Blood Gene Expression and Immune Cell Subtypes Associated with COPD Exacerbations.

Rationale: Acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) are associated with a significant disease burden. Blood immune phenotyping may improve our understanding of a COPD endotype at increased risk of exacerbations. Objective: To determine the relationship between the transcriptome of circulating leukocytes and COPD exacerbations. Methods: Blood RNA sequencing data (n=3618) from the COPDGene study were analyzed. Blood microarray data (n=646) from the ECLIPSE study were used for validation. We tested the association between blood gene expression and AE-COPD. We imputed the abundance of leukocyte subtypes and tested their association with prospective AE-COPD. Flow cytometry was performed on blood in SPIROMICS (n=127), and activation markers for T cells were tested for the association with prospective AE-COPD. Measurements and Main Results: Exacerbations were reported 4030 and 2368 times during the follow-up in COPDGene (5.3±1.7 years) and ECLIPSE (3 years), respectively. We identified 890, 675, and 3217 genes associated with a history of AE-COPD, persistent exacerbations (1 exacerbation per year), and prospective exacerbation rate, respectively. In COPDGene, the number of prospective exacerbations in COPD subjects (GOLD ≥2) was negatively associated with circulating CD8 + T cells, CD4 + T cells, and resting NK cells. The negative association with naïve CD4 + T cells was replicated in ECLIPSE. In the flow cytometry study, an increase in CTLA4 on CD4 + T cells was positively associated with AE-COPD. Conclusions: Individuals with COPD having lower circulating lymphocytes, particularly decreased CD4 + T cells, are more susceptible to AE-COPD, including persistent exacerbations.