Abstract Rationale Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide, with acute exacerbations driving disease progression and healthcare burden. Respiratory viruses, particularly rhinoviruses (RVs), are key triggers of COPD exacerbations. Controlled experimental infection models provide an opportunity to investigate mechanisms underlying virus-induced exacerbations under standardised conditions. Methods In this single-cohort, non-randomised study, 30 subjects with moderate (GOLD Stage II) COPD aged 40–75 years were inoculated intranasally with rhinovirus-A16 (RV-A16, 100 TCID50). One subject was withdrawn due to baseline wild-type RV infection. Participants could be taking inhaled corticosteroids (ICS) and/or long-acting bronchodilators and were permitted a past history of asthma/allergic rhinitis. Clinical, virologic, inflammatory, and transcriptomic responses were assessed over 42 days. Primary outcomes were safety and clinical response to infection; secondary outcomes included airway/systemic inflammation, viral kinetics, and lung transcriptional responses. Results RV infection was confirmed in 22 of 29 analysed participants (76%), 21 (95%) developed upper respiratory symptoms and 20 (91%) experienced lower respiratory symptoms consistent with COPD exacerbation. Symptom onset followed a chronology consistent with naturally-occurring viral exacerbations, with upper airway symptoms peaking at day 4 and lower airway symptoms at day 9–10. Median peak lower respiratory symptom scores were significantly higher in infected compared to uninfected subjects, 6.1 vs 2.2 respectively, p = 0.021; EXACerbations of Chronic pulmonary disease Tool (EXACT) score 15.1 vs 9.0, p = 0.046. Infected participants demonstrated significant reductions below baseline in post-bronchodilator FEV1 (nadir day 9, 8.4% reduction, p = 0.028) and peak flow (nadir day 9, 11.2% reduction, p = 0.007), and increases above baseline in fractional exhaled nitric oxide (FeNO) (peak day 4, 10.6ppb increase, p = 0.049), sputum neutrophil percentage (peak day 12, 18% increase, p = 0.012), Bronchoalveolar lavage (BAL) eosinophil percentage (pre-infection 1.98%, post-infection 4.6%, p = 0.021), serum IL-6 (peak day 3, 2.59 pg/mL increase, p = 0.0004), CXCL10 (peak day 3, 263.2 pg/mL increase, p = 0.0004), and Granulocyte-colony stimulating factor (G-CSF) (peak day 3, 9.0 pg/mL increase, p = 0.0004). Three participants received antibiotics for worsening respiratory symptoms, one of whom also required corticosteroids; no hospitalisations or study withdrawals occurred. RNA sequencing of bronchial brushings, biopsies, and BAL cell pellets identified robust activation of innate immune, interferon, and cytokine response pathways. Conclusions Experimental RV-A16 infection in COPD was safe and reproducibly induced mild to moderate exacerbations that closely resembled naturally occurring events. This model effectively captures the clinical, inflammatory, and transcriptional hallmarks of virus-induced COPD exacerbation and provides a powerful platform for mechanistic investigation and early-phase therapeutic evaluation. This abstract is funded by: Roche/Genetech
Wilkins et al. (Fri,) studied this question.