Children developing liver inflammation (hepatitis) without a known cause is not entirely unusual, but the number and severity of cases reported to the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) have prompted a worldwide investigation.
According to WHO surveillance, most pediatric hepatitis cases with unknown origin are younger than 5 years of age, 30% have required intensive care unit admission, and 8% required a liver transplant. Of those tested for adenovirus, just over half have been positive and adenovirus 41 was the most frequently identified strain. Of those with SARS-CoV-2 test information available, 11% were positive on PCR and 64% had antibodies to previous infection.
US and UK researchers implicate adenovirus
In the U.S., the hepatitis outbreak investigation first started in October 2021 when five children in Alabama were hospitalized with severe hepatitis. When researchers opened a wider investigation in collaboration with the CDC, they found nine children with hepatitis without a known cause. Eight (89%) of these children were found to have an adenovirus infection but liver biopsies found no evidence of the virus. Seven of the nine patients were found to have other viral coinfections, including enterovirus/rhinovirus, metapneumovirus, respiratory syncytial virus and human coronavirus OC43. All of these are routinely circulating viruses tracked by the CDC. None had a history of SARS-CoV-2 infection, nor infection with hepatitis A-E. (Vaccination is available for hepatitis A and hepatitis B.) Three patients had liver failure, and two required a liver transplant; all are recovering. The US authors concluded that if adenovirus was responsible, it was “not an outbreak driven by a single strain.”
In a separate UK study of 44 children, adenovirus was also implicated in 90% of the 30 children tested. The median age of these children seen at a liver transplantation center was 4 years. Six patients required a liver transplant, but all were discharged home. The UK researchers explored multiple causal pathways, such as toxic exposures, increased susceptibility among young children due to lower levels of circulating virus, the possibility of a post-SARS-CoV-2 complication, or a new adenovirus. Although adenovirus has been detected in the majority of cases and one serotype (adenovirus 41) has figured prominently, the virus is not typically associated with such severe disease in otherwise healthy children.
Two UK teams identify a triad of suspects
Meanwhile, two groups of scientists in Glasgow and London have just published research supporting remarkably similar hypotheses: coinfection with two common viruses coupled with a genetic susceptibility to hepatitis. Scientists at the University of Glasgow Centre for Virus Research analyzed nine early cases and 58 controls in three groups: healthy children, those with adenovirus but normal liver function, and the opposite (abnormal liver function but no adenovirus). These three groups were compared to the cases with hepatitis of unknown cause, none of whom were immunocompromised or had been vaccinated against COVID-19. Patients were hospitalized for a median of 10 days; two patients were transferred to a special liver unit and subsequently improved. No deaths resulted.
Advanced sequencing helped narrow down a culprit—adeno-associated virus 2 (AAV2) was found in all nine patients but not in the controls. This AAV2 virus requires another co-infecting virus to replicate, usually adenovirus or human herpesvirus, both of which were found in cases. Further complicating the picture, eight of the nine children (89%) had a genetic susceptibility to non-A-E hepatitis much higher than the background rate (15.6%).
In another study at the Great Ormond Street Hospital in London, using a similar approach examining cases and controls, AAV2 was found in all five livers in cases needing a transplant, and in the blood or throat swab of all the cases not requiring a transplant. Consistent with the Glasgow team’s findings, adenovirus and human herpesvirus were also detected in the liver samples.
Perhaps the strongest piece of evidence gathered by the London team is the presence of AAV2 in 94% of cases, of whom 91% had high viral loads, compared to 6% of immunocompetent controls and 31% of immunosuppressed controls. The authors suggest that the young children in the age cohort at peak risk (without antibodies) had their first exposures to adenovirus and AAV2 at the same time. Given the lack of evidence for the viruses causing direct damage on the liver, the consensus at the moment is that coinfection combined with a genetic susceptibility is the most likely scenario.
Collateral effects of the pandemic response
There is little evidence that SARS-CoV-2 has any direct role in the hepatitis outbreak, despite the fact that Omicron preceded the increase in hepatitis cases. However, the pandemic may have had an indirect effect on the hepatitis outbreak. Changes in how children interact and mix due to pandemic-related controls may have influenced the circulation of common childhood viruses. Adenovirus is a common childhood infection, and usually rather benign—aside from upper respiratory complaints or stomach illness. Antibodies are high at birth and shortly after due to maternal transfer, then decline in late infancy, only to rise again with normal childhood exposures. As society engages in more social activities, unusually frequent coinfections may collide with genetic susceptibilities.
However, there remains the possibility that better surveillance picked up a small spike against a background of otherwise unexplained cases of hepatitis of unknown origin. Recall that CDC estimates “30-50% of hepatitis cases in children are from unknown causes.” A silver lining may be that this spike was the catalyst to finding some answers for these children and their families.