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

Antonia Ho; DIAMONDS consortium; ISARIC4C investigators; Brian J. Willett; Judith Breuer; Malcolm G. Semple; David Turner; J. Kenneth Baillie; Emma C. Thomson

doi:10.1038/s41586-023-05948-2

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

Antonia Ho, DIAMONDS consortium, ISARIC4C investigators, Brian J. Willett, Judith Breuer, Malcolm G. Semple, David Turner, J. Kenneth Baillie, Emma C. Thomson^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland in April 20221 and has now been identified in 35 countries². Several recent studies have suggested an association with human adenovirus (HAdV), a virus not commonly associated with hepatitis. Here we report a detailed case-control investigation and find an association between adeno-associated virus (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing (NGS), reverse transcription-polymerase chain reaction (RT-PCR), serology and in situ hybridisation (ISH), we detected recent infection with AAV2 in the plasma and liver samples of 26/32 (81%) hepatitis cases versus 5/74 (7%) of controls. Further, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsies. In keeping with a CD4+ T-cell-mediated immune pathology, the Human Leucocyte Antigen (HLA) class II DRB1*04:01 allele was identified in 25/27 cases (93%), compared with a background frequency of 10/64 (16%; p=5.49 x 10^-12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a coinfection with HAdV which is required as a "helper virus" to support AAV2 replication) and HLA class II-related disease susceptibility.

Original language	English
Pages (from-to)	555-563
Journal	Nature
Volume	617
Early online date	30 Mar 2023
DOIs	https://doi.org/10.1038/s41586-023-05948-2
Publication status	Published - 18 May 2023

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Copyright © 2023 the Authors. This work has been made available online in accordance with the Rights Retention Strategy This accepted manuscript is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The final published version of this work is available at https://doi.org/10.1038/s41586-023-05948-2.
Accepted author manuscript, 35.3 MBLicence: CC BY

Cite this

@article{a31a9804411e47f9b4a91c4b9b04f455,

title = "Adeno-associated virus 2 infection in children with non-A-E hepatitis",

abstract = "An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland in April 20221 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus (HAdV), a virus not commonly associated with hepatitis. Here we report a detailed case-control investigation and find an association between adeno-associated virus (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing (NGS), reverse transcription-polymerase chain reaction (RT-PCR), serology and in situ hybridisation (ISH), we detected recent infection with AAV2 in the plasma and liver samples of 26/32 (81%) hepatitis cases versus 5/74 (7%) of controls. Further, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsies. In keeping with a CD4+ T-cell-mediated immune pathology, the Human Leucocyte Antigen (HLA) class II DRB1*04:01 allele was identified in 25/27 cases (93%), compared with a background frequency of 10/64 (16%; p=5.49 x 10-12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a coinfection with HAdV which is required as a {"}helper virus{"} to support AAV2 replication) and HLA class II-related disease susceptibility.",

author = "Antonia Ho and Richard Orton and Rachel Tayler and Patawee Asamaphan and Vanessa Herder and Chris Davis and Lily Tong and Katherine Smollett and Maria Manali and Jay Allan and Konrad Rawlik and McDonald, {Sarah E} and Elen Vink and Louisa Pollock and Louise Gannon and Clair Evans and Jim McMenamin and Kirsty Roy and Kimberly Marsh and Titus Divala and Holden, {Matthew T G} and Michael Lockhart and David Yirrell and Sandra Currie and Maureen O'Leary and David Henderson and Shepherd, {Samantha J} and Celia Jackson and Rory Gunson and Alasdair MacLean and Neil McInnes and Amanda Bradley-Stewart and Richard Battle and Jill Hollenbach and Paul Henderson and Miranda Odam and Primrose Chikowore and Wilna Oosthuyzen and Meera Chand and Hamilton, {Melissa Shea} and Diego Estrada-Rivadeneyra and Michael Levin and Nikos Avramidis and Erola Pairo-Castineira and Veronique Vitart and Craig Wilkie and {DIAMONDS consortium} and {ISARIC4C investigators} and Massimo Palmarini and Surajit Ray and Robertson, {David L} and {da Silva Filipe}, Ana and Willett, {Brian J.} and Judith Breuer and Semple, {Malcolm G.} and David Turner and Baillie, {J. Kenneth} and Thomson, {Emma C.}",

note = "Funding: 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 & MC_PC_22004). DIAMONDS is funded by the European Union Horizon 2020 programme; grant 848196). MP acknowledges funding support from the Wellcome Trust (206369/Z/17/Z). MGS gratefully 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 United Kingdom Health Security Agency (United KingdomHSA). JKB gratefully 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 United Kingdom Intensive Care Society.",

year = "2023",

month = may,

day = "18",

doi = "10.1038/s41586-023-05948-2",

language = "English",

volume = "617",

pages = "555--563",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature publishing group",

}

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

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 - Wilkie, Craig

AU - DIAMONDS consortium

AU - ISARIC4C investigators

AU - Palmarini, Massimo

AU - Ray, Surajit

AU - Robertson, David L

AU - da Silva Filipe, Ana

AU - Willett, Brian J.

AU - Breuer, Judith

AU - Semple, Malcolm G.

AU - Turner, David

AU - Baillie, J. Kenneth

AU - Thomson, Emma C.

N1 - Funding: 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 & MC_PC_22004). DIAMONDS is funded by the European Union Horizon 2020 programme; grant 848196). MP acknowledges funding support from the Wellcome Trust (206369/Z/17/Z). MGS gratefully 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 United Kingdom Health Security Agency (United KingdomHSA). JKB gratefully 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 United Kingdom Intensive Care Society.

PY - 2023/5/18

Y1 - 2023/5/18

N2 - An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland in April 20221 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus (HAdV), a virus not commonly associated with hepatitis. Here we report a detailed case-control investigation and find an association between adeno-associated virus (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing (NGS), reverse transcription-polymerase chain reaction (RT-PCR), serology and in situ hybridisation (ISH), we detected recent infection with AAV2 in the plasma and liver samples of 26/32 (81%) hepatitis cases versus 5/74 (7%) of controls. Further, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsies. In keeping with a CD4+ T-cell-mediated immune pathology, the Human Leucocyte Antigen (HLA) class II DRB1*04:01 allele was identified in 25/27 cases (93%), compared with a background frequency of 10/64 (16%; p=5.49 x 10-12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a coinfection with HAdV which is required as a "helper virus" to support AAV2 replication) and HLA class II-related disease susceptibility.

AB - An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland in April 20221 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus (HAdV), a virus not commonly associated with hepatitis. Here we report a detailed case-control investigation and find an association between adeno-associated virus (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing (NGS), reverse transcription-polymerase chain reaction (RT-PCR), serology and in situ hybridisation (ISH), we detected recent infection with AAV2 in the plasma and liver samples of 26/32 (81%) hepatitis cases versus 5/74 (7%) of controls. Further, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsies. In keeping with a CD4+ T-cell-mediated immune pathology, the Human Leucocyte Antigen (HLA) class II DRB1*04:01 allele was identified in 25/27 cases (93%), compared with a background frequency of 10/64 (16%; p=5.49 x 10-12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a coinfection with HAdV which is required as a "helper virus" to support AAV2 replication) and HLA class II-related disease susceptibility.

U2 - 10.1038/s41586-023-05948-2

DO - 10.1038/s41586-023-05948-2

M3 - Article

C2 - 36996873

SN - 0028-0836

VL - 617

SP - 555

EP - 563

JO - Nature

JF - Nature

ER -

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

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