Novel Respiratory Disability Score Predicts COPD Exacerbations and Mortality in the SPIROMICS Cohort

Abstract

Rationale

Some COPD patients develop extreme breathlessness, decreased exercise capacity and poor health status yet respiratory disability is poorly characterized as a distinct phenotype.

Objective

To define respiratory disability in COPD based on available functional measures and to determine associations with risk for exacerbations and death.

Methods

We analyzed baseline data from a multi-center observational study (SPIROMICS). This analysis includes 2332 participants (472 with severe COPD, 991 with mild/moderate COPD, 726 smokers without airflow obstruction and 143 non-smoking controls).

Measurements

We defined respiratory disability by ≥4 of 7 criteria: mMRC dyspnea scale ≥3; Veterans Specific Activity Questionnaire <5; 6-minute walking distance <250 m; St George’s Respiratory Questionnaire activity domain >60; COPD Assessment Test >20; fatigue (FACIT-F Trial Outcome Index) <50; SF-12 <20.

Results

Using these criteria, respiratory disability was identified in 315 (13.5%) participants (52.1% female). Frequencies were severe COPD 34.5%; mild-moderate COPD 11.2%; smokers without obstruction 5.2% and never-smokers 2.1%. Compared with others, participants with disability had more emphysema (13.2 vs. 6.6%) and air-trapping (37.0 vs. 21.6%) on HRCT (P<0.0001). Using principal components analysis to derive a disability score, two factors explained 71% of variance, and a cut point −1.0 reliably identified disability. This disability score independently predicted future exacerbations (ß=0.34; CI 0.12, 0.64; P=0.003) and death (HR 2.97; CI 1.54, 5.75; P=0.001). Thus, participants with disability by this criterion had almost three times greater mortality compared to those without disability.

Conclusion

Our novel SPIROMICS respiratory disability score in COPD was associated with worse airflow obstruction as well as airway wall thickening, lung parenchymal destruction and certain inflammatory biomarkers. The disability score also proved to be an independent predictor of future exacerbations and death. These findings validate disability as an important phenotype in the spectrum of COPD.

Keywords:

• disability
• frailty
• exacerbation rate
• mortality
• SPIROMICS

Acknowledgments

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. We would like to acknowledge the following current and former investigators of the SPIROMICS sites and reading centers: Neil E Alexis, MD; Wayne H Anderson, PhD; Mehrdad Arjomandi, MD; Igor Barjaktarevic, MD, PhD; R Graham Barr, MD, DrPH; Lori A Bateman, MSc; Surya P Bhatt, MD; Eugene R Bleecker, MD; Richard C Boucher, MD; Russell P Bowler, MD, PhD; Elizabeth E Carretta, Stephanie A Christenson, MD; Alejandro P Comellas, MD; Christopher B Cooper, MD, PhD; David J Couper, PhD; Gerard J Criner, MD; Ronald G Crystal, MD; Jeffrey L Curtis, MD; Claire M Doerschuk, MD; Mark T Dransfield, MD; Brad Drummond, MD; Christine M Freeman, PhD; Craig Galban, PhD; MeiLan K Han, MD, MS; Nadia N Hansel, MD, MPH; Annette T Hastie, PhD; Eric A Hoffman, PhD; Yvonne Huang, MD; Robert J Kaner, MD; Richard E Kanner, MD; Eric C Kleerup, MD; Jerry A Krishnan, MD, PhD; Lisa M LaVange, PhD; Stephen C Lazarus, MD; Fernando J Martinez, MD, MS; Deborah A Meyers, PhD; Wendy C Moore, MD; John D Newell Jr, MD; Robert Paine, III, MD; Laura Paulin, MD, MHS; Stephen P Peters, MD, PhD; Cheryl Pirozzi, MD; Nirupama Putcha, MD, MHS; Elizabeth C Oelsner, MD, MPH; Wanda K O’Neal, PhD; Victor E Ortega, MD, PhD; Sanjeev Raman, MBBS, MD; Stephen I. Rennard, MD; Donald P Tashkin, MD; J Michael Wells, MD; Robert A Wise, MD; and Prescott G Woodruff, MD, MPH. The project officers from the Lung Division of the National Heart, Lung, and Blood Institute were Lisa Postow, PhD, and Lisa Viviano, BSN.

Author Contributions

All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

CBC has consulted with PulmonX, has received research funding from Equinox Fitness Clubs, Amgen and was employed part-time by the GlaxoSmithKline Global Respiratory Franchise, and reports personal fees from GlaxoSmithKline, outside the submitted work. RP reports grants from NHLBI, grants from COPD Foundation, NHLBI and Department of Veterans Affairs, outside the submitted work. JLC is supported by Merit Review award I01 CX000911 from the Department of Veterans Affairs, and reports grants from 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, personal fees from AstraZeneca, outside the submitted work. REK has no conflicts other than NHLBI contracts. CHM has NIH grants NHLBI R01HL122438-02S1 and K23 HL128936-01; personal fees, non-financial support and COPD Ad Boards, Steering Committee (honoraria, travel support) from AtraZeneca, IPF Steering Committee (publication) from Afferent/Merck, personal fees, non-financial support and COPD Advisory Board (honorarium travel) support; ILD DSMB, IPF Steering Committee, Study presentations (honoraria, travel support, publication) from Boheringer Ingelheim, teleconference without compensation from Bristol Myers Squibb, COPD Ad Board (travel support) from Chiesi, personal fees and non-financial support from Canadian Respiratory Society, personal fees and non-financial support from CME Outfitters, personal fees and non-financial support from CSL Behring, personal fees from Dartmouth University, personal fees from France Foundation, personal fees from Gala, personal fees and non-financial support from Genentech, grants, personal fees, non-financial support and COPD Ad Boards, Steering Committee, DSMB (honoraria and travel support) from GlaxoSmithKline, personal fees and non-financial support from Inova Fairfax, personal fees and non-financial support from MDMagazine, personal fees and non-financial support from NYP Methodist Hospital Brooklyn, personal fees and non-financial support from Miller Communications, personal fees and non-financial support from National Association for Continuing Education, Steering Committee without compensation from Nitto, personal fees and non-financial support from Novartis, personal fees from New York University, personal fees and non-financial support from Patara/Respivant, personal fees from Pearl, personal fees and non-financial support from Peer View, personal fees from Physicians Education Resource, personal fees from ProMedior, personal fees and non-financial support from Rare Diseases Healthcare Communications, personal fees from Rockpointe Communications, personal fees and non-financial support from Sanofi/Regeneron, DSMB and Steering Committee without compensation from Biogen, personal fees and non-financial support from Sunovion, personal fees and non-financial support from Teva, teleconference without compensation from twoXR, personal fees from University of Birmingham Alabama, personal fees from UpToDate, non-financial support from Veracyte, personal fees from Vindico, personal fees and non-financial support from WebMD/MedScape, non-financial support and PF Ad Board (travel support) and NIH study in kind suppoRt from Zambon, non-financial support from ProTerrix Bio, personal fees from IQVIA, outside the submitted work. CM does not report any conflicts of interest. 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. WO’N does not report any conflicts of interest. 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. DC has grants from the NIH, reports grants from NHLBI, grants from COPD Foundation, during the conduct of the study and no other conflicts. MQ reports no conflicts. GC reports grants from Boehringer-Ingelheim, Novartis, Astra Zeneca, Respironics, MedImmune, Actelion, Forest, Pearl, Ikaria, Aeris, PneumRx, Pulmonx, personal fees from HE Health Care Solutions, Inc, Amirall, Boehringer-Ingelheim, Holaira. 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, contracted clinical trial from Gala and Nuvaira, 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, NHLBI, and from COPD Foundation, during the conduct of the study; and Consulting for GSK, BI, Mylan, Merck and AstraZeneca, research support from Sunovion and Novartis. NNH reports grants and personal fees from AstraZeneca, GSK, Mylan, Boehringer Ingelheim, grants from NIH, COPD Foundation, outside the submitted work. JAK has received research grants from NIH and the Patient Centered Outcomes Research Institute. SCL reports grants from NIH/NHLBI, during the conduct of the study. SPP reports grants from MIH, HNLBI, during the conduct of the study. The authors report no other conflicts of interest in this work. RGB 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. 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, COPD Advisory Board (honorarium travel) support; ILD DSMB, IPF Steering Committee, Study presentations (honoraria, travel support, publication) 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 from Physicians Education Resource, personal fees from ProMedior, personal fees, non-financial support from Sunovion, personal fees, non-financial support from Teva, personal fees from Veracyte, teleconference without compensation from Bristol Myers Squibb, twoXR, personal fees and non-financial support from Canadian Respiratory Society, CME Outfitters, Inova Fairfax, MDMagazine, NYP Methodist Hospital Brooklyn, Miller Communications, Rare Diseases Healthcare Communications, Sanofi/Regeneron, CSL Behring, Novartis, WebMD/MedScape, personal fees from France Foundation, New York University, Rockpointe Communications, University of Birmingham Alabama, Vindico, Dartmouth University, DSMB and Steering Committee without compensation from Biogen, and IPF Ad Board (travel support) and NIH study in kind support from Zambon, during the conduct of the study. PGW reports personal fees from Glenmark Pharmaceuticals, personal fees from GSK, personal fees from NGM Pharma, personal fees from Amgen, Regeneron, 23andMe, Theravance, AstraZeneca, Sanofi, Glenmark Pharmaceuticals, Theravance, NGM Pharma, Amgen, and Genentech, outside the submitted work. The authors report no other conflicts of interest in this work.