Inflammatory Endotype Associated Airway Microbiome in COPD Clinical Stability and Exacerbations - A Multi-Cohort Longitudinal Analysis

RATIONALE: Understanding the role of airway microbiome in chronic obstructive pulmonary disease (COPD) inflammatory endotypes may help to develop microbiome-based diagnostic and therapeutic approaches.

OBJECTIVES: To understand the association of airway microbiome with neutrophilic and eosinophilic COPD at stability and exacerbations.

METHODS: An integrative analysis was performed on 1,706 sputum samples collected longitudinally from 510 COPD patients recruited at four UK sites in BEAT-COPD, COPDMAP and AERIS cohorts. The microbiome was analyzed using COPDMAP and AERIS as discovery dataset and BEAT-COPD as validation dataset.

RESULTS: The airway microbiome in neutrophilic COPD was heterogeneous with two primary community types differentiated by the predominance of Haemophilus. The Haemophilus-predominant subgroup had elevated sputum IL-1b and TNFa and was relatively stable over time. The other neutrophilic subgroup with a balanced microbiome profile had elevated sputum and serum IL-17A and was temporally dynamic. Patients in this state at stability were susceptible to greatest microbiome shifts during exacerbations. This subgroup can temporally switch to both neutrophilic-Haemophilus-predominant and eosinophilic states which were otherwise mutually exclusive. Time-series analysis on the microbiome showed the temporal trajectories of Campylobacter and Granulicatella were indicative of intra-patient switches from neutrophilic to eosinophilic inflammation, and in track with patient sputum eosinophilia over time. Network analysis revealed distinct host-microbiome interaction patterns between neutrophilic-Haemophilus-predominant, neutrophilic-balanced-microbiome and eosinophilic subgroups.

CONCLUSIONS: The airway microbiome can stratify neutrophilic COPD into subgroups that justify different therapies. Neutrophilic and eosinophilic COPD are inter-changeable in some patients. Monitoring temporal variability of the airway microbiome may track patient inflammatory status over time.