High serum G-CSF characterises neutrophilic COPD exacerbations associated with dysbiosis

Introduction COPD exacerbations are heterogeneous and can be triggered by bacterial, viral, or non-infectious insults. Exacerbations are also heterogeneous in neutrophilic or eosinophilic inflammatory responses. A non-invasive peripheral biomarker of COPD exacerbations characterised by bacterial/neutrophilic inflammation is lacking. G-CSF is a key cytokine elevated during bacterial infection and mediates survival, proliferation, differentiation, and function of neutrophils. Objective We hypothesized that high peripheral G-CSF would be indicative of COPD exacerbations with a neutrophilic and bacterial phenotype associated with microbial dysbiosis. Methods Serum G-CSF was measured during hospitalised exacerbation and after 30 days of recovery in 37 subjects. In a second cohort, serum and sputum cytokines were measured in 59 COPD patients during stable disease, at exacerbation, and 2- and 6-weeks following exacerbations. Results Serum G-CSF is increased during exacerbation in a subset of patients. These exacerbations were enriched for bacterial and not viral or type-2 biologies. The median serum G-CSF levels was 1.6-fold higher in bacterial exacerbation compared to non-bacterial exacerbation (22 pg·mL−1versus 13 pg·mL−1, p=0.0007). Serum G-CSF classified bacterial exacerbations with an AUROC=0.76. Exacerbations with a ≥2-fold increase in serum G-CSF were characterised by neutrophilic inflammation, with increased sputum and blood neutrophils and high sputum IL-1β, IL-6, and SAA. These exacerbations were preceded by dysbiosis, with decreased microbiome diversity and enrichment of respiratory pathogens such as Haemophilus and Moraxella. Furthermore, serum G-CSF at exacerbation classified neutrophilic-dysbiotic exacerbations (AUROC=0.75). Conclusions High serum G-CSF enriches for COPD exacerbations characterised by neutrophilic inflammation with underlying bacterial dysbiosis.