Severe Acute Hepatitis of Unknown Aetiology in Children

Research investigation into the outbreak of unexplained paediatric non A-E hepatitis

The ISARIC Clinical Characterisation Protocol UK (CCP-UK) protocol was activated in April 2022, to investigate the outbreak of severe paediatric hepatitis in children in Scotland. The research investigation was led by the MRC-University of Glasgow Centre for Virus Research (CVR), in collaboration with Public Health Scotland (PHS), NHS clinicians across Scotland, the University of Edinburgh (CCP-UK co-CI Kenny Baillie), the University of Liverpool (CCP-UK co-CI Calum Semple), Imperial College London, and other institutions. It led to the world’s first discovery that a severe paediatric hepatitis outbreak in 2022 may have arisen due to co-infection with two viruses, adenovirus and AAV2 in children that possess a certain genetic background, which was published in Nature in March 2023. This is an outstanding example of a rapid and collaborative research response to viral outbreaks and will contribute to future national and global preparedness. Importantly, it shows the strength and collaborative links between UK academic institutions, NHS and public health.

On 31 March 2022, Dr Rachel Tayler, a paediatric liver specialist at the Royal Hospital for Children in Glasgow noted a cluster of young children presenting with severe hepatitis and jaundice, who tested negative for the usual causes of hepatitis, such as viral hepatitis A-E, autoimmune or drug causes. She informed Public Health Scotland (PHS), which sparked a national public health and research investigation. The UK Health Security Agency (UKHSA) subsequently identified 270 cases (15 of whom needed liver transplantation) that matched this definition elsewhere in the UK and set-up an expert technical group, including CVR researchers. UKHSA and PHS requested metagenomic analysis to be carried out by the CVR to investigate a potential underlying cause. The ISARIC CCP-UK protocol was activated and a rapid detailed research investigation was completed, comprising clinical data collection, genomic sequencing, antibody testing, histopathology and host genetic analysis of clinical samples from the recruited children.

A week later, on 7 April, CVR reported a metagenomic analysis on these samples, raising the possibility of an unusual association between hepatitis and Adeno-Associated Virus-2 (AAV2), subsequently confirmed by the UCL Great Ormond Street Institute of Child Health. In August 2022, CVR scientists confirmed the metagenomic data by a variety of approaches including the addition of paediatric control samples and sophisticated histopathology imaging techniques, revealing AAV2 RNA in liver cells, and positive serology responses in affected children. Adenovirus and AAV2 have not been known to cause hepatitis in immunocompetent children previously. The World Health Organization (WHO) has now registered 1,010 probable cases that fulfil their definition of this illness in 35 countries.

In February 2024, clinicians, public health officials, researchers, parents/carers and children met in Glasgow to discuss challenges, successes, and lessons learned throughout this study. Outcomes in development include a video and resource pack to encourage clinical research study participation, as well as a report of key findings and recommendations that may influence future clinical practice. A diagnostic test for AAV2 has also recently been made available by NHS England.