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Ho, Antonia; Orton, Richard; Tayler, Rachel; Asamaphan, Patawee; Herder, Vanessa; Davis, Chris; Tong, Lily; Smollett, Katherine; Manali, Maria; Allan, Jay; Rawlik, Konrad; McDonald, Sarah E; Vink, Elen; Pollock, Louisa; Gannon, Louise; Evans, Clair; McMenamin, Jim; Roy, Kirsty; Marsh, Kimberly; Divala, Titus; Holden, Matthew T G; Lockhart, Michael; Yirrell, David; Currie, Sandra; O'Leary, Maureen; Henderson, David; Shepherd, Samantha J; Jackson, Celia; Gunson, Rory; MacLean, Alasdair; McInnes, Neil; Bradley-Stewart, Amanda; Battle, Richard; Hollenbach, Jill A; Henderson, Paul; Odam, Miranda; Chikowore, Primrose; Oosthuyzen, Wilna; Chand, Meera; Hamilton, Melissa Shea; Estrada-Rivadeneyra, Diego; Levin, Michael; Avramidis, Nikos; Pairo-Castineira, Erola; Vitart, Veronique; Wilkie, Craig; Palmarini, Massimo; Ray, Surajit; Robertson, David L; da Silva Filipe, Ana; Willett, Brian J; Breuer, Judith; Semple, Malcolm G; Turner, David; Baillie, J Kenneth; Thomson, Emma C
Nature (London), 05/2023, Volume: 617, Issue: 7961Journal Article
An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland in April 2022 and has now been identified in 35 countries . 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 ). 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.
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