Persistent Mucus Plugs Linked to Faster Decline in Lung Function for Patients with COPD

May 14, 2025

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States, most often caused by cigarette smoking or long-term exposure to air pollutants. While there is no cure, progression can be slowed by reducing exposure to these factors.

A new study from Mass General Brigham researchers uncovered another factor linked to progression of the disease: the accumulation of mucus in the lungs. People with COPD who had persistent airway-clogging mucus plugs over a five-year period had a faster decline in lung function than those who didn’t have the plugs. The study points toward therapies that disrupt these plugs as a promising strategy to slow down the progression of the disease and improve the quality of life for affected patients. Results are published in The New England Journal of Medicine (NEJM).

“Mucus plugs can come and go; in some people they resolve, and in others they seem to stick around,” said lead author Sofia Mettler, MD, MSc, a clinical fellow in the Division of Pulmonary and Critical Care Medicine at Brigham and Women’s Hospital (BWH), a founding member of the Mass General Brigham healthcare system. “If the mucus plugs resolve, the patients have a slower lung function decline than those who have a persisting block.”

Computer tomography images of mucus plugs (arrowheads) in the lower lobes from a participant in the COPDGene Study. (Picture provided by Alejandro Diaz.)

Senior author Alejandro Diaz, MD, MPH, of the BWH Division of Pulmonary and Critical Care Medicine, and team previously published a paper linking mucus plugs to increased mortality in patients with COPD, even for those who were not experiencing the hallmark symptoms like cough and phlegm production. The researchers next wanted to figure out how the persistence or resolution of mucus plugs influence the progression of the disease.

They examined data from 2,118 participants in the NIH-funded COPDGene study, which included participants who smoked at least 10 pack-years and were diagnosed with COPD. The researchers assessed the participants’ forced expiratory volume in one second (FEV1)—a measure of lung function—and looked at whether mucus plugs were present. They looked for evidence of mucus plugs on CT scans at two timepoints: the initial assessment and a follow-up conducted five years later.

They found that the group of patients with persistent mucus plugs (present at both assessments), and the group who had newly developed mucus plugs by the follow-up, had significantly faster lung function decline (23.2ml/year and 17.7ml/year less FEV1 respectively) compared to the group who did not have mucus plugs at either time. This decline in function was more pronounced among those who resumed or continued smoking during the study period.

Notably, patients whose mucus plugs were present during the initial screening, but resolved by the follow-up, showed no difference in lung function decline compared to those without mucus plugs at either time.

“Because it is an observational study, we cannot conclude a causal relationship,” said Mettler. “So the next logical step is to conduct a clinical trial to see if mucus plugs are really what’s responsible for the change in lung function decline.”

The team also aims to uncover what biochemical or demographic or other extrinsic factors are causing some people’s mucus plugs to resolve and identify potential interventions that can help fight the progression of the disease to improve the lives of patients.

Read the paper

Authorship: In addition to Mettler and Diaz, Mass General Brigham authors include Carrie L Pistenmaa, George R. Washko, Michael H. Cho, Pietro Nardelli, Monica Iturrioz Campo, Rubén San José Estépar, Raúl San José Estépar, and Wei Wang. Other authors include Padma P Manapragada, Mostafa Abozeed, Muhammad Usman Aziz, Mohd Zahid, Scott Grumley, Hrudaya P. Nath, Andrew Yen, Sushilkumar Sonavane, and Christian F Clarenbach.

Disclosures: Diaz 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 SAMBA trial; participation on Study Steering Committee for Sanofi; participation on Advisory Board for Sanofi, Verona Pharma, and Polarean; speaker fees from Zambon. All unrelated to this work.

Funding: This work was supported by NHLBI grants U01 HL089897 and U01 HL089856 and by NIH contract 75N92023D00011. The COPDGene study (NCT00608764) has also been supported by the COPD Foundation through contributions made to an Industry Advisory Committee that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion. Dr. Diaz is supported by NHLBI grants R01-HL149861, R01-HL164824, and R01-HL173017.

Paper cited: Mettler, S et al. “Longitudinal Changes in Airway Mucus Plugs and Forced Expiratory Volume in 1 second in COPD” NEJM DOI: 10.1056/NEJMc2502456

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