Distinguishing smoking related lung disease phenotypes via imaging and molecular features.

Abstract Background Chronic tobacco smoke exposure results in a broad range of lung pathologies including emphysema, airway disease and parenchymal fibrosis as well as a multitude of extra-pulmonary comorbidities. Prior work using computed tomography imaging has identified several clinically relevant subgroups of smoking related lung disease, but these investigations have generally lacked organ specific molecular correlates. Research Question Can computed tomography imaging be used to identify clinical phenotypes of smoking related lung disease that have specific bronchial epithelial gene expression patterns in order to better understand disease pathogenesis? Study Design and Methods: Using K-means clustering, we clustered participants from the COPDGene study (n=5273) based on CT imaging characteristics and then evaluated their clinical phenotypes. These clusters were replicated in the Detection of Early Lung Cancer Among Military Personnel (DECAMP) cohort (n=360), and were further characterized using bronchial epithelial gene expression. Results Three clusters (preserved, interstitial predominant and emphysema predominant) were identified. Compared to the preserved cluster, the interstitial and emphysema clusters had worse lung function, exercise capacity and quality of life. In longitudinal follow-up, individuals from the emphysema group had greater declines in exercise capacity and lung function, more emphysema, more exacerbations, and higher mortality. Similarly, genes involved in inflammatory pathways (TNF-α, interferon-β) are more highly expressed in bronchial epithelial cells from individuals in the emphysema cluster, while genes associated with T-cell related biology are decreased in these samples. Samples from individuals in the interstitial cluster generally had intermediate levels of expression of these genes. Interpretation Using quantitative CT imaging, we identified three groups of individuals in older ever-smokers that replicate in two cohorts. Airway gene expression differences between the three groups suggests increased levels of inflammation in the most severe clinical phenotype, possibly mediated by the TNF-α and interferon-β pathways. Clinical Trial Registration COPDGene (NCT00608764), DECAMP-1 (NCT01785342), DECAMP-2 (NCT02504697)