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expert reaction to two preprints looking at acute hepatitis of unknown cause in children in the UK

Two preprints, unpublished non-peer reviewed studies, investigate cases of acute hepatitis of unknown cause in children in the UK.

This Roundup accompanied a SMC Briefing.


Prof Will Irving, Professor of Virology, University of Nottingham, said:

“These two excellent manuscripts contribute more pieces to the jigsaw that is the outbreak of severe hepatitis in young children, without quite generating a complete picture.  Two independent research groups find evidence of high level ongoing replication of adeno-associated viruses (AAV) in these young patients, not present in a variety of control groups.  However, AAVs have not previously been associated with any disease, and in one of the manuscripts, there is no evidence of expression of viral proteins or viral particles in the damaged livers, thereby raising the question as to whether AAV replication is the cause or a consequence of the liver damage or even simply a marker of recent adenovirus infection.  The HLA linkage reported from Scotland strongly suggests a host genetic susceptibility, which would go some way towards explaining, if the disease is caused by an infectious agent, why there are so few epidemiological links between the cases.

“As both sets of authors conclude – there is considerably more work to be done to evaluate their novel and unexpected data, but I congratulate them all in producing these tantalising leads in the hunt for the underlying cause of severe hepatitis.”


Dr Tassos Grammatikopoulos, Consultant in Paediatric Hepatology & Honorary Clinical Senior Lecturer, King’s College Hospital NHS Foundation Trust, said:

“The data from these two studies supports the hypothesis of a multiple hit effect on very young children whose immune system had not been exposed to the wider variety of community acquired common viruses and infections.  Previous infection with COVI19 in 2/3 of the cases should be considered as a possible cause for immunoparesis in these children.  There are still some questions that remain unanswered but it is reassuring that the incidence of the condition is reducing over the past couple of months.”


Prof Anil Dhawan, Professor of Paediatric Hepatology and Head of the Hepatocyte Biology and Transplantation Group at King’s College London; and Director of the Paediatric Liver GI and Nutrition Center and MowatLabs, and Director of Research and Innovation at King’s College Hospital, said:

“AAV2 appears to be a biomarker of this outbreak but without a direct causative effect.

“As I have commented before we are seeing this condition in a subpopulation of immunologically predisposed children whose immune system activation leads to exaggerated hepatic immune activation.  This is not proven but could be due to molecular mimicry with hepatocyte antigens.  AAV 2 with adenovirus F41, or SARs Covid previous or active exposure may be producing the super antigen leading to acute hepatic injury.

“The importance of this study could be that new cases if found to be AAV2 positive may be candidates for immune therapy to dampen the exaggerated immune mediated hepatic injury.”


Prof Deirdre Kelly, Professor of Paediatric Hepatology at the University of Birmingham; and Liver Unit at the Birmingham Women’s & Children’s Hospital, said:

“The UK HSA preprint is the biggest study looking at this so far.  The Scotland study shows similar data.

“I think this is a plausible explanation for these cases.  It looks like coinfection is the key, but it is still not clear why some children develop severe disease and require transplantation.  Could one possibility be coinfection with more than one virus?

“There is a real need for collaboration and examination of all samples in one place.”


Dr Anna Kinsey, Head of Epidemic Preparedness at the Medical Research Council, which part-funded the research, said:

“This project is an excellent example of how rapid collaboration between leading virology and clinical experts at the MRC-University of Glasgow Centre for Virus Research and MRC-supported ISARIC-4C, and public health agencies, is uncovering the likely cause of the recent outbreak of acute viral hepatitis in young children.  These two studies pave the way towards understanding why these children have become severely unwell.”



Preprint title: ‘Genomic investigations of acute hepatitis of unknown aetiology in children’ by Sofia Morfopoulou et al.

This work is not peer-reviewed.

Preprint title: ‘Adeno-associated virus 2 infection in children with non-A-E hepatitis’ by Antonia Ho et al.

This work is not peer-reviewed.



Declared interests

No reply to our request for DOIs was received.

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