Aspergillus spp. in Non-Cystic Fibrosis Bronchiectasis: Clinical Phenotypes, Molecular Endotypes, and Practical...

Non-cystic fibrosis bronchiectasis (NCFB) is a heterogeneous chronic airway disease characterized by irreversible bronchial dilatation, impaired mucociliary clearance, and recurrent infection. Historically, research and clinical practice have focused mainly on bacteria, particularly Pseudomonas aeruginosa, as major drivers of exacerbations and disease progression, whereas the contribution of fungi has received far less attention. Over the last decade, evidence from mycobiome studies, large registries, and prospective cohorts has increasingly identified Aspergillus spp. as clinically relevant contributors in a substantial subset of patients with bronchiectasis. Data from the European Bronchiectasis Registry (EMBARC) indicate that approximately one quarter of patients exhibit Aspergillus-related immunological signals, including allergic bronchopulmonary aspergillosis (ABPA), Aspergillus sensitization, and elevated Aspergillus-specific IgG, and that these phenotypes are associated with more severe disease and worse clinical outcomes. Mechanistic studies further suggest that Aspergillus-related disease in bronchiectasis is underpinned by distinct molecular and immunological programs involving epithelial dysfunction, impaired mucociliary clearance, innate fungal sensing, inflammasome-related signaling, and divergent type-2 versus non-type-2 inflammatory responses. In parallel, mycobiome and multi-biome studies indicate that Aspergillus should be interpreted within a broader airway interactome shaped by cross-kingdom relationships with bacterial pathogens and by host immune tone. In this review, we synthesize current evidence on the epidemiology, molecular pathobiology, inflammatory endotypes, biomarker profiles, clinical-radiologic spectrum, and therapeutic implications of Aspergillus in bronchiectasis. Current evidence suggests that Aspergillus-related findings in bronchiectasis should be interpreted within a structured clinical, radiological, microbiological, and immunological framework rather than considered solely as isolated culture results. However, most data remain observational or extrapolated from related airway diseases, and bronchiectasis-specific interventional evidence is limited. A cautious biomarker-informed approach may help standardize phenotyping, identify patients requiring closer follow-up, and define priorities for future prospective trials.