Endotyping COPD, Bronchiectasis and the ‘COPD-bronchiectasis Association’

Rationale Bronchiectasis and chronic obstructive pulmonary disease (COPD) are two disease entities with overlapped clinical features and co-diagnosis frequently occurs (termed as the 'COPD-bronchiectasis association'). Objectives To investigate the sputum microbiome and proteome in patients with bronchiectasis, COPD, and the 'COPD-bronchiectasis association' with the aim of identifying endotypes that may inform treatment. Methods Sputum microbiome and protein profiling were carried out using 16S rRNA amplicon sequencing and a label-free proteomics workflow, respectively, in a cohort comprising patients with COPD (n=43), bronchiectasis (n=30) and the 'COPD-bronchiectasis association' (n=48). Results were validated in an independent cohort of 91 patients (n=28-31 each group) using targeted measurements of inflammatory markers, mucins and bacterial culture. Measurements and main results Principal component analysis of sputum microbiome and protein profiles showed a partial separation between the COPD and the 'COPD-bronchiectasis association' group. Further analyses revealed that patients with the 'COPD-bronchiectasis association' had a higher abundance of proteobacteria, higher expression of mucin-5AC and proteins from the "neutrophil degranulation" pathway compared to those with COPD. In contrast, COPD patients had an elevated expression of mucin-5B and several peptidase inhibitors, higher abundance of common commensal taxa, and a greater microbiome diversity. The profiles of 'COPD-bronchiectasis association' and bronchiectasis groups were largely overlapping. Five endotypes were proposed with differential inflammatory, mucin and microbiological features. The key features related to the 'COPD-bronchiectasis association' were validated in an independent cohort. Conclusion Neutrophilic inflammation, differential mucin expression and Gram-negative infection are dominant traits in patients with the 'COPD-bronchiectasis association'.