Mysterious 2022 childhood hepatitis outbreak linked to common childhood respiratory virus, studies find

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An outbreak of severe, unexplained acute hepatitis in previously healthy children in 2022 may be linked to adeno-associated virus 2, or AAV2, according to three independent studies published Thursday in the journal Nature.

Between April and July 2022, more than 1,000 children worldwide — including at least 350 in the United States — were diagnosed with hepatitis, a disease involving inflammation of the liver, with no known cause. Nearly 50 liver transplants needed and 22 children deceased, according to the World Health Organization.

New research suggests that AAV2 may be involved in the disease. This common childhood virus can reproduce only in the presence of another “helper” virus, such as adenovirus or herpesvirus. AAV2 was present in nearly all children with unexplained acute hepatitis, and many were infected with multiple helper viruses, the researchers found.

Although researchers cannot say for sure, the timing of the outbreak may have been associated with the global easing of Covid-19 pandemic restrictions after periods of relative isolation.

“Children were suddenly exposed to a barrage of viruses after the lockdowns or had malformed immune systems that led to increased susceptibility to otherwise harmless viruses,” wrote Dr. Frank Tacke, a German gastroenterologist who doesn’t did not participate in the research. editorial published alongside new studies.

One of the new studies, which analyzed tissue samples from children in the United States, detected AAV2 in 93% of 14 cases but only 4% of 113 controls. The researchers found that all children infected with AAV2 were co-infected with a ‘helper’ virus – either human herpesvirus 6 or Epstein-Barr virus – which could promote AAV2 replication.

“Our results suggest that co-infection with AAV2 may cause more severe liver disease than infection with adenovirus or herpesvirus alone,” the authors wrote.

A second study, which took place in the UK, reported high levels of AAV2 in 96% of 28 affected children and only low levels in a control group. Low levels of human adenovirus and human herpesvirus 6 were found in the liver in most cases, which the authors believe also enabled AAV2 replication and liver damage.

A third study suggests that an abnormal immune response may promote AAV2 liver damage. Researchers in the UK found high levels of AAV2 in blood and liver samples from 81% of 32 affected children and detected only low levels of AAV2 in 7% of 74 unaffected children. Of the affected group, 93% carried a genetic mutation that predisposes a person to autoimmune diseases involving T cells, a type of immune cell.

Scientists previously believed that human adenovirus, which usually causes a mild cold or flu-like illness, may have been responsible for the outbreak. However, the adenovirus usually only affects people with very weak immune systems, and various strains indicated that a single virus strain could not explain the outbreak, casting doubt on this hypothesis.

The new findings are “likely to generate debate and could influence disease management,” Tacke said.

Finding out the mechanism will be important for treatment. If AAV2 is responsible, antivirals would be appropriate. If this is due to an unusual immune response, drugs that suppress the immune system may be needed.

Although the consistent results across two continents provide strong evidence, several uncertainties remain, including whether AAV2 directly causes liver damage or is “just a bystander.”

For example, because they cannot replicate on their own, adeno-associated viruses are commonly used as vehicles for gene therapy. Although liver damage has been observed in trials involving AAV-based approaches, it is rare and usually non-fatal, scientists say.

“If AAV2 directly caused hepatitis, we would expect more cases to be reported,” Tacke said.

More studies are needed to understand how AAV2 infection alone, or with another virus, might affect liver cells, he recommended.

“Until then, surveillance for AAV2 (and related viruses) in such cases should be advised,” he said.