Persistent low-level variants in a subset of viral genes are highly predictive of poor outcome in immunocompromised patients with cytomegalovirus infection

Cristina Venturini; Julia M Colston; Oscar Charles; Anastasia Lankina; Timothy Best; Claire Atkinson; Calum Forrest; Charlotte A Williams; Kanchan Rao; Austen Worth; Doug Thorburn; Mark Harber; Paul Griffiths; Judith Breuer

doi:10.1093/infdis/jiae001

Persistent low-level variants in a subset of viral genes are highly predictive of poor outcome in immunocompromised patients with cytomegalovirus infection

J Infect Dis. 2024 Jan 5:jiae001. doi: 10.1093/infdis/jiae001. Online ahead of print.

Authors

Cristina Venturini¹, Julia M Colston², Oscar Charles¹, Anastasia Lankina¹, Timothy Best³, Claire Atkinson^{4

5}, Calum Forrest⁵, Charlotte A Williams⁶, Kanchan Rao⁷, Austen Worth⁸, Doug Thorburn⁹, Mark Harber⁹, Paul Griffiths⁵, Judith Breuer^{1

3}

Affiliations

¹ Infection, Immunity&Inflammation, Institute of Child Health, University College London, London, UK.
² North Bristol NHS Trust, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.
³ Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁴ Applied Science, London South Bank University, London, UK.
⁵ Division of Infection and Immunity, Institute for Immunity and Transplantation, University College London, London, UK.
⁶ Department of Genetics and Genomic Medicine, GOS Institute of Child Health, University College London, London, UK.
⁷ Department of Bone Marrow Transplant, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁸ Department of Immunology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁹ Royal Free London, NHS Foundation Trust, London, UK.

PMID: 38181168
DOI: 10.1093/infdis/jiae001

Abstract

Background: Human cytomegalovirus is the most common and serious opportunistic infection after solid organ and haematopoietic stem cell transplantation. In this study, we used whole-genome cytomegalovirus data to investigate viral factors associated with the clinical outcome.

Methods: We sequenced cytomegalovirus samples from 16 immunocompromised paediatric patients with persistent viraemia. 8/16 patients died of complications due to cytomegalovirus infection. We also sequenced samples from 35 infected solid organ adult recipients of whom one died with cytomegalovirus infection.

Results: We showed that samples from both groups have fixed variants at resistance sites and mixed infections. NGS sequencing also revealed non-fixed variants at resistance sites in most of the patients who died (6/9). A machine learning approach identified 10 genes with non-fixed variants in these patients. These genes formed a viral signature which discriminated patients with cytomegalovirus infection who died from those that survived with high accuracy (AUC=0.96). Lymphocyte numbers for a subset of patients showed no recovery post-transplant in the patients who died.

Conclusions: We hypothesise that the viral signature identified in this study may be a useful biomarker for poor response to antiviral drug treatment and indirectly for poor T cell function, potentially identifying early, those patients requiring non-pharmacological interventions.

Keywords: cytomegalovirus infection; genomics; transplant; viral signature.