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

Antonia Ho, Richard Orton, Rachel Tayler, Patawee Asamaphan, Vanessa Herder, Chris Davis, Lily Tong, Katherine Smollett, Maria Manali, Jay Allan, Konrad Rawlik, Sarah E. McDonald, Elen Vink, Louisa Pollock, Louise Gannon, Clair Evans, Jim McMenamin, Kirsty Roy, Kimberly Marsh, Titus Divala, Matthew T. G. Holden, Michael Lockhart, David Yirrell, Sandra Currie, Maureen O’Leary, David Henderson, Samantha J. Shepherd, Celia Jackson, Rory Gunson, Alasdair MacLean, Neil McInnes, Amanda Bradley-Stewart, Richard Battle, Jill A. Hollenbach, Paul Henderson, Miranda Odam, Primrose Chikowore, Wilna Oosthuyzen, Meera Chand, Melissa Shea Hamilton, Diego Estrada-Rivadeneyra, Michael Levin, Nikos Avramidis, Erola Pairo-Castineira, Veronique Vitart, Craig Wilkie, Massimo Palmarini, Surajit Ray, David L. Robertson, Ana Filipe, Brian J. Willett, Judith Breuer, Malcolm G. Semple, David Turner, J. Kenneth Baillie and Emma C. Thomson ()
Additional contact information
Antonia Ho: Medical Research Council–University of Glasgow Centre for Virus Research
Richard Orton: Medical Research Council–University of Glasgow Centre for Virus Research
Rachel Tayler: Royal Hospital for Children
Patawee Asamaphan: Medical Research Council–University of Glasgow Centre for Virus Research
Vanessa Herder: Medical Research Council–University of Glasgow Centre for Virus Research
Chris Davis: Medical Research Council–University of Glasgow Centre for Virus Research
Lily Tong: Medical Research Council–University of Glasgow Centre for Virus Research
Katherine Smollett: Medical Research Council–University of Glasgow Centre for Virus Research
Maria Manali: Medical Research Council–University of Glasgow Centre for Virus Research
Jay Allan: Medical Research Council–University of Glasgow Centre for Virus Research
Konrad Rawlik: University of Edinburgh
Sarah E. McDonald: Medical Research Council–University of Glasgow Centre for Virus Research
Elen Vink: Medical Research Council–University of Glasgow Centre for Virus Research
Louisa Pollock: Medical Research Council–University of Glasgow Centre for Virus Research
Louise Gannon: NHS Tayside
Clair Evans: Queen Elizabeth University Hospital
Jim McMenamin: Public Health Scotland
Kirsty Roy: Public Health Scotland
Kimberly Marsh: Public Health Scotland
Titus Divala: Public Health Scotland
Matthew T. G. Holden: Public Health Scotland
Michael Lockhart: Public Health Scotland
David Yirrell: Public Health Scotland
Sandra Currie: Public Health Scotland
Maureen O’Leary: Public Health Scotland
David Henderson: Public Health Scotland
Samantha J. Shepherd: West of Scotland Specialist Virology Centre
Celia Jackson: West of Scotland Specialist Virology Centre
Rory Gunson: West of Scotland Specialist Virology Centre
Alasdair MacLean: West of Scotland Specialist Virology Centre
Neil McInnes: West of Scotland Specialist Virology Centre
Amanda Bradley-Stewart: Ninewells Hospital
Richard Battle: Edinburgh Royal Infirmary
Jill A. Hollenbach: University of California San Francisco
Paul Henderson: University of Edinburgh
Miranda Odam: University of Edinburgh
Primrose Chikowore: University of Edinburgh
Wilna Oosthuyzen: University of Edinburgh
Meera Chand: UK Health Security Agency
Melissa Shea Hamilton: Imperial College London
Diego Estrada-Rivadeneyra: Imperial College London
Michael Levin: Imperial College London
Nikos Avramidis: University of Edinburgh
Erola Pairo-Castineira: University of Edinburgh
Veronique Vitart: University of Edinburgh
Craig Wilkie: University of Glasgow
Massimo Palmarini: Medical Research Council–University of Glasgow Centre for Virus Research
Surajit Ray: University of Glasgow
David L. Robertson: Medical Research Council–University of Glasgow Centre for Virus Research
Ana Filipe: Medical Research Council–University of Glasgow Centre for Virus Research
Brian J. Willett: Medical Research Council–University of Glasgow Centre for Virus Research
Judith Breuer: University College London
Malcolm G. Semple: University of Liverpool
David Turner: Edinburgh Royal Infirmary
J. Kenneth Baillie: University of Edinburgh
Emma C. Thomson: Medical Research Council–University of Glasgow Centre for Virus Research

Nature, 2023, vol. 617, issue 7961, 555-563

Abstract: Abstract An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case–control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10−12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a ‘helper virus’ to support AAV2 replication) and disease susceptibility related to HLA class II status.

Date: 2023
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DOI: 10.1038/s41586-023-05948-2

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