Mucus plugs correlate with small airway remodelling in Asthma: A multi-resolution study

Rationale: The observation of mucus plugs in proximal large airways on high-resolution computed tomography (HRCT) has highlighted the role of persistent mucus plugs in asthma, which correlate with disease severity and airflow obstruction. Due to the resolution of HRCT, it is unknown if mucus plugs within the distal small airways (<2mm in diameter) contribute to airflow obstruction. Objectives: To determine the prevalence of distal mucus plugs and their association with small airway remodelling in asthma. Methods: Lungs from 12 control, 5 non-fatal, and 11 fatal asthma patients underwent systematic uniform random sampling to obtain 239 lung tissue samples. The samples were imaged using micro-CT to assess mucus plugs and airway morphology, while histology and imaging mass spectrometry were used to evaluate airway wall remodelling and mucus composition. Main Results: Within the distal lung, 34% of pre-terminal bronchioles, 32% of terminal bronchioles, and 27% of transitional bronchioles had mucus plugs in fatal and non-fatal asthmatic patients. Mucus plugs comprised of 80% MUC5AC and 20% MUC5B, and 85% were ‘stringy’ in shape, extending over 90% of the bronchiole length. Mucus-plugged airways had thickened airway walls, narrowed airway lumens, and luminal folding compared to unplugged airways from the same patient due to increased epithelial, basement membrane, and smooth muscle thickening. Conclusion: In asthma, over 31% of distal small airways are obstructed by mucus plugs, which are associated with airway wall remodelling and lumen narrowing, making them a critical target for improving lung ventilation and patient outcomes.