Bronchial gene expression clustering in COPD identifies a subgroup of patients with higher level of bronchial T-cells and accelerated lung function decline

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with varying degrees of airway wall thickening, chronic bronchitis, and emphysema. A better understanding of the underlying pathology is needed to improve the personalized treatment of the disease and identify new therapeutic targets. Available data from 56 COPD patients included in the GLUCOLD study were used (61.1{+/-}7.7 years, 89% male, and FEV1 of 62.5{+/-}8.9% predicted). Clinical characterization was performed including bronchoscopy and collection of bronchial biopsies at baseline. RNA from bronchial biopsies was sequenced and used for unsupervised clustering, using a 98 COPD gene signature previously identified in bronchial brushes comparing patients with COPD to non-COPD controls. Next, we assessed differences in the clinical expression of COPD, lung function decline, inflammatory cell counts, and gene expression between clusters. Validation was performed in an independent dataset. We identified two clusters: CAGE1 (n=39) and CAGE2 (n=17). CAGE2 patients had higher percentage of sputum lymphocytes, and more CD4+ and CD8+ T-cell counts in their bronchial biopsies. In addition, their FEV1 improved less in response to 30-months treatment with inhaled corticosteroids (ICS) (change in FEV1- CAGE1: +24.4mL; CAGE2: -29.1mL; p-value=0.048), and they experienced a faster decline in their lung function follow-up (CAGE1: -44.0mL/year; CAGE2: -69.9mL/year; p-value=0.002). Gene expression analysis showed more activation of T- and B-cell immune responses in CAGE2. We identified a new COPD endotype, CAGE2, characterized by ICS unresponsiveness and faster lung function decline. Additionally, we show a different pathobiology in CAGE2 with more activation of T- and B-cell immune responses.