Journal article
Genomic investigations of unexplained acute hepatitis in children
- Abstract:
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 10.2MB, Terms of use)
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- Publisher copy:
- 10.1038/s41586-023-06003-w
Authors
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+ DIAMONDS Consortium
- Role:
- Contributor
+ PERFORM Consortium
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- Contributor
+ ISARIC 4C Investigators
- Role:
- Contributor
- Publisher:
- Springer Nature
- Journal:
- Nature More from this journal
- Volume:
- 617
- Issue:
- 7961
- Pages:
- 564–573
- Place of publication:
- England
- Publication date:
- 2023-03-30
- Acceptance date:
- 2023-03-23
- DOI:
- EISSN:
-
1476-4687
- ISSN:
-
0028-0836
- Pmid:
-
36996872
- Language:
-
English
- Keywords:
- Subjects:
- Pubs id:
-
1335247
- Local pid:
-
pubs:1335247
- Deposit date:
-
2023-06-19
Terms of use
- Copyright holder:
- Morfopoulou et al.
- Copyright date:
- 2023
- Rights statement:
- © The Author(s) 2023. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Licence:
- CC Attribution (CC BY)
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