Systemic Markers of Inflammation in Smokers With Symptoms Despite Preserved Spirometry in SPIROMICS

Suresh Garudadri; Prescott G. Woodruff; Mei Lan K. Han; Jeffrey L. Curtis; R. Graham Barr; Eugene R. Bleecker; Russell P. Bowler; Alejandro Comellas; Christopher B. Cooper; Gerard Criner; Mark T. Dransfield; Nadia N. Hansel; Robert Paine; Jerry A. Krishnan; Stephen P. Peters; Annette T. Hastie; Fernando J. Martinez; Wanda K. O'Neal; David J. Couper; Neil E. Alexis; Stephanie A. Christenson

doi:10.1016/j.chest.2018.12.022

Systemic Markers of Inflammation in Smokers With Symptoms Despite Preserved Spirometry in SPIROMICS

Suresh Garudadri, Prescott G. Woodruff, Mei Lan K. Han, Jeffrey L. Curtis, R. Graham Barr, Eugene R. Bleecker, Russell P. Bowler, Alejandro Comellas, Christopher B. Cooper, Gerard Criner, Mark T. Dransfield, Nadia N. Hansel, Robert Paine, Jerry A. Krishnan, Stephen P. Peters, Annette T. Hastie, Fernando J. Martinez, Wanda K. O'Neal, David J. Couper, Neil E. AlexisStephanie A. Christenson

Medicine

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Background: Chronic respiratory symptoms and exacerbation-like events are common among ever-smokers without airflow limitation on spirometry. The pathobiology of respiratory disease in this subgroup remains poorly defined, but may be due to underlying inflammation that overlaps with COPD or asthma. We hypothesized that symptoms, exacerbations, and functional measures of disease severity among smokers with preserved spirometry would be associated with markers of systemic inflammation, similar to what is reported in bone fide COPD, rather than elevated type 2 inflammation, which is often present in asthma. Methods: We measured inflammatory markers associated with COPD (C-reactive protein [CRP], fibrinogen, soluble tumor necrosis factor receptors [sTNFRSF1A and sTNFRSF1B], and blood/sputum neutrophils) and type 2 inflammation (IgE and blood/sputum eosinophils) in smokers with preserved spirometry (postbronchodilator FEV₁/FVC ≥ 0.70) from the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). We evaluated the relationship of these markers with respiratory symptom burden (dichotomized by a COPD assessment test score cutoff of 10, diagnosis of chronic bronchitis), exacerbations, 6-minute walk distance, and lung function on the basis of FEV₁. Results: CRP was associated with increased symptom burden (on the basis of COPD assessment test score and diagnosis of chronic bronchitis) and a greater number of exacerbations in the year before study enrollment. sTNFRSF1A was associated with symptom burden on the basis of COPD assessment test score. CRP and sTNFRSF1A levels negatively correlated with 6-minute walk distance. IgE and eosinophils were not associated with these outcomes. Conclusions: Markers of inflammation including CRP and sTNFRSF1A are enriched among symptomatic smokers with preserved spirometry, suggesting an overlap with the underlying pathophysiology of COPD.

Original language	English (US)
Pages (from-to)	908-917
Number of pages	10
Journal	CHEST
Volume	155
Issue number	5
DOIs	https://doi.org/10.1016/j.chest.2018.12.022
State	Published - May 2019

Keywords

C-reactive protein
COPD
bronchitis
smoking

ASJC Scopus subject areas

Pulmonary and Respiratory Medicine
Critical Care and Intensive Care Medicine
Cardiology and Cardiovascular Medicine

Access to Document

10.1016/j.chest.2018.12.022

Cite this

Garudadri, S., Woodruff, P. G., Han, M. L. K., Curtis, J. L., Barr, R. G., Bleecker, E. R., Bowler, R. P., Comellas, A., Cooper, C. B., Criner, G., Dransfield, M. T., Hansel, N. N., Paine, R., Krishnan, J. A., Peters, S. P., Hastie, A. T., Martinez, F. J., O'Neal, W. K., Couper, D. J., ... Christenson, S. A. (2019). Systemic Markers of Inflammation in Smokers With Symptoms Despite Preserved Spirometry in SPIROMICS. CHEST, 155(5), 908-917. https://doi.org/10.1016/j.chest.2018.12.022

Garudadri, S, Woodruff, PG, Han, MLK, Curtis, JL, Barr, RG, Bleecker, ER, Bowler, RP, Comellas, A, Cooper, CB, Criner, G, Dransfield, MT, Hansel, NN, Paine, R, Krishnan, JA, Peters, SP, Hastie, AT, Martinez, FJ, O'Neal, WK, Couper, DJ, Alexis, NE & Christenson, SA 2019, 'Systemic Markers of Inflammation in Smokers With Symptoms Despite Preserved Spirometry in SPIROMICS', CHEST, vol. 155, no. 5, pp. 908-917. https://doi.org/10.1016/j.chest.2018.12.022

@article{23d15cb6febe41178cd17640e365ab35,

title = "Systemic Markers of Inflammation in Smokers With Symptoms Despite Preserved Spirometry in SPIROMICS",

abstract = "Background: Chronic respiratory symptoms and exacerbation-like events are common among ever-smokers without airflow limitation on spirometry. The pathobiology of respiratory disease in this subgroup remains poorly defined, but may be due to underlying inflammation that overlaps with COPD or asthma. We hypothesized that symptoms, exacerbations, and functional measures of disease severity among smokers with preserved spirometry would be associated with markers of systemic inflammation, similar to what is reported in bone fide COPD, rather than elevated type 2 inflammation, which is often present in asthma. Methods: We measured inflammatory markers associated with COPD (C-reactive protein [CRP], fibrinogen, soluble tumor necrosis factor receptors [sTNFRSF1A and sTNFRSF1B], and blood/sputum neutrophils) and type 2 inflammation (IgE and blood/sputum eosinophils) in smokers with preserved spirometry (postbronchodilator FEV1/FVC ≥ 0.70) from the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). We evaluated the relationship of these markers with respiratory symptom burden (dichotomized by a COPD assessment test score cutoff of 10, diagnosis of chronic bronchitis), exacerbations, 6-minute walk distance, and lung function on the basis of FEV1. Results: CRP was associated with increased symptom burden (on the basis of COPD assessment test score and diagnosis of chronic bronchitis) and a greater number of exacerbations in the year before study enrollment. sTNFRSF1A was associated with symptom burden on the basis of COPD assessment test score. CRP and sTNFRSF1A levels negatively correlated with 6-minute walk distance. IgE and eosinophils were not associated with these outcomes. Conclusions: Markers of inflammation including CRP and sTNFRSF1A are enriched among symptomatic smokers with preserved spirometry, suggesting an overlap with the underlying pathophysiology of COPD.",

keywords = "C-reactive protein, COPD, bronchitis, smoking",

author = "Suresh Garudadri and Woodruff, {Prescott G.} and Han, {Mei Lan K.} and Curtis, {Jeffrey L.} and Barr, {R. Graham} and Bleecker, {Eugene R.} and Bowler, {Russell P.} and Alejandro Comellas and Cooper, {Christopher B.} and Gerard Criner and Dransfield, {Mark T.} and Hansel, {Nadia N.} and Robert Paine and Krishnan, {Jerry A.} and Peters, {Stephen P.} and Hastie, {Annette T.} and Martinez, {Fernando J.} and O'Neal, {Wanda K.} and Couper, {David J.} and Alexis, {Neil E.} and Christenson, {Stephanie A.}",

note = "Funding Information: Financial/nonfinancial disclosures: The authors have reported to CHEST the following: E. R. B. has undertaken clinical trials administered through his employers, 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; he has also served as a paid consultant for AztraZeneca, MedImmune, Boehringer Ingelheim, Glaxo Smith Kline, Novartis, Regeneron, and Sanofi Genzyme, outside the submitted work. S. A. C. reports personal fees from AstraZeneca, nonfinancial support from Genentech , and grants from MedImmune , outside the submitted work. A. C. reports grants from the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH), during the conduct of the study; grants from NHLBI/NIH , grants from National Institute of Environmental Health Sciences /NIH; and personal fees from VIDA Diagnostics, outside the submitted work. C. B. C. reports grants from Equinox Health Clubs, personal fees from Equinox Health Clubs, grants from Amgen, personal fees from PulmonX, other from GlaxoSmithKline, outside the submitted work; and part-time employment in scientific engagement for the GlaxoSmithKline Global Respiratory Franchise. D. J. C. reports grants from NHLBI/NIH , during the conduct of the study; and grants from COPD Foundation , outside the submitted work. G. C. reports grants from Boehringer Ingelheim , Novartis , AstraZeneca , Respironics , MedImmune , Actelion , Forest , Pearl , Ikaria , Aeris , PneumRx , and Pulmonx ; equity interest in HGE Health Care Solutions, Inc.; and consultation for Amirall, Boehringer Ingelheim, and Holaira, outside the submitted work. J. C. reports grants from NHLBI/NIH during the conduct of the study; grants from National Institute of Allergy and Infectious Diseases/NIH , Department of Veterans Affairs , Department of Defense , and MedImmune Corporation, Ltd. , outside the submitted work. M. T. D. reports grants from NHLBI , during the conduct of the study; and grants from Department of Defense , personal fees and contracted clinical trials from Boehringer-Ingeheim, GlaxoSmithKline, AstraZeneca, and Boston Scientific; contracted clinical trials from Novartis, Yungjin, PneumRx/BTG, and Pulmonx; and personal fees from Genentech, outside the submitted work. M. K. H. reports personal fees from GlaxoSmithKline, Boehringer Ingelheim, and AstraZeneca, and nonfinancial support from Novartis and Sunovion, outside the submitted work. N. N. H. reports grants and personal fees from AstraZeneca and GSK , grants Boehringer Ingelheim , NIH , and the COPD Foundation , outside the submitted work. A. T. H. reports grants from NHLBI and the Foundation for the National Institutes of Health, during the conduct of the study. J. A. K. reports grants from NIH/NHLBI , during the conduct of the study. F. J. M. reports grants from NHLBI , during the conduct of the study; personal fees and nonfinancial support from American College of Chest Physicians , AstraZeneca , Boehringer Ingelheim , Continuing Education , ConCert , Genentech , GlaxoSmithKline , Inova Fairfax Health System , Miller Communications , National Association for Continuing Education , Novartis , Pearl Pharmaceuticals , PeerView Communications , Prime Communications , Puerto Rican Respiratory Society , Chiesi , Roche , Sunovion , and Theravance ; nonfinancial support from ProterrixBio ; personal fees from Columbia University, Haymarket Communications, Integritas, Inthought Research, MD Magazine, Methodist Hospital Brooklyn, New York University, Unity, UpToDate, WebMD/MedScape, Western Connecticut Health Network, and American Thoracic Society; and grants from NIH , outside the submitted work. R. P. III reports grants from NHLBI and COPD Foundation , during the conduct of the study; and grants from Department of Veterans Affairs , outside the submitted work. S. P. P. reports grants from NIH and NHLBI , during the conduct of the study. P. G. W. reports grants from NIH/NHLBI , during the conduct of the study; and personal fees from AstraZeneca , Theravance , Regeneron , Sanofi , Genentech , and Novartis , outside the submitted work. None declared (S. G., R. P. B., W. K. O., N. E. A.). Funding Information: FUNDING/SUPPORT: The Subpopulations and Intermediate Outcome Measures In COPD Study was supported by contracts from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute [Grants HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C], and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer Ingelheim Pharmaceuticals, Inc; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc; GlaxoSmithKline; Grifols Therapeutics, Inc; Ikaria, Inc; Nycomed GmbH; Takeda Pharmaceutical Company; Novartis Pharmaceuticals Corporation; ProterixBio; Regeneron Pharmaceuticals, Inc; Sanofi; and Sunovion.Author contributions: S. G. S. A. C. and P. G. W. conceived the hypothesis, designed the study, and interpreted data. S. G. drafted the initial manuscript. P. G. W. S. A. C. M. K. H. J. L. C. R. G. B. E. R. B. R. P. B. A. C. C. B. C. G. C. M. T. D. N. N. H. R. P. J. A. K. S. P. P. A. T. H. F. J. M. W. K. O. D. J. C. and N. E. A. were involved in data collection and processing. All authors participated in manuscript editing for critical intellectual content and approved the final manuscript. S. G. S. A. C. and P. G. W. are guarantors of the manuscript and take responsibility for the integrity of the data and the accuracy of the data analysis. Financial/nonfinancial disclosures: The authors have reported to CHEST the following: E. R. B. has undertaken clinical trials administered through his employers, 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; he has also served as a paid consultant for AztraZeneca, MedImmune, Boehringer Ingelheim, Glaxo Smith Kline, Novartis, Regeneron, and Sanofi Genzyme, outside the submitted work. S. A. C. reports personal fees from AstraZeneca, nonfinancial support from Genentech, and grants from MedImmune, outside the submitted work. A. C. reports grants from the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH), during the conduct of the study; grants from NHLBI/NIH, grants from National Institute of Environmental Health Sciences/NIH; and personal fees from VIDA Diagnostics, outside the submitted work. C. B. C. reports grants from Equinox Health Clubs, personal fees from Equinox Health Clubs, grants from Amgen, personal fees from PulmonX, other from GlaxoSmithKline, outside the submitted work; and part-time employment in scientific engagement for the GlaxoSmithKline Global Respiratory Franchise. D. J. C. reports grants from NHLBI/NIH, during the conduct of the study; and grants from COPD Foundation, outside the submitted work. G. C. reports grants from Boehringer Ingelheim, Novartis, AstraZeneca, Respironics, MedImmune, Actelion, Forest, Pearl, Ikaria, Aeris, PneumRx, and Pulmonx; equity interest in HGE Health Care Solutions, Inc.; and consultation for Amirall, Boehringer Ingelheim, and Holaira, outside the submitted work. J. C. reports grants from NHLBI/NIH during the conduct of the study; grants from National Institute of Allergy and Infectious Diseases/NIH, Department of Veterans Affairs, Department of Defense, and MedImmune Corporation, Ltd., outside the submitted work. M. T. D. reports grants from NHLBI, during the conduct of the study; and grants from Department of Defense, personal fees and contracted clinical trials from Boehringer-Ingeheim, GlaxoSmithKline, AstraZeneca, and Boston Scientific; contracted clinical trials from Novartis, Yungjin, PneumRx/BTG, and Pulmonx; and personal fees from Genentech, outside the submitted work. M. K. H. reports personal fees from GlaxoSmithKline, Boehringer Ingelheim, and AstraZeneca, and nonfinancial support from Novartis and Sunovion, outside the submitted work. N. N. H. reports grants and personal fees from AstraZeneca and GSK, grants Boehringer Ingelheim, NIH, and the COPD Foundation, outside the submitted work. A. T. H. reports grants from NHLBI and the Foundation for the National Institutes of Health, during the conduct of the study. J. A. K. reports grants from NIH/NHLBI, during the conduct of the study. F. J. M. reports grants from NHLBI, during the conduct of the study; personal fees and nonfinancial support from American College of Chest Physicians, AstraZeneca, Boehringer Ingelheim, Continuing Education, ConCert, Genentech, GlaxoSmithKline, Inova Fairfax Health System, Miller Communications, National Association for Continuing Education, Novartis, Pearl Pharmaceuticals, PeerView Communications, Prime Communications, Puerto Rican Respiratory Society, Chiesi, Roche, Sunovion, and Theravance; nonfinancial support from ProterrixBio; personal fees from Columbia University, Haymarket Communications, Integritas, Inthought Research, MD Magazine, Methodist Hospital Brooklyn, New York University, Unity, UpToDate, WebMD/MedScape, Western Connecticut Health Network, and American Thoracic Society; and grants from NIH, outside the submitted work. R. P. III reports grants from NHLBI and COPD Foundation, during the conduct of the study; and grants from Department of Veterans Affairs, outside the submitted work. S. P. P. reports grants from NIH and NHLBI, during the conduct of the study. P. G. W. reports grants from NIH/NHLBI, during the conduct of the study; and personal fees from AstraZeneca, Theravance, Regeneron, Sanofi, Genentech, and Novartis, outside the submitted work. None declared (S. G. R. P. B. W. K. O. N. E. A.). Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. Additional information: The e-Appendix, e-Figure, and e-Tables can be found in the Supplemental Materials section of the online article. Publisher Copyright: {\textcopyright} 2019 American College of Chest Physicians",

year = "2019",

month = may,

doi = "10.1016/j.chest.2018.12.022",

language = "English (US)",

volume = "155",

pages = "908--917",

journal = "Diseases of the chest",

issn = "0012-3692",

publisher = "American College of Chest Physicians",

number = "5",

}

TY - JOUR

T1 - Systemic Markers of Inflammation in Smokers With Symptoms Despite Preserved Spirometry in SPIROMICS

AU - Garudadri, Suresh

AU - Woodruff, Prescott G.

AU - Han, Mei Lan K.

AU - Curtis, Jeffrey L.

AU - Barr, R. Graham

AU - Bleecker, Eugene R.

AU - Bowler, Russell P.

AU - Comellas, Alejandro

AU - Cooper, Christopher B.

AU - Criner, Gerard

AU - Dransfield, Mark T.

AU - Hansel, Nadia N.

AU - Paine, Robert

AU - Krishnan, Jerry A.

AU - Peters, Stephen P.

AU - Hastie, Annette T.

AU - Martinez, Fernando J.

AU - O'Neal, Wanda K.

AU - Couper, David J.

AU - Alexis, Neil E.

AU - Christenson, Stephanie A.

N1 - Funding Information: Financial/nonfinancial disclosures: The authors have reported to CHEST the following: E. R. B. has undertaken clinical trials administered through his employers, 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; he has also served as a paid consultant for AztraZeneca, MedImmune, Boehringer Ingelheim, Glaxo Smith Kline, Novartis, Regeneron, and Sanofi Genzyme, outside the submitted work. S. A. C. reports personal fees from AstraZeneca, nonfinancial support from Genentech , and grants from MedImmune , outside the submitted work. A. C. reports grants from the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH), during the conduct of the study; grants from NHLBI/NIH , grants from National Institute of Environmental Health Sciences /NIH; and personal fees from VIDA Diagnostics, outside the submitted work. C. B. C. reports grants from Equinox Health Clubs, personal fees from Equinox Health Clubs, grants from Amgen, personal fees from PulmonX, other from GlaxoSmithKline, outside the submitted work; and part-time employment in scientific engagement for the GlaxoSmithKline Global Respiratory Franchise. D. J. C. reports grants from NHLBI/NIH , during the conduct of the study; and grants from COPD Foundation , outside the submitted work. G. C. reports grants from Boehringer Ingelheim , Novartis , AstraZeneca , Respironics , MedImmune , Actelion , Forest , Pearl , Ikaria , Aeris , PneumRx , and Pulmonx ; equity interest in HGE Health Care Solutions, Inc.; and consultation for Amirall, Boehringer Ingelheim, and Holaira, outside the submitted work. J. C. reports grants from NHLBI/NIH during the conduct of the study; grants from National Institute of Allergy and Infectious Diseases/NIH , Department of Veterans Affairs , Department of Defense , and MedImmune Corporation, Ltd. , outside the submitted work. M. T. D. reports grants from NHLBI , during the conduct of the study; and grants from Department of Defense , personal fees and contracted clinical trials from Boehringer-Ingeheim, GlaxoSmithKline, AstraZeneca, and Boston Scientific; contracted clinical trials from Novartis, Yungjin, PneumRx/BTG, and Pulmonx; and personal fees from Genentech, outside the submitted work. M. K. H. reports personal fees from GlaxoSmithKline, Boehringer Ingelheim, and AstraZeneca, and nonfinancial support from Novartis and Sunovion, outside the submitted work. N. N. H. reports grants and personal fees from AstraZeneca and GSK , grants Boehringer Ingelheim , NIH , and the COPD Foundation , outside the submitted work. A. T. H. reports grants from NHLBI and the Foundation for the National Institutes of Health, during the conduct of the study. J. A. K. reports grants from NIH/NHLBI , during the conduct of the study. F. J. M. reports grants from NHLBI , during the conduct of the study; personal fees and nonfinancial support from American College of Chest Physicians , AstraZeneca , Boehringer Ingelheim , Continuing Education , ConCert , Genentech , GlaxoSmithKline , Inova Fairfax Health System , Miller Communications , National Association for Continuing Education , Novartis , Pearl Pharmaceuticals , PeerView Communications , Prime Communications , Puerto Rican Respiratory Society , Chiesi , Roche , Sunovion , and Theravance ; nonfinancial support from ProterrixBio ; personal fees from Columbia University, Haymarket Communications, Integritas, Inthought Research, MD Magazine, Methodist Hospital Brooklyn, New York University, Unity, UpToDate, WebMD/MedScape, Western Connecticut Health Network, and American Thoracic Society; and grants from NIH , outside the submitted work. R. P. III reports grants from NHLBI and COPD Foundation , during the conduct of the study; and grants from Department of Veterans Affairs , outside the submitted work. S. P. P. reports grants from NIH and NHLBI , during the conduct of the study. P. G. W. reports grants from NIH/NHLBI , during the conduct of the study; and personal fees from AstraZeneca , Theravance , Regeneron , Sanofi , Genentech , and Novartis , outside the submitted work. None declared (S. G., R. P. B., W. K. O., N. E. A.). Funding Information: FUNDING/SUPPORT: The Subpopulations and Intermediate Outcome Measures In COPD Study was supported by contracts from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute [Grants HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C], and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer Ingelheim Pharmaceuticals, Inc; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc; GlaxoSmithKline; Grifols Therapeutics, Inc; Ikaria, Inc; Nycomed GmbH; Takeda Pharmaceutical Company; Novartis Pharmaceuticals Corporation; ProterixBio; Regeneron Pharmaceuticals, Inc; Sanofi; and Sunovion.Author contributions: S. G. S. A. C. and P. G. W. conceived the hypothesis, designed the study, and interpreted data. S. G. drafted the initial manuscript. P. G. W. S. A. C. M. K. H. J. L. C. R. G. B. E. R. B. R. P. B. A. C. C. B. C. G. C. M. T. D. N. N. H. R. P. J. A. K. S. P. P. A. T. H. F. J. M. W. K. O. D. J. C. and N. E. A. were involved in data collection and processing. All authors participated in manuscript editing for critical intellectual content and approved the final manuscript. S. G. S. A. C. and P. G. W. are guarantors of the manuscript and take responsibility for the integrity of the data and the accuracy of the data analysis. Financial/nonfinancial disclosures: The authors have reported to CHEST the following: E. R. B. has undertaken clinical trials administered through his employers, 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; he has also served as a paid consultant for AztraZeneca, MedImmune, Boehringer Ingelheim, Glaxo Smith Kline, Novartis, Regeneron, and Sanofi Genzyme, outside the submitted work. S. A. C. reports personal fees from AstraZeneca, nonfinancial support from Genentech, and grants from MedImmune, outside the submitted work. A. C. reports grants from the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH), during the conduct of the study; grants from NHLBI/NIH, grants from National Institute of Environmental Health Sciences/NIH; and personal fees from VIDA Diagnostics, outside the submitted work. C. B. C. reports grants from Equinox Health Clubs, personal fees from Equinox Health Clubs, grants from Amgen, personal fees from PulmonX, other from GlaxoSmithKline, outside the submitted work; and part-time employment in scientific engagement for the GlaxoSmithKline Global Respiratory Franchise. D. J. C. reports grants from NHLBI/NIH, during the conduct of the study; and grants from COPD Foundation, outside the submitted work. G. C. reports grants from Boehringer Ingelheim, Novartis, AstraZeneca, Respironics, MedImmune, Actelion, Forest, Pearl, Ikaria, Aeris, PneumRx, and Pulmonx; equity interest in HGE Health Care Solutions, Inc.; and consultation for Amirall, Boehringer Ingelheim, and Holaira, outside the submitted work. J. C. reports grants from NHLBI/NIH during the conduct of the study; grants from National Institute of Allergy and Infectious Diseases/NIH, Department of Veterans Affairs, Department of Defense, and MedImmune Corporation, Ltd., outside the submitted work. M. T. D. reports grants from NHLBI, during the conduct of the study; and grants from Department of Defense, personal fees and contracted clinical trials from Boehringer-Ingeheim, GlaxoSmithKline, AstraZeneca, and Boston Scientific; contracted clinical trials from Novartis, Yungjin, PneumRx/BTG, and Pulmonx; and personal fees from Genentech, outside the submitted work. M. K. H. reports personal fees from GlaxoSmithKline, Boehringer Ingelheim, and AstraZeneca, and nonfinancial support from Novartis and Sunovion, outside the submitted work. N. N. H. reports grants and personal fees from AstraZeneca and GSK, grants Boehringer Ingelheim, NIH, and the COPD Foundation, outside the submitted work. A. T. H. reports grants from NHLBI and the Foundation for the National Institutes of Health, during the conduct of the study. J. A. K. reports grants from NIH/NHLBI, during the conduct of the study. F. J. M. reports grants from NHLBI, during the conduct of the study; personal fees and nonfinancial support from American College of Chest Physicians, AstraZeneca, Boehringer Ingelheim, Continuing Education, ConCert, Genentech, GlaxoSmithKline, Inova Fairfax Health System, Miller Communications, National Association for Continuing Education, Novartis, Pearl Pharmaceuticals, PeerView Communications, Prime Communications, Puerto Rican Respiratory Society, Chiesi, Roche, Sunovion, and Theravance; nonfinancial support from ProterrixBio; personal fees from Columbia University, Haymarket Communications, Integritas, Inthought Research, MD Magazine, Methodist Hospital Brooklyn, New York University, Unity, UpToDate, WebMD/MedScape, Western Connecticut Health Network, and American Thoracic Society; and grants from NIH, outside the submitted work. R. P. III reports grants from NHLBI and COPD Foundation, during the conduct of the study; and grants from Department of Veterans Affairs, outside the submitted work. S. P. P. reports grants from NIH and NHLBI, during the conduct of the study. P. G. W. reports grants from NIH/NHLBI, during the conduct of the study; and personal fees from AstraZeneca, Theravance, Regeneron, Sanofi, Genentech, and Novartis, outside the submitted work. None declared (S. G. R. P. B. W. K. O. N. E. A.). Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. Additional information: The e-Appendix, e-Figure, and e-Tables can be found in the Supplemental Materials section of the online article. Publisher Copyright: © 2019 American College of Chest Physicians

PY - 2019/5

Y1 - 2019/5

N2 - Background: Chronic respiratory symptoms and exacerbation-like events are common among ever-smokers without airflow limitation on spirometry. The pathobiology of respiratory disease in this subgroup remains poorly defined, but may be due to underlying inflammation that overlaps with COPD or asthma. We hypothesized that symptoms, exacerbations, and functional measures of disease severity among smokers with preserved spirometry would be associated with markers of systemic inflammation, similar to what is reported in bone fide COPD, rather than elevated type 2 inflammation, which is often present in asthma. Methods: We measured inflammatory markers associated with COPD (C-reactive protein [CRP], fibrinogen, soluble tumor necrosis factor receptors [sTNFRSF1A and sTNFRSF1B], and blood/sputum neutrophils) and type 2 inflammation (IgE and blood/sputum eosinophils) in smokers with preserved spirometry (postbronchodilator FEV1/FVC ≥ 0.70) from the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). We evaluated the relationship of these markers with respiratory symptom burden (dichotomized by a COPD assessment test score cutoff of 10, diagnosis of chronic bronchitis), exacerbations, 6-minute walk distance, and lung function on the basis of FEV1. Results: CRP was associated with increased symptom burden (on the basis of COPD assessment test score and diagnosis of chronic bronchitis) and a greater number of exacerbations in the year before study enrollment. sTNFRSF1A was associated with symptom burden on the basis of COPD assessment test score. CRP and sTNFRSF1A levels negatively correlated with 6-minute walk distance. IgE and eosinophils were not associated with these outcomes. Conclusions: Markers of inflammation including CRP and sTNFRSF1A are enriched among symptomatic smokers with preserved spirometry, suggesting an overlap with the underlying pathophysiology of COPD.

AB - Background: Chronic respiratory symptoms and exacerbation-like events are common among ever-smokers without airflow limitation on spirometry. The pathobiology of respiratory disease in this subgroup remains poorly defined, but may be due to underlying inflammation that overlaps with COPD or asthma. We hypothesized that symptoms, exacerbations, and functional measures of disease severity among smokers with preserved spirometry would be associated with markers of systemic inflammation, similar to what is reported in bone fide COPD, rather than elevated type 2 inflammation, which is often present in asthma. Methods: We measured inflammatory markers associated with COPD (C-reactive protein [CRP], fibrinogen, soluble tumor necrosis factor receptors [sTNFRSF1A and sTNFRSF1B], and blood/sputum neutrophils) and type 2 inflammation (IgE and blood/sputum eosinophils) in smokers with preserved spirometry (postbronchodilator FEV1/FVC ≥ 0.70) from the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). We evaluated the relationship of these markers with respiratory symptom burden (dichotomized by a COPD assessment test score cutoff of 10, diagnosis of chronic bronchitis), exacerbations, 6-minute walk distance, and lung function on the basis of FEV1. Results: CRP was associated with increased symptom burden (on the basis of COPD assessment test score and diagnosis of chronic bronchitis) and a greater number of exacerbations in the year before study enrollment. sTNFRSF1A was associated with symptom burden on the basis of COPD assessment test score. CRP and sTNFRSF1A levels negatively correlated with 6-minute walk distance. IgE and eosinophils were not associated with these outcomes. Conclusions: Markers of inflammation including CRP and sTNFRSF1A are enriched among symptomatic smokers with preserved spirometry, suggesting an overlap with the underlying pathophysiology of COPD.

KW - C-reactive protein

KW - COPD

KW - bronchitis

KW - smoking

UR - http://www.scopus.com/inward/record.url?scp=85064561551&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064561551&partnerID=8YFLogxK

U2 - 10.1016/j.chest.2018.12.022

DO - 10.1016/j.chest.2018.12.022

M3 - Article

C2 - 30684474

AN - SCOPUS:85064561551

VL - 155

SP - 908

EP - 917

JO - Diseases of the chest

JF - Diseases of the chest

SN - 0012-3692

IS - 5

ER -

Systemic Markers of Inflammation in Smokers With Symptoms Despite Preserved Spirometry in SPIROMICS

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