Adeno-associated Virus 2 Infection in Children with Non-A-E Hepatitis

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.

Citing Articles

Case Report: HLA-DRB1 04:01 found in a child with adenovirus type 2 -linked hepatitis.

Katsumi Y, Nishimura Y, Goto S, Ozawa S, Nishiura T, Kotera A Front Immunol. 2025; 16:1544622.

PMID: 40079016 PMC: 11896997. DOI: 10.3389/fimmu.2025.1544622.

Recombinant AAV batch profiling by nanopore sequencing elucidates product-related DNA impurities and vector genome length distribution.

Dunker-Seidler F, Breunig K, Haubner M, Sonntag F, Horer M, Feiner R Mol Ther Methods Clin Dev. 2025; 33(1):101417.

PMID: 40008087 PMC: 11850753. DOI: 10.1016/j.omtm.2025.101417.

Genetic Variants of GBP4: Reduced Risks for Drug-Induced Acute Liver Failure in Non-Finnish European Population.

Liao T, Xia M, Hayashi P, Pan B, Aithal G, Lucena M Liver Int. 2025; 45(2):e70011.

PMID: 39868816 PMC: 11850085. DOI: 10.1111/liv.70011.

Using Laboratory Test Results for Surveillance During a New Outbreak of Acute Hepatitis in 3-Week- to 5-Year-Old Children in the United Kingdom, the Netherlands, Ireland, and Curaçao: Observational Cohort Study.

Swets M, Kerr S, Mackenna B, Fisher L, van Wijnen M, Brandwagt D JMIR Public Health Surveill. 2025; 10:e55376.

PMID: 39864403 PMC: 11770233. DOI: 10.2196/55376.

A Metagenomic Survey of Virological Hazards in Market-Ready Oysters.

Dirks R, Sosef N, Zwartkruis-Nahuis J, Thijssen M, Jansen C, Boxman I Food Environ Virol. 2025; 17(1):16.

PMID: 39794645 PMC: 11723887. DOI: 10.1007/s12560-024-09630-2.

References

Dunning J, Merson L, Rohde G, Gao Z, Semple M, Tran D . Open source clinical science for emerging infections. Lancet Infect Dis. 2013; 14(1):8-9. PMC: 7158987. DOI: 10.1016/S1473-3099(13)70327-X. View

Knodell R, Ishak K, Black W, Chen T, Craig R, Kaplowitz N . Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology. 1981; 1(5):431-5. DOI: 10.1002/hep.1840010511. View

Rodriguez-Inigo E, Lopez-Alcorocho J, Bartolome J, Ortiz-Movilla N, Pardo M, Carreno V . Percentage of hepatitis C virus-infected hepatocytes is a better predictor of response than serum viremia levels. J Mol Diagn. 2005; 7(4):535-43. PMC: 1888497. DOI: 10.1016/S1525-1578(10)60585-5. View

Tomlinson J, Jager M, Struzyna A, Laverack M, Fortier L, Dubovi E . Tropism, pathology, and transmission of equine parvovirus-hepatitis. Emerg Microbes Infect. 2020; 9(1):651-663. PMC: 7144241. DOI: 10.1080/22221751.2020.1741326. View

Srivastava A, Lusby E, Berns K . Nucleotide sequence and organization of the adeno-associated virus 2 genome. J Virol. 1983; 45(2):555-64. PMC: 256449. DOI: 10.1128/JVI.45.2.555-564.1983. View

ATCHISON R, CASTO B, HAMMON W . ADENOVIRUS-ASSOCIATED DEFECTIVE VIRUS PARTICLES. Science. 1965; 149(3685):754-6. DOI: 10.1126/science.149.3685.754. View

Li C, Narkbunnam N, Samulski R, Asokan A, Hu G, Jacobson L . Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia. Gene Ther. 2011; 19(3):288-94. DOI: 10.1038/gt.2011.90. View

Martino A, Basner-Tschakarjan E, Markusic D, Finn J, Hinderer C, Zhou S . Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsid-specific CD8+ T cells. Blood. 2013; 121(12):2224-33. PMC: 3606062. DOI: 10.1182/blood-2012-10-460733. View

Manno C, Pierce G, Arruda V, Glader B, Ragni M, Rasko J . Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med. 2006; 12(3):342-7. DOI: 10.1038/nm1358. View

10.

Mingozzi F, Maus M, Hui D, Sabatino D, Murphy S, Rasko J . CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nat Med. 2007; 13(4):419-22. DOI: 10.1038/nm1549. View

11.

Ertl H . Immunogenicity and toxicity of AAV gene therapy. Front Immunol. 2022; 13:975803. PMC: 9411526. DOI: 10.3389/fimmu.2022.975803. View

12.

Chowdary P, Shapiro S, Makris M, Evans G, Boyce S, Talks K . Phase 1-2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B. N Engl J Med. 2022; 387(3):237-247. DOI: 10.1056/NEJMoa2119913. View

13.

Sebode M, Weiler-Normann C, Liwinski T, Schramm C . Autoantibodies in Autoimmune Liver Disease-Clinical and Diagnostic Relevance. Front Immunol. 2018; 9:609. PMC: 5880919. DOI: 10.3389/fimmu.2018.00609. View

14.

Rafie K, Lenman A, Fuchs J, Rajan A, Arnberg N, Carlson L . The structure of enteric human adenovirus 41-A leading cause of diarrhea in children. Sci Adv. 2021; 7(2). PMC: 7793593. DOI: 10.1126/sciadv.abe0974. View

15.

Echavarria M . Adenoviruses in immunocompromised hosts. Clin Microbiol Rev. 2008; 21(4):704-15. PMC: 2570151. DOI: 10.1128/CMR.00052-07. View

16.

Baker J, Buchfellner M, Britt W, Sanchez V, Potter J, Ingram L . Acute Hepatitis and Adenovirus Infection Among Children - Alabama, October 2021-February 2022. MMWR Morb Mortal Wkly Rep. 2022; 71(18):638-640. PMC: 9098244. DOI: 10.15585/mmwr.mm7118e1. View

17.

van Gerven N, de Boer Y, Zwiers A, Verwer B, Drenth J, Van Hoek B . HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1. Genes Immun. 2015; 16(4):247-52. DOI: 10.1038/gene.2014.82. View

18.

Lanchbury J, Jaeger E, Sansom D, Hall M, Wordsworth P, Stedeford J . Strong primary selection for the Dw4 subtype of DR4 accounts for the HLA-DQw7 association with Felty's syndrome. Hum Immunol. 1991; 32(1):56-64. DOI: 10.1016/0198-8859(91)90117-r. View

19.

Gay D, Maddon P, Sekaly R, Talle M, Godfrey M, Long E . Functional interaction between human T-cell protein CD4 and the major histocompatibility complex HLA-DR antigen. Nature. 1987; 328(6131):626-9. DOI: 10.1038/328626a0. View

20.

Aurnhammer C, Haase M, Muether N, Hausl M, Rauschhuber C, Huber I . Universal real-time PCR for the detection and quantification of adeno-associated virus serotype 2-derived inverted terminal repeat sequences. Hum Gene Ther Methods. 2012; 23(1):18-28. DOI: 10.1089/hgtb.2011.034. View