Introduction
COPD Classification Systems
Characteristics, stability and outcomes of the 2011 GOLD COPD groups in the ECLIPSE cohort. Agusti et al.1 Eur Respir J 2013;42:636-46.
1. Comments
Biomarker
The association of adiponectin with computed tomography phenotypes in chronic obstructive pulmonary disease. Carolan et al.4 Am J Respir Care Med 2013;188:561-6.
RATIONALE: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder associated with systemic manifestations that contribute to its morbidity and mortality. Recent work suggests that biomarker signatures in the blood may be useful in evaluating COPD phenotypes and may provide insight into the pathophysiology of systemic manifestations. Adiponectin, primarily produced by fat cells, has been implicated in the pathophysiology of emphysema.
OBJECTIVES: To investigate the association of adiponectin with clinical and radiologic COPD phenotypes.
METHODS: Adiponectin levels were determined in 633 individuals, including 432 individuals with COPD from a cohort of former or current smokers enrolled in the COPDGene study. Univariate and multiple regression analysis were used to examine the association of adiponectin with clinical and physiologic data together with quantitative high-resolution computed tomography parameters.
MEASUREMENTS AND MAIN RESULTS: Multiple regression analysis confirmed that higher plasma adiponectin levels were independently associated with emphysema, decreasing body mass index, female sex, older age, and lower percentage change in prebronchodilator/post-bronchodilator FEV1.
CONCLUSIONS: The association between plasma adiponectin and computed tomography-assessed emphysema suggests a contribution of adiponectin to the development of emphysema and highlights a role for metabolic derangements in the pathophysiology of emphysema. (Carlolan et al.4, 2013, p. 561; Reprinted with permission of the American Thoracic Society. Copyright © 2014 American Thoracic Society. Official Journal of the American Thoracic Society.)
1. Comments
Exacerbations
Outgrowth of the bacterial airway microbiome after rhinovirus exacerbation of chronic obstructive pulmonary disease. Molyneaux et al.7 Am J Respir Crit Care Med 2013;188:1224-31.
RATIONALE: Rhinovirus infection is followed by significantly increased frequencies of positive, potentially pathogenic sputum cultures in chronic obstructive pulmonary disease (COPD). However, it remains unclear whether these represent de novo infections or an increased load of organisms from the complex microbial communities (microbiome) in the lower airways.
OBJECTIVES: To investigate the effect of rhinovirus infection on the airway bacterial microbiome.
METHODS: Subjects with COPD (n = 14) and healthy control subjects with normal lung function (n = 17) were infected with rhinovirus. Induced sputum was collected at baseline before rhinovirus inoculation and again on Days 5, 15, and 42 after rhinovirus infection and DNA was extracted. The V3-V5 region of the bacterial 16S ribosomal RNA gene was amplified and pyrosequenced, resulting in 370,849 high-quality reads from 112 of the possible 124 time points.
MEASUREMENTS AND MAIN RESULTS: At 15 days after rhinovirus infection, there was a sixfold increase in 16S copy number (P = 0.007) and a 16% rise in numbers of proteobacterial sequences, most notably in potentially pathogenic Haemophilus influenzae (P = 2.7 × 10(-20)), from a preexisting community. These changes occurred only in the sputum microbiome of subjects with COPD and were still evident 42 days after infection. This was in contrast to the temporal stability demonstrated in the microbiome of healthy smokers and nonsmokers.
CONCLUSIONS: After rhinovirus infection, there is a rise in bacterial burden and a significant outgrowth of Haemophilus influenzae from the existing microbiota of subjects with COPD. This is not observed in healthy individuals. Our findings suggest that rhinovirus infection in COPD alters the respiratory microbiome and may precipitate secondary bacterial infections. (Molyneaux et al.7, 2013, p.1224, Reprinted with permission of American Thoracic Society. Copyright © 2014 American Thoracic Society. Official Journal of the American Thoracic Society.)
1. Comments
Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. Leuppi et al.11 JAMA 2013;309:2223-31.
IMPORTANCE: International guidelines advocate a 7- to 14-day course of systemic glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, the optimal dose and duration are unknown.
OBJECTIVE: To investigate whether a short-term (5 days) systemic glucocorticoid treatment in patients with COPD exacerbation is noninferior to conventional (14 days) treatment in clinical outcome and whether it decreases the exposure to steroids.
DESIGN, SETTING, AND PATIENTS REDUCE: (Reduction in the Use of Corticosteroids in Exacerbated COPD), a randomized, noninferiority multicenter trial in 5 Swiss teaching hospitals, enrolling 314 patients presenting to the emergency department with acute COPD exacerbation, past or present smokers (≥20 pack-years) without a history of asthma, from March 2006 through February 2011.
INTERVENTIONS: Treatment with 40 mg of prednisone daily for either 5 or 14 days in a placebo-controlled, double-blind fashion. The predefined noninferiority criterion was an absolute increase in exacerbations of at most 15%, translating to a critical hazard ratio of 1.515 for a reference event rate of 50%.
MAIN OUTCOME AND MEASURE: Time to next exacerbation within 180 days.
RESULTS: Of 314 randomized patients, 289 (92%) of whom were admitted to the hospital, 311 were included in the intention-to-treat analysis and 296 in the per-protocol analysis. Hazard ratios for the short-term vs conventional treatment group were 0.95 (90% CI, 0.70 to 1.29; P = .006 for noninferiority) in the intention-to-treat analysis and 0.93 (90% CI, 0.68 to 1.26; P = .005 for noninferiority) in the per-protocol analysis, meeting our noninferiority criterion. In the short-term group, 56 patients (35.9%) reached the primary end point; 57 (36.8%) in the conventional group. Estimates of reexacerbation rates within 180 days were 37.2% (95% CI, 29.5% to 44.9%) in the short-term; 38.4% (95% CI, 30.6% to 46.3%) in the conventional, with a difference of -1.2% (95% CI, -12.2% to 9.8%) between the short-term and the conventional. Among patients with a reexacerbation, the median time to event was 43.5 days (interquartile range [IQR], 13 to 118) in the short-term and 29 days (IQR, 16 to 85) in the conventional. There was no difference between groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function. In the conventional group, mean cumulative prednisone dose was significantly higher (793 mg [95% CI, 710 to 876 mg] vs 379 mg [95% CI, 311 to 446 mg], P < .001), but treatment-associated adverse reactions, including hyperglycemia and hypertension, did not occur more frequently.
CONCLUSIONS AND RELEVANCE: In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to 14-day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure. These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD. (Leuppi et al.11, 2013, p. 2223; Reprinted with permission of American Medical Association)
1. Comments
Management
Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Bateman et al.15 Eur Respir J 2013;42:1484-94
1. Comments
Tiotropium Respimat inhaler and the risk of death in COPD. Wise et al.20 N Engl J Med 2013;396:1491-501
BACKGROUND: Tiotropium delivered at a dose of 5 µg with the Respimat inhaler showed efficacy similar to that of 18 µg of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo.
METHODS: In this randomized, double-blind, parallel-group trial involving 17,135 patients with COPD, we evaluated the safety and efficacy of tiotropium Respimat at a once-daily dose of 2.5 µg or 5 µg, as compared with tiotropium HandiHaler at a once-daily dose of 18 µg. Primary end points were the risk of death (noninferiority study, Respimat at a dose of 5 µg or 2.5 µg vs. HandiHaler) and the risk of the first COPD exacerbation (superiority study, Respimat at a dose of 5 µg vs. HandiHaler). We also assessed cardiovascular safety, including safety in patients with stable cardiac disease.
RESULTS: During a mean follow-up of 2.3 years, Respimat was noninferior to HandiHaler with respect to the risk of death (Respimat at a dose of 5 µg vs. HandiHaler: hazard ratio, 0.96; 95% confidence interval [CI], 0.84 to 1.09; Respimat at a dose of 2.5 µg vs. HandiHaler: hazard ratio, 1.00; 95% CI, 0.87 to 1.14) and not superior to HandiHaler with respect to the risk of the first exacerbation (Respimat at a dose of 5 µg vs. HandiHaler: hazard ratio, 0.98; 95% CI, 0.93 to 1.03). Causes of death and incidences of major cardiovascular adverse events were similar in the three groups.
CONCLUSIONS: Tiotropium Respimat at a dose of 5 µg or 2.5 µg had a safety profile and exacerbation efficacy similar to those of tiotropium HandiHaler at a dose of 18 µg in patients with COPD. (Wise et al.20, 2013, p. 1491; Reprinted with permission of Massachusetts Medical Society)