Using multiomics to define mechanisms of rhinovirus-induced COPD exacerbations to develop novel therapies/therapeutic targets

Chronic Obstructive Pulmonary Disease (COPD) is the 3rd cause of mortality worldwide, causing 3.23 million deaths in 2019. Acute exacerbations of COPD (AECOPD) are the major cause of COPD morbidity, mortality and healthcare costs. Developing novel targeted treatments for AECOPD requires a better understanding of AECOPD mechanisms. Respiratory virus (mostly rhinovirus [RV]) infections are the major cause of AECOPD. Studying disease mechanisms in naturally-occurring AECOPD is difficult because of variability in: time from AECOPD onset to clinical sampling; causative agent; therapeutic background and interventional treatment and repeated lower airway sampling during naturally occurring AECOPD is impractical/potentially dangerous. We therefore developed experimental RV challenge in COPD as an experimental model of AECOPD (the model is unique worldwide), in which the above factors are standardised, and repeated lower airway sampling is safely and easily performed. Previous studies in this model demonstrated that RV infection induced prolonged (~5 weeks to full recovery) AECOPD in 95% of successfully infected subjects. Further, 60% of RV-induced exacerbations were followed by secondary bacterial infections, with more severe RV infection increasing risk and severity of secondary bacterial infection. Thus, strategies that reduce severity of virus infection in COPD, are likely to reduce secondary bacterial infections, thereby enhancing antibiotic stewardship. These COPD subjects had increased susceptibility to RV infections due to deficient interferon-responses and RV-infection in COPD, but not control subjects, provoked bronchial neutrophilia, but surprisingly also marked bronchial eosinophilia in 16/17 COPD subjects, which correlated with adverse clinical outcomes.