Lung Tissue Heterogeneity in Non-smokers, Smokers without Airflow Obstruction, and COPD

Chronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory disease characterised by airflow obstruction and heterogeneous tissue microstructure. We hypothesised that lung tissue with normal attenuation on CT imaging in COPD (GOLD 1-4) would have higher heterogeneity than lung tissue in never-smokers and smokers without airflow obstruction (GOLD0). We examined CT imaging from 520 participants from the COPDGene study, comprising never-smokers (N=71), GOLD0 (N=76), and COPD (128, 90, 99, 56 in GOLD stages 1-4, respectively). Tissue heterogeneity was assessed using a quadtree decomposition metric (QtD) applied to full tissue (QtD_Full), low density (QtD_LD) tissue (< -900 HU), and medium density (QtD_MD) tissue (> -900 HU and < -700 HU). MD tissue was assumed representative of ‘normal’. Multivariable models adjusted for age, sex, race, smoking status and BMI were fitted to test associations of FEV1% and metrics of respiratory morbidity with QtD. QtD_Full and QtD_LD were higher (p < 0.001) in GOLD0 (QtD_Full: 0.21 ± 0.07; QtD_LD: 0.07 ± 0.05) than never-smokers (QtD_Full: 0.15 ± 0.05; QtD_LD: 0.04 ± 0.03). QtD_MD and QtD_LD were higher (p < 0.001) in the COPD group (N=373; QtD_MD: 0.27 ± 0.09; QtD_LD: 0.07 ± 0.04) than in never-smokers (QtD_MD: 0.18 ± 0.06); QtD_MD tended to increase with GOLD stage. Multivariable models (derived for N=361 COPD with complete data) showed that the QtD metrics were independently associated with FEV1% predicted and metrics of respiratory morbidity (p < 0.05 for all associations), including when adjusted for emphysema% and gas trapping%. Heterogeneity in low-density and medium-density tissues is associated with lung function and patient outcomes in COPD.