Mucus Plugs Correlate with Small Airway Remodeling in Asthma: A Case–Control Study

Abstract Rationale The observation that mucus plugs in proximal airways on computed tomography (CT) correlate with disease severity and airflow obstruction has highlighted their role in asthma. Because of the resolution of CT, it is unknown if mucus plugs within the distal small airways (<2 mm in diameter) also contribute to asthma severity. Objectives To assess the prevalence of distal mucus plugs and their association with small airway remodeling in asthma. Methods Twelve control, five nonfatal asthma, and eleven fatal asthma lungs underwent systematic uniform random sampling to obtain 239 lung tissue samples that were imaged using micro-CT and used for matched histology to assess mucus plugs, airway wall remodeling, and mucus composition. Measurements and Main Results Within the distal lung of nonfatal and fatal asthmatics, 30% and 38% of preterminal bronchioles, 29% and 34% of terminal bronchioles, and 33% and 21% of transitional bronchioles contained mucus plugs, with a high coefficient of variation in their spatial location. Mucus plugs were composed of 84% and 82% MUC5AC and 16% and 18% MUC5B in nonfatal and fatal asthma, and 67% extended over 80% of the bronchiole path length. In asthmatic lungs, mucus-plugged airways had thickened airway walls, narrowed airway lumens, and luminal folding compared with unplugged airways because of increased epithelial, basement membrane, and smooth muscle thickening. Conclusions In asthma, mucus plugs are a prominent and spatially heterogeneous feature within the distal small airways, and are associated with airway wall remodeling and luminal narrowing, making them a key target for improving lung ventilation and patient outcomes.