Using Whole Genome Sequences to Investigate Adenovirus Outbreaks in a Hematopoietic Stem Cell Transplant Unit.

Chloe E Myers,Kanchan Rao,Rachel Williams,Charlotte A Williams,John C Hartley,Charlotte J Houldcroft,Judith Breuer,Ben K Margetts,Kathryn J Rolfe,Jose A Guerra-Assunção,Sunando Roy,Helen Dunn,Timothy Best,Cristina Venturini

doi:10.3389/fmicb.2021.667790

Abstract

A recent surge in human mastadenovirus (HAdV) cases, including five deaths, amongst a haematopoietic stem cell transplant population led us to use whole genome sequencing (WGS) to investigate. We compared sequences from 37 patients collected over a 20-month period with sequences from GenBank and our own database of HAdVs. Maximum likelihood trees and pairwise differences were used to evaluate genotypic relationships, paired with the epidemiological data from routine infection prevention and control (IPC) records and hospital activity data. During this time period, two formal outbreaks had been declared by IPC, while WGS detected nine monophyletic clusters, seven were corroborated by epidemiological evidence and by comparison of single-nucleotide polymorphisms. One of the formal outbreaks was confirmed, and the other was not. Of the five HAdV-associated deaths, three were unlinked and the remaining two considered the source of transmission. Mixed infection was frequent (10%), providing a sentinel source of recombination and superinfection. Immunosuppressed patients harboring a high rate of HAdV positivity require comprehensive surveillance. As a consequence of these findings, HAdV WGS is being incorporated routinely into clinical practice to influence IPC policy contemporaneously.

Highlights

Clinical infections caused by human mastadenoviruses (HAdVs) are associated with significant morbidity (10–89%) and mortality (6–70%) in the immunocompromised host (Echavarría, 2008)
No seasonality was observed (Brown et al, 2016); cases increased each year with a marked rise between 2017 and 2018 (Figure 1A)
18% of new positives are detected from patients admitted to the high-risk hematopoietic stem cell transplant (HSCT) unit (Figure 1C)

Summary

Introduction

Clinical infections caused by human mastadenoviruses (HAdVs) are associated with significant morbidity (10–89%) and mortality (6–70%) in the immunocompromised host (Echavarría, 2008). Risk factors for poor outcome include pediatric patients (who are susceptible to primary infection), unrelated donor stem cell transplants (SCTs), graft-vs.-host disease, T-cell depletion of graft, and certain immunosuppressive drug regimens (Shields et al, 1985; Runde et al, 2001; Chakrabarti et al, 2004). Amongst pediatric patients undergoing hematopoietic stem cell transplant (HSCT), HAdV viremia and stool shedding were found in 15 and 42% of patients, respectively (Hiwarkar et al, 2013; Kosulin et al, 2018). As non-enveloped viruses, HAdVs can be resistant to standard alcohol cleaning regimens and can survive as clinically infectious particles for up to 4 weeks (Gordon et al, 1993). Nosocomial transmission has been frequently reported in the literature (Russell et al, 2006; Rutala et al, 2006); the identification of these outbreaks is likely to be under-reported due to the limitations of existing HAdV typing protocols that are performed infrequently and target only small regions of selected genes (Seto et al, 2013)

Methods

Results

Conclusion