Mucus Plugs Correlate with Small Airway Remodelling in Asthma: A Case-Control Study

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. Due to the resolution of CT, it is unknown if mucus plugs within the distal small airways (<2mm in diameter) also contribute to asthma severity. Objectives: To assess the prevalence of distal mucus plugs and their association with small airway remodelling in asthma. Methods: 12 control, 5 non-fatal, and 11 fatal asthma lungs underwent systematic uniform random sampling to obtain 239 lung tissue samples that were imaged using micro-CT and matched histology to assess mucus plugs, airway wall remodelling and mucus composition. Main Results: Within the distal lung of non-fatal and fatal asthmatics, 30% and 38% of pre-terminal 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 comprised of 84% and 82% MUC5AC and 16% and 18% MUC5B in non-fatal and fatal asthma, and 67% extended over 80% of the bronchiole pathlength. In asthmatic lungs, mucus-plugged airways had thickened airway walls, narrowed airway lumens, and luminal folding compared to unplugged airways, due to increased epithelial, basement membrane, and smooth muscle thickening. Conclusion: In asthma, mucus plugs are a prominent and spatially heterogeneous feature within the distal small airways, and are associated with airway wall remodelling and lumen narrowing, making them a key target for improving lung ventilation and patient outcomes.