Deciphering an Adenovirus F41 Outbreak in Pediatric Hematopoietic Stem Cell Transplant Recipients by Whole-Genome Sequencing

Abstract

Human adenovirus (HAdV) represent a major cause of mortality and morbidity in pediatric recipients of allogeneic hematopoietic stem cells transplantation (HSCT). HAdV F type 41 (HAdV-F41) infections in HSCT patients are scarce whereas HAdV-F41 circulates commonly in healthy individuals. Between March and July 2018, HAdV-F41 infections were identified in four children (A, B, C and E) with allogeneic HSCT and one child before HSCT (D) at Robert Debré hospital, Paris, France. We report the clinical course of HAdV-F41 infection and the phylogenetic investigation to identify inter-patient transmission. HAdV DNA was quantified in stool and plasma samples by real-time PCR. HAdV type was determined by sequencing of the fiber and hexon genes. Phylogenetic investigation was done with whole genome sequences obtained by next generation sequencing. HAdV loads in stool samples ranged from 6.60 to 10.10 log10 copies/ml. HAdV-F41 detection in plasma was observed in four patients but no disseminated disease was reported. Two patients died, but no death was attributed to HAdV. While sequencing limited to fiber gene suggested a cluster with four patients, phylogenetic analysis with whole genome sequencing and HVR7 revealed a cluster including three patients (C, D and E), suggesting an inter-patient transmission and two other independent infections. HAdV-F41 levels in stool specimens of pediatric HSCT patients are high and represent a risk of inter-patient transmission. Whole genome sequencing helped to identify related cases. Prompt detection of HAdV in stool and control measures are warranted to limit any risk of nosocomial transmission.

Dissemination and Genome Characterization of a Human Adenovirus F41 in a Patient with B-Cell Lymphoma

“…gastrointestinal tract, especially in view of the patient's initial presentation with diarrhea and dehydration. The HAdV-F41 detected in this study has a similarity of 99.8% per blast with strains that have previously been identi ed as being associated with an outbreak in pediatric hematopoietic stem cell transplant recipients with two fatal cases in France (27). Although dissemination of HAdV F41 is not common, clinicians should be aware that it can happen even in immunocompromised adult patients without history of HSCT.…”

Molecular Phylogeny of human adenovirus type 41 lineages

“…Sublineage 3a genomes, on the other hand, were first identified by complete genomic sequencing of two samples from South Africa originating between 2009 and 2014 (MK962806 and MK962807). Furthermore, sublineage 3a genomes were found in Iraq (MG925783) and France (MW567963) as late as 2018 (Lefeuvre et al, 2021), but not in the present sequencing effort. The latter sequence originated from an HSCT patient and detailed virus load data were published (patient B in Lefeuvre et al, 2021).…”

“…Furthermore, sublineage 3a genomes were found in Iraq (MG925783) and France (MW567963) as late as 2018 (Lefeuvre et al, 2021), but not in the present sequencing effort. The latter sequence originated from an HSCT patient and detailed virus load data were published (patient B in Lefeuvre et al, 2021). Interestingly, virus loads in stool were rather low (about 10 6 c/ml) compared to other patients and DNAaemia appeared rather late and not in parallel to the peak virus load in stool as in other patients.…”

“…Moreover, adenovirus hepatitis is associated with life-threatening disseminated disease in severely immunosuppressed patients, e. g. haematopoietic stem cell transplant recipients (Forstmeyer et al, 2008; Lion, 2014; Onda et al, 2021). However, these hepatitis cases are rather caused by HAdV types of species C whereas HAdV-F41 infection remained limited to the gastrointestinal tract even in haematopoietic stem cell transplant recipients (Mattner et al, 2008; Lefeuvre et al, 2021). In the recent cases of severe hepatitis in children, detection of adenovirus antigens or viral particles failed in explanted liver specimens (Baker et al, 2022), whereas in typical adenovirus hepatitis, these can be found in abundance (Forstmeyer et al, 2008; Onda et al, 2021).…”

“…HAdV-F41 is associated almost exclusively with gastroenteritis, most frequently in the toddler age and is the second most frequent cause of diarrhoea in this age group, only second to Rotavirus (Lee et al, 2020). HAdV-F41 frequently causes nosocomial outbreaks in paediatric wards and community facilities such as kindergartens, but the disease remains limited to the gut even in severely immunosuppressed children (Mattner et al, 2008; Gonçalves et al, 2011; Lefeuvre et al, 2021). Only a single case of severe HAdV-F41 dissemination has been reported in a stem cell transplant recipient (Slatter et al, 2005).…”