Endotyping Chronic Obstructive Pulmonary Disease, Bronchiectasis, and the "Chronic Obstructive Pulmonary Disease-Bronchiectasis Association".

Abstract

<b>Rationale:</b> Bronchiectasis and chronic obstructive pulmonary disease (COPD) are two disease entities with overlapped clinical features, and codiagnosis frequently occurs (termed the "COPD-bronchiectasis association"). <b>Objectives:</b> 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. <b>Methods:</b> 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 (<i>n</i> = 43), bronchiectasis (<i>n</i> = 30), and the COPD-bronchiectasis association (<i>n</i> = 48). Results were validated in an independent cohort of 91 patients (<i>n</i> = 28-31 each group) using targeted measurements of inflammatory markers, mucins, and bacterial culture. <b>Measurements and Main Results:</b> 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. <b>Conclusions:</b> Neutrophilic inflammation, differential mucin expression, and Gram-negative infection are dominant traits in patients with the "COPD-bronchiectasis association."