By Dean L. Winslow, MD, MACP, FIDSA, FPIDS
Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine
SYNOPSIS: With next-generation sequencing and real-time polymerase chain reaction, researchers detected adeno-associated virus 2 in the plasma of 9/9 patients and in the liver of 4/4 patients but not in healthy controls, children with adenovirus infection and normal liver function, or children admitted to the hospital with hepatitis of another etiology.
SOURCE: Ho A, Orton R, Tayler R, et al. Adeno-associated virus 2 infection in children with non-A-E hepatitis. medRxiv. https://www.medrxiv.org/content/10.1101/2022.07.19.22277425v1.full-text
An outbreak of acute hepatitis of unknown etiology in children was first reported in Scotland in April 2022.1 Since then, other cases have been identified in 35 countries.2 In this paper, the researchers reported a detailed investigation of nine cases and 58 control subjects. With next-generation sequencing and real-time polymerase chain reaction (PCR), the researchers detected adeno-associated virus 2 (AAV2) in the plasma of all nine children and from the liver tissue of four patients from whom biopsies were obtained, but in none of the sera/plasma of 13 age-matched healthy controls, none of 13 children with adenovirus (HAdV) infection and normal liver function, and none of 33 children admitted to the hospital with hepatitis of another known etiology. HAdV (species C and F) and human herpesvirus 6B (HHV-6B) were detected in 6/9 and 3/9 affected cases. The class II HLA-DRB1*04:01 allele was identified in 8/9 cases (89%), compared with a background frequency of 15.6% in Scottish blood donors, suggesting a genetic component of susceptibility to hepatitis related to AAV2 infection.
COMMENTARY
Just as many of us in the infectious diseases field were hoping for a breather after two years of battling COVID-19, reports emerged early this year of children in many countries developing unexplained hepatitis.2 Although this is a preliminary report that looks at only a few cases of unexplained hepatitis in children, I found it fascinating from the perspective of a former virologist. Some of the initial case reports focused on the identification of adenovirus in some (but not all) blood and liver samples from these children. The identification of AAV2 in all nine of the blood samples and in all four of the liver samples examined makes a compelling case that this is the etiologic pathogen in a majority of the cases seen.
Adeno-associated viruses (AAV) are small viruses that infect humans and some other non-human primates. They are members of the genus Dependoparvovirus, which belongs to the family Parvoviridae. AAV are small (20 nm) replication-defective, non-enveloped viruses and have a linear single-stranded deoxyribonucleic acid (ssDNA) genome of approximately 4.8 (kb).
These AAVs require coinfection of a cell with a helper virus, typically adenovirus or a herpesvirus (such as HHV-6). In the presence of a helper virus, AAV can use the host cell’s polymerase to complete a lytic cycle. In the absence of a helper virus, AAV enters a lysogenic cycle.
AAV2 is known to be tropic for hepatocytes as well as some other tissues, including skeletal muscle, neurons, and vascular smooth muscle. The strong association between AAV and two common helper viruses (adenovirus and HHV-6) in these cases makes a compelling story.
REFERENCES
- Marsh K, Tayler R, Pollock L, et al. Investigation into cases of hepatitis of unknown aetiology among young children, Scotland, 1 January 2022 to 12 April 2022. Euro Surveill 2022;27:2200318.
- World Health Organization. Severe acute hepatitis of unknown aetiology in children - Multi-country. July 12, 2022. https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON400
