Komatsu H. Comparison of three pediatric studies investigating acute hepatitis of unknown etiology. World J Virol 2025; 14(4): 110435 [DOI: 10.5501/wjv.v14.i4.110435]
Corresponding Author of This Article
Haruki Komatsu, MD, PhD, Department of Pediatrics, Komatsu Children’s Clinic, 4-2-1 Midorigaoka-nishi, Yachiyo 276-0040, Chiba, Japan. haruki-komatsu@chive.ocn.ne.jp
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Virology
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Minireviews
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Dec 25, 2025 (publication date) through Dec 25, 2025
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Publication Name
World Journal of Virology
ISSN
2220-3249
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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
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Komatsu H. Comparison of three pediatric studies investigating acute hepatitis of unknown etiology. World J Virol 2025; 14(4): 110435 [DOI: 10.5501/wjv.v14.i4.110435]
World J Virol. Dec 25, 2025; 14(4): 110435 Published online Dec 25, 2025. doi: 10.5501/wjv.v14.i4.110435
Comparison of three pediatric studies investigating acute hepatitis of unknown etiology
Haruki Komatsu
Haruki Komatsu, Department of Pediatrics, Komatsu Children’s Clinic, Yachiyo 276-0040, Chiba, Japan
Author contributions: Komatsu H wrote this article and prepared all the figures and tables.
Conflict-of-interest statement: Komatsu H has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Haruki Komatsu, MD, PhD, Department of Pediatrics, Komatsu Children’s Clinic, 4-2-1 Midorigaoka-nishi, Yachiyo 276-0040, Chiba, Japan. haruki-komatsu@chive.ocn.ne.jp
Received: June 6, 2025 Revised: August 12, 2025 Accepted: September 19, 2025 Published online: December 25, 2025 Processing time: 202 Days and 10.1 Hours
Abstract
Between 2021 and 2023, approximately 400 pediatric cases of acute hepatitis of unknown etiology (AHUE) were reported in European countries and the United States. In 2023, three pediatric studies revealed that adeno-associated virus serotype 2 (AAV-2) infection was associated with AHUE. This article presents a summary and comparison of the results of metagenomic sequencing, viral whole-genome sequencing, virus-specific real-time polymerase chain reaction (PCR) and histological analysis of the liver, all of which were among the common investigative methods used in the three pediatric studies. All three pediatric studies revealed 80% or greater rates of positivity for AAV-2 in cases of AHUE according to metagenomic sequencing. Moreover, on the basis of PCR results, two studies revealed high AAV-2 positivity rates (96.4% and 81.2%) among cases of AHUE. These findings suggest that AAV-2 is a pathogen in AHUE. Coinfection with AAV-2 and one or more helper viruses (human adenovirus, human herpesvirus 6B, Epstein–Barr virus, etc.), high viral loads of AAV-2 in blood, anti-AAV-2 IgM and human leukocyte antigen typing could be candidate diagnostic criteria for AHUE. AAV-2 infection should be incorporated into clinical guidelines for the management of acute liver failure. Cidofovir can be administered if coinfection with AAV-2 and HAdV is detected.
Core Tip: The rate of positivity for adeno-associated virus serotype 2 (AAV-2) was 80% or greater in cases of acute hepatitis of unknown etiology (AHUE) according to metagenomic sequencing and real-time polymerase chain reaction. AAV-2 RNA was detected in the nuclei and cytoplasm of ballooned hepatocytes through in situ hybridization. No distinct clade was observed in the phylogenetic tree analysis of whole genomes of AAV-2 isolated from cases. Coinfection of AAV-2 with one or more helper viruses (HAdV, HHV-6B, EBV, etc.), a high viral load of AAV-2 in blood, anti-AAV-2 IgM and human leukocyte antigen (HLA) typing (HLA-DRB1*04:01, HLA-DQA1*03:03 and HLA-DRB4*01:03) could be candidate diagnostic criteria for AHUE.
