A sudden surge in cases of hepatitis among young children around the world was triggered by viruses that cause the common cold, according to new research.
The mysterious outbreak began appearing in otherwise healthy under-16s after COVID-19 lockdowns eased last spring.
There have been more than 1,000 infections to date - with 50 patients needing liver transplants. At least 22 have died.
Now scientists have linked the spate to adenoviruses (AAVs) which cause colds and flu.
A small subset became vulnerable because they had not built up sufficient immunity due to school closures.
Senior author Professor Charles Chiu, of the University of California, San Francisco, said: "Once they returned, children were more susceptible to infections with these common pathogens."
The phenomenon alarmed doctors. Hepatitis in children is rare. The study identified a particular strain known as AAV2 (adeno-associated virus type 2).
AAVs need 'helper' viruses, such as adenoviruses, to replicate in the liver. Getting more than one infection at the same time may have made a small subset vulnerable to severe hepatitis.
Prof Chiu said: "We were surprised by the fact the infections we detected in these children were caused not by an unusual, emerging virus, but by common childhood viral pathogens.
"That is what led us to speculate the timing of the outbreak was probably related to the really unusual situations we were going through with COVID-19 related school and daycare closures and social restrictions.
"It may have been an unintended consequence of what we have experienced during the last two to three years of the pandemic."
By August clusters of affected children, many under the age of five, were reported in 35 countries including the US, where 358 cases were under investigation.
Prof Chiu and colleagues combined PCR testing with gene sequencing to analyze plasma, whole blood, nasal swab and stool samples from 16 pediatric patients across six states - Alabama, California, Florida, Illinois, North Carolina and South Dakota.
The specimens collected between October 1, 2021, and May 22, 2022, were compared with those from 113 controls.
AAV2 was detected in 93 percent of cases and human adenoviruses (HAdVs) in all of them. A specific type of adenovirus linked to gastroenteritis (HAdV-41) was found in eleven cases.
Additional co-infections with Epstein-Barr, herpes and enterovirus were found in 86 percent of cases.
The results back two studies in the UK, which identified the same AAV2 strain. All three studies identified co-infections from multiple viruses. Three in four of the children in the US study had three or four viral infections.
Since AAVs are not considered pathogenic on their own, a direct causal link with severe acute hepatitis has yet to be established.
Children may be especially vulnerable to more severe hepatitis triggered by co-infections.
While infections from adeno-associated viruses can occur at any age, the peak is typically between one and five years old. The average age of the affected children in the study was three years old.
Hepatitis causes inflammation of the liver. In rare cases, it can be life-threatening. The clusters of acute severe hepatitis in children have recently waned.
Some children in the UK have needed liver transplants. No children have died from the illness in the UK.
Writing in the journal Nature, Prof Chiu said the best way to protect children is by washing hands frequently and staying home when sick.
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