Temporal trends and clinical characteristics of acute hepatitis with unknown aetiology and human adenovirus infections in Oxfordshire from 2016 to 2022

Background An outbreak of severe acute hepatitis of unknown aetiology (AS-Hep-UA) in children during 2022 has subsequently been linked to infections by adenovirus-associated virus 2 (AAV2) and other ‘helper viruses’, including human adenovirus (HAdV). Aim We investigated clinical characteristics and temporal distribution of acute hepatitis with unknown aetiology (AHUA) and of HAdV infections in Oxfordshire, UK population between 2016-2022. Methods We used anonymised electronic health records (EHR) to collate retrospective data for presentations of AHUA and/or HAdV infection between 2016-2022. We reviewed records of >900,000 acute presentations to emergency care at Oxford University Hospitals NHS Foundation Trust (OUH; UK) and performed a descriptive analysis of case numbers and clinical characteristics. Results Over the full study period, patients coded as AHUA had significantly higher critical care admission rates (p<0.0001, OR=41.7, 95% CI:26.3-65.0) and longer inpatient admissions (p<0.0001) compared with the rest of the patient population. Comparing events within the outbreak period (1st Oct 2021 - 31 Aug 2022), to those occurring outside this period, significantly more adults were diagnosed with AHUA (p<0.0001, OR=3.01, 95% CI: 2.20-4.12), and there were significantly more HAdV infections in children (p<0.001, OR=1.78, 95% CI:1.27-2.47). There were also more HAdV tests administered during the outbreak (p<0.0001, OR=1.27, 95% CI:1.17-1.37). There was no evidence of more acute hepatitis or increased severity of illness among patients who tested HAdV-positive compared to those testing HAdV-negative. Conclusion Our results highlight an increase in the number of AHUA in adults coinciding with the reported AS-Hep-UA outbreak in children, but not linked to documented HAdV infection. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement CCST is supported by doctoral funding from Agency for Science, Technology and Research (A*STAR). PCM is supported by core funding from the Francis Crick Institute, a Wellcome fellowship (ref 110110/Z/15/Z), and University College London NIHR Biomedical Research Centre (BRC). PCM receives funding from GSK to support a doctoral student in her team, outside the scope of this paper. ASW is supported by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at the University of Oxford in partnership with the UK Health Security Agency (UK HSA) (NIHR200915), by the NIHR Oxford Biomedical Research Centre, has core support from the Medical Research Council UK to the MRC Clinical Trials Unit [MC\_UU\_12023/22] and is an NIHR Senior Investigator. DWE is supported by a Robertson Fellowship and an NIHR Oxford BRC Senior Fellowship. NS is an Oxford Martin Fellow and holds an NIHR Oxford BRC Senior Fellowship. ### 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: Infections in Oxfordshire Research Database (iORD) of Oxford University Hospitals (OUH) NHS Foundation Trust gave approval for data access. 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The complete datasets analysed during the current study are not publicly available as they contain personal data but are available from the Infections in Oxfordshire Research Database (), subject to an application and research proposal meeting the ethical and governance requirements of the Database. For further details on how to apply for access to the data and for a research proposal template please email iord{at}ndm.ox.ac.uk.