Mucus Plug Reduction with Type 2 Biologics: Lessons for COPD

Targeting type 2 inflammation can reduce mucus plugging and may modify the course of airway disease, according to Mario Castro, MD, MPH, who drew largely on severe asthma research in a session at the GOLD 2026 COPD International Conference.¹

Castro, chief of pulmonary, critical care, and sleep medicine at the University of Kansas, said mucus plugs have historically received little attention. Interest has grown as therapeutic trials have begun to show their clinical importance.

Castro described plug formation as a product of inflammatory cell-related cross-linking within mucus and altered mucus hydration, leading to mucus stasis. Impaired mucociliary clearance leaves patients unable to clear inhaled pathogens, activating inflammatory, antimicrobial peptide, oxidant, and protease-antiprotease pathways.

How Does IL-13 Drive Mucus Plugging?

Interleukin (IL)-13 is a central cytokine in this process, increasing MUC5AC expression in both adult and pediatric bronchial epithelial cells. Work from Castro’s lab, published last year in the American Journal of Respiratory and Critical Care Medicine, showed IL-13 also reduces ciliary beating and ciliary beat frequency in cultured airway epithelial cells.

“When you expose it to IL-13, the cilia do not like it,” said Castro during his session at GOLD.

Adding dupilumab, which blocks the IL-4 receptor alpha and thus both IL-4 and IL-13 signaling, partially restored ciliary beating and frequency at increasing concentrations. Castro suggested this incomplete restoration may help explain variability in patient response to the drug.

In Severe Asthma Research Program airway biopsies, goblet cells nearly replaced the epithelium despite high-dose inhaled and even systemic corticosteroids. “We know this pathway is not modified by corticosteroids,” said Castro, adding the finding matters as clinicians consider its application in COPD.

Can Quantitative Imaging Detect the Mucus Phenotype?

Not all mucus plugs are alike, according to Castro. Plugs persist longitudinally but change phenotype over time, ranging from short, stubby plugs under 12 mm to longer, stringy plugs, and the stringy form carries greater consequences because it spans multiple branches of the airway tree.

Castro also presented Severe Asthma Research Program data, collected when few patients used biologics, linking higher mucus scores with declines in both FEV1 and FVC over time. He suggested the FVC decline may reflect airway closure, with effects reaching from the proximal airways to the distal small airways.

“History from the patient is not sufficient to help us detect this mucus phenotype. What we need really is quantitative technology,” said Castro.

He cited quantitative CT and hyperpolarized xenon MRI as tools able to reproducibly measure airway dimensions, lung density, mucus plugs, and ventilation defects. Castro called for trials to define the minimal clinically important difference (MCID) for each measure so regulators can accept them as meaningful endpoints.

What Did the CASCADE and VESTIGE Trials Show?

In the CASCADE trial of patients with uncontrolled moderate to severe asthma, the anti-thymic stromal lymphopoietin antibody tezepelumab reduced mucus plug scores by an average of 1.7, significantly more than placebo.² Castro proposed the MCID for mucus plug score likely sits around 1. Reductions correlated with declines in blood eosinophils and fractional exhaled nitric oxide (FeNO) and with gains in FEV1 and FEF25-75.

VESTIGE, which Castro led, randomized 109 patients with moderate to severe asthma, blood eosinophils of 300 cells/µL or higher, and FeNO of 25 ppb or higher 2:1 to dupilumab or placebo for 24 weeks. CT scans were obtained at baseline, week 4, and week 24.

About two-thirds of dupilumab-treated patients, whose baseline FeNO ranged from 50 to 60 ppb, reached FeNO below 25 ppb. Airway volume improved, but the difference did not reach statistical significance, which Castro attributed to variability in CT coaching methods.

Editor's Note: This summary has been edited for grammar and clarity using artificial intelligence tools.

References

1. Castro M. Targeting mucus with precision: disease modification with improved outcomes. Presented at: GOLD 2026 COPD International Conference; November 5, 2026; Philadelphia, PA.

2. Nordenmark LH, Hellqvist Å, Emson C, et al. Tezepelumab and mucus plugs in patients with moderate-to-severe asthma. NEJM Evid. 2023;2(10):EVIDoa2300135. doi:10.1056/EVIDoa2300135.