Bronchodilator Responsiveness in Tobacco-Exposed People With or Without COPD

Abstract

Background: Bronchodilator responsiveness (BDR) in obstructive lung disease varies over time and may be associated with distinct clinical features.

Research question: Is consistent BDR over time (always present) differentially associated with obstructive lung disease features relative to inconsistent (sometimes present) or never (never present) BDR in tobacco-exposed people with or without COPD?

Study design and methods: We retrospectively analyzed data from 2,269 tobacco-exposed participants in the Subpopulations and Intermediate Outcome Measures in COPD Study with or without COPD. We used various BDR definitions: change of ≥ 200 mL and ≥ 12% in FEV₁ (FEV₁-BDR), change in FVC (FVC-BDR), and change in in FEV₁, FVC or both (ATS-BDR). Using generalized linear models adjusted for demographics, smoking history, FEV₁ % predicted after bronchodilator administration, and number of visits that the participant completed, we assessed the association of BDR group: (1) consistent BDR, (2) inconsistent BDR, and (3) never BDR with asthma, CT scan features, blood eosinophil levels, and FEV₁ decline in participants without COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 0) and the entire cohort (participants with or without COPD).

Results: Both consistent and inconsistent ATS-BDR were associated with asthma history and greater small airways disease (%parametric response mapping functional small airways disease) relative to never ATS-BDR in participants with GOLD stage 0 disease and the entire cohort. We observed similar findings using FEV₁-BDR and FVC-BDR definitions. Eosinophils did not vary consistently among BDR groups. Consistent BDR was associated with FEV₁ decline over time relative to never BDR in the entire cohort. In participants with GOLD stage 0 disease, both the inconsistent ATS-BDR group (OR, 3.20; 95% CI, 2.21-4.66; P < .001) and consistent ATS-BDR group (OR, 9.48; 95% CI, 3.77-29.12; P < .001) were associated with progression to COPD relative to the never ATS-BDR group.

Interpretation: Demonstration of BDR, even once, describes an obstructive lung disease phenotype with a history of asthma and greater small airways disease. Consistent demonstration of BDR indicated a high risk of lung function decline over time in the entire cohort and was associated with higher risk of progression to COPD in patients with GOLD stage 0 disease.

Keywords: COPD; bronchodilator; bronchodilator response; bronchodilator responsiveness; bronchodilator reversibility.

Graphical abstract

Figure 1

Flowchart showing participant disposition through the study.

Figure 2

Graphs showing the association of BDR group with asthma in participants with GOLD stage 0 disease (ie, normal spirometry findings; n = 1,481) and the entire cohort (n = 2,269). We categorized tobacco-exposed participants with or without COPD based on BDR variability into three groups: consistent BDR when it is present at every visit; inconsistent BDR when it is present at some, but not all, visits; and never BDR when it is not present at any visit. Multivariate logistic regression models used BDR group as the independent variable and asthma diagnosis as the dependent variable. All models included the following covariates: age, sex, race, smoking status, pack-years smoked, and FEV₁ % predicted after bronchodilator administration at first visit, as well as number of visits. ATS-BDR = increase in FEV₁, FVC, or both of ≥ 12% and ≥ 200 mL after bronchodilator administration; BDR = bronchodilator responsiveness; FEV₁-BDR = increase in FEV₁ of ≥ 12% and ≥ 200 mL after bronchodilator administration; FVC-BDR = increase in FVC of ≥ 12% and ≥ 200 mL after bronchodilator administration; GOLD = Global Initiative for Chronic Obstructive Lung Disease.

Figure 3

Bar graphs showing the association of BDR group with chest CT scan findings in participants with GOLD stage 0 disease (ie, normal spirometry findings; n = 1,481). We categorized tobacco-exposed participants with normal spirometry findings based on BDR variability into three groups: consistent BDR when it is present at every visit; inconsistent BDR when it is present at some, but not all, visits; and never BDR when it is not present at any visit. Multivariate linear regression models with BDR group as the independent variable and Pi10, % PRM^fSAD, % emphysema, and % gas trapping as the dependent variables. All models included the following covariates: age, sex, race, smoking status and pack-years smoked, and FEV₁ % predicted after bronchodilator administration at first visit, as well as number of visits. Based on these models, we calculated the least square mean (LSM). Pairwise comparisons using Tukey’s method correction for LSM were used. Values in the figures are presented as LSM with 95% CI. ^aP < .05. ^bP < .01. ^cP < .001. ATS-BDR = increase in FEV₁, FVC, or both of ≥ 12% and ≥ 200 mL after bronchodilator administration; BDR = bronchodilator responsiveness; FEV₁-BDR = increase in FEV₁ of ≥ 12% and ≥ 200 mL after bronchodilator administration; FVC-BDR = increase in FVC of ≥ 12% and ≥ 200 mL after bronchodilator administration; Pi10 = square root of the airway wall area for a hypothetical airway with an internal perimeter of 10 mm; PRM^fSAD = parametric response mapping functional small airways disease.

Figure 4

Bar graphs showing the association of BDR group with chest CT scan findings in the entire cohort (n = 2,269). We categorized tobacco-exposed participants with or without COPD based on BDR variability into three groups: consistent BDR when it is present at every visit; inconsistent BDR when it is present at some, but not all, visits; and never BDR when it is not present at any visit. Multivariate linear regression models used BDR group as the independent variable and Pi10, % PRM^fSAD, % emphysema, and % gas trapping as the dependent variables. All models included the following covariates: age, sex, race, smoking status and pack-years smoked, and FEV₁ % predicted after bronchodilator administration at first visit, as well as number of visits. Based on these models, we calculated the least square mean (LSM). Pairwise comparisons using Tukey’s method correction for LSM were used. Values in the figures are presented as LSM with 95% CI. ^aP < .05. ^bP < .01. ^cP < .001. ATS-BDR = increase in FEV₁, FVC, or both of ≥ 12% and ≥ 200 mL after bronchodilator administration; BDR = bronchodilator responsiveness; FEV₁-BDR = increase in FEV₁ of ≥ 12% and ≥ 200 mL after bronchodilator administration; FVC-BDR = increase in FVC of ≥ 12% and ≥ 200 mL after bronchodilator administration; Pi10 = square root of the airway wall area for a hypothetical airway with an internal perimeter of 10 mm; PRM^fSAD = parametric response mapping functional small airways disease.

Figure 5

Bar graphs showing the association of BDR group with blood eosinophil counts at baseline and decline in FEV₁ after bronchodilator administration over time in participants with GOLD stage 0 disease (ie, normal spirometry findings; n = 1,481) and the entire cohort (n = 2,269). We categorized tobacco-exposed participants with or without COPD based on BDR variability into three groups: consistent BDR when it is present in every visit; inconsistent BDR when it is present at some, but not all, visits; and never BDR when it is not present at any visit. Multivariate linear regression models used BDR group as the independent variable and plasma eosinophil levels at baseline or decline in FEV₁ % predicted after bronchodilator administration over time as the dependent variable. All models included the following covariates: age, sex, race, smoking status and pack-years smoked, and FEV₁ % predicted after bronchodilator administration at first visit, as well as number of visits. Based on these models, we calculated the least square mean (LSM). Pairwise comparisons using Tukey method correction LSM were used. Values in the figures are presented as LSM with 95% CI. ^aP < .05. ^bP < .01. ^cP < .001. ATS-BDR = increase in FEV₁, FVC, or both of ≥ 12% and ≥ 200 mL after bronchodilator administration; BDR = bronchodilator responsiveness; FEV₁-BDR = increase in FEV₁ of ≥ 12% and ≥ 200 mL after bronchodilator administration; FVC-BDR = increase in FVC of ≥ 12% and ≥ 200 mL after bronchodilator administration; GOLD = Global Initiative for Chronic Obstructive Lung Disease.

Figure 6

Bar graphs showing BDR group and COPD at visit 5 in participants with GOLD stage 0 disease (ie, normal spirometry findings; n = 756). We categorized tobacco-exposed participants with or without COPD based on BDR variability into three groups: consistent BDR when it is present at every visit; inconsistent BDR when it is present at some, but not all, visits; and never BDR when it is not present at any visit. ATS-BDR = increase in FEV₁, FVC, or both of ≥ 12% and ≥ 200 mL after bronchodilator administration; BDR = bronchodilator responsiveness; FEV₁-BDR = increase in FEV₁ of ≥ 12% and ≥ 200 mL after bronchodilator administration; FVC-BDR = increase in FVC of ≥ 12% and ≥ 200 mL after bronchodilator administration; GOLD = Global Initiative for Chronic Obstructive Lung Disease.