Increased mortality associated with frequent exacerbations in COPD patients with mild-to-moderate lung function impairment, and smokers with normal spirometry

Spyridon Fortis; Emily S. Wan; Ken Kunisaki; Patrick Tel Eyck; Zuhair K. Ballas; Russell P. Bowler; James D. Crapo; John E. Hokanson; Chris Wendt; Edwin K. Silverman; Alejandro P. Comellas

doi:10.1016/j.yrmex.2020.100025

Increased mortality associated with frequent exacerbations in COPD patients with mild-to-moderate lung function impairment, and smokers with normal spirometry

Spyridon Fortis, Emily S. Wan, Ken Kunisaki, Patrick Tel Eyck, Zuhair K. Ballas, Russell P. Bowler, James D. Crapo, John E. Hokanson, Chris Wendt, Edwin K. Silverman, Alejandro P. Comellas

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10 Scopus citations

Abstract

Background: The burden of frequent respiratory exacerbations in COPD patients with mild-to-moderate spirometric impairment and smokers with preserved lung function is unknown. Methods: We categorized COPD participants in COPDGene with post-bronchodilator FEV1%predicted≥50% by the annual exacerbation frequency into three groups: i)frequent exacerbators (top 5%; n = 109), ii)exacerbators (>0 but less than frequent exacerbators; n = 1,009), and iii)No exacerbation (n = 981). Exacerbations were defined as respiratory episodes requiring antibiotics and/or systemic steroids. We performed a Cox proportional hazards regression analysis to examine the association with mortality. We repeated the same process in current/former smokers with preserved spirometry (FEV1≥80%predicted and FEV1/FVC≥0.7). Results: Among 2,099 COPD participants, frequent exacerbators had ≥1.8 exacerbations/year and were responsible for 34.3% of the total exacerbations. There were 102 (10.4%) deaths in the group with no exacerbations, 119 (11.8%) in the exacerbator group, and 24 (22%) in the frequent exacerbators. Adjusted mortality in frequent exacerbators was higher relative to individuals with no exacerbations (hazard ratio (HR) = 1.98; 95%CI = 1.25–3.13). An increase in frequency of exacerbations by one exacerbation/year was associated with increased mortality (HR = 1.40,95%CI = 1.21–1.62). Among 3,143 participants with preserved spirometry, frequent exacerbators had ≥0.8 exacerbations/year and were responsible for more than half of the exacerbations. There were 93 (4.2%) deaths in the group with no exacerbations, 28 (3.8%) in the exacerbator group, and 14 (7.6%) in the frequent exacerbators. The adjusted mortality was increased in frequent exacerbators with preserved spirometry relative to those with no exacerbations (HR = 2.25; 95%CI = 1.26–4.01). Conclusions: In COPD participants with mild-to-moderate spirometric impairment and smokers with preserved spirometry, the frequent exacerbator phenotype is responsible for a large proportion of total exacerbations and associated with high mortality.

Original language	English (US)
Article number	100025
Journal	Respiratory Medicine: X
Volume	3
DOIs	https://doi.org/10.1016/j.yrmex.2020.100025
State	Published - Nov 2021

Bibliographical note

Funding Information:
The project described was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion. SF was supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Rural Health, Veterans Rural Health Resource Center (Award # 14380), and the Health Services Research and development (HSR&D) Service through the Comprehensive Access and Delivery Research and Evaluation (CADRE) Center (CIN 13?412), and has received grants from the American Thoracic Society and Fisher &Paykel.SF has received grants from the American Thoracic Society and Fisher &Paykel. RPB has received consulting fees from Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline. In the past three years, EKS received honoraria from Novartis for Continuing Medical Education Seminars and grant and travel support from GlaxoSmithKline. The rest of authors declare no competing interests.

Funding Information:
SF has received grants from the American Thoracic Society and Fisher &Paykel. RPB has received consulting fees from Boehringer Ingelheim , AstraZeneca , and GlaxoSmithKline . In the past three years, EKS received honoraria from Novartis for Continuing Medical Education Seminars and grant and travel support from GlaxoSmithKline. The rest of authors declare no competing interests.

Funding Information:
The project described was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the National Heart, Lung, and Blood Institute . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca , Boehringer-Ingelheim, Genentech , GlaxoSmithKline , Novartis , Pfizer , Siemens , and Sunovion . SF was supported by the Department of Veterans Affairs , Veterans Health Administration, Office of Rural Health, Veterans Rural Health Resource Center (Award # 14380), and the Health Services Research and development (HSR&D) Service through the Comprehensive Access and Delivery Research and Evaluation (CADRE) Center ( CIN 13–412), and has received grants from the American Thoracic Society and Fisher &Paykel.

Publisher Copyright:
© 2020

Keywords

Chronic obstructive pulmonary disease
Exacerbations
Mortality

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10.1016/j.yrmex.2020.100025

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Fortis, S., Wan, E. S., Kunisaki, K., Eyck, P. T., Ballas, Z. K., Bowler, R. P., Crapo, J. D., Hokanson, J. E., Wendt, C., Silverman, E. K., & Comellas, A. P. (2021). Increased mortality associated with frequent exacerbations in COPD patients with mild-to-moderate lung function impairment, and smokers with normal spirometry. Respiratory Medicine: X, 3, Article 100025. https://doi.org/10.1016/j.yrmex.2020.100025

Fortis, S, Wan, ES, Kunisaki, K, Eyck, PT, Ballas, ZK, Bowler, RP, Crapo, JD, Hokanson, JE, Wendt, C, Silverman, EK & Comellas, AP 2021, 'Increased mortality associated with frequent exacerbations in COPD patients with mild-to-moderate lung function impairment, and smokers with normal spirometry', Respiratory Medicine: X, vol. 3, 100025. https://doi.org/10.1016/j.yrmex.2020.100025

@article{86f422206f4f4f6795a17f0914198208,

title = "Increased mortality associated with frequent exacerbations in COPD patients with mild-to-moderate lung function impairment, and smokers with normal spirometry",

abstract = "Background: The burden of frequent respiratory exacerbations in COPD patients with mild-to-moderate spirometric impairment and smokers with preserved lung function is unknown. Methods: We categorized COPD participants in COPDGene with post-bronchodilator FEV1%predicted≥50% by the annual exacerbation frequency into three groups: i)frequent exacerbators (top 5%; n = 109), ii)exacerbators (>0 but less than frequent exacerbators; n = 1,009), and iii)No exacerbation (n = 981). Exacerbations were defined as respiratory episodes requiring antibiotics and/or systemic steroids. We performed a Cox proportional hazards regression analysis to examine the association with mortality. We repeated the same process in current/former smokers with preserved spirometry (FEV1≥80%predicted and FEV1/FVC≥0.7). Results: Among 2,099 COPD participants, frequent exacerbators had ≥1.8 exacerbations/year and were responsible for 34.3% of the total exacerbations. There were 102 (10.4%) deaths in the group with no exacerbations, 119 (11.8%) in the exacerbator group, and 24 (22%) in the frequent exacerbators. Adjusted mortality in frequent exacerbators was higher relative to individuals with no exacerbations (hazard ratio (HR) = 1.98; 95%CI = 1.25–3.13). An increase in frequency of exacerbations by one exacerbation/year was associated with increased mortality (HR = 1.40,95%CI = 1.21–1.62). Among 3,143 participants with preserved spirometry, frequent exacerbators had ≥0.8 exacerbations/year and were responsible for more than half of the exacerbations. There were 93 (4.2%) deaths in the group with no exacerbations, 28 (3.8%) in the exacerbator group, and 14 (7.6%) in the frequent exacerbators. The adjusted mortality was increased in frequent exacerbators with preserved spirometry relative to those with no exacerbations (HR = 2.25; 95%CI = 1.26–4.01). Conclusions: In COPD participants with mild-to-moderate spirometric impairment and smokers with preserved spirometry, the frequent exacerbator phenotype is responsible for a large proportion of total exacerbations and associated with high mortality.",

keywords = "Chronic obstructive pulmonary disease, Exacerbations, Mortality",

author = "Spyridon Fortis and Wan, {Emily S.} and Ken Kunisaki and Eyck, {Patrick Tel} and Ballas, {Zuhair K.} and Bowler, {Russell P.} and Crapo, {James D.} and Hokanson, {John E.} and Chris Wendt and Silverman, {Edwin K.} and Comellas, {Alejandro P.}",

note = "Funding Information: The project described was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion. SF was supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Rural Health, Veterans Rural Health Resource Center (Award # 14380), and the Health Services Research and development (HSR&D) Service through the Comprehensive Access and Delivery Research and Evaluation (CADRE) Center (CIN 13?412), and has received grants from the American Thoracic Society and Fisher &Paykel.SF has received grants from the American Thoracic Society and Fisher &Paykel. RPB has received consulting fees from Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline. In the past three years, EKS received honoraria from Novartis for Continuing Medical Education Seminars and grant and travel support from GlaxoSmithKline. The rest of authors declare no competing interests. Funding Information: SF has received grants from the American Thoracic Society and Fisher &Paykel. RPB has received consulting fees from Boehringer Ingelheim , AstraZeneca , and GlaxoSmithKline . In the past three years, EKS received honoraria from Novartis for Continuing Medical Education Seminars and grant and travel support from GlaxoSmithKline. The rest of authors declare no competing interests. Funding Information: The project described was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the National Heart, Lung, and Blood Institute . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca , Boehringer-Ingelheim, Genentech , GlaxoSmithKline , Novartis , Pfizer , Siemens , and Sunovion . SF was supported by the Department of Veterans Affairs , Veterans Health Administration, Office of Rural Health, Veterans Rural Health Resource Center (Award # 14380), and the Health Services Research and development (HSR&D) Service through the Comprehensive Access and Delivery Research and Evaluation (CADRE) Center ( CIN 13–412), and has received grants from the American Thoracic Society and Fisher &Paykel. Publisher Copyright: {\textcopyright} 2020",

year = "2021",

month = nov,

doi = "10.1016/j.yrmex.2020.100025",

language = "English (US)",

volume = "3",

journal = "Respiratory Medicine: X",

issn = "2590-1435",

publisher = "Elsevier Ltd",

}

TY - JOUR

T1 - Increased mortality associated with frequent exacerbations in COPD patients with mild-to-moderate lung function impairment, and smokers with normal spirometry

AU - Fortis, Spyridon

AU - Wan, Emily S.

AU - Kunisaki, Ken

AU - Eyck, Patrick Tel

AU - Ballas, Zuhair K.

AU - Bowler, Russell P.

AU - Crapo, James D.

AU - Hokanson, John E.

AU - Wendt, Chris

AU - Silverman, Edwin K.

AU - Comellas, Alejandro P.

N1 - Funding Information: The project described was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion. SF was supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Rural Health, Veterans Rural Health Resource Center (Award # 14380), and the Health Services Research and development (HSR&D) Service through the Comprehensive Access and Delivery Research and Evaluation (CADRE) Center (CIN 13?412), and has received grants from the American Thoracic Society and Fisher &Paykel.SF has received grants from the American Thoracic Society and Fisher &Paykel. RPB has received consulting fees from Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline. In the past three years, EKS received honoraria from Novartis for Continuing Medical Education Seminars and grant and travel support from GlaxoSmithKline. The rest of authors declare no competing interests. Funding Information: SF has received grants from the American Thoracic Society and Fisher &Paykel. RPB has received consulting fees from Boehringer Ingelheim , AstraZeneca , and GlaxoSmithKline . In the past three years, EKS received honoraria from Novartis for Continuing Medical Education Seminars and grant and travel support from GlaxoSmithKline. The rest of authors declare no competing interests. Funding Information: The project described was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the National Heart, Lung, and Blood Institute . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca , Boehringer-Ingelheim, Genentech , GlaxoSmithKline , Novartis , Pfizer , Siemens , and Sunovion . SF was supported by the Department of Veterans Affairs , Veterans Health Administration, Office of Rural Health, Veterans Rural Health Resource Center (Award # 14380), and the Health Services Research and development (HSR&D) Service through the Comprehensive Access and Delivery Research and Evaluation (CADRE) Center ( CIN 13–412), and has received grants from the American Thoracic Society and Fisher &Paykel. Publisher Copyright: © 2020

PY - 2021/11

Y1 - 2021/11

N2 - Background: The burden of frequent respiratory exacerbations in COPD patients with mild-to-moderate spirometric impairment and smokers with preserved lung function is unknown. Methods: We categorized COPD participants in COPDGene with post-bronchodilator FEV1%predicted≥50% by the annual exacerbation frequency into three groups: i)frequent exacerbators (top 5%; n = 109), ii)exacerbators (>0 but less than frequent exacerbators; n = 1,009), and iii)No exacerbation (n = 981). Exacerbations were defined as respiratory episodes requiring antibiotics and/or systemic steroids. We performed a Cox proportional hazards regression analysis to examine the association with mortality. We repeated the same process in current/former smokers with preserved spirometry (FEV1≥80%predicted and FEV1/FVC≥0.7). Results: Among 2,099 COPD participants, frequent exacerbators had ≥1.8 exacerbations/year and were responsible for 34.3% of the total exacerbations. There were 102 (10.4%) deaths in the group with no exacerbations, 119 (11.8%) in the exacerbator group, and 24 (22%) in the frequent exacerbators. Adjusted mortality in frequent exacerbators was higher relative to individuals with no exacerbations (hazard ratio (HR) = 1.98; 95%CI = 1.25–3.13). An increase in frequency of exacerbations by one exacerbation/year was associated with increased mortality (HR = 1.40,95%CI = 1.21–1.62). Among 3,143 participants with preserved spirometry, frequent exacerbators had ≥0.8 exacerbations/year and were responsible for more than half of the exacerbations. There were 93 (4.2%) deaths in the group with no exacerbations, 28 (3.8%) in the exacerbator group, and 14 (7.6%) in the frequent exacerbators. The adjusted mortality was increased in frequent exacerbators with preserved spirometry relative to those with no exacerbations (HR = 2.25; 95%CI = 1.26–4.01). Conclusions: In COPD participants with mild-to-moderate spirometric impairment and smokers with preserved spirometry, the frequent exacerbator phenotype is responsible for a large proportion of total exacerbations and associated with high mortality.

AB - Background: The burden of frequent respiratory exacerbations in COPD patients with mild-to-moderate spirometric impairment and smokers with preserved lung function is unknown. Methods: We categorized COPD participants in COPDGene with post-bronchodilator FEV1%predicted≥50% by the annual exacerbation frequency into three groups: i)frequent exacerbators (top 5%; n = 109), ii)exacerbators (>0 but less than frequent exacerbators; n = 1,009), and iii)No exacerbation (n = 981). Exacerbations were defined as respiratory episodes requiring antibiotics and/or systemic steroids. We performed a Cox proportional hazards regression analysis to examine the association with mortality. We repeated the same process in current/former smokers with preserved spirometry (FEV1≥80%predicted and FEV1/FVC≥0.7). Results: Among 2,099 COPD participants, frequent exacerbators had ≥1.8 exacerbations/year and were responsible for 34.3% of the total exacerbations. There were 102 (10.4%) deaths in the group with no exacerbations, 119 (11.8%) in the exacerbator group, and 24 (22%) in the frequent exacerbators. Adjusted mortality in frequent exacerbators was higher relative to individuals with no exacerbations (hazard ratio (HR) = 1.98; 95%CI = 1.25–3.13). An increase in frequency of exacerbations by one exacerbation/year was associated with increased mortality (HR = 1.40,95%CI = 1.21–1.62). Among 3,143 participants with preserved spirometry, frequent exacerbators had ≥0.8 exacerbations/year and were responsible for more than half of the exacerbations. There were 93 (4.2%) deaths in the group with no exacerbations, 28 (3.8%) in the exacerbator group, and 14 (7.6%) in the frequent exacerbators. The adjusted mortality was increased in frequent exacerbators with preserved spirometry relative to those with no exacerbations (HR = 2.25; 95%CI = 1.26–4.01). Conclusions: In COPD participants with mild-to-moderate spirometric impairment and smokers with preserved spirometry, the frequent exacerbator phenotype is responsible for a large proportion of total exacerbations and associated with high mortality.

KW - Chronic obstructive pulmonary disease

KW - Exacerbations

KW - Mortality

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UR - http://www.scopus.com/inward/citedby.url?scp=85099006353&partnerID=8YFLogxK

U2 - 10.1016/j.yrmex.2020.100025

DO - 10.1016/j.yrmex.2020.100025

M3 - Article

C2 - 35911870

AN - SCOPUS:85099006353

SN - 2590-1435

VL - 3

JO - Respiratory Medicine: X

JF - Respiratory Medicine: X

M1 - 100025

ER -

Increased mortality associated with frequent exacerbations in COPD patients with mild-to-moderate lung function impairment, and smokers with normal spirometry

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