Signs of Gas Trapping in Normal Lung Density Regions in Smokers

Abstract

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 β = -0.020; 95% confidence interval [CI], -0.032 to -0.007; P = 0.001), St. George's Respiratory Questionnaire scores (adjusted β = 0.952; 95% CI, 0.529 to 1.374; P < 0.001), 6-minute-walk distance (adjusted β = -10.412; 95% CI, -12.267 to -8.556; P < 0.001), and body mass index, airflow obstruction, dyspnea, and exercise capacity index (adjusted β = 0.169; 95% CI, 0.148 to 0.190; P < 0.001), and also with FEV1 change at follow-up (adjusted β = -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. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

Keywords: chronic obstructive pulmonary disease; computed tomography; expiratory/inspiratory mean lung density ratio; small airway disease.

Figures

Figure 1.

Estimation of the normal-density ratio of expiratory to inspiratory mean lung density in a representative subject. First, the lung parenchyma was delineated into regions with disease and normal regions on the basis of traditional fixed-density thresholds for mild emphysema (−910 Hounsfield units [HU]) and gas trapping (−856 HU), as shown by the bold vertical lines. All voxels with density greater than −910 HU on inspiratory scans were classified as normal lung parenchyma at inspiration, and all voxels greater than −856 HU on expiratory scans were classified as normal at expiration. We then separately calculated the mean lung density of these normal regions at expiration (E) and inspiration (I), as shown by the red dashed lines. The ratio of E over I was referred to as ND-E/I, where ND represents the normal-density regions in the lung. CT = computed tomography.

Figure 2.

Mean normal-density ratio of expiratory to inspiratory mean lung density (ND-E/I) ratio in lifelong nonsmoking control subjects and in participants by Global Initiative for Chronic Obstructive Lung Disease (GOLD, G) stage. Box plots show means and 95% confidence intervals.

Figure 3.

The proportion of participants in each Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage with normal-density ratio of expiratory to inspiratory mean lung density (calculated as mean lung density of voxels greater than −856 HU at expiration and greater than −910 HU at inspiration, multiplied by 100) above the 90th percentile of normal (0.94).