2% in group C, and 3.4 and 20.1% in group D. Groups B and D, characterized by a higher degree of dyspnea than groups A and C, had five to eight times higher mortality from cardiovascular disease and cancer than did groups A and C. Conclusions: The new stratification performs well by identifying individuals at risk of exacerbations. Surprisingly, subgroup B, characterized by more severe dyspnea, had significantly poorer survival than group C, in spite of a higher FEV(1) level. This subgroup warrants special attention, as the poor prognosis could be caused by cardiovascular disease or cancer, requiring additional assessment and treatment. [ABSTRACT FROM AUTHOR]

Rationale: Accurate prediction of mortality helps select patients for interventions aimed at improving outcome.Objectives: Because chronic obstructive pulmonary disease is characterized by low-grade systemic inflammation, we hypothesized that addition of inflammatory biomarkers to established predictive factors will improve accuracy.Methods: A total of 1,843 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study were followed for 3 years. Kaplan-Meier curves, log-rank analysis, and Cox proportional hazards analyses determined the predictive value for mortality of clinical variables, while C statistics assessed the added discriminative power offered by addition of biomarkers.Measurements and Main Results: At recruitment we measured anthropometrics, spirometry, 6-minute walk distance, dyspnea, BODE index, history of hospitalization, comorbidities, and computed tomography scan emphysema. White blood cell and neutrophil counts, serum or plasma levels of fibrinogen, chemokine ligand 18, surfactant protein D, C-reactive protein, Clara cell secretory protein-16, IL-6 and -8, and tumor necrosis factor-α were determined at recruitment and subsequent visits. A total of 168 of the 1,843 patients (9.1%) died. Nonsurvivors were older and had more severe airflow limitation, increased dyspnea, higher BODE score, more emphysema, and higher rates of comorbidities and history of hospitalizations. The best predictive model for mortality using clinical variables included age, BODE, and hospitalization history (C statistic of 0.686; P < 0.001). One single biomarker (IL-6) significantly improved the C statistic to 0.708, but this was further improved to 0.726 (P = 0.003) by the addition of all biomarkers.Conclusions: The addition of a panel of selected biomarkers improves the ability of established clinical variables to predict mortality in chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT00292552). [ABSTRACT FROM AUTHOR]

RATIONALE: There is limited knowledge regarding sex differences and outcomes in patients with chronic obstructive pulmonary disease (COPD). Objectives: Determine sex differences in survival, causes of death, and patient-centered outcomes in the 3-year Toward a Revolution in COPD Health (TORCH) study. METHODS: A total of 1,481 women and 4,631 men with COPD were enrolled in TORCH, a trial comparing salmeterol, 50 [mu]g, plus fluticasone propionate, 500 [mu]g, twice a day and each component individually. Causes of death were determined by an endpoint committee. Sex differences in survival were explored using a Cox proportional hazards model adjusted for other baseline factors. Exacerbation rate was compared using a negative binomial model. Dyspnea was evaluated using the Medical Research Council scale and health status using the St. George's Respiratory Questionnaire. MEASUREMENTS AND MAIN RESULTS: At baseline, women were younger (63 vs. 66 yr), had higher FEV(1) (47% vs. 44% predicted), and worse St. George's Respiratory Questionnaire (51.3 vs. 48.7) and Medical Research Council score. During the study, 707 (15.3%) men and 168 (11.3%) women died. After adjusting for differences in baseline factors, the risk of dying was 16% higher in men than in women; however, this was not statistically significant (hazard ratio 1.16 [95% CI, 0.98-1.39]). Causes of death were similar in women and men. Exacerbation rate was 25% higher in women than in men. CONCLUSIONS: Women enrolled in TORCH had a lower mortality rate than men but similar causes of death. The risk of dying was similar in women and men after adjusting for important baseline variables. Women reported more exacerbations, and worse dyspnea and health status scores than men. Clinical trial registered with www.clinicaltrials.gov (NCT00268216). [ABSTRACT FROM AUTHOR]

Rationale: Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q.Objectives: We hypothesized that merging results of high-resolution single nucleotide polymorphism (SNP) mapping in four separate populations would lead to the identification of chronic obstructive pulmonary disease (COPD) susceptibility genes on chromosome 2q.Methods: Within the chromosome 2q linkage region, 2,843 SNPs were genotyped in 806 COPD cases and 779 control subjects from Norway, and 2,484 SNPs were genotyped in 309 patients with severe COPD from the National Emphysema Treatment Trial and 330 community control subjects. Significant associations from the combined results across the two case-control studies were followed up in 1,839 individuals from 603 families from the International COPD Genetics Network (ICGN) and in 949 individuals from 127 families in the Boston Early-Onset COPD Study.Measurements and Main Results: Merging the results of the two case-control analyses, 14 of the 790 overlapping SNPs had a combined P < 0.01. Two of these 14 SNPs were consistently associated with COPD in the ICGN families. The association with one SNP, located in the gene XRCC5, was replicated in the Boston Early-Onset COPD Study, with a combined P = 2.51 x 10(-5) across the four studies, which remains significant when adjusted for multiple testing (P = 0.02). Genotype imputation confirmed the association with SNPs in XRCC5.Conclusions: By combining data from COPD genetic association studies conducted in four independent patient samples, we have identified XRCC5, an ATP-dependent DNA helicase, as a potential COPD susceptibility gene. [ABSTRACT FROM AUTHOR]

Rationale: Overproduction of mucus is a contributory factor in the progression of chronic obstructive pulmonary disease (COPD). The polymeric mucins are major macromolecules in the secretion. Therefore, we hypothesized that the polymeric mucin composition or properties may be different in the sputum from individuals with COPD and smokers without airflow obstruction.Objectives: To determine the major polymeric mucins in COPD sputum and whether these are different in the sputum from individuals with COPD compared with that from smokers without airflow obstruction.Methods: The polymeric mucin composition of sputum from patients with COPD and smokers without airflow obstruction was analyzed by Western blotting analysis. The tissue localization of the mucins was determined by immunohistochemistry, and their size distribution was analyzed by rate-zonal centrifugation.Measurements and Main Results: MUC5AC and MUC5B were the major mucins. MUC5AC was the predominant mucin in the smoker group, whereas MUC5B was more abundant from the patients with COPD, with a significant difference in the ratio of MUC5B to MUC5AC (P = 0.004); this ratio was correlated with FEV(1) in the COPD group (r = 0.63; P = 0.01). The lower-charged glycosylated form of MUC5B was more predominant in COPD (P = 0.012). No significant associations were observed with respect to sex, age, or pack-year history. In both groups, MUC5AC was produced by surface epithelial cells and MUC5B by submucosal gland cells. Finally, there was a shift toward smaller mucins in the COPD group.Conclusions: Our data indicate that there are differences in mucin amounts and properties between smokers with and without COPD. Further studies are needed to examine how this may impact disease progression. [ABSTRACT FROM AUTHOR]

Rationale: It is unclear whether airway wall thickening and emphysema make independent contributions to airflow limitation in chronic obstructive pulmonary disease (COPD) and whether these phenotypes cluster within families.Objectives: To determine whether airway wall thickening and emphysema (1) make independent contributions to the severity of COPD and (2) show independent aggregation in families of individuals with COPD.Methods: Index cases with COPD and their smoking siblings underwent spirometry and were offered high-resolution computed tomography scans of the thorax to assess the severity of airway wall thickening and emphysema.Measurements and Main Results: A total of 3,096 individuals were recruited to the study, of whom 1,159 (519 probands and 640 siblings) had technically adequate high-resolution computed tomography scans without significant non-COPD-related thoracic disease. Airway wall thickness correlated with pack-years smoked (P < or = 0.001) and symptoms of chronic bronchitis (P < 0.001). FEV(1) (expressed as % predicted) was independently associated with airway wall thickness at a lumen perimeter of 10 mm (P = 0.0001) and 20 mm (P = 0.0013) and emphysema at -950 Hounsfield units (P < 0.0001). There was independent familial aggregation of both the emphysema (adjusted odds ratio, 2.1; 95% confidence interval, 1.1-4.0; P < or = 0.02) and airway disease phenotypes (P < 0.0001) of COPD.Conclusions: Airway wall thickening and emphysema make independent contributions to airflow obstruction in COPD. These phenotypes show independent aggregation within families of individuals with COPD, suggesting that different genetic factors influence these disease processes. [ABSTRACT FROM AUTHOR]

RATIONALE: Chronic obstructive pulmonary disease (COPD) is characterized by an accelerated decline in lung function. No drug has been shown conclusively to reduce this decline. OBJECTIVES: In a post hoc analysis of the Toward a Revolution in COPD Health (TORCH) study, we investigated the effects of combined salmeterol 50 microg plus fluticasone propionate 500 microg, either component alone or placebo, on the rate of post-bronchodilator FEV(1) decline in patients with moderate or severe COPD. METHODS: A randomized, double-blind, placebo-controlled study was conducted from September 2000 to November 2005 in 42 countries. Of 6,112 patients from the efficacy population, 5,343 were included in this analysis. MEASUREMENTS AND MAIN RESULTS: Spirometry was measured every 24 weeks for 3 years. There were 26,539 on-treatment observations. The adjusted rate of decline in FEV(1) was 55 ml/year for placebo, 42 ml/year for salmeterol, 42 ml/year for fluticasone propionate, and 39 ml/year for salmeterol plus fluticasone propionate. Salmeterol plus fluticasone propionate reduced the rate of FEV(1) decline by 16 ml/year compared with placebo (95% confidence interval [CI], 7-25; P < 0.001). The difference was smaller for fluticasone propionate and salmeterol compared with placebo (13 ml/year; 95% CI, 5-22; P = 0.003). Rates of decline were similar among the active treatment arms. FEV(1) declined faster in current smokers and patients with a lower body mass index, and varied between world regions. Patients who exacerbated more frequently had a faster FEV(1) decline. CONCLUSIONS: Pharmacotherapy with salmeterol plus fluticasone propionate, or the components, reduces the rate of decline of FEV(1) in patients with moderate-to-severe COPD, thus slowing disease progression. Clinical trial (GSK Study Code SCO30003) registered with www.clinicaltrials.gov (NCT00268216). [ABSTRACT FROM AUTHOR]

RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) have an ongoing systemic inflammation, which can be assessed by measuring serum C-reactive protein (CRP). OBJECTIVE: To determine whether increased serum CRP in individuals with airway obstruction predicts future hospitalization and death from COPD. METHODS: We performed a cohort study with a median of 8-yr follow-up of 1,302 individuals with airway obstruction selected from the ongoing Copenhagen City Heart Study. MEASUREMENTS AND MAIN RESULTS: We measured serum CRP at baseline, and recorded COPD admissions and deaths as outcomes. During follow-up, 185 (14%) individuals were hospitalized due to COPD and 83 (6%) died of COPD. Incidences of COPD hospitalization and COPD death were increased in individuals with baseline CRP > 3 mg/L versus < or = 3 mg/L (log rank: p < 0.001). After adjusting for sex, age, FEV(1)% predicted, tobacco consumption, and ischemic heart disease, the hazard ratios for hospitalization and death due to COPD were increased at 1.4 (95% confidence interval, 1.0-2.0) and 2.2 (1.2-3.9) in individuals with baseline CRP > 3 mg/L versus < or = 3 mg/L. After close matching for FEV(1)% predicted and adjusting for potential confounders, baseline CRP was, on average, increased by 1.2 mg/L (analysis of variance: p = 0.002) and 4.1 mg/L (p = 0.001) in those who were subsequently hospitalized or died of COPD, respectively. The absolute 10-yr risks for COPD hospitalization and death in individuals with CRP above 3 mg/L were 54 and 57%, respectively, among those older than 70 yr with a tobacco consumption above 15 g/d and an FEV(1)% predicted of less than 50. CONCLUSIONS: CRP is a strong and independent predictor of future COPD outcomes in individuals with airway obstruction. [ABSTRACT FROM AUTHOR]

Rationale: Low body mass index (BMI) is a marker of poor prognosis in chronic obstructive pulmonary disease (COPD). In the general population, the harmful effect of low BMI is due to the deleterious effects of a low fat-free mass index (FFMI; fat-free mass/weight[2]).Objectives: We explored distribution of low FFMI and its association with prognosis in a population-based cohort of patients with COPD.Methods: We used data on 1,898 patients with COPD identified in a population-based epidemiologic study in Copenhagen. FFM was measured using bioelectrical impedance analysis. Patients were followed up for a mean of 7 yr and the association between BMI and FFMI and mortality was examined taking age, sex, smoking, and lung function into account.Main Results: The mean FFMI was 16.0 kg/m[2] for women and 18.7 kg/m[2] for men. Among subjects with normal BMI, 26.1% had an FFMI lower than the lowest 10th percentile of the general population. BMI and FFMI were significant predictors of mortality, independent of relevant covariates. Being in the lowest 10th percentile of the general population for FFMI was associated with a hazard ratio of 1.5 (95% confidence interval, 1.2-1.8) for overall mortality and 2.4 (1.4-4.0) for COPD-related mortality. FFMI was also a predictor of overall mortality when analyses were restricted to subjects with normal BMI.Conclusions: FFMI provides information in addition to BMI and assessment of FFM should be considered in the routine assessment of COPD. [ABSTRACT FROM AUTHOR]

Rationale: Recent cohort studies in chronic obstructive pulmonary disease (COPD) have questioned the validity of previously reported associations between inhaled corticosteroids (ICS) and reductions in mortality and rehospitalization in observational studies. Using time-dependent versions of statistical survival models, these studies have suggested immortal time bias as responsible for the proposed beneficial association. Objectives: We explored the extent of this bias in a study of patients with COPD monitored for a year from COPD discharge with two designs free of any immortal time bias in the General Practice Research Database in the United Kingdom. Methods: In Design 1, we used only patients whose treatment status was defined on the same day of discharge to obtain a matched cohort based on propensity scores, which were derived from the patient-level baseline characteristics. In Design 2, we identified all in the study cohort who experienced death or rehospitalization and then matched each case to up to four noncases by randomly sampling from the cohort risk sets without regard to treatment status. Measurements and Main Results: The propensity scores matched cohort analysis of 786 patients without a wait time found a significant risk reduction associated with use of ICS: hazard ratio, 0.69 (95% confidence interval, 0.52-0.93). The matched nested case-control analysis of 2,222 patients, designed without regard to exposure status and hence free of immortal time bias, gave a similar association with exposure to ICS in the last 6-month period: hazard ratio, 0.71 (0.56-0.90). Conclusions: We conclude that immortal time bias cannot account for the risk reduction associated with ICS exposure in observational studies. [ABSTRACT FROM AUTHOR]