Computed Tomography Measure of Lung at Risk and Lung Function Decline in Chronic Obstructive Pulmonary Disease

Abstract

Rationale: The rate of decline of lung function is greater than age-related change in a substantial proportion of patients with chronic obstructive pulmonary disease, even after smoking cessation. Regions of the lung adjacent to emphysematous areas are subject to abnormal stretch during respiration, and this biomechanical stress likely influences emphysema initiation and progression.

Objectives: To assess whether quantifying this penumbra of lung at risk would predict FEV₁ decline.

Methods: We analyzed paired inspiratory-expiratory computed tomography images at baseline of 680 subjects participating in a large multicenter study (COPDGene) over approximately 5 years. By matching inspiratory and expiratory images voxel by voxel using image registration, we calculated the Jacobian determinant, a measure of local lung expansion and contraction with respiration. We measured the distance between each normal voxel to the nearest emphysematous voxel, and quantified the percentage of normal voxels within each millimeter distance from emphysematous voxels as mechanically affected lung (MAL). Multivariable regression analyses were performed to assess the relationship between the Jacobian determinant, MAL, and FEV₁ decline.

Measurements and main results: The mean (SD) rate of decline in FEV₁ was 39.0 (58.6) ml/yr. There was a progressive decrease in the mean Jacobian determinant of both emphysematous and normal voxels with increasing disease stage (P < 0.001). On multivariable analyses, the mean Jacobian determinant of normal voxels within 2 mm of emphysematous voxels (MAL₂) was significantly associated with FEV₁ decline. In mild-moderate disease, for participants at or above the median MAL₂ (threshold, 36.9%), the mean decline in FEV₁ was 56.4 (68.0) ml/yr versus 43.2 (59.9) ml/yr for those below the median (P = 0.044).

Conclusions: Areas of normal-appearing lung are mechanically influenced by emphysematous areas and this lung at risk is associated with lung function decline. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

Keywords: FEV1; biomechanical; emphysema; image registration; lung at risk.

Figure 1.

Graphic representation of the spatial mapping methodology showing spatial mapping for a representative subject. (A) Deformed inspiratory image with (B) emphysema regions (low-attenuation areas less than −950 Hounsfield units [HU]) highlighted in red on inspiratory computed tomography scan. (C) Example of emphysematous region in the lung. (D) Three-dimensional Euclidean distance-based clustering: distance was calculated for each normal voxel to the nearest emphysema voxel in three dimensions, and the surrounding normal tissue was clustered into different groups based on their spatial distance to the nearest emphysema voxels. Clustering of the surrounding tissue was performed in 1-mm increments up to 5 mm based on distance to nearest emphysematous voxels. (E) Color map representing the distances of normal voxels to the nearby emphysematous regions, from 1 to 5 mm. Red represents emphysema regions, labeled as 0 mm in the color scale. CT = computed tomography.

Figure 2.

Comparison of lung density and mechanics by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage for emphysematous and normal voxels. (A) With increasing severity of chronic obstructive pulmonary disease by GOLD grade, the percentage of voxels of the lung parenchyma with density less than −950 Hounsfield units (computed tomography emphysema) increases, whereas the number of normal voxels progressively decreases. (B) With progressive disease severity the mean Jacobian determinant, a measure of regional lung expansion, of the emphysematous voxels progressively decreases. Of note, the mean Jacobian determinant of the normal voxels also decreases with progressive GOLD grade. COPD = chronic obstructive pulmonary disease; CT = computed tomography.

Figure 3.

Spatial mapping of emphysema and surrounding normal areas depicting relative contributions of mechanically affected lung to FEV₁ change. Graphic of a hypothetical central emphysematous area and surrounding normal voxels. β represents adjusted regression coefficient for mean Jacobian determinant for each 1-mm incremental distance of normal voxels from emphysematous voxels. Computed tomography (CT) emphysema was defined as percentage of voxels less than −950 Hounsfield units (HU). All models for predicting FEV₁ change were adjusted for age, race, sex, body mass index, smoking pack-years, current smoking status, FEV₁ at baseline, CT emphysema, CT gas trapping, segmental wall area %, and CT scanner protocol. *Significant at P < 0.05.