Endotyping Chronic Obstructive Pulmonary Disease, Bronchiectasis, and the “Chronic Obstructive Pulmonary Disease–Bronchiectasis Association”

Abstract Rationale Bronchiectasis and chronic obstructive pulmonary disease (COPD) are two disease entities with overlapped clinical features, and codiagnosis frequently occurs (termed 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, patients with COPD 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. Conclusions Neutrophilic inflammation, differential mucin expression, and Gram-negative infection are dominant traits in patients with the “COPD–bronchiectasis association.”