Clinical Significance of Bronchodilator Responsiveness Evaluated by Forced Vital Capacity in COPD: SPIROMICS Cohort Analysis

Abstract

Objective

Bronchodilator responsiveness (BDR) is prevalent in COPD, but its clinical implications remain unclear. We explored the significance of BDR, defined by post-bronchodilator change in FEV₁ (BDR_FEV1) as a measure reflecting the change in flow and in FVC (BDR_FVC) reflecting the change in volume.

Methods

We analyzed 2974 participants from a multicenter observational study designed to identify varying COPD phenotypes (SPIROMICS). We evaluated the association of BDR with baseline clinical characteristics, rate of prospective exacerbations and mortality using negative binomial regression and Cox proportional hazards models.

Results

A majority of COPD participants exhibited BDR (52.7%). BDR_FEV1 occurred more often in earlier stages of COPD, while BDR_FVC occurred more frequently in more advanced disease. When defined by increases in either FEV₁ or FVC, BDR was associated with a self-reported history of asthma, but not with blood eosinophil counts. BDR_FVC was more prevalent in subjects with greater emphysema and small airway disease on CT. In a univariate analysis, BDR_FVC was associated with increased exacerbations and mortality, although no significance was found in a model adjusted for post-bronchodilator FEV₁.

Conclusion

With advanced airflow obstruction in COPD, BDR_FVC is more prevalent in comparison to BDR_FEV1 and correlates with the extent of emphysema and degree of small airway disease. Since these associations appear to be related to the impairment of FEV₁, BDR_FVC itself does not define a distinct phenotype nor can it be more predictive of outcomes, but it can offer additional insights into the pathophysiologic mechanism in advanced COPD.

Clinical trials registration

ClinicalTrials.gov: NCT1969344T4.

Keywords:

• bronchodilator responsiveness
• inspiratory capacity
• FVC
• FEV₁
• SPIROMICS

View correction statement:

Clinical Significance of Bronchodilator Responsiveness Evaluated by Forced Vital Capacity in COPD: SPIROMICS Cohort Analysis [Corrigendum]

Acknowledgements

Participants: The authors thank the SPIROMICS participants and participating physicians, investigators, and staff for making this research possible. More information about the study and how to access SPIROMICS data is at www.spiromics.org. In addition to coauthors of this manuscript, we would like to acknowledge the following current and former investigators of the SPIROMICS sites and reading centers: Neil E Alexis, PhD, Eugene R Bleecker, MD, Richard C Boucher, MD, Alejandro P Cornellas, MD, Ronald G Crystal, MD, Brett Dolezal, PhD, Freeman, PhD, Annette T Hastie, PhD, Eric C Kleerup, MD, Lisa M LaVange, PhD, Stephen C Lazarus, MD, Deborah A Meyers, PhD, John D Newell Jr, MD, Elizabeth C Oelsner, MD, MPH, Nirupama Putcha, MD, MHS, Mary Beth Scholand, MD, and Robert A Wise, MD. The project officers from the Lung Division of the National Heart, Lung, and Blood Institute were Lisa Postow, PhD, and Thomas Croxton, PhD, MD.

Data Sharing Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author Contributions

IB and CBC had full access to all of the data in the study and take responsibility for the integrity of the data and accuracy of the analysis. IB, CBC, SH, XW, RGB, DT contributed to the conception and design of the study. All authors contributed to data analysis, drafting and revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

IB has received research grants from AMGEN and GE Healthcare; and reports personal fees from Astra Zeneca, GSK, Boehringer Ingelheim, GE Healthcare, Theravance, Mylan, GRIFOLS, CSL Behring, Verona Pharma and Fisher & Pykel Healthcare. SPB is supported by NIH Grant K23HL133438 and he has served on an advisory board for Sunovion and reports grants from NIH, personal fees from Sunovion, personal fees from GlaxoSmithKline, outside the submitted work. JLC is supported by Merit Review award I01 CX000911 from the Department of Veterans Affairs, and reports grants the Department of Defense, the National Institutes of Health, and from MedImmune Corporation, Ltd., and reports grants from NIH/NHLBI, during the conduct of the study; grants from NIH/NIAID, grants from Department of Veterans Affairs, grants from Department of Defense, outside the submitted work. MKH has consulted for GSK, Boehringer Ingelheim and AstraZeneca, has received research support from Novartis and Sunovion and reports grants from NIH, during the conduct of the study; and Consulting for GSK, BI, Mylan and AstraZeneca, research support from Sunovion and Novartis. FJM reports grants from NHLBI, National Institutes of Health, personal fees from Continuing Education, personal fees from Forest Laboratories, Janssen, GlaxoSmithKline, Nycomed/Takeda, AstraZeneca, Boehringer Ingelheim, Bellerophon (formerly Ikaria), Genentech, Novartis, Pearl, Roche, Sunovion, Theravance, CME Incite, Annenberg Center for Health Sciences at Eisenhower, Integritas, InThought, National Association for Continuing Education, Paradigm Medical Communications, LLC, PeerVoice, UpToDate, Haymarket Communications, Western Society of Allergy and Immunology, Proterixbio (formerly Bioscale), Unity Biotechnology, ConCert Pharmaceuticals, Lucid, Methodist Hospital, Columbia University, Prime Healthcare Ltd, WebMD, PeerView Network, California Society of Allergy and Immunology, Chiesi, Puerto Rico Thoracic Society, outside the submitted work, and reports personal fees from Afferent/Merck, personal fees from American Thoracic Society, grants, personal fees, non-financial support from AstraZeneca, personal fees from Bayer, non-financial support from Boehringer Ingelehim, personal fees from ProTerrix Bio, personal fees from Bridge Biotherapeutics, personal fees, non-financial support from Chiesi, personal fees from Gala, personal fees, non-financial support, personal fees from Genentech, grants, personal fees, non-financial support from GlaxoSmithKline, grants, personal fees from Nitto, personal fees from ProMedior, personal fees from ProMetic, personal fees from Patara/Respivant, personal fees from Biogen, personal fees, non-financial support from Sunovion, personal fees, non-financial support from Teva, personal fees from Veracyte, during the conduct of the study. NH reports grants and personal fees from AstraZeneca, GSK, Boehringer Ingelheim, grants from NIH, COPD Foundation, outside the submitted work. GB has grants from the NIH, Foundation for the NIH, COPD Foundation and Alpha-1 Foundation, and reports grants, personal fees from AstraZeneca, grants from Boehringer Ingelheim, grants from NIH, grants from COPD Foundation, personal fees from Mylan, outside the submitted work. JMW has received grant support from the NIH, contracts to conduct research from GSK, Bayer, MereoBioPharma,Quintiles, and reports grants from NIH/NHLBI, during the conduct of the study; grants from NIH/NCATS, grants from Bayer, grants, personal fees from GSK, personal fees from Boehringer Ingelheim, grants, personal fees from Mereo BioPharma, personal fees from Quintiles, outside the submitted work. EAH a founder and shareholder of VIDA Diagnostics, a company commercializing lung image analysis software developed, and reports personal fees from VIDA Diagnostics, during the conduct of the study. VK has consulted for Boehringer Ingelheim, Gala Therapeutics and AstraZeneca and received personal fees from ABIM, and reports personal fees from Medscape, personal fees from Gala Therapeutics, personal fees from ABIM Critical Care Testwriting Committee, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, outside the submitted work. MTD reports receiving grants from the NIH, the Department of Defense, and the American Heart Association; consulting fees from Boehringer Ingelheim, GlaxoSmithKline, Novartis, Astra Zeneca, Yungjin, PneumRx/BTG, Pulmonx, Genentech, Boston Scientific, Quark Pharmaceuticals, Mereo and received grants from American Lung Association and NIH, and reports grants from NIH, during the conduct of the study; personal fees from Boehringer Ingelheim, personal fees from AstraZeneca, personal fees from GlaxoSmithKline, personal fees from Boston Scientific, grants from American Lung Association, grants from Department of Defense, grants from Department of Veterans Affairs, personal fees from Mereo, personal fees from Quark, outside the submitted work. MBD has received research grants from the NIH and reports personal fees from Boehringer-Ingelheim, GlaxoSmithKline, AstraZeneca, and Mylan-Theravance, outside the submitted work, and reports grants from NIH-NHLBI, during the conduct of the study; grants, personal fees from Boehringer-Ingelheim, personal fees from GlaxoSmithKline, personal fees from AstraZeneca, personal fees from Mylan-Theravance, grants from Department of Defense, personal fees from Novavax, personal fees from Parion, personal fees from Midmark, personal fees from Philips, outside the submitted work. SAC reports personal fees from AstraZeneca, GSK, Amgen, Glenmark, Sunovion, UpToDate, and received personal fees and non-financial support from Genentech, grants from MedImmune, outside the submitted work, and reports personal fees from AstraZeneca, personal fees from GlaxoSmithKline, personal fees from Amgen, personal fees from Glenmark, personal fees from Sunovion, personal fees from Genentech, non-financial support from Medimmune, outside the submitted work. JAK has received research grants from NIH and the Patient Centered Outcomes Research Institute. DPT reports personal fees from Boehringer-Ingelheim, AstraZeneca, Sunovion, Theravance/Innoviva, Mylan, outside the submitted work, and reports personal fees from AstraZeneca, personal fees from Sunovion, during the conduct of the study; personal fees from AstraZeneca, personal fees from Sunovion, personal fees from Boehringer-Ingelheim, personal fees from Mylan, outside the submitted work. CBC has consulted with PulmonX, has received research funding from Equinox Fitness Clubs, Amgen and is employed part-time by the GlaxoSmithKline Global Respiratory Franchise, and reports personal fees from GlaxoSmithKline, outside the submitted work. DC has grants from the NIH, reports grants from NHLBI, grants from COPD Foundation, during the conduct of the study and no other conflicts. RB served on the advisory boards (GlaxoSmithKline, Boehringer Ingelheim, and Mylan Pharmaceuticals) and received research grants from GlaxoSmithKline and Boehringer Ingelheim, and reports personal fees from GlaxoSmithKline, personal fees from Boehringer Ingelheim, personal fees from Mylan Pharmaceuticals, grants from GlaxoSmithKline, grants from Boehringer Ingelheim, outside the submitted work. RP reports grants from NHLBI, grants from COPD Foundation, NHLBI and Department of Veterans Affairs, outside the submitted work. RGB received personal fees from GlaxoSmithKline, grants from NIH/National Center for Advancing Translational Sciences, grants from NIH/NHLBI, and reports grants from NIH/NCATS, during the conduct of the study; personal fees from GlaxoSmithKline, grants from NIH/NHLBI, outside the submitted work; and Dr. Buhr is employed part-time by the Veterans Health Administration; the content of this manuscript does not necessarily reflect the views of the US Department of Veterans Affairs. RJK received grants and personal fees from Genentech, Boehringer Ingelheim, Medimmune/Astra Zeneca, and Gilead and reports grants from NIH, during the conduct of the study; grants, personal fees from Boehringer Ingelheim, grants, personal fees from Roche/Genentech, outside the submitted work. GC reports grants from Boehringer- Ingelheim, Novartis, Astra Zeneca, Respironics, MedImmune, Actelion, Forest, Pearl, Ikaria, Aeris, PneumRx, Pulmonx, personal fees from HGE Health Care Solutions, Inc, Amirall, Boehringer- Ingelheim, Holaira. NB reports grants from NIH, outside the submitted work. PW reports personal fees from Glenmark Pharmaceuticals, personal fees from GSK, personal fees from NGM Pharma, personal fees from Amgen, nothing from Regeneron, nothing from 23andMe, nothing from Theravance, nothing from AstraZeneca, outside the submitted work. CMD reports grants from NIH, during the conduct of the study. SP reports grants from MIH, HNLBI, during the conduct of the study. The authors report no other conflicts of interest in this work.