Combined Forced Expiratory Volume in 1 Second and Forced Vital Capacity Bronchodilator Response, Exacerbations, and Mortality in Chronic Obstructive Pulmonary Disease

Abstract

Rationale: The American Thoracic Society (ATS)/European Respiratory Society defines a positive bronchodilator response (BDR) by a composite of BDR in either forced expiratory volume in 1 second (FEV1) and/or forced vital capacity (FVC) greater than or equal to 12% and 200 ml (ATS-BDR). We hypothesized that ATS-BDR components would be differentially associated with important chronic obstructive pulmonary disease (COPD) outcomes. Objectives: To examine whether ATS-BDR components are differentially associated with clinical, functional, and radiographic features in COPD. Methods: We included subjects with COPD enrolled in the COPDGene study. In the main analysis, we excluded subjects with self-reported asthma. We categorized BDR into the following: 1) No-BDR, no BDR in either FEV1 or FVC; 2) FEV1-BDR, BDR in FEV1 but no BDR in FVC; 3) FVC-BDR, BDR in FVC but no BDR in FEV1; and 4) Combined-BDR, BDR in both FEV1 and FVC. We constructed multivariable logistic, linear, zero-inflated negative binomial, and Cox hazards models to examine the association of BDR categories with symptoms, computed tomography findings, change in FEV1 over time, respiratory exacerbations, and mortality. We also created models using the ATS BDR definition (ATS-BDR) as the main independent variable. Results: Of 3,340 COPD subjects included in the analysis, 1,083 (32.43%) had ATS-BDR, 182 (5.45%) had FEV1-BDR, 522 (15.63%) had FVC-BDR, and 379 (11.34%) had Combined-BDR. All BDR categories were associated with FEV1 decline compared with No-BDR. Compared with No-BDR, both ATS-BDR and Combined-BDR were associated with higher functional residual capacity %predicted, greater internal perimeter of 10 mm, and greater 6-minute-walk distance. In contrast to ATS-BDR, Combined-BDR was independently associated with less emphysema (adjusted beta regression coefficient, -1.67; 95% confidence interval [CI], -2.68 to -0.65; P = 0.001), more frequent respiratory exacerbations (incidence rate ratio, 1.25; 95% CI, 1.03-1.50; P = 0.02) and severe exacerbations (incidence rate ratio, 1.34; 95% CI, 1.05-1.71; P = 0.02), and lower mortality (adjusted hazards ratio, 0.76; 95% CI, 0.58-0.99; P = 0.046). Sensitivity analysis that included subjects with self-reported history of asthma showed similar findings. Conclusions: BDR in both FEV1 and FVC indicates a COPD phenotype with asthma-like characteristics, and provides clinically more meaningful information than current definitions of BDR.

Trial registration: ClinicalTrials.gov NCT00608764.

Keywords: asthma; bronchodilator agents; chronic obstructive pulmonary disease; mortality; spirometry.

Figures

Figure 1.

Bronchodilator response rates in subjects with chronic obstructive pulmonary disease at enrollment and follow-up visit. ATS = American Thoracic Society; ATS-BDR = increase in prebronchodilator FEV1 and/or FVC ≥12% and ≥200 ml after bronchodilator administration; BDR = bronchodilator response; Combined-BDR = an increase in both FEV1 and FVC ≥12% and ≥200 ml after bronchodilator administration; COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; FEV1-BDR = increase in FEV1 ≥12% and ≥200 ml but a change in FVC <12% and 200 ml after bronchodilator administration; FVC-BDR = increase in FVC ≥12% and ≥200 ml but a change in FEV1 <12% and 200 ml after bronchodilator administration; No-BDR = a change in both FEV1 and FVC <12% and <200 ml after bronchodilator administration.