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A Case Series of Children with Acute Hepatitis and Human Adenovirus Infection

List of authors.
  • L. Helena Gutierrez Sanchez, M.D.,
  • Henry Shiau, M.D.,
  • Julia M. Baker, Ph.D.,
  • Stephanie Saaybi, M.D.,
  • Markus Buchfellner, M.D.,
  • William Britt, M.D.,
  • Veronica Sanchez, Ph.D.,
  • Jennifer L. Potter, M.P.H.,
  • L. Amanda Ingram, M.P.H.,
  • David Kelly, M.D.,
  • Xiaoyan Lu, M.S.,
  • Stephanie Ayers-Millsap, M.P.H.,
  • Wesley G. Willeford, M.D.,
  • Negar Rassaei, M.D.,
  • Julu Bhatnagar, Ph.D.,
  • Hannah Bullock, Ph.D.,
  • Sarah Reagan-Steiner, M.D.,
  • Ali Martin, B.S.,
  • Michael E. Rogers, D.O., M.P.H.,
  • Anna M. Banc-Husu, M.D.,
  • Sanjiv Harpavat, M.D., Ph.D.,
  • Daniel H. Leung, M.D.,
  • Elizabeth A. Moulton, M.D., Ph.D.,
  • Daryl M. Lamson, B.S.,
  • Kirsten St. George, Ph.D.,
  • Aron J. Hall, D.V.M.,
  • Umesh Parashar, M.D.,
  • Adam MacNeil, Ph.D.,
  • Jacqueline E. Tate, Ph.D.,
  • and Hannah L. Kirking, M.D.

Abstract

Background

Human adenoviruses typically cause self-limited respiratory, gastrointestinal, and conjunctival infections in healthy children. In late 2021 and early 2022, several previously healthy children were identified with acute hepatitis and human adenovirus viremia.

Methods

We used International Classification of Diseases, 10th Revision, codes to identify all children (<18 years of age) with hepatitis who were admitted to Children’s of Alabama hospital between October 1, 2021, and February 28, 2022; those with acute hepatitis who also tested positive for human adenovirus by whole-blood quantitative polymerase chain reaction (PCR) were included in our case series. Demographic, clinical, laboratory, and treatment data were obtained from medical records. Residual blood specimens were sent for diagnostic confirmation and human adenovirus typing.

Results

A total of 15 children were identified with acute hepatitis — 6 (40%) who had hepatitis with an identified cause and 9 (60%) who had hepatitis without a known cause. Eight (89%) of the patients with hepatitis of unknown cause tested positive for human adenovirus. These 8 patients plus 1 additional patient referred to this facility for follow-up were included in this case series (median age, 2 years 11 months; age range, 1 year 1 month to 6 years 5 months). Liver biopsies indicated mild-to-moderate active hepatitis in 6 children, some with and some without cholestasis, but did not show evidence of human adenovirus on immunohistochemical examination or electron microscopy. PCR testing of liver tissue for human adenovirus was positive in 3 children (50%). Sequencing of specimens from 5 children showed three distinct human adenovirus type 41 hexon variants. Two children underwent liver transplantation; all the others recovered with supportive care.

Conclusions

Human adenovirus viremia was present in the majority of children with acute hepatitis of unknown cause admitted to Children’s of Alabama from October 1, 2021, to February 28, 2022, but whether human adenovirus was causative remains unclear. Sequencing results suggest that if human adenovirus was causative, this was not an outbreak driven by a single strain. (Funded in part by the Centers for Disease Control and Prevention.)

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Funding and Disclosures

Supported in part by the CDC (cooperative agreement 5NU600E000104) through the Association of Public Health Laboratories.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC), the Department of Health and Human Services, the Association of Public Health Laboratories, the Jefferson County Department of Health, the Alabama Department of Public Health, Children’s of Alabama, the University of Alabama at Birmingham, Cincinnati Children’s Hospital Medical Center, the University of Cincinnati, Texas Children’s Hospital, Baylor College of Medicine, the Wadsworth Center, and the University of Albany.

This article was published on July 13, 2022, at NEJM.org.

We thank the patients and their parents for providing informed consent for the publication of the case details; Paige A. Armstrong, Neil Gupta, Senad Handanagic, Megan Hofmeister, and Philip Spradling (CDC) for their guidance in interpreting and contextualizing pediatric hepatitis data; Luciana Flannery (CDC) for performing adenovirus immunohistochemical testing; Jana M. Ritter (CDC) for assistance with preparing histology images; James J. Dunn (Texas Children’s Hospital) for running previously negative adenovirus plasma samples using whole blood; the Wadsworth Center Advanced Genomics Technology Core for performing the sequencing reactions; and Simon Ogbamikael for performing the hexon gene-sequencing assays.

Author Affiliations

From the Division of Pediatric Gastroenterology, Hepatology, and Nutrition (L.H.G.S., H.S., S.S.) and the Division of Pediatric Infectious Diseases, (M.B., W.B., V.S., J.L.P.), Department of Pediatrics, and the Department of Pathology (D.K.), University of Alabama at Birmingham, Children’s of Alabama (L.H.G.S., H.S., S.S., M.B., D.K.), and Jefferson County Department of Health (S.A.-M., W.G.W.), Birmingham, and the Alabama Department of Public Health, Montgomery (L.A.I., A. Martin) — all in Alabama; the Division of Viral Diseases (J.M.B., X.L., A.J.H., U.P., A. MacNeil, J.E.T., H.L.K.), the Epidemic Intelligence Service (J.M.B.), and the Division of High-Consequence Pathogens and Pathology (N.R., J.B., H.B., S.R.-S.), Centers for Disease Control and Prevention, Atlanta, and Synergy America, Duluth (H.B.) — both in Georgia; the Department of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center (M.E.R.), and the Department of Pediatrics, University of Cincinnati College of Medicine (M.E.R.) — both in Cincinnati; the Division of Pediatric Gastroenterology, Hepatology and Nutrition (A.M.B.-H., S.H., D.H.L.) and the Division of Pediatric Infectious Diseases (E.A.M.), Texas Children’s Hospital, and the Department of Pediatrics, Baylor College of Medicine (A.M.B.H., S.H., D.H.L., E.A.M.) — both in Houston; and the Wadsworth Center, New York State Department of Health (D.M.L., K.S.G.), and the Department of Biomedical Sciences, University at Albany (K.S.G.) — both in Albany.

Dr. Gutierrez Sanchez can be contacted at or at the Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Alabama at Birmingham, 5604 McWane Bldg., Dearth Tower, 1600 7th Ave. South, Birmingham, AL 35233-1711.