TY - JOUR T1 - High serum G-CSF characterises neutrophilic COPD exacerbations associated with dysbiosis JF - ERJ Open Research JO - erjor DO - 10.1183/23120541.00836-2020 SP - 00836-2020 AU - Arindam Chakrabarti AU - Jordan S. Mar AU - David F. Choy AU - Yi Cao AU - Nisha Rathore AU - Xiaoying Yang AU - Gaik W. Tew AU - Olga Li AU - Prescott G. Woodruff AU - Christopher E. Brightling AU - Michele Grimbaldeston AU - Stephanie A. Christenson AU - Mona Bafadhel AU - Carrie M. Rosenberger Y1 - 2021/01/01 UR - http://openres.ersjournals.com/content/early/2021/03/11/23120541.00836-2020.abstract N2 - 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−1 versus 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.FootnotesThis manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.Conflict of interest: A. Chakrabarti reports personal fees from and stock in Genentech, Inc., during the conduct of the study and outside the submitted work.Conflict of interest: J.S. Mar reports personal fees from and equity in Genentech, Inc., outside the submitted work.Conflict of interest: D.F. Choy reports is am employee of Genentech, Inc.Conflict of interest: Y. Cao reports personal fees from and stock in Genentech, Inc., during the conduct of the study and outside the submitted work.Conflict of interest: N. Rathore reports personal fees from and stock in Genentech, Inc., during the conduct of the study and outside the submitted work.Conflict of interest: Dr. Yang reports personal fees from Genentech, Inc., during the conduct of the study; personal fees from Genentech, Inc., outside the submitted work.Conflict of interest: Dr. Tew reports personal fees from Genentech Inc, during the conduct of the study; personal fees from Genentech Inc, outside the submitted work.Conflict of interest: Olga Li is a salaried employee of Genentech, Inc. and received non-financial support from Genentech, Inc., during the conduct of the study.Conflict of interest: P.G. Woodruff reports consulting fees from Regeneron, Sanofi, Glenmark Pharma, Theravance and NGM Pharma, and visiting professor honoraria from Amgen and Genentech, outside the submitted work.Conflict of interest: Dr. Brightling is an employee of University of LeicesterConflict of interest: Dr. Grimbaldeston is an employee of Genentech Inc., reporting personal fees and non-financial support during the conduct of the study.Conflict of interest: S.A. Christenson reports consulting fees from AstraZeneca, GlaxoSmithKline, Amgen and Glenmark; personal fees for invited lectures from Sunovion and Genentech; personal fees for writing for UpToDate, all outside the submitted work.Conflict of interest: M. Bafadhel reports grants from AZ; and honoraria for consulting and advisory boards, and travel to conferences from AZ, Chiesi and GSK; and that she is a scientific advisor to and minor shareholder in AlbusHealth, all outside the submitted work.Conflict of interest: C.M. Rosenberger reports personal fees from and stock in Genentech, Inc., during the conduct of the study and outside the submitted work. ER -