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Observational Study
. 2023 Jun 6;329(21):1832-1839.
doi: 10.1001/jama.2023.2065.

Airway-Occluding Mucus Plugs and Mortality in Patients With Chronic Obstructive Pulmonary Disease

Alejandro A Diaz  1   2 , José L Orejas  1   2 , Scott Grumley  3 , Hrudaya P Nath  3 , Wei Wang  2   4 , Wojciech R Dolliver  1 , Andrew Yen  5 , Seth J Kligerman  5   6 , Kathleen Jacobs  5 , Padma P Manapragada  3 , Mostafa Abozeed  3 , Muhammad Usman Aziz  3 , Mohd Zahid  3 , Asmaa N Ahmed  3 , Nina L Terry  3 , Ruben San José Estépar  2   7 , Victor Kim  8 , Barry J Make  9 , MeiLan K Han  10 , Sushilkumar Sonavane  11 , George R Washko  1   2 , Michael Cho  1   2   12 , Raúl San José Estépar  2   7
Affiliations
Observational Study

Airway-Occluding Mucus Plugs and Mortality in Patients With Chronic Obstructive Pulmonary Disease

Alejandro A Diaz et al. JAMA. .

Abstract

Importance: Airway mucus plugs are common in patients with chronic obstructive pulmonary disease (COPD); however, the association of airway mucus plugging and mortality in patients with COPD is unknown.

Objective: To determine whether airway mucus plugs identified on chest computed tomography (CT) were associated with increased all-cause mortality.

Design, setting, and participants: Observational retrospective analysis of prospectively collected data of patients with a diagnosis of COPD in the Genetic Epidemiology of COPD cohort. Participants were non-Hispanic Black or White individuals, aged 45 to 80 years, who smoked at least 10 pack-years. Participants were enrolled at 21 centers across the US between November 2007 and April 2011 and were followed up through August 31, 2022.

Exposures: Mucus plugs that completely occluded airways on chest CT scans, identified in medium- to large-sized airways (ie, approximately 2- to 10-mm lumen diameter) and categorized as affecting 0, 1 to 2, or 3 or more lung segments.

Main outcomes and measures: The primary outcome was all-cause mortality, assessed with proportional hazard regression analysis. Models were adjusted for age, sex, race and ethnicity, body mass index, pack-years smoked, current smoking status, forced expiratory volume in the first second of expiration, and CT measures of emphysema and airway disease.

Results: Among the 4483 participants with COPD, 4363 were included in the primary analysis (median age, 63 years [IQR, 57-70 years]; 44% were women). A total of 2585 (59.3%), 953 (21.8%), and 825 (18.9%) participants had mucus plugs in 0, 1 to 2, and 3 or more lung segments, respectively. During a median 9.5-year follow-up, 1769 participants (40.6%) died. The mortality rates were 34.0% (95% CI, 32.2%-35.8%), 46.7% (95% CI, 43.5%-49.9%), and 54.1% (95% CI, 50.7%-57.4%) in participants who had mucus plugs in 0, 1 to 2, and 3 or more lung segments, respectively. The presence of mucus plugs in 1 to 2 vs 0 and 3 or more vs 0 lung segments was associated with an adjusted hazard ratio of death of 1.15 (95% CI, 1.02-1.29) and 1.24 (95% CI, 1.10-1.41), respectively.

Conclusions and relevance: In participants with COPD, the presence of mucus plugs that obstructed medium- to large-sized airways was associated with higher all-cause mortality compared with patients without mucus plugging on chest CT scans.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cho reported receiving grants from Bayer. Dr Diaz reported receiving personal fees from Boehringer Ingelheim and having a patent for Methods and Compositions Relating to Airway Dysfunction pending (701586-190200USPT). Dr Terry reported that she and/or her husband are general stockholders with no controlling interest in the following: Johnson & Johnson, Kimberly-Clark Corp, Microsoft Corp, Amgen Inc, Bristol Myers Squibb, Cisco Systems Inc, Medtronic, Merck & Co Inc, Procter & Gamble, Crisper Therapeutics, Nvidia, Texas Instruments, Hewlett Packard, United Health, Abbott Labs, Eli Lilly and Co, AbbVie Inc, and LyondellBasell Industries. Mr Ruben San José Estépar reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Kim reported receiving personal fees from Gala Therapeutics, the American Board of Internal Medicine critical care test writing committee, AstraZeneca, and Boehringer Ingelheim. Dr Make reported receiving grants from National Heart, Lung, and Blood Institute provided to and controlled by National Jewish Health; fees for CME activity from the American College of Chest Physicians, Eastern Pulmonary Conference, Integritas Communications, Novartis, Pri-Med, Projects in Knowledge, and WebMD; grants from the American Lung Association, AstraZeneca, and Department of Defense paid to National Jewish Health; and royalties from Wolters Kluwer Health. Dr Make also reported serving on the data and safety monitoring board for Baystate Medical Center, Quintiles Laboratories, Spiration, and the University of Wisconsin; medical advisory board for Boehringer Ingelheim and Mylan; advisory board for GlaxoSmithKline and Mount Sinai; as a consultant for Optimum Patient Care Global and Third Pole Therapeutics; and on committees for the RECOVER trial. Dr Han reported receiving grants from the NIH and COPD Foundation and personal fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Cipla, Chiesi, Novartis, Pulmonx, Teva Pharmaceutical Industries, Verona Pharma, Merck, Mylan, Sanofi, DevPro Biopharma, Aerogen, Polarian, Regeneron, Amgen, UpToDate, Altesa Biopharma, Medscape, National Association of Colleges and Employers, MDBriefCase, and Integrity; research support paid to the institution from the NIH, Novartis, Sunovion, Nuvaira, Sanofi, AstraZeneca, Boehringer Ingelheim, Gala Therapeutics, Biodesix, the COPD Foundation, and the American Lung Association; data and safety monitoring board funds paid to the institution from Novartis and Medtronic; and stock options from Meissa Vaccines and Altesa BioSciences. Dr Washko reported receiving personal fees from Actelion, Vertex Pharmaceuticals, Intellia Therapeutics, and Janssen Pharmaceuticals; grants from the Department of Defense and Boehringer Ingelheim; and support from Pulmonx, Janssen Pharmaceuticals, and CSL Behring; and is a co-founder of Quantitative Imaging Solutions, a company focused on image analytics and software development. Dr Washko’s spouse is an employee of Biogen. Dr Raúl San José Estépar reported being a founder and equity holder of Quantitative Imaging Solutions and receiving grants from Boehringer Ingelheim, contracts to serve as image core from Insmed and Lung Biotechnology; and personal fees from LeukoLab and Chiesi. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. COPDGene Participants Who Currently and Formerly Smoked Cigarettes
COPD indicates chronic obstructive pulmonary disease; COPDGene, Genetic Epidemiology of COPD; and CT, computed tomography.
Figure 2.
Figure 2.. Mortality Plots by Mucus Plug Score Category
Of the 4363 participants with chronic obstructive pulmonary disease (COPD) included in the analysis, 1769 died from any cause. A, Unadjusted plot included all the 4363 participants with COPD. B, Plot adjusted for age, sex, race and ethnicity, body mass index, smoking status, pack-years of smoking, postbronchodilator forced expiratory volume in 1 second, and computed tomography measures of emphysema and airway wall thickness and included 4166 participants with COPD. The median years of follow-up were 10.3 (IQR, 5.4-12.3), 8.7 (IQR, 5.0-12.0), and 7.1 (IQR, 3.9-11.6) for participants in mucus plug score categories of 0, 1 to 2, and 3 or more, respectively.
Figure 3.
Figure 3.. All-Cause Mortality by Mucus Plug Score Category and Chronic Obstructive Pulmonary Disease (COPD) Severity (N = 4363)
Values represent proportion of all-cause mortality (A) and the percentage of participants (B) by Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity stage of COPD and mucus plug score category. Mortality rate was calculated as the number of participants who died divided by the number of participants (GOLD and mucus plug score category) × 100. GOLD stages were defined with postbronchodilator forced expiratory volume in the first second of expiration (FEV1) percentage of predicted (pp) values as follows: 1 (mild, n = 766), FEV1 pp ≥80; 2 (moderate, n = 1887), FEV1 pp ≥50 to <80; 3 (severe, n = 1127) FEV1 pp ≥30 to <50; and 4 (very severe, n = 583), FEV1 pp <30.
See this image and copyright information in PMC

Comment in

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