Is an HAdV an Underrecognized Cause of Hepatitis?

Child in a hospital bed. Is it due to human adenovirus? (Adobe Stock)

A common cause of respiratory and gastrointestinal infections in humans, human adenovirus (HAdV), it is an uncommon cause of end-organ disease in children. It surprised clinicians when, from October 2021 to February 2022, in a single center for significant hepatitis, several previously healthy children were admitted and, ultimately, tested positive for human adenovirus (HAdV).

HAdVs are nonenveloped viruses containing double-stranded deoxyribonucleic acid. While it can be serious and even fatal in immunocompromised individuals, HAdV disease is typically mild. Of note, HAdVs establish persistent infections due to reactivation that can contribute to risk in the immunocompromised, said a study published in Science Direct.

In another study presented in a poster at the IDWeek Conference in Washington, DC, on October 19-23, 2022, Markus A. Buchfellner, MD, the presenting author, pediatric infectious diseases fellow at Division of Pediatric Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, and his coauthors note that the intention of the investigation was to describe these children’s characteristics.

In the study, “Case Series of Children with Hepatitis and Adenovirus Infection, Alabama, October 2021—February 2022,” the investigators propose that HAdV is a potentially underrecognized cause of hepatitis, and that other clinicians may prefer whole blood specimens over plasma for HAdV RT-PCR testing. In all the child patients, HAdV type 41 was identified typing results available. Buchfellner and his team added that determining HAdV patterns of circulation and informing future diagnostic testing by improved type-based surveillance may help.

The investigators only included children admitted to Children’s of Alabama (COA) with hepatitis who tested positive for HAdV by whole blood RT-PCR from October 2021 to February 2022. From medical records, the team collected demographic, clinical, laboratory, and treatment data. The children’s residual blood specimens were sent by Buchfellner and his team for adenovirus typing.

A total of 9 pediatric patients with hepatitis and HAdV infection were identified, of whom 78% were female with a median age of 3.0 years. The interquartile range (IQR) was 1.7-3.0 years. Before the children were admitted, 6 reported diarrhea, and 3 had respiratory symptoms.

The investigators noted on the poster: “At presentation, 8 had scleral icterus, 6 had jaundice, 7 had hepatomegaly, and 1 was encephalopathic. All patients had elevated transaminases (AST range: 447-4000 U/L, ALT range: 784-4695 U/L); initial total bilirubin varied [range 0.23-13.5 mg/dL]). All had confirmed HAdV by RT-PCR on whole blood (initial qPCR range: 991-70,680 copies/mL).”

Markedly, 2 children who had been transferred to another facility and whose plasma had been tested instead of whole blood were negative for HAdV by RT-PCR.

Of the children tested, 6 children ultimately underwent liver biopsy showing varying degrees of hepatitis with no adenovirus detected on immunohistochemistry stains. HAdV type 41 was confirmed in 5 patients. Of the tested children, three patients presented or progressed to acute liver failure; 2 children were treated with cidofovir, and, eventually, 2 underwent successful liver transplantation.

Of mention, no known epidemiologic links between patients were identified, and all the children were from geographically distinct parts of Alabama.

The total number of children whose blood was tested was not noted in the description of the poster.

Co-Authors of this study are the following: L. Amanda Ingram, MPH, Alabama Department of Public Health, Montgomery, Alabama; Henry Shiau, MD, Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Alabama at Birmingham, Children's of Alabama, Birmingham, Alabama; Luz Helena Gutierrez Sanchez, MD, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Alabama at Birmingham, Children's of Alabama, Birmingham, Alabama; Stephanie Saaybi, MD, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Alabama at Birmingham, Birmingham, Alabama; William Britt, MD, Division of Pediatric Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama; Veronica Sanchez, PhD, Division of Pediatric Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama; Jennifer L. Potter, MPH, Division of Pediatric Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama; David Kelly, MD, Division of Pathology, University of Alabama at Birmingham, Children's of Alabama
Birmingham, Alabama; Xiaoyan Lu, MS, epidemiologist, Centers for Disease Control and Prevention, Atlanta, Georgia; Stephanie Ayers-Millsap, MPH, Jefferson County Department of Health, Birmingham, Alabama; Wesley G. Willeford, MD, Jefferson County Department of Health, Birmingham, Alabama; Negar Rassaei, MD, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, CDC, Atlanta, Georgia; Hannah Bullock, PhD, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, CDC, Atlanta, Georgia; Sarah Reagen-Steiner, MD, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, CDC, Atlanta, Georgia; Ali Martin, Alabama Department of Public Health, Montgomery, Alabama; Daryl M. Lamson, Wadsworth Center, New York State Department of Health, Albany, New York; Umesh D. Parashar, MD, MBBS, medical officer, Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, CDC, Atlanta, Georgia; Aron J. Hall, DVM,Respiratory Viruses branch chief (acting), Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, CDC, Atlanta, Georgia; Adam MacNeil, PhD, epidemiologist, Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, CDC, Atlanta, Georgia; Jacqueline E. Tate, PhD, lead, epidemiology team, Viral Gastroenteritis branch, Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, CDC, Atlanta, Georgia; Hannah L. Kirking, MD, Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, CDC, Atlanta, Georgia.