Objectively Measured Chronic Lung Injury on Chest CT

Background: Tobacco smoke exposure is associated with emphysema and pulmonary fibrosis, both of which are irreversible. We have developed a new objective CT analysis tool that combines densitometry with machine learning to detect high attenuation changes in visually normal appearing lung (Norm_HA) that may precede these diseases. Methods: We trained the classification tool by placing 34,528 training points in chest CT scans from 297 COPDGene participants. The tool was then used to classify lung tissue in 9,038 participants as normal, emphysema, fibrotic/interstitial, or Norm_HA. Associations between the quartile of Norm_HA and plasma-based biomarkers, clinical severity, and mortality were evaluated using Jonckheere-Terpstra, pairwise Wilcoxon rank-sum tests, and multivariable linear and Cox regression. Results: A higher percentage of lung occupied by Norm_HA was associated with higher C-reactive protein and intercellular adhesion molecule 1 (P for trend for both <.001). In analyses adjusted for multiple covariates, including high and low attenuation area, compared with those in the lowest quartile of Norm_HA, those in the highest quartile had a 6.50 absolute percent lower percent predicted lower FEV₁ (P <.001), an 8.48 absolute percent lower percent predicted forced expiratory volume, a 10.78-meter shorter 6-min walk distance (P =.011), and a 56% higher risk of death (P =.003). These findings were present even in those individuals without visually defined interstitial lung abnormalities. Conclusions: A new class of Norm_HA on CT may represent a unique tissue class associated with adverse outcomes, independent of emphysema and fibrosis.