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

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.).

Figure 1.. Acute Hepatitis Cases Identified by Retrospective Review.

Patients younger than 18 years of age with the following International Classification of Diseases, 10th Revision, codes at admission were included in the case series: hepatitis (K75.9), transaminitis (R74.01), elevated liver enzymes (R74.8), liver failure (K72.9), and acute liver failure (K72.00). Identified causes of hepatitis included cholangitis associated with complications of biliary atresia (1 patient), autoimmune hepatitis (2 patients), liver shock after a code event (1 patient), acetaminophen overdose (1 patient), and complicated urinary tract infection (1 patient). A total of 9 patients with acute hepatitis and human adenovirus viremia were included in this case series.

Figure 2.. Phylogenetic Analysis.

Results of the analysis of human adenovirus 41 hexon hypervariable regions 1 through 6 in specimens obtained from five patients in this study and representative sequences available in GenBank are shown. Sequences obtained in this study are marked with solid circles; red circles indicate specimens obtained from two patients with acute liver failure who underwent liver transplantation, and blue circles indicate specimens obtained from three patients with acute hepatitis who did not have acute liver failure. The tree was constructed by the maximum-likelihood method with a Kimura two-parameter model of nucleotide substitution and five rate categories of gamma distribution, and bootstrap resampling values (1000 replicates) of at least 70% are indicated above the respective nodes. The scale bar indicates genetic distance in nucleotide substitutions per site.