Introduction: Airway immunohistochemistry in COPD indicates that Epstein-Barr virus (EBV) detection is associated with CD8+ accumulation and depletion of host defence proteins including secretory IgA. The effects of EBV suppression on airway inflammation and microbiome have not been studied previously.

Methods: Sputum biomarkers and microbiota were pre-specified exploratory outcomes from EViSCO (NCT03699904) a randomised, double-blind, placebo-controlled trial of valaciclovir (1 gram TID for 8 weeks) for EBV suppression in COPD. Sputum cell counts, cytokines, microbiome, bacterial 16S and H. influenzae load were characterised at baseline and week 8 using ELISA, 16S rRNA and qPCR.

Results: Valaciclovir was associated with a between-group reduction in sputum total leukocyte count (difference 2.89;[95% CI 1.5 x106-7.4 x 106];p=0.003) and a 6-fold within-group reduction in IP-10 (p=0.008). An exploratory cohort underwent microbiome characterisation demonstrating that Firmicutes, Proteobacteria and Bacteroidetes were the dominant taxa in both groups. There was no between-group difference in α-diversity or bacterial load (p=0.61) at week 8. However, valaciclovir was associated with a -0.7 (±1.8) log reduction in H. influenzae load (p=0.03) and a within-group trend towards increased relative abundance of Bacteroidetes (p=0.07).

Conclusion: EBV suppression with valaciclovir attenuated airway inflammation and H. influenza load. These findings justify further mechanistic evaluation through a trial adequately powered to evaluate sputum microbiome as a pre-specified primary outcome.