From mucus plugging to airway dilatation in chronic airway diseases: A perspective on the contribution of the airway microbiome and inflammation.

Airway mucus plugs are the main pathological and computed tomography (CT) findings that affect clinical outcomes in patients with asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap. Despite the introduction of biologics targeting type 2 inflammation, mucus plug removal remains challenging and understanding its pathogenesis is critical for improved management. In eosinophilic airways, elevated MUC5AC and eosinophil-derived molecules (galectin-10 and extracellular traps) cause highly viscoelastic plugs detectable as high-density regions on ultra-high-resolution CT. In neutrophilic airways, where phylum Proteobacteria and genus Haemophilus are predominant, excessive neutrophil elastase impairs mucociliary clearance, induces neutrophil extracellular traps (NETs), and promotes mucus overproduction. Since mucus plugs could be reservoirs for bacterial colonization, an altered airway microbiome and airway inflammation may be associated with mucus plugging. Phylum Firmicutes and genus Streptococcus are positively and genus Fusobacterium is negatively associated with mucus plugging in severe eosinophilic inflammation. Anaerobic commensals produce short-chain fatty acids, which suppress eosinophilic inflammation. In moderate eosinophilic inflammation, anaerobic commensals may be replaced by pathogenic bacteria of the phylum Proteobacteria and genus Haemophilus, which triggers severe neutrophilic inflammation and exacerbates mucus plugging. Finally, in eosinophilic inflammation, mucus plugs containing aggregated eosinophils may induce mechanical dilation of the airways. In contrast, the presence of mucus plugs in a neutrophilic milieu may reflect severe inflammation characterized by excessive neutrophil extracellular traps and degenerative tissue remodeling, which is consistent with the pathological features of bronchiectasis. This review provides clues regarding how inflammation and microbiome alterations interact with mucus plugging in chronic airway disease.