COPD Mucus Plugs Often Go Unnoticed but Predict Hospitalization, Death

Airway mucus plugs visible on routine chest CT are emerging as a marker of who is likely to be hospitalized, lose lung function faster, or die from chronic obstructive pulmonary disease (COPD). This holds even in patients with no cough or phlegm, and early biologic data suggest the plugs may be treatable, according to 3 pulmonologists who spoke at the 2026 Global Initiative for Chronic Obstructive Lung Disease (GOLD) International COPD Conference.

The session highlighted a practical gap for health systems, with radiology reports often noting when there is mucus plugging without quantifying it.

What Mucus Plug Studies Show About COPD Outcomes

Mucus plugs are not a new finding. A 1968 bronchographic study first tied them to airway obstruction.¹ What is new is the effort to measure them, said Emily Wan, MD, MPH, adjunct assistant professor of pulmonary, allergy, sleep, and critical care medicine at VA Boston, Brigham and Women's Hospital, and Harvard Medical School.

Prevalence of plugs has varied widely across research cohorts, from 31% in RealDTC to 45% in COPDGene and 67% in SPIROMICS.^2-4 Wan attributed the spread to differences in cohorts and in how plugs are scored. Both prevalence and plug count rose with worsening spirometry grade.

Plugs were not always symptomatic, and there are patients with mucus plugs that are not associated with cough and phlegm. One analysis found about one-third of patients had silent mucus plugs.⁵

“Silent mucus plugs are associated with worse exercise tolerance, worse quality of life, decreasing lung function, increased radiographic features of worse disease, and an increased history of exacerbations,” Wan said. “So, silent mucus plugs do appear to matter.”

Each 1-point rise in plug score was tied to a higher risk, and plugs were also associated with all-cause mortality, Wan noted. In COPDGene, mortality was 34.0%, 46.7%, and 54.1% among patients with plugs in 0, 1-2, and 3 or more lung segments, respectively.³

Finally, mucus plugs are dynamic, which also affects outcomes. Patients with persistently negative or resolved mucus plugs have a lower loss of lung function at 5 years compared with patients who have persistently positive or new plugs.⁶

"In a subset of individuals, mucus plugs are dynamic, which is exciting, right? This is potentially changeable," Wan said.

Why Triple Therapy May Not Be Enough

Monica Kraft, MD, the Murray M. Rosenberg Professor of Medicine and system chair of the Samuel Bronfman Department of Medicine at the Icahn School of Medicine at Mount Sinai, framed plugs as one driver of the exacerbations that persist on maximal inhaled therapy.

"I'm very happy we have triple therapy available. I think it's really helped a lot of our patients, but there's still some room to move," she said. In a retrospective cohort she cited, more than half of patients still had at least 2 moderate exacerbations during follow-up, and 44% had a severe one.⁷

Kraft called hospitalization "a profound sentinel event," noting that about 1 in 10 patients die during the stay and 1 in 4 within a year. "In the setting of hospitalization for COPD, it's a real call to action," she said.

She pointed to type 2 cytokines IL-4, IL-5, and IL-13, along with IL-33, as contributors to plug biology. Biologics in asthma, she said, have shown reduced plugging, which has driven lung function improvements. “I can't imagine the same thing isn't happening or something very similar in COPD," she said.

Can Biologics Reverse Mucus Plugs in COPD?

Mucus plug formation is driven in part by IL-13, which increases production of the mucin MUC5AC and impairs the cilia that clear mucus. Corticosteroids do not address that pathway, which is important to consider, said Mario Castro, MD, MPH, the L.E. Phillips and Lenora Carr Phillips Professor and chief of pulmonary critical care and sleep medicine at the University of Kansas School of Medicine, said the pathway is poorly served by existing therapy.

He presented a randomized trial in asthma of 109 patients with type 2-high disease in which dupilumab (Dupixent; Sanofi and Regeneron) reduced mucus plugs within 4 weeks, while patients on placebo averaged 1 more plug over time.⁸

"This is a dynamic process that is reversible at a much earlier time point," Castro said. Lung function also improved, by more than 600 mL in pre-bronchodilator forced expiratory volume in 1 second versus placebo.

In COPD, the stakes are higher because of a mortality signal, he said. "Now we should be classifying our patients not only by GOLD stage, but also what is their mucus plug burden," Castro said.

References

1. Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med. 1968;278(25):1355-1360.
2. Lin L, Li T, Zhang P, et al. Airway mucus plugs in COPD clinical phenotypes and prognosis across stable and exacerbation states. Sci Rep . 2026;16(1):8178. doi:10.1038/s41598-026-38985-8.
3. Diaz AA, et al. Airway-occluding mucus plugs and mortality in patients with chronic obstructive pulmonary disease. JAMA. 2023. PMID 37210745. doi:10.1001/jama.2023.2065
4. Duncan EM, Elicker BM, Henry T, et al. Mucus plugs and emphysema in the pathophysiology of airflow obstruction and hypoxemia in smokers. Am J Respir Crit Care Med. 2021;203(8):957-968. doi:10.1164/rccm.202006-2248OC
5. Mettler SK, et al. Silent airway mucus plugs in COPD and clinical implications. Chest. 2024;166(5):1010-1019. PMID 38013161.
6. Mettler SK, et al. Longitudinal changes in airway mucus plugs and FEV1 in COPD. N Engl J Med. 2025. doi:10.1056/NEJMc2502456
7. Nordon C, Carstens D, Fagerås M, et al. Characteristics and outcomes of people with COPD who experience exacerbations while on inhaled triple therapy: results of the SIRIUS I cohort study in the US (2015–2019). Int J Chron Obstruct Pulmon Dis. 2025;20:1851-1864. doi:10.2147/COPD.S513573
8. Castro M, Papi A, Porsbjerg C, et al. Effect of dupilumab on exhaled nitric oxide, mucus plugs, and functional respiratory imaging in patients with type 2 asthma (VESTIGE): a randomised, double-blind, placebo-controlled, phase 4 trial. Lancet Respir Med. 2025;13(3):208-220. doi:10.1016/S2213-2600(24)00362-X