Clinical and transcriptomic characterization of mixed granulocytic phenotype in chronic obstructive pulmonary disease.

Abstract

In chronic obstructive pulmonary disease (COPD), patients with peripheral airways infiltrated by eosinophils and neutrophils ("mixed granulocytic COPD") show worse outcomes than those without. We sought to examine the expression of immune response and lung tissue remodeling pathways in patients with mixed granulocytic COPD. In this post hoc study of the DISARM (A Study to Investigate the Differential Effects of Inhaled Symbicort and Advair on Lung Microbiota) randomized controlled trial, mixed granulocytic COPD was defined by eosinophils >1% and neutrophils >3% of the total leukocyte count in bronchoalveolar lavage (BAL). We compared clinical outcomes of mixed granulocytic COPD with 2 other phenotypes (neutrophilic, pauci-granulocytic). We then examined canonical pathways using gene set enrichment analysis and expression of immune cell and tissue remodeling gene signatures in BAL across phenotypes. Among 54 patients, 33% had mixed granulocytic COPD. Patients with mixed granulocytic COPD had the lowest FEV₁, the most radiographic emphysema, and the highest annualized exacerbation rates. Cell pellets of BAL in mixed granulocytic COPD showed upregulated gene expression of type 1 (TNFA, IL6, and IFNG signaling) and type 2 (IL4/13 signaling) immune responses relative to the neutrophilic and pauci-granulocytic phenotypes. Mixed granulocytic COPD was marked by increased expression of gene signatures for natural killer cells, B cells, and CD4 and CD8 naive and memory/effector T cells. Mixed granulocytic COPD showed the highest expression of tissue remodeling processes, which significantly associated with lower FEV₁. Mixed granulocytic COPD is marked by complex immune responses in the peripheral airways and is associated with increased tissue remodeling that associates with more severe airflow limitation.