TY - JOUR
T1 - Adeno-associated virus 2 infection in children with non-A–E hepatitis
AU - Ho, Antonia
AU - Orton, Richard
AU - Tayler, Rachel
AU - Asamaphan, Patawee
AU - Herder, Vanessa
AU - Davis, Chris
AU - Tong, Lily
AU - Smollett, Katherine
AU - Manali, Maria
AU - Allan, Jay
AU - Rawlik, Konrad
AU - McDonald, Sarah E.
AU - Vink, Elen
AU - Pollock, Louisa
AU - Gannon, Louise
AU - Evans, Clair
AU - McMenamin, Jim
AU - Roy, Kirsty
AU - Marsh, Kimberly
AU - Divala, Titus
AU - Holden, Matthew T.G.
AU - Lockhart, Michael
AU - Yirrell, David
AU - Currie, Sandra
AU - O’Leary, Maureen
AU - Henderson, David
AU - Shepherd, Samantha J.
AU - Jackson, Celia
AU - Gunson, Rory
AU - MacLean, Alasdair
AU - McInnes, Neil
AU - Bradley-Stewart, Amanda
AU - Battle, Richard
AU - Hollenbach, Jill A.
AU - Henderson, Paul
AU - Odam, Miranda
AU - Chikowore, Primrose
AU - Oosthuyzen, Wilna
AU - Chand, Meera
AU - Hamilton, Melissa Shea
AU - Estrada-Rivadeneyra, Diego
AU - Levin, Michael
AU - Avramidis, Nikos
AU - Pairo-Castineira, Erola
AU - Vitart, Veronique
AU - Thomson, Emma C.
AU - DIAMONDS Consortium
AU - ISARIC4C Investigators
A2 - Zavadska, Dace
A2 - Laivacuma, Sniedze
A2 - Rudzate, Aleksandra
A2 - Stoldere, Diāna
A2 - Barzdina, Arta
A2 - Barzdina, Elza
A2 - Madelane, Monta
A2 - Grāvele, Dagne
N1 - Funding Information:
We wish to acknowledge the contribution of the participating children and their parents who agreed to participate in the ISARIC CCP-UK and DIAMONDS studies, and the research teams who recruited the patients; S. Bennett-Slater from NHS Greater Glasgow and Clyde for assisting with sample location and testing; the histopathology team, Veterinary Diagnostic, University of Glasgow, for excellent technical assistance; P. Murcia for providing resources and advice; P. Olmo for administrative assistance; and E. J. Kremer from the Institut de Génétique Moléculaire de Montpellier, Université de Montpellier and A. Baker, University of Edinburgh, for advice. The work was funded by Public Health Scotland, the National Institute for Health Research (NIHR; award CO-CIN-01) and the Medical Research Council (MRC; grants MR/X010252/1, MC_UU_1201412, MC_UU_12018/12, MC_PC_19059, MC_PC_19025 and MC_PC_22004). DIAMONDS is funded by the European Union Horizon 2020 programme; grant 848196). M.P. acknowledges funding support from the Wellcome Trust (206369/Z/17/Z). M.G.S. acknowledges funding support from The Pandemic Institute, Liverpool and the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, and UK Health Security Agency. J.K.B. acknowledges funding support from a Wellcome Trust Senior Research Fellowship (223164/Z/21/Z), and MC_PC_20029, Sepsis Research (Fiona Elizabeth Agnew Trust), a BBSRC Institute Strategic Programme Grant to the Roslin Institute (BB/P013732/1, BB/P013759/1), and the Intensive Care Society of the United Kingdom. We acknowledge the support of Baillie Gifford and the Baillie Gifford Science Pandemic Hub at the University of Edinburgh. Parts of this research has been conducted using the UK Biobank Resource under project 788 and we would like to acknowledge the assistance of A. Tenesa in making this possible. Additional replication was also conducted using the UK Biobank Resource (Project 26041). This research was also funded by the National Institute for Health and Care Research (CO-CIN-01) and jointly by NIHR and UK Research and Innovation (CV220-169, MC_PC_19059). The views expressed in this article are those of the author(s) and not necessarily those of UKRI, the NIHR, or the Department of Health and Social Care. We also acknowledge the support of NHS Research Scotland (NRS) Greater Glasgow and Clyde Biorepository team. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Funding Information:
We wish to acknowledge the contribution of the participating children and their parents who agreed to participate in the ISARIC CCP-UK and DIAMONDS studies, and the research teams who recruited the patients; S. Bennett-Slater from NHS Greater Glasgow and Clyde for assisting with sample location and testing; the histopathology team, Veterinary Diagnostic, University of Glasgow, for excellent technical assistance; P. Murcia for providing resources and advice; P. Olmo for administrative assistance; and E. J. Kremer from the Institut de Génétique Moléculaire de Montpellier, Université de Montpellier and A. Baker, University of Edinburgh, for advice. The work was funded by Public Health Scotland, the National Institute for Health Research (NIHR; award CO-CIN-01) and the Medical Research Council (MRC; grants MR/X010252/1, MC_UU_1201412, MC_UU_12018/12, MC_PC_19059, MC_PC_19025 and MC_PC_22004). DIAMONDS is funded by the European Union Horizon 2020 programme; grant 848196). M.P. acknowledges funding support from the Wellcome Trust (206369/Z/17/Z). M.G.S. acknowledges funding support from The Pandemic Institute, Liverpool and the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, and UK Health Security Agency. J.K.B. acknowledges funding support from a Wellcome Trust Senior Research Fellowship (223164/Z/21/Z), and MC_PC_20029, Sepsis Research (Fiona Elizabeth Agnew Trust), a BBSRC Institute Strategic Programme Grant to the Roslin Institute (BB/P013732/1, BB/P013759/1), and the Intensive Care Society of the United Kingdom. We acknowledge the support of Baillie Gifford and the Baillie Gifford Science Pandemic Hub at the University of Edinburgh. Parts of this research has been conducted using the UK Biobank Resource under project 788 and we would like to acknowledge the assistance of A. Tenesa in making this possible. Additional replication was also conducted using the UK Biobank Resource (Project 26041). This research was also funded by the National Institute for Health and Care Research (CO-CIN-01) and jointly by NIHR and UK Research and Innovation (CV220-169, MC_PC_19059). The views expressed in this article are those of the author(s) and not necessarily those of UKRI, the NIHR, or the Department of Health and Social Care. We also acknowledge the support of NHS Research Scotland (NRS) Greater Glasgow and Clyde Biorepository team. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/5/18
Y1 - 2023/5/18
N2 - An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland 1 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.
AB - An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland 1 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.
UR - http://www.scopus.com/inward/record.url?scp=85159304324&partnerID=8YFLogxK
U2 - 10.1038/s41586-023-05948-2
DO - 10.1038/s41586-023-05948-2
M3 - Article
C2 - 36996873
AN - SCOPUS:85159304324
SN - 0028-0836
VL - 617
SP - 555
EP - 563
JO - Nature
JF - Nature
IS - 7961
ER -
