• Ehab Billatos, Samuel Y Ash, Fenghai Duan, Ke Xu, Justin Romanoff, Helga Marques, Elizabeth Moses, MeiLan K Han, Elizabeth A Regan, Russell P Bowler, Stefanie E Mason, Tracy J Doyle, Rubén San José Estépar, Ivan O Rosas, James C Ross, Xiaohui Xiao, Hanqiao Liu, Gang Liu, Gauthaman Sukumar, Matthew Wilkerson, Clifton Dalgard, Christopher Stevenson, Duncan Whitney, Denise Aberle, Avrum Spira, San José EstéparRaúlRApplied Chest Imaging Laboratory, Brigham and Women's Hospital, Boston, MA; Department of Radiology, Brigham and Women's Hospital, Boston, MA., Marc E Lenburg, George R Washko, and DECAMP and COPDGene Investigators.
• Department of Medicine, Section of Pulmonary and Critical Care Medicine, Boston University, Boston, MA; Department of Medicine, Section of Computational Biomedicine, Boston University, Boston, MA. Electronic address: ebillato@bu.edu.
• Chest. 2021 Feb 1; 159 (2): 549563549-563.

BackgroundChronic 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 CT imaging has identified several clinically relevant subgroups of smoking related lung disease, but these investigations have generally lacked organ specific molecular correlates.Research QuestionCan CT imaging be used to identify clinical phenotypes of smoking related lung disease that have specific bronchial epithelial gene expression patterns to better understand disease pathogenesis?Study Design And MethodsUsing K-means clustering, we clustered participants from the COPDGene study (n = 5,273) 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.ResultsThree 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 (tumor necrosis factor-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.InterpretationUsing 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 tumor necrosis factor-α and interferon-β pathways.Clinical Trial RegistrationCOPDGene (NCT00608764), DECAMP-1 (NCT01785342), DECAMP-2 (NCT02504697).Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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