Endotyping of COPD, bronchiectasis and their overlap syndrome by integrated sputum proteome/microbiome

<b>Introduction:</b> Bronchiectasis and COPD are two disease entities with overlapped clinical features but whether underlying biology supports a “treatable traits” approach is unknown. <b>Aim:</b> To investigate the endotypic differences in sputum microbiome and proteome between patients with BE, COPD, and the overlap. <b>Methods:</b> Patients with BE (n=61, age 72±8 years, FEV₁(pred) 85±23), COPD (n=56, age 72±9 years, FEV₁(pred) 67±22%), and the overlap (n=63, age 72±8 years, FEV₁(pred) 66±24%) were included. Sputum microbiome and protein profiling were carried out using 16S rRNA sequencing and a label-free proteomics workflow, respectively. <b>Results:</b> Principle component analysis of combined sputum microbiome (1,393 OTUs) and proteome profiles (614 proteins) revealed two clusters that partially separate COPD patients with BE from those without (Figure). COPD patients with BE were co-clustered with patients with BE. Patients with BE (regardless of COPD status) were predominantly associated with a proteobacteria dominant microbiome profile and a proteome profile over-represented with the “neutrophil degranulation” pathway (over-representation p=8E^-13). In contrast, COPD patients without BE displayed a higher microbiome diversity, a firmicutes dominant microbiome profile and higher expression of IGK, PIGR, AZGP1 and TCN1. <b>Conclusion:</b> Independent of COPD status, BE is a dominant trait associated with a proteobacteria and neutrophilic endotype.