Adeno-associated virus type 2 in children from the United States with acute severe hepatitis

Servellita, Venice; Sotomayor-González, Alicia; Lamson, Daryl M.; Foresythe, Abiodun; Huh, Hee Jae; Bazinet, Adam L.; Bergman, Nicholas H.; Bull, Robert L.; Garcia, Karla; Goodrich, Jennifer S.; Lovett, Sean; Parker, Kisha; Radune, Diana; Hatada, April; Pan, Chao-Yang; Rizzo, Kyle; Bertumen, J Bradford; Morales, Christina; Oluniyi, Paul E.; Nguyen, Jenny; Tan, Jessica; Stryke, Doug; Jaber, Rayah; Leslie, Matthew T.; Lyons, Zin; Hedman, Hayden D.; Parashar, Umesh D.; Sullivan, Maureen; Wroblewski, Kelly; Oberste, M. Steven; Tate, Jacqueline E.; Baker, Julia M; Sugerman, David; Cubeñas-Potts, Caelin; Lu, Xiaoyan; Chhabra, Preeti; Ingram, L. Amanda; Shiau, Henry; Britt, William J.; Sanchez, Luz Helena Gutierrez; Ciric, Caroline; Rostad, Christina A.; Vinjé, Jan; Kirking, Hannah L.; Wadford, Debra A.; Raborn, R. Taylor; George, Kirsten St.; Chiu, Charles Y.

doi:10.1101/2022.09.19.22279829

Cited by 4 publications

(6 citation statements)

References 41 publications

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“…positive for AAV-2 in their livers 17 ; the second study in the United States found 12/13 patients were positive for AAV-2. 18 In addition, another study demonstrated that AAV-2 was not detected in the plasma of any children in a control group (healthy children). 17 The presence of AAV-2 in pediatric cases may be an association and may not represent direct etiology; rather the AAV-2 may be a biomarker of recent HAdV infection and can fulfill the role of a helper for HAdV-F41.…”

Section: Discussionmentioning

confidence: 99%

“…Most recently, reports of the presence of AAV‐2 in almost all the children in two studies of acute hepatitis have added to the confusion. Indeed, the first study in the United Kingdom showed 9/9 patients were positive for AAV‐2 in their plasma and 4/4 were positive for AAV‐2 in their livers 17 ; the second study in the United States found 12/13 patients were positive for AAV‐2 18 . In addition, another study demonstrated that AAV‐2 was not detected in the plasma of any children in a control group (healthy children) 17 .…”

Section: Discussionmentioning

confidence: 99%

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Adenovirus F41 infection and liver cytolysis in adult hematopoietic stem cell transplant recipients

Lefeuvre,

Thepot,

Mercier‐Delarue

et al. 2023

Journal of Medical Virology

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Human adenoviruses (HAdVs) of the F species are commonly responsible for acute gastroenteritis. A few cases of systemic infections have been described in adults or children who have received a hematopoietic stem cell transplant (HSCT), but with no report of liver cytolysis. Since January 2022, several countries have reported an increase in cases of acute hepatitis of unknown cause in children. Adenovirus species F type 41 (HAdV‐F41) infection was predominantly identified. The objective of this study is to describe HAdV‐F41 infections diagnosed since January 2022 in adult HSCT recipients in two French hospitals. All four patients had diarrhea and liver cytolysis at the time of diagnosis of infection. HAdV viremia was observed in three patients (#1, #3, and #4), but no disseminated disease was reported. HAdV whole genome sequencing and metagenomics characterization were performed on stool and blood samples. The complete HAdV‐F41 genome sequence was obtained for three patients and phylogenetic analysis showed that the strains consisted of similar lineage (2b). We did not identify any new HAdV‐F41 strains. Metagenomics analysis found adeno‐associated virus 2 and torque‐teno virus infection in patient #1 and Epstein–Barr virus in patient #4. This is the first case series reporting liver cytolysis during HAdV‐F41 infection in adult HSCT patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Adenovirus F41 infection and liver cytolysis in adult hematopoietic stem cell transplant recipients

Lefeuvre,

Thepot,

Mercier‐Delarue

et al. 2023

Journal of Medical Virology

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“…Both the transcriptomic and proteomic data revealed an immune dysregulation associated with an activation of B cells and T cells, neutrophils and macrophages as well as an activation of innate immunity pathways in the livers of affected patients. Servellita et al (2023) analysed whole blood samples from 16 hospitalized US children fulfilling the US Centers for Disease Control and Prevention (CDC) criteria for this novel form of hepatitis. Overall, 358 cases were reported in the US, 6% of whom needed liver transplantation and 4% died.…”

Section: Molecul Ar Studiesmentioning

confidence: 99%

“…Three reports published in Nature provided a wealth of molecular information on non‐A to E hepatitis in children from both the UK (Ho et al, 2023; Morfopoulou et al, 2023) and the US (Servellita et al, 2023). The epidemic in Scotland occurred between March and August 2022.…”

Section: Molecular Studiesmentioning

confidence: 99%

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Non‐A to E hepatitis in children: Detecting a novel viral epidemic during the COVID‐19 pandemic

Brüssow

2023

Microbial Biotechnology

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During the COVID‐19 pandemic, two further novel viral epidemics were described in 2022, monkeypox virus infections in men having sex with men and non‐A to E hepatitis in children. The latter occurred in the first half of 2022 with about 1000 cases worldwide, necessitating liver transplantation in 5% and causing death in 2% of patients. It took some effort to clarify the cause of the novel hepatitis epidemic. Researchers were confronted with a polymicrobial viral infection consisting of an adenovirus‐associated virus type 2 (AAV2) infection, co‐occurring with either human adenovirus type 41 (HAdV41) or herpesvirus infections; most prominently human herpesvirus type 6 (HHV‐6). AAV‐2, a small Dependovirus of the Parvovirus family, needs these helper viruses for its replication. AAV2 is used as a vector for liver‐targeting gene therapy but was not previously known to cause acute hepatitis. HAdV41 and HHV‐6 are mostly known to cause diarrhoea and febrile illnesses associated with skin rashes in children, respectively. Except for a few case reports of HHV‐6 hepatitis, HAdV and HHV‐6 are mostly known as major pathogens in immunosuppressed transplantation patients. A potential role of SARS‐CoV‐2 has also been discussed but the most popular hypothesis involves an indirect role of the COVID‐19 pandemic for this novel disease. Exposure to HHV‐6 infections occurs nearly quantitatively during the first year of life. Social distancing measures, followed by the lifting of these measures in 2022 might have caused a delayed exposure to multiple, normally benign childhood viral infections eliciting a dysregulated immune response with pathological effects for liver cells. In the fall of 2022, when these conditions were not longer met, case numbers dwindled. The hypothesis of an unequilibrated immune response instead of intrinsic cytopathic activity of the implicated viruses is further supported by the enrichment of a particular HLA allele in cases over controls.

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Pan-Enterovirus Characterization Reveals Cryptic Circulation of Clinically Relevant Subtypes in Arizona Wastewater

Erickson,

Simmons,

Barrand

et al. 2023

Preprint

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BackgroundMost seasonally circulating enteroviruses result in asymptomatic or mildly symptomatic infections. In rare cases, however, infection with some subtypes can result in paralysis or death. Of the 300 subtypes known, only poliovirus is reportable, limiting our understanding of the distribution of other enteroviruses that can cause clinical disease.ObjectiveThe overarching objectives of this study were to: 1) describe the distribution of enteroviruses in Arizona during the late summer and fall of 2022, the time of year when they are thought to be most abundant, and 2) demonstrate the utility of viral pan-assay approaches for semi-agnostic discovery that can be followed up by more targeted assays and phylogenomics.MethodsThis study utilizes pooled nasal samples collected from school-aged children and long-term care facility residents, and wastewater from multiple locations in Arizona during July– October of 2022. We used PCR to amplify and sequence a region common to all enteroviruses, followed by species-level bioinformatic characterization using the QIIME 2 platform. For Enterovirus-D68 (EV-D68), detection was carried out using RT-qPCR, followed by confirmation using near-complete whole EV-D68 genome sequencing using a newly designed tiled amplicon approach.ResultsIn the late summer and early fall of 2022, multiple enterovirus species were identified in Arizona wastewater, with Coxsackievirus A6, EV-D68, and Coxsackievirus A19 composing 86% of the characterized reads sequenced. While EV-D68 was not identified in pooled human nasal samples, and the only reported acute flaccid myelitis case in Arizona did not test positive for the virus, an in-depth analysis of EV-D68 in wastewater revealed that the virus was circulating from August through mid-October. A phylogenetic analysis revealed just one importation into the state led to local circulation.SignificanceThis study further supports the utility of wastewater-based epidemiology to identify potential public health threats. Our further investigations into EV-D68 shows how these data might help inform healthcare diagnoses for children presenting with concerning neurological symptoms.IMPACT STATEMENTMuch of our response to infectious disease threats is reactive, even in the case of seasonally circulating viruses. Wastewater-based epidemiology has been successfully used for mitigation purposes throughout the SARS-CoV-2 pandemic, and has potential to be implemented for other pathogens that can cause severe infections. While vaccines and treatment beyond supportive care are not available for many infections, this method of surveillance can provide situational awareness to public health agencies, medical professionals, and the general population, possibly paving the way for earlier public health response.

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Adeno-associated virus type 2 in children from the United States with acute severe hepatitis

Cited by 4 publications

References 41 publications

Adenovirus F41 infection and liver cytolysis in adult hematopoietic stem cell transplant recipients

Adenovirus F41 infection and liver cytolysis in adult hematopoietic stem cell transplant recipients

Non‐A to E hepatitis in children: Detecting a novel viral epidemic during the COVID‐19 pandemic

Pan-Enterovirus Characterization Reveals Cryptic Circulation of Clinically Relevant Subtypes in Arizona Wastewater

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