Adeno-associated virus 2 infection in children with non-A-E hepatitis

An outbreak of acute hepatitis of unknown aetiology in children was first reported in Scotland in April 2022.[1][1] Cases aged <16 years have since been identified in 35 countries.[2][2] Here we report a detailed investigation of 9 early cases and 58 control subjects. Using next-generation sequencing and real-time PCR, adeno-associated virus 2 (AAV2), was detected in the plasma of 9/9 and liver of 4/4 patients but in 0/13 sera/plasma of age-matched healthy controls, 0/12 children with adenovirus (HAdV) infection and normal liver function and 0/33 children admitted to hospital with hepatitis of other aetiology. AAV2 typically requires a coinfecting ‘helper’ virus to replicate, usually HAdV or a herpesvirus. HAdV (species C and F) and human herpesvirus 6B (HHV6B) were detected in 6/9 and 3/9 affected cases, including 3/4 and 2/4 liver biopsies, respectively. The class II HLA-DRB1*04:01 allele was identified in 8/9 cases (89%), compared with a background frequency of 15.6% in Scottish blood donors, suggestive of increased susceptibility in affected cases. Acute non-A-E paediatric hepatitis is associated with the presence of AAV2 infection, which could represent a primary pathogen or a useful biomarker of recent HAdV or HHV6B infection. Population and mechanistic studies are required to explore these findings further. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The work was funded by Public Health Scotland and the National Institute for Health Research (NIHR award COCIN01) and the Medical Research Council (MRC grants MC\_UU\_1201412, MC\_PC\_19059 & MC\_PC\_22004). DIAMONDS is funded by the European Union Horizon 2020 programme grant 848196). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All patients (cases and controls) were recruited with the informed written consent of parents or guardians. Ethical approval was given for the recruitment of cases by the South Central Oxford C Research Ethics Committee in England (13/SC/0149), the Scotland A Research Ethics Committee (20/SS/0028), and the WHO Ethics Review Committee (RPC571 and RPC572) for the International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCPUK). Control samples were obtained from the Diagnosis and Management of Febrile Illness using RNA Personalised Molecular Signature Diagnosis study cohort (DIAMONDS). The DIAMONDS study was approved by the London Dulwich Research Ethics Committee (20/HRA/1714). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors, other than patient-specific data that cannot be released for reasons of confidentiality under the relevant ethical approvals. [1]: #ref-1 [2]: #ref-2