To the editor,
Background
Individuals with normal spirometry and preserved ratio and impaired spirometry (PRISm) frequently experience worsening of their respiratory symptoms requiring treatment,1 episodes termed exacerbations. In persons with COPD, airway-occluding mucus plugs (MPs) may be a source of infection and inflammation, triggering exacerbations.2–5 However, whether MPs are associated with exacerbations in tobacco-exposed individuals without COPD remains to be explored. Therefore, we aimed to assess the relationship between MPs and exacerbations in persons with normal spirometry and PRISm.
Methods
We scored MPs on computed tomography (CT) from persons exposed to tobacco (smoking history of ≥10 pack years) without COPD from the multi-center COPDGene Study. Of the 10,305 enrolled participants, 5,831 were excluded, including non-smoker controls (n=107), those with COPD (n=4,483), and those with missing data on spirometry (n=66), MPs (n=566), and exacerbation over time (n=609). The remaining 4,474 participants had normal spirometry—defined as FEV1/FVC ≥0.70 and FEV1 ≥80% predicted— and PRISm —defined as FEV1/FVC ≥0.70 and FEV1 <80% predicted. Trained readers determined the scores by counting the number of lung segments with MPs, ranging from 0 to 18.6 For this analysis, the scores were categorized into 0, 1–3, and ≥4.2,3,7 At enrollment, participants were exacerbation-free for at least 4 weeks and asked to report the frequency of exacerbations in the prior year. Prospective moderate exacerbations were defined as new onset or increased cough, phlegm, and dyspnea requiring prescription of antibiotics or systemic steroids, ascertained every six months through the COPDGene follow-up program using telephone and web-based interfaces.1 Severe exacerbations were defined as those resulting in hospitalization or an emergency room visit.1
To account for the overdispersion of exacerbations during follow-up, we used a multivariable zero-inflated Poisson regression model to test the association between mucus plug (1–3 vs. 0 and ≥4 vs. 0) and moderate-to-severe exacerbations (hereafter, exacerbations) over time.2 A priori- selected covariates included age, sex, self-reported race, body mass index (BMI), current smoking status, pack-years smoked, physician-diagnosed asthma, self-reported history of ≥1 exacerbation in the year before enrollment, post-bronchodilator FEV1 (liters), center, and CT measures of emphysema (defined as the percentage of lung attenuation areas <−950 Hounsfield units) and airway wall thickness (square root of wall area for a standardized 10-mm-perimeter airway).2,3 Model estimates for exacerbations are reported as incidence rate ratios. All analyses were performed using SAS 9.4.
Results
Table 1 shows participants’ characteristics. Among 3,500 participants with normal spirometry, 663 (18.9%) had a MP score of 1–3 and 66 (1.9%) had a score of ≥4; among the 974 PRISm participants, 224 (23%) had 1–3 lung segments with MPs and 37 (3.8%) had ≥4 (normal spirometry vs. PRISm comparison, p < 0.0001). The crude exacerbation rates per 100 person-years were 14 (95% confidence interval [CI]: 14, 15) for participants with normal spirometry and 28 (95% CI: 27, 29) for those with PRISm (p <0.0001). Next, we conducted analyses separately in each spirometry group to evaluate the association between MPs and exacerbation rates.
Table 1.
Participants’ characteristics by spirometrie group and number of lung segments with mucus plugs.
| Normal Spirometry | PRISm | |||||
|---|---|---|---|---|---|---|
| Characteristic | Number of lung segments with mucus plugs | |||||
| 0 (n=2771) | 1–3 (n=663) | ≥4 (n=66) | 0 (n=713) | 1–3 (n=224) | ≥4 (n=37) | |
| Age, years | 56.8 (8.1) | 58.8 (9.2) | 64.6 (9.6) | 57.5 (8.0) | 59.0 (9.0) | 60.1 (8.5) |
| Male, n (%) | 1448 (52.3) | 291 (43.9) | 19 (28.8) | 339 (47.6) | 80 (35.7) | 9 (24.3) |
| Female, n (%) | 1323 (47.7) | 372 (56.1) | 47 (71.2) | 374 (52.5) | 144 (64.3) | 28 (75.7) |
| Non-Hispanic White, n (%)a | 1721 (62.1) | 460 (69.4) | 51 (77.3) | 426 (59.8) | 145 (64.7) | 31 (83.8) |
| Non-Hispanic Black, n (%)a | 1050 (37.9) | 203 (30.6) | 15 (22.7) | 287 (40.3) | 79 (35.3) | 6 (16.2) |
| Body mass index (BMI), kg/m2 | 29.6 (5.9) | 27.7 (5.5) | 25.1 (4.0) | 32.8 (7.4) | 31.2 (6.9) | 26.7 (5.1) |
| Current smoking status, n (%) | 1533 (55.3) | 349 (52.6) | 26 (39.4) | 419 (58.8) | 135 (60.3) | 24 (64.9) |
| Pack-Years smoked | 37.3 (19.8) | 37.3 (21.8) | 36.8 (22.2) | 42.6 (23.8) | 42.5 (25.0) | 43.0 (23.9) |
| History of asthma, n (%) | 160 (5.8) | 59 (8.9) | 6 (9.1) | 94 (13.2) | 45 (20.1) | 10 (27.0) |
| ≥1 exacerbation in the year prior to enrollment, n (%) | 251 (9.1) | 62 (9.4) | 8 (12.1) | 131 (18.4) | 54 (24.1) | 12 (32.4) |
| FEV1, Lb | 2.9 (0.7) | 2.8 (0.7) | 2.5 (0.6) | 2.1 (0.5) | 1.9 (0.5) | 2.0 (0.5) |
| FEV1, % predictedb | 97.5 (11.4) | 96.8 (11.7) | 98.0 (11.8) | 71.1 (7.7) | 68.6 (9.0) | 69.2 (7.5) |
| FEV1/FVCb | 0.8 (0.1) | 0.8 (0.0) | 0.8 (0.0) | 0.8 (0.0) | 0.7 (0.0) | 0.8 (0.0) |
| Emphysema on CT, %c | 2.0 (2.7) | 2.2 (2.8) | 2.0 (2.0) | 1.5 (2.7) | 1.5 (2.4) | 1.1 (1.4) |
| Airway wall thickness, mmd | 2.0 (0.4) | 2.1 (0.5) | 2.0 (0.6) | 2.4 (0.5) | 2.7 (0.6) | 2.7 (0.6) |
Data are presented as mean (standard deviation) and frequency (percentage). Missing data for emphysema on CT and airway wall thickness, 17 participants. PRISm = preserved ratio and impaired spirometry; FEV1 = forced expiratory volume in first second of expiration; FVC = forced vital capacity.
Race was self-reported by the participants.
Postbronchodilator pulmonary function measurements are presented.
Measured as percentage of voxels <−950 Housefield units at baseline inspiratory CT scans.
Measured as the square root of the wall area of an ideal 10-mm-inner-perimeter airway at baseline inspiratory CT scans.
Over a median follow-up of 12 years (with differing follow-up durations across participants), in the normal spirometry group, those with no MPs had an exacerbation rate of 14 per 100 person-years while those with 1–3 and ≥4 lung segments affected with MPs each had a rate of 19 per 100 person-years. In adjusted models, exacerbation rates were 28% (p <0.0001) and 35% (p = 0.003) higher for participants with 1–3 and ≥4 lung segments with MPs respectively during follow-up, compared to those without MPs (Figure 1).
Figure 1.
Mucus Plugs (MPs) and exacerbations in tobacco-exposed people with normal spirometry (top) and PRISm (bottom).
Adjusted incidence rate ratios with 95% confidence intervals are shown and were estimated using multivariable zero-inflated Poisson regression models conducted for each group (See text). The models included a log link and the log of follow-up time as an offset; FEV1 (liters) was included as a predictor in the zero model.
In PRISm group, exacerbation rates per 100 person-years by MP group were as follows: 27 for those with no MPs, 28 for 1–3 lung segments affected with MPs, and 57 for ≥4 segments. In adjusted models, participants with ≥4 lung segments with MPs experienced a 78% (p <0.0001) higher rate of exacerbations than those without MPs, whereas those with 1–3 lung segments with MPs showed no significant difference (p = 0.21) (Figure 1).
In sensitivity analyses using post-bronchodilator FEV1 percent predicted instead of absolute FEV1 (liters) as a covariate, results remained consistent with the primary analysis.
Compared to those with no MPs, adjusted exacerbation rates were 28% (p < 0.0001) and 35% (p = 0.003) higher for participants with 1–3 and ≥4 lung segments with MPs in the normal spirometry group, and 8% (p = 0.18) and 76% (p < 0.0001) higher in the PRISm group, respectively. Sensitivity analyses excluding participants with more than 10 exacerbations per year yielded results consistent with the primary analysis (data not shown).8
Discussion
In this study, we demonstrated that approximately 1 in 4 to 5 people who smoke with normal spirometry and PRISm have MPs blocking their airways. The results align with data from another U.S. COPD-enhanced study.9 We found that the prevalence of MPs was slightly higher in PRISm than in those with normal lung function, consistent with observations indicating an increase in MPs with more severe lung function impairment.5,6 Also, differential susceptibility to mucus pathology might play a role.
Furthermore, in tobacco-exposed people without COPD, the presence of MPs in ≥4 lung segments was associated with significantly higher exacerbation rates in both groups, whereas in the PRISm group, the association was not definitive in those with 1–3 MP-affected lung segments. These novel findings were observed after adjusting for important confounders, including demographics, histories of asthma and smoking, lung function, and prior history of exacerbations. The lack of association in the lower burden PRISm group could reflect the influence of other unmeasured factors (e.g., sputum pathogens) that may play a more dominant role in exacerbation risk. The findings suggest that these clinical events may be triggered when ≥4 lung segments are affected, and this could be informative for testing interventions. The findings also expand those observed in persons with COPD and support that in susceptible individuals who smoke but do not meet the criteria for COPD, MP might be a risk factor for exacerbations.2,3,9
Our work on tobacco-exposed individuals without spirometric COPD is supported by prior studies demonstrating that these episodes are clinically important.1 A recent study has shown that in persons with normal lung function, exacerbations are linked to a faster decline in lung function and increased mortality.8 As effective therapies for tobacco-exposed persons with normal lung function and PRISm are lacking, the findings support considering mucus plugs as a potential target for preventive and therapeutic strategies.10 While our study was not intended to uncover the mechanisms underlying the association between mucus plugs and exacerbations, animal and human studies have shown that local inflammation, local hypoxia, and the presence of trapped pathogens are facilitated by mucus plugs, likely triggering exacerbations.11–13 Overall, our findings encourage further investigation into mucus pathology in these smoking populations.
Study limitations include a lack of individuals with <10 pack-years of smoking and racial/ethnic groups other than non-Hispanic White and Black, which may limit the generalizability of our findings. Other limitations include a lack of sputum measures (e.g., microbiome, mucins),14 time-consuming visual lung segment-based MP scoring, which may underestimate the burden of mucus as it does not account for partially blocked airways, and the potential for recall bias in self-reported exacerbation events. That bias is unlikely to affect differentially the spirometric and MP groups. Finally, due to the observational nature of this study, no conclusions about causality can be drawn.
Despite these limitations, this study demonstrates that mucus plugs are prevalent in smokers with normal spirometry and PRISm, representing a novel risk factor for exacerbations. Further investigations are warranted to gain a deeper understanding of mucus pathology and test mucus plugs as a target for preventive and therapeutic strategies in these populations.
Funding/Support
Dr. Diaz is supported by funding from the US National Heart, Lung, and Blood Institute (R01-HL149861, R01-HL164824, R01-HL173017). COPDGene is supported by NHLBI grants U01 HL089897 and U01 HL089856 and by NIH contract 75N92023D00011. The COPD Foundation has also supported the COPDGene study (NCT00608764) through contributions made to an Industry Advisory Committee that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion. Dr. Wan is supported through the U.S. Department of Veterans Affairs, Merit Award CX002193.
The COPDGene Ancillary Studies and Publications Committee approved an earlier version of this manuscript.
The content is solely the authors’ responsibility and does not necessarily represent the official views of the funding sponsors.
Artificial Intelligence Disclaimer: No artificial intelligence tools were used in writing this manuscript
Footnotes
Conflict of interest statement
RB, MIC, PN, SKM, PPM, MA, MUA, MZ, HPN, SG, SS, WW, and JCR have no conflict of interest to declare. AY reports salary support from National Institutes of Health. MHC reports grant support from Bayer and consulting fees from Apogee. RSJE reports personal fees from Sanofi, Lung Biotechnology, and Boehringer Ingelheim and is a founder and equity holder of Quantitative Imaging Solutions, which are unrelated to this work. ESW has served on a scientific advisory board for Verona Pharma, outside the current work, and reports research funding from the U.S. Department of Veteran Affairs. AAD declares USPTO Patent No.: 11,946,928 B2 “Methods and compositions relating to airway dysfunction”; participation on Data and Safety Monitoring Board for NIH COPD trial SAMBA; participation on Advisory Board for Sanofi, Verona Pharma, and Polarean; participation on a Study Steering Committee for Sanofi; speaker fees from Zambon. All unrelated to this work.
Contributor Information
Ruchita Borgaonkar, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA.
Monica Iturrioz-Campo, Harvard Medical School, Boston, MA, USA; Department of Radiology, Brigham and Women’s Hospital, Boston, MA, USA.
Pietro Nardelli, Harvard Medical School, Boston, MA, USA; Department of Radiology, Brigham and Women’s Hospital, Boston, MA, USA.
Sofia K. Mettler, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA.
Padma P. Manapragada, Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Mostafa Abozeed, Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Muhammad Usman Aziz, Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Mohd Zahid, Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Hrudaya P. Nath, Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Scott Grumley, Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Andrew Yen, Department of Radiology, University of California San Diego, San Diego, CA, USA.
Sushilkumar Sonavane, Department of Radiology, Mayo Clinic, Jacksonville, FL, USA.
Wei Wang, Harvard Medical School, Boston, MA, USA; Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Boston, MA, USA.
Michael H. Cho, Harvard Medical School, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA.
Raul San José Estépar, Harvard Medical School, Boston, MA, USA; Department of Radiology, Brigham and Women’s Hospital, Boston, MA, USA.
James C. Ross, Harvard Medical School, Boston, MA, USA; Department of Radiology, Brigham and Women’s Hospital, Boston, MA, USA.
Emily S. Wan, Harvard Medical School, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA; VA Boston Healthcare System, Boston, MA, US.
Alejandro A. Diaz, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
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