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In 2023, three pediatric studies showed that adeno-associated virus serotype 2 (AAV-2) infection was linked to AHUE. The article compares metagenomic sequencing, whole-genome sequencing, virus-specific real-time PCR, and liver histology, showing ≥80% AAV-2 positivity by metagenomics. PCR results indicated high AAV-2 positivity (96.4% and 81.2%), supporting AAV-2 as a pathogen and proposing coinfection and related markers as diagnostic criteria.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/comparison-of-three-pediatric-studies-investigating-acute-hepatitis-of-unknown-etiology/406819/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/comparison-of-three-pediatric-studies-investigating-acute-hepatitis-of-unknown-etiology/406819.png","ImageObject",300,407,{"name":92,"@type":93},"Alexandar","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-06","2026-09-28",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What did the three pediatric studies find about AAV-2 and AHUE?","Question",{"text":112,"@type":113},"All three studies reported AAV-2 positivity rates of 80% or greater in AHUE cases by metagenomic sequencing, and PCR showed high positivity in two studies (96.4% and 81.2%).","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which investigative methods are compared in the article?",{"text":117,"@type":113},"The article compares metagenomic sequencing, viral whole-genome sequencing, virus-specific real-time PCR, and histological analysis of liver tissue.",{"name":119,"@type":110,"acceptedAnswer":120},"What diagnostic criteria does the article suggest for AHUE?",{"text":121,"@type":113},"It proposes that AAV-2 infection plus coinfection with helper viruses, high AAV-2 viral loads in blood, anti-AAV-2 IgM, and HLA typing could be candidate diagnostic criteria.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},406819,1790794867,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},962090768658,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","| W | J | V | World Journal of\u003Cbr>Virology |\n| --- | --- | --- | --- |\n\nSubmit a Manuscript: [https://www.f6publishing.com](https://www.f6publishing.com) World J Virol 2025 December 25; 14(4): 110435  \nDOI: 10.5501/wjv.v14.i4.110435 ISSN 2220-3249 (online)  \nMINIREVIEWS  \nComparison of three pediatric studies investigating acute hepatitis of unknown etiology  \nHaruki Komatsu  \nSpecialty type: Virology  \nProvenance and peer review:  \nInvited article; Externally peer reviewed.  \nPeer-review model: Single blind  \nPeer-review report’s classification Scientific Quality: Grade B, Grade B  \nNovelty: Grade B, Grade B  \nCreativity or Innovation: Grade C, Grade C  \nScientific Significance: Grade B, Grade B  \nP-Reviewer: Sitkin S, MD, PhD, Associate Professor, Russia  \nReceived: June 6, 2025  \nRevised: August 12, 2025  \nAccepted: September 19, 2025  \nPublished online: December 25, 2025  \nProcessing time: 202 Days and 9.5 Hours  \nHaruki Komatsu, Department of Pediatrics, Komatsu Children’s Clinic, Yachiyo 276-0040, Chiba, Japan  \nCorresponding author: Haruki Komatsu, MD, PhD, Department of Pediatrics, Komatsu Children’s Clinic, 4-2-1 Midorigaoka-nishi, Yachiyo 276-0040, Chiba, Japan.  \n[haruki-komatsu@chive.ocn.ne.jp](haruki-komatsu@chive.ocn.ne.jp)  \nAbstract  \nBetween 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 wholegenome 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 IgMand 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.  \nKey Words: Adeno-associated virus; Cidofovir; Coinfection; Helper virus; Herpes virus; Human adenovirus; Human leukocyte antigen; Metagenomic sequencing; Phylogenetic tree analysis; Real-time PCR  \n©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.  \n WJV  [https://www.wjgnet.com](https://www.wjgnet.com) 1 December 25, 2025  Volume 14  Issue 4   \nKomatsu H. Pediatric hepatitis caused by AAV-2  \nCore 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 ofAAV-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.  \nCitation: Komatsu H. Comparison of three pediatric studies investigating acute hepatitis of unknown etiology. World J Virol 2025;  \n14(4): 110435  \nURL: [https://www.wjgnet.com/2220-3249/full/v14/i4/110435.h","cbCaivFYlkmRmSRM","https://ap.wps.com/l/cbCaivFYlkmRmSRM","pdf",1043020,27,"English","# Abstract\n# Core Tip\n# Introduction","[{\"question\":\"What did the three pediatric studies find about AAV-2 and AHUE?\",\"answer\":\"All three studies reported AAV-2 positivity rates of 80% or greater in AHUE cases by metagenomic sequencing, and PCR showed high positivity in two studies (96.4% and 81.2%).\"},{\"question\":\"Which investigative methods are compared in the article?\",\"answer\":\"The article compares metagenomic sequencing, viral whole-genome sequencing, virus-specific real-time PCR, and histological analysis of liver tissue.\"},{\"question\":\"What diagnostic criteria does the article suggest for AHUE?\",\"answer\":\"It proposes that AAV-2 infection plus coinfection with helper viruses, high AAV-2 viral loads in blood, anti-AAV-2 IgM, and HLA typing could be candidate diagnostic criteria.\"}]","Comparison of three pediatric studies investigating acute hepatitis of unknown etiology | PDF",1790568143,68]