Title: Epstein-Barr Virus suppression in Chronic Obstructive Pulmonary Disease (EViSCO): A mechanistic study to evaluate the sputum transcriptome and microbiome in moderate-to-severe COPD
Funder: The Academy of Medical Sciences

Abstract: Background: COPD is the third most common cause of global mortality. The disease is associated with persistent adaptive immune cell infiltration of the airway culminating in tertiary lymphoid organ (TLO) formation potentially indicating an antiviral response. We previously identified high levels of Epstein-Barr virus (EBV) in sputum in COPD and conducted a randomised-controlled trial of valaciclovir (1 gram thrice daily for 8 weeks) in individuals with COPD and sputum EBV detection (EViSCO trial, ClinicalTrials.gov (NCT03699904). Aims: We wish to conduct sputum transcriptional profiling analysis and Nanopore sequencing of the sputum samples from the EViSCO trial. Objectives: Using the stored sputum samples accrued during the EViSCO trial we will collaborate with the Queen’s University Genomics Core and conduct sputum transcriptomic analysis (RNA-seq) to measure gene-expression profiles before and after viral suppression. We will evaluate the presence of differentially expressed genes between treatment groups. We will examine how chemokine and adaptive immune cell associated gene expression is affected by EBV suppression following valaciclovir. We also wish to conduct metagenomic sequencing (Nanopore) on the sputum of the EViSCO microbiome cohort to enable greater taxonomic resolution and speciation of pathogenic bacteria implicated in disease progression (primarily proteobacteria). Using this state of the art translational methodology we hope to further elucidate the potential role of persistent EBV infection in COPD and whether viral suppression is associated with alterations in transcriptional gene expression or microbiome composition. It is anticipated that this analysis will enable further characterisation of a distinct and poorly characterised COPD endotype.

Lay abstract: COPD is the third most common cause of death globally. We have found Epstein-Barr virus (EBV) at high levels in the phlegm of patients with COPD. A separate research group (Vanderbilt, USA) have shown airway biopsy samples are significantly more likely to show this virus in patients with COPD. EBV is rarely detected in people who smoke but do not have COPD. We want to see if treatment of EBV using an approved antivirus medicine (valaciclovir) could clear the virus from the phlegm and whether this would be beneficial. We carried out a trial where patients were randomly put into one of two treatment groups. One group received valaciclovir whilst the other received matching placebo for 8 weeks. This ensured that the treatment was fair. Patients had a sample of phlegm taken at the beginning and end of the study. There was an 87% reduction in the virus in the valaciclovir group. We also found that the damaging inflammatory cells in the phlegm were reduced in this group after 8 weeks. This study was cut short due to the pandemic and we now have stored samples of phlegm which we would like to analyse further. We will collaborate with The Queen’s University Genomics Core who will perform a detailed analysis of gene expression and bacteria in the phlegm. We will then validate the findings from this analysis independently ourselves. We wish to learn more about the significant of EBV in COPD and identify who will benefit most from treating it.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY