Many viruses behind 2022 outbreak of hepatitis in children: Study

Isolation during lockdown may have weakened children's immune systems

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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An illustration shows a close-up view of the hepatitis virus.

A global outbreak of severe hepatitis in children just after COVID-19 restrictions were lifted could have been caused by infections with multiple viruses at once, according to a new study reviewing published reports from the period.

Scientists found evidence that co-infection with adeno-associated virus 2 (AAV2) and other common childhood viruses might have predisposed children to developing hepatitis, particularly when isolation due to the COVID-19 pandemic left their immune systems untrained to fight off these invaders.

But, they said, inconsistencies in monitoring and reporting during the outbreak leave many open questions about its cause.

“The lesson from all past and present disease outbreaks is the need to be continually vigilant,” Guy Eslick, PhD, director of research in the Australian Paediatric Surveillance Unit at the University of Sydney and a study author, said in a university press release. “This is something we need to continue investigating.”

The study, “Demystifying the global outbreak of severe acute hepatitis of unknown etiology in children: A systematic review and meta-analysis,” was published in the Journal of Infection.

Hepatitis is a general term referring to liver inflammation. There are multiple types, each with a different underlying cause. The most common forms are due to infection with the hepatitis viruses, but autoimmune disease or liver-damaging toxins also may be responsible.

Sudden outbreak of hepatitis in children ‘baffling’ to scientists

Reports of hepatitis have occurred in which the cause of the outbreak cannot be identified. That was the case in the 2021-2022 global outbreak, which affected children younger than 10.

Cases emerged first in Alabama in the U.S., and in Scotland, with more than 1,000 pediatric cases across 35 countries reported to the World Health Organization (WHO) from October 2021 to July 2022. The clinical manifestations of the outbreak were severe, with higher rates of liver failure than those previously reported for acute hepatitis in children.

“When the outbreak unfolded, the increase of cases was baffling,” Eslick said.

It was a medical mystery we wanted to investigate.

It wasn’t clear what caused the severe outbreak, how it spread between countries, and why cases stopped as quickly as they appeared.

“It was a medical mystery we wanted to investigate,” Eslick added, adding that understanding the outbreak would be “crucial for the identification and prevention of future outbreaks.”

The team systematically reviewed all published studies that reported on pediatric cases of hepatitis of unknown cause from 2019-2023. Some 33 studies — covering more than 3,000 children from January 2019 to December 2022 — were included in the final analysis.

More cases than reported during outbreak

The number of cases was more than threefold higher than what was reported to the WHO during the outbreak, although “there is a possible overlap between patients and health centers reported in different studies,” the researchers wrote.

The children’s median age was 3.5 — they ranged in age from newborn to 16 years — and just more than half (51%) were girls. The presentation of acute hepatitis in these children was “unorthodox,” the team wrote, with higher than expected rates of gastrointestinal symptoms, and a generally more severe nature.

About a third of children experienced acute liver failure, about 6% received a liver transplant, and nearly 2% died.

Across the studies, many of the children with unexplained hepatitis were found to be infected with viruses other than those typically causing hepatitis.

“Adenovirus was the most frequently detected [microbe] in multi-center studies, with a positivity rate of 40%, whilst AAV2 was most common among single-center studies, being detected in 83% of cases,” the researchers wrote.

AAV2 is a common virus that generally does not cause disease in humans. To multiply in the body, AAV2 needs the aid of a so-called helper virus to stimulate the infection. Helper viruses can include other common childhood viruses, such as those causing the common cold or other respiratory and gastrointestinal infections.

Several of these helper viruses were detected in many of the children. SARS-CoV-2, the virus that causes COVID-19 disease, was less commonly detected, but when present, was associated with more severe outcomes.

Altogether, the findings indicate that the presence of multiple types of viruses at once could have induced liver inflammation in these children.

Lockdowns may have weakened children’s immune systems

The scientists believe that the backdrop of the COVID-19 pandemic had an important role.

As pandemic restrictions were lifted, children who had been isolated were exposed to a variety of common microbes. The children’s immune systems might not have been properly trained to fight them off due to a lack of exposure during lockdowns. A dysregulated immune response could then have driven liver inflammation.

There are other potential causes — like foodborne or environmental toxins — that can’t be ruled out. And many questions remain as to how the outbreak started and spread in certain countries, and whether “there could be a genetic link that made some children more vulnerable in developing severe hepatitis than others,” the researchers wrote.

Inconsistent reporting and surveillance across different countries contributes to the confusion, Eslick said. A standardized system would be useful in future outbreaks, he said.

“Global disease surveillance provides an invaluable network for researchers and medical professionals to monitor and share information on emerging disease outbreaks, so we can be better prepared,” Eslick said.