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@article{Morfopoulou:2023:10.1038/s41586-023-06003-w,
author = {Morfopoulou, S and Buddle, S and Torres, Montaguth OE and Atkinson, L and Guerra-Assunção, JA and Moradi, Marjaneh M and Zennezini, Chiozzi R and Storey, N and Campos, L and Hutchinson, JC and Counsell, JR and Pollara, G and Roy, S and Venturini, C and Antinao, Diaz JF and Siam, A and Tappouni, LJ and Asgarian, Z and Ng, J and Hanlon, KS and Lennon, A and McArdle, A and Czap, A and Rosenheim, J and Andrade, C and Anderson, G and Lee, JCD and Williams, R and Williams, CA and Tutill, H and Bayzid, N and Martin, Bernal LM and Macpherson, H and Montgomery, K-A and Moore, C and Templeton, K and Neill, C and Holden, M and Gunson, R and Shepherd, SJ and Shah, P and Cooray, S and Voice, M and Steele, M and Fink, C and Whittaker, TE and Santilli, G and Gissen, P and Kaufer, BB and Reich, J and Andreani, J and Simmonds, P and Alrabiah, DK and Castellano, S and Chikowore, P and Odam, M and Rampling, T and Houlihan, C and Hoschler, K and Talts, T and Celma, C and Gonzalez, S and Gallagher, E and S},
doi = {10.1038/s41586-023-06003-w},
journal = {Nature},
pages = {564--573},
title = {Genomic investigations of unexplained acute hepatitis in children},
url = {http://dx.doi.org/10.1038/s41586-023-06003-w},
volume = {617},
year = {2023}
}

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TY  - JOUR
AB  - Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.
AU  - Morfopoulou,S
AU  - Buddle,S
AU  - Torres,Montaguth OE
AU  - Atkinson,L
AU  - Guerra-Assunção,JA
AU  - Moradi,Marjaneh M
AU  - Zennezini,Chiozzi R
AU  - Storey,N
AU  - Campos,L
AU  - Hutchinson,JC
AU  - Counsell,JR
AU  - Pollara,G
AU  - Roy,S
AU  - Venturini,C
AU  - Antinao,Diaz JF
AU  - Siam,A
AU  - Tappouni,LJ
AU  - Asgarian,Z
AU  - Ng,J
AU  - Hanlon,KS
AU  - Lennon,A
AU  - McArdle,A
AU  - Czap,A
AU  - Rosenheim,J
AU  - Andrade,C
AU  - Anderson,G
AU  - Lee,JCD
AU  - Williams,R
AU  - Williams,CA
AU  - Tutill,H
AU  - Bayzid,N
AU  - Martin,Bernal LM
AU  - Macpherson,H
AU  - Montgomery,K-A
AU  - Moore,C
AU  - Templeton,K
AU  - Neill,C
AU  - Holden,M
AU  - Gunson,R
AU  - Shepherd,SJ
AU  - Shah,P
AU  - Cooray,S
AU  - Voice,M
AU  - Steele,M
AU  - Fink,C
AU  - Whittaker,TE
AU  - Santilli,G
AU  - Gissen,P
AU  - Kaufer,BB
AU  - Reich,J
AU  - Andreani,J
AU  - Simmonds,P
AU  - Alrabiah,DK
AU  - Castellano,S
AU  - Chikowore,P
AU  - Odam,M
AU  - Rampling,T
AU  - Houlihan,C
AU  - Hoschler,K
AU  - Talts,T
AU  - Celma,C
AU  - Gonzalez,S
AU  - Gallagher,E
AU  - Simmons,R
AU  - Watson,C
AU  - Mandal,S
AU  - Zambon,M
AU  - Chand,M
AU  - Hatcher,J
AU  - De,S
AU  - Baillie,K
AU  - Semple,MG
AU  - DIAMONDS,Consortium
AU  - PERFORM,Consortium
AU  - ISARIC4C,Investigators
AU  - Martin,J
AU  - Ushiro-Lumb,I
AU  - Noursadeghi,M
AU  - Deheragoda,M
AU  - Hadzic,N
AU  - Grammatikopoulos,T
AU  - Brown,R
AU  - Kelgeri,C
AU  - Thalassinos,K
AU  - Waddington,SN
AU  - Jacques,TS
AU  - Thomson,E
AU  - Levin,M
AU  - Brown,JR
AU  - Breuer,J
DO  - 10.1038/s41586-023-06003-w
EP  - 573
PY  - 2023///
SN  - 0028-0836
SP  - 564
TI  - Genomic investigations of unexplained acute hepatitis in children
T2  - Nature
UR  - http://dx.doi.org/10.1038/s41586-023-06003-w
UR  - https://www.ncbi.nlm.nih.gov/pubmed/36996872
UR  - https://www.nature.com/articles/s41586-023-06003-w
UR  - http://hdl.handle.net/10044/1/105327
VL  - 617
ER  -

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