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Mucus plugging on computed tomography and chronic bronchitis in chronic obstructive pulmonary disease

To the Editor,

Chronic bronchitis (CB) is associated with more dyspnea, increased respiratory exacerbations, reduced exercise capacity, and mortality [1]. The hallmark of CB is mucus overproduction and goblet cell hyperplasia [2]. Mucus plugging (MP) on CT scan has been associated with decreased lung function, worse health-related quality of life, and amount of emphysema in Chronic Obstructive Pulmonary Disease (COPD) [3]. How it relates to CB in smokers with COPD is unclear. We hypothesized that those with MP are more likely to have CB compared to those without MP.

We analyzed 2089 randomly chosen subjects from the Genetic Epidemiology Study of COPD (COPDGene) [4]. Briefly, this cohort was comprised of African American and non-Hispanic White current and former smokers (≥ 10 pack year history) 45–80 years of age with COPD. Measurement of MP has been described previously [3]. A mucus plug was defined as an opacity that completely occludes the lumen, regardless of the airway size, orientation or generation. Major airways such as the trachea, main stem and lobar bronchi were excluded. In a standardized fashion, all airway paths were examined in each out of 18 bronchopulmonary segments of both lungs. An MP score was generated for each CT scan as an aggregation of the number of bronchopulmonary segments with MP (0–18). If a CT scan required more than one reading, the final MP score was an average of the scores from two or three readers.

We divided subjects into those with at least one airway plugged with mucus (MP+) and those without MP (MP−). Additionally, based on prior research in asthma showing that mucus plugging of ≥ 4 segments was associated with worse lung function [5], we divided subjects into those with an MP score ≥ 4 and compared them to those with an MP score < 4. We compared subject characteristics between groups with either an unpaired t test or Chi-square test. Odds ratios for CB were calculated with MP scores using multivariable logistic regression models. Covariates included demographics, lung function, smoking, and radiologic parameters.

Subject characteristics are presented in Table 1. 658 (31.5%) subjects had mucus plugging on CT scan. 133 (6.4%) subjects had an MP score of ≥ 4. Compared to the MP− group, the MP+ group was more likely to have CB by either the classic definition (cough and phlegm for at least 3 months/year for 2 consecutive years, 29.2 vs. 22.9%) or the Saint George’s Respiratory Questionnaire (SGRQ) definition (cough and phlegm for the past 4 weeks almost every day or several days a week, 39.1 vs. 25.4%). In the MP ≥ 4 group, the differences were more significant with 57.7% and 41.4% of the subjects having SGRQ CB and classic CB, respectively, compared to 27.6% and 23.8% of the MP < 4 group. In those with classic CB (n = 519), 36.9% of them had MP compared to 29.7% of those without classic CB (n = 1570, p = 0.002). 10.6% of the classic CB group had an MP score ≥ 4 compared to 5.0% of those without classic CB (p < 0.0001). Similar values were found when comparing those with and without SGRQ CB (38.8 vs. 25.1%, p < 0.0001 for MP+ vs. MP− and 11.4 vs. 3.5%, p < 0.0001 for MP ≥ 4 vs. MP < 4). Dyspnea, health-related quality of life, and lung function were worse in the MP+ group (p < 0.05 for all). Percent emphysema, percent gas trapping, airway wall thickness, exacerbation frequency and severe exacerbation frequency were all significantly higher in the MP+ group (p < 0.05 for all). Except for %emphysema, findings were similarly significant in the MP ≥ 4 group compared to the MP < 4 group.

Table 1 Subject characteristics

Odds ratios (OR) for classic CB and SGRQ CB are shown in Table 2. MP+ was associated with an OR of 1.21 and 1.38 for classic CB and SGRQ CB, respectively when adjusting for demographics, lung function, smoking, and CT measures of emphysema and airway wall thickness. Similarly, MP ≥ 4 was associated with an OR of 1.67 and 2.05 for classic CB and SGRQ CB, respectively.

Table 2 Odds ratios (OR) for chronic bronchitis

These data also show that more subjects with MP, looking at two different thresholds (MP+ versus—and MP ≥ 4 versus < 4) had CB using two different definitions. Additionally, regardless of the presence or absence of CB, those with MP have worse symptoms, health-related quality of life and lung function compared to those without MP, showing that radiographic assessment of MP provides complementary information to the clinical assessment of CB.

Plugging of the small airways is a central pathologic feature of COPD. In a large study of pathologic specimens, patients with worse lung function were more likely to have small airway mucus luminal occlusion [6]. Radiologically, MP has been linked to severity of airflow obstruction, eosinophilic inflammation, and interleukin-4 blood levels in asthma [5, 7]. In two smaller studies, MP was associated with worse lung function and health-related quality of life in smokers with and without COPD, but neither CB nor eosinophilia [3, 8]. To date, this is the first study finding a significant association between mucus plugging and CB in a large cohort of COPD subjects. While the percent of our MP+ subjects who had CB was similar compared to prior studies, our findings likely differ because of the size of our cohort and differences in subject characteristics (other studies included never smokers and smokers without airflow obstruction).

The relationship between mucus plugging and emphysema is an interesting one. More mucus plugs have been found in COPD subjects with worse airflow obstruction; additionally, more emphysema is seen in COPD patients with worse airflow obstruction. Previous smaller studies in smokers with and without COPD have found weak but significant correlations between mucus plugging scores and percent emphysema [3, 8]. Our analysis was restricted to those with COPD, and we found statistically different amounts of percent emphysema between those with and without mucus plugs but the difference was not great. This suggests that mucus plugging may play a role in the pathophysiology of airflow obstruction in COPD, independent of emphysema.

We found that using a high threshold for MP scores (≥ 4) was significantly associated with CB, particularly when defined using the SGRQ. This may be related to the SGRQ CB definition identifying “active” symptoms (cough and phlegm in the past 4 weeks), compared to the classic CB definition which is better at identifying chronic symptoms (2 years). However, the higher threshold of MP was only present in 6.4%, suggesting that using any MP as a threshold may be more practical. Regardless of the definition, in this well-characterized cohort of COPD subjects, MP on CT scan was significantly associated with CB. Compared to those without MP, those with MP had worse symptoms, health-related quality of life, and lung function regardless of the presence or absence of CB. The findings suggest that imaging is a useful tool to objectively measure mucus dysfunction, a central pathophysiologic feature of CB. Further study is necessary to identify the consequences of MP on other patient reported outcomes.

Availability of data and materials

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

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Acknowledgements

Grant Support and Disclaimer: 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. COPD Foundation Funding: 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. COPDGene® Investigators – Core Units: Administrative Center: James D. Crapo, MD (PI); Edwin K. Silverman, MD, PhD (PI); Barry J. Make, MD; Elizabeth A. Regan, MD, PhD. Genetic Analysis Center: Terri Beaty, PhD; Ferdouse Begum, PhD; Peter J. Castaldi, MD, MSc; Michael Cho, MD; Dawn L. DeMeo, MD, MPH; Adel R. Boueiz, MD; Marilyn G. Foreman, MD, MS; Eitan Halper-Stromberg; Lystra P. Hayden, MD, MMSc; Craig P. Hersh, MD, MPH; Jacqueline Hetmanski, MS, MPH; Brian D. Hobbs, MD; John E. Hokanson, MPH, PhD; Nan Laird, PhD; Christoph Lange, PhD; Sharon M. Lutz, PhD; Merry-Lynn McDonald, PhD; Margaret M. Parker, PhD; Dmitry Prokopenko, Ph.D; Dandi Qiao, PhD; Elizabeth A. Regan, MD, PhD; Phuwanat Sakornsakolpat, MD; Edwin K. Silverman, MD, PhD; Emily S. Wan, MD; Sungho Won, PhD. Imaging Center: Juan Pablo Centeno; Jean-Paul Charbonnier, PhD; Harvey O. Coxson, PhD; Craig J. Galban, PhD; MeiLan K. Han, MD, MS; Eric A. Hoffman, Stephen Humphries, PhD; Francine L. Jacobson, MD, MPH; Philip F. Judy, PhD; Ella A. Kazerooni, MD; Alex Kluiber; David A. Lynch, MB; Pietro Nardelli, PhD; John D. Newell Jr., MD; Aleena Notary; Andrea Oh, MD; Elizabeth A. Regan, MD, PhD; James C. Ross, PhD; Raul San Jose Estepar, PhD; Joyce Schroeder, MD; Jered Sieren; Berend C. Stoel, PhD; Juerg Tschirren, PhD; Edwin Van Beek, MD, PhD; Bram van Ginneken, PhD; Eva van Rikxoort, PhD; Gonzalo Vegas Sanchez-Ferrero, PhD; Lucas Veitel; George R. Washko, MD; Carla G. Wilson, MS; PFT QA Center, Salt Lake City, UT: Robert Jensen, PhD. Data Coordinating Center and Biostatistics, National Jewish Health, Denver, CO: Douglas Everett, PhD; Jim Crooks, PhD; Katherine Pratte, PhD; Matt Strand, PhD; Carla G. Wilson, MS. Epidemiology Core, University of Colorado Anschutz Medical Campus, Aurora, CO: John E. Hokanson, MPH, PhD; Gregory Kinney, MPH, PhD; Sharon M. Lutz, PhD; Kendra A. Young, PhD. Mortality Adjudication Core: Surya P. Bhatt, MD; Jessica Bon, MD; Alejandro A. Diaz, MD, MPH; MeiLan K. Han, MD, MS; Barry Make, MD; Susan Murray, ScD; Elizabeth Regan, MD; Xavier Soler, MD; Carla G. Wilson, MS. Biomarker Core: Russell P. Bowler, MD, PhD; Katerina Kechris, PhD; Farnoush Banaei-Kashani, Ph.D. COPDGene® Investigators – Clinical Centers: Ann Arbor VA: Jeffrey L. Curtis, MD; Perry G. Pernicano, MD. Baylor College of Medicine, Houston, TX: Nicola Hanania, MD, MS; Mustafa Atik, MD; Aladin Boriek, PhD; Kalpatha Guntupalli, MD; Elizabeth Guy, MD; Amit Parulekar, MD; Brigham and Women’s Hospital, Boston, MA: Dawn L. DeMeo, MD, MPH; Alejandro A. Diaz, MD, MPH; Lystra P. Hayden, MD; Brian D. Hobbs, MD; Craig Hersh, MD, MPH; Francine L. Jacobson, MD, MPH; George Washko, MD. Columbia University, New York, NY: R. Graham Barr, MD, DrPH; John Austin, MD; Belinda D’Souza, MD; Byron Thomashow, MD. Duke University Medical Center, Durham, NC: Neil MacIntyre Jr., MD; H. Page McAdams, MD; Lacey Washington, MD. Grady Memorial Hospital, Atlanta, GA: Eric Flenaugh, MD; Silanth Terpenning, MD. HealthPartners Research Institute, Minneapolis, MN: Charlene McEvoy, MD, MPH; Joseph Tashjian, MD. Johns Hopkins University, Baltimore, MD: Robert Wise, MD; Robert Brown, MD; Nadia N. Hansel, MD, MPH; Karen Horton, MD; Allison Lambert, MD, MHS; Nirupama Putcha, MD, MHS. Lundquist Institute for Biomedical Innovationat Harbor UCLA Medical Center, Torrance, CA: Richard Casaburi, PhD, MD; Alessandra Adami, PhD; Matthew Budoff, MD; Hans Fischer, MD; Janos Porszasz, MD, PhD; Harry Rossiter, PhD; William Stringer, MD. Michael E. DeBakey VAMC, Houston, TX: Amir Sharafkhaneh, MD, PhD; Charlie Lan, DO. Minneapolis VA: Christine Wendt, MD; Brian Bell, MD; Ken M. Kunisaki, MD, MS. National Jewish Health, Denver, CO: Russell Bowler, MD, PhD; David A. Lynch, MB. Reliant Medical Group, Worcester, MA: Richard Rosiello, MD; David Pace, MD. Temple University, Philadelphia, PA: Gerard Criner, MD; David Ciccolella, MD; Francis Cordova, MD; Chandra Dass, MD; Gilbert D’Alonzo, DO; Parag Desai, MD; Michael Jacobs, PharmD; Steven Kelsen, MD, PhD; Victor Kim, MD; A. James Mamary, MD; Nathaniel Marchetti, DO; Aditi Satti, MD; Kartik Shenoy, MD; Robert M. Steiner, MD; Alex Swift, MD; Irene Swift, MD; Maria Elena Vega-Sanchez, MD. 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Funding

The National Heart, Lung, and Blood Institute (NHLBI) supports the COPDGene Study [Grants U01 HL089897, U01 HL089856]. The COPD Foundation also supports the COPDGene Study [Grant NCT00608764] through contributions made to an Industry Advisory Committee composed of AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, and Sunovion. Dr. Diaz is supported by the NHLBI [Grants R01HL149861 and R01-HL133137] and the Brigham and Women’s Hospital Minority Faculty Career Development Award.

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VK conceived and designed the analysis plan, performed data analysis and contributed significantly to the writing of the manuscript; WRD, HPN, SAG, NT, AA, AY, KJ, and SK generated much of the data and contributed significantly to the writing of the manuscript; AD contributed significantly to the data analysis and the writing of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Victor Kim.

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Written informed consent was obtained from all participants prior to enrollment and the study protocol was approved by the institutional review boards of all participating centers. Consent to participate is not applicable.

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Competing interests

VK reports personal fees from Gala Therapeuatics, personal fees from ABIM Critical Care Testwriting Committee, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, outside the submitted work; WRD, HPN, SAG, NT, AA, AY, KJ, SK, and AD have no competing interests to declare.

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Kim, V., Dolliver, W.R., Nath, H.P. et al. Mucus plugging on computed tomography and chronic bronchitis in chronic obstructive pulmonary disease. Respir Res 22, 110 (2021). https://doi.org/10.1186/s12931-021-01712-0

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