Heterogeneous burden of lung disease in smokers with borderline airflow obstruction

Cheryl S Pirozzi, Tian Gu, Pedro M Quibrera, Elizabeth E Carretta, MeiLan K Han, Susan Murray, Christopher B Cooper, Donald P Tashkin, Eric C Kleerup, Igor Barjaktarevic, Eric A Hoffman, Carlos H Martinez, Stephanie A Christenson, Nadia N Hansel, R Graham Barr, Eugene R Bleecker, Victor E Ortega, Fernando J Martinez, Richard E Kanner, Robert Paine 3rd, NHLBI SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), Neil E Alexis, Wayne H Anderson, R Graham Barr, Eugene R Bleecker, Richard C Boucher, Russell P Bowler, Elizabeth E Carretta, Stephanie A Christenson, Alejandro P Comellas, Christopher B Cooper, David J Couper, Gerard J Criner, Ronald G Crystal, Jeffrey L Curtis, Claire M Doerschuk, Mark T Dransfield, Christine M Freeman, MeiLan Lan K Han, Nadia N Hansel, Annette T Hastie, Eric A Hoffman, Robert J Kaner, Richard E Kanner, Eric C Kleerup, Jerry A Krishnan, Lisa M LaVange, Stephen C Lazarus, Fernando J Martinez, Deborah A Meyers, John D Newell Jr, Elizabeth C Oelsner, Wanda K O'Neal, Robert Paine 3rd, Nirupama Putcha, Stephen I Rennard, Donald P Tashkin, Mary Beth Scholand, J Michael Wells, Robert A Wise, Prescott G Woodruff, Lisa Postow, Thomas Croxton, Cheryl S Pirozzi, Tian Gu, Pedro M Quibrera, Elizabeth E Carretta, MeiLan K Han, Susan Murray, Christopher B Cooper, Donald P Tashkin, Eric C Kleerup, Igor Barjaktarevic, Eric A Hoffman, Carlos H Martinez, Stephanie A Christenson, Nadia N Hansel, R Graham Barr, Eugene R Bleecker, Victor E Ortega, Fernando J Martinez, Richard E Kanner, Robert Paine 3rd, NHLBI SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), Neil E Alexis, Wayne H Anderson, R Graham Barr, Eugene R Bleecker, Richard C Boucher, Russell P Bowler, Elizabeth E Carretta, Stephanie A Christenson, Alejandro P Comellas, Christopher B Cooper, David J Couper, Gerard J Criner, Ronald G Crystal, Jeffrey L Curtis, Claire M Doerschuk, Mark T Dransfield, Christine M Freeman, MeiLan Lan K Han, Nadia N Hansel, Annette T Hastie, Eric A Hoffman, Robert J Kaner, Richard E Kanner, Eric C Kleerup, Jerry A Krishnan, Lisa M LaVange, Stephen C Lazarus, Fernando J Martinez, Deborah A Meyers, John D Newell Jr, Elizabeth C Oelsner, Wanda K O'Neal, Robert Paine 3rd, Nirupama Putcha, Stephen I Rennard, Donald P Tashkin, Mary Beth Scholand, J Michael Wells, Robert A Wise, Prescott G Woodruff, Lisa Postow, Thomas Croxton

Abstract

Background: The identification of smoking-related lung disease in current and former smokers with normal FEV1 is complex, leading to debate regarding using a ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) of less than 0.70 versus the predicted lower limit of normal (LLN) for diagnosis of airflow obstruction. We hypothesized that the discordant group of ever-smokers with FEV1/FVC between the LLN and 0.70 is heterogeneous, and aimed to characterize the burden of smoking-related lung disease in this group.

Methods: We compared spirometry, chest CT characteristics, and symptoms between 161 ever-smokers in the discordant group and 940 ever-smokers and 190 never-smokers with normal FEV1 and FEV1/FVC > 0.70 in the SPIROMICS cohort. We also estimated sensitivity and specificity for diagnosing objective radiographic evidence of chronic obstructive pulmonary disease (COPD) using different FEV1/FVC criteria thresholds.

Results: The discordant group had more CT defined emphysema and non-emphysematous gas trapping, lower post-bronchodilator FEV1 and FEF25-75, and higher respiratory medication use compared with the other two groups. Within the discordant group, 44% had radiographic CT evidence of either emphysema or non-emphysematous gas trapping; an FEV1/FVC threshold of 0.70 has greater sensitivity but lower specificity compared with LLN for identifying individuals with CT abnormality.

Conclusions: Ever-smokers with normal FEV1 and FEV1/FVC < 0.70 but > LLN are a heterogeneous group that includes significant numbers of individuals with and without radiographic evidence of smoking-related lung disease. These findings emphasize the limitations of diagnosing COPD based on spirometric criteria alone.

Keywords: Airway obstruction; Chronic obstructive pulmonary disease; Emphysema; Forced expiratory volume; Maximal Midexpiratory flow rate; Pulmonary function tests; Spirometry.

Conflict of interest statement

Ethics approval and consent to participate

The research protocol was approved by the institutional review boards of all participating institutions and all participants gave written informed consent. Institutional review board approval reference numbers for each clinical site are available as Additional file 5.

Consent for publication

Not applicable

Competing interests

Dr. Tashkin reports personal fees from Boehringer-Ingelheim, personal fees from AstraZeneca, personal fees from Sunovion, personal fees from Theravance/Innoviva, personal fees from Mylan, outside the submitted work. Dr. Kleerup reports grants from NIH, grants from Foundation for the NIH, during the conduct of the study; grants from Boehringer Ingelheim, grants from Novartis, grants from Pearl/AstraZeneca, grants from Sunovion/Sepracor, outside the submitted work. Boehringer Ingelheim and GlaxoSmithKline supplied inhalers for pulmonary function testing in this study. Dr. Han reports personal fees from GSK, personal fees from BI, personal fees from AZ, non-financial support from Sunovion, non-financial support from Novartis, outside the submitted work. Dr. Cooper reports grants from Equinox Health Clubs, personal fees from Equinox Health Clubs, grants from Amgen, personal fees from PulmonX, GlaxoSmithKline, outside the submitted work; and works with scientific engagement for the GlaxoSmithKline Global Respiratory Franchise. Dr. Barjaktarevic reports grants from NIH, during the conduct of the study; personal fees from Astra Zeneca, from Grifols, from CSL Behring, outside the submitted work. Dr. Hoffman is a founder and shareholder of VIDA Diagnostics, a company commercializing lung image analysis software developed, in part, at the University of Iowa. Dr. Christenson reports personal fees from AstraZeneca, non-financial support from Genentech, grants from MedImmune, outside the submitted work. Dr. Hansel reports grants and personal fees from AstraZeneca, grants and personal fees from GSK, grants from Boehringer Ingelheim, grants from NIH, grants from COPD Foundation, outside the submitted work. Dr. Bleecker has undertaken clinical trials through his employer, Wake Forest School of Medicine and University of Arizona, for AstraZeneca, MedImmune, Boehringer Ingelheim, Cephalon/Teva, Genentech, Johnson and Johnson (Janssen), Novartis, Regeneron, and Sanofi Genzyme, personal fees from ERB, has also served as a paid consultant for AztraZeneca, MedImmune, Boehringer Ingelheim, Glaxo Smith Kline, Novartis, Regeneron, and Sanofi Genzyme, outside the submitted work. Dr. Martinez reports grants from NHLBI, during the conduct of the study; grants from National Institutes of Health, personal fees from Continuing Education, personal fees from Forest Laboratories, other from Janssen, personal fees from GlaxoSmithKline, personal fees from Nycomed/Takeda, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Bellerophon (formerly Ikaria), personal fees from Genentech, personal fees from Novartis, personal fees from Pearl, personal fees from Roche, personal fees from Sunovion, personal fees from Theravance, personal fees from CME Incite, personal fees from Annenberg Center for Health Sciences at Eisenhower, personal fees from Integritas, personal fees from InThought, personal fees from National Association for Continuing Education, personal fees from Paradigm Medical Communications, LLC, personal fees from PeerVoice, personal fees from UpToDate, personal fees from Haymarket Communications, personal fees from Western Society of Allergy and Immunology, from Proterixbio (formerly Bioscale), personal fees from Unity Biotechnology, personal fees from ConCert Pharmaceuticals, personal fees from Lucid, personal fees from Methodist Hospital, personal fees from Columbia University, personal fees from Prime Healthcare Ltd., personal fees from WebMD, personal fees from PeerView Network, personal fees from California Society of Allergy and Immunology, personal fees from Chiesi, personal fees from Puerto Rico Thoracic Society, outside the submitted work. Ms. Carretta reports funding from the National Heart, Lung, and Blood Institute, the Foundation for the NIH, Genentech, and the COPD Foundation during the conduct of the study. Dr. Paine reports grants from National Heart Lung and Blood Institute, grants from COPD Foundation, during the conduct of the study; grants from Department of Veterans Affairs, outside the submitted work.

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Figures

Fig. 1
Fig. 1
Box plots demonstrating percent of predicted forced expiratory volume in 1 s (FEV1%), forced expiratory flow rate between 25 and 75% of forced vital capacity (FEF25–75%), percent emphysema, and functional small airways disease by parametric response mapping (fSAD) in the three groups
Fig. 2
Fig. 2
Percent of patients in each group with emphysema and functional small airways disease (fSAD) present greater than the age-adjusted upper limit of normal (ULN) as measured by parametric response mapping (PRM) on chest CT

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