Signs of Gas Trapping in Normal Lung Density Regions in Smokers

Rationale: A substantial proportion of subjects without overt airflow obstruction have significant respiratory morbidity and structural abnormalities as visualized by computed tomography. Whether regions of the lung that appear normal using traditional computed tomography criteria have mild disease is not known. Objectives: To identify subthreshold structural disease in normal-appearing lung regions in smokers. Methods: We analyzed 8,034 subjects with complete inspiratory and expiratory computed tomographic data participating in the COPDGene Study, including 103 lifetime nonsmokers. The ratio of the mean lung density at end expiration (E) to end inspiration (I) was calculated in lung regions with normal density (ND) by traditional thresholds for mild emphysema (-910 Hounsfield units) and gas trapping (-856 Hounsfield units) to derive the ND-E/I ratio. Multivariable regression analysis was used to measure the associations between ND-E/I, lung function, and respiratory morbidity. Measurements and Main Results: The ND-E/I ratio was greater in smokers than in nonsmokers, and it progressively increased from mild to severe chronic obstructive pulmonary disease severity. A proportion of 26.3% of smokers without airflow obstruction had ND-E/I greater than the 90th percentile of normal. ND-E/I was independently associated with FEV1 (adjusted beta=-0.020; 95% confidence interval [CI], -0.032 to -0.007; P=0.001), St. George's Respiratory Questionnaire scores (adjusted beta=0.952; 95% CI, 0.529 to 1.374; P<0.001), 6-minute-walk distance (adjusted beta=-10.412; 95% CI, -12.267 to -8.556; P<0.001), and body mass index, airflow obstruction, dyspnea, and exercise capacity index (adjusted beta=0.169; 95% CI, 0.148 to 0.190; P<0.001), and also with FEV1 change at follow-up (adjusted beta=-3.013; 95% CI, -4.478 to -1.548; P=0.001). Conclusions: Subthreshold gas trapping representing mild small airway disease is prevalent in normal-appearing lung regions in smokers without airflow obstruction, and it is associated with respiratory morbidity.