Covid-19 could be linked to a spate of cases involving severe liver inflammation in children reported in more than a dozen countries worldwide, scientists have said.
At least 348 children have been diagnosed with unexplained hepatitis, forcing some to undergo liver transplants. A small number have died.
The cases are predominantly in children under 5, who showed initial symptoms of gastroenteritis, including diarrhoea and nausea, followed by the onset of jaundice.
Many of the children were found to be infected with an adenovirus infection, which is believed to play a role in the development of the condition.
Adenoviruses are a group of common viruses that infect the lining of the eyes, airways and lungs, intestines, urinary tract, and nervous system.
Yet experts said it does not fully explain their symptoms, because adenovirus does not typically cause hepatitis in healthy children.
However, a new theory shared in The Lancet, the British medical journal, said a coronavirus infection could be at the root of the cause.
According to the hypothesis, a Covid-19 infection could linger in the gastroenterological tract of the children affected, where it could come into contact with the adenovirus, causing the immune system to overreact.
“Sars-CoV-2 viral persistence in the gastrointestinal tract can lead to the repeated release of viral proteins across the intestinal epithelium, giving rise to immune activation,” wrote the authors of the correspondence, which appeared in the Lancet Gastroenterology & Hepatology.
Everything you need to know about the hepatitis outbreak in young children
Investigations recently turned towards previous exposure and infections with Covid.
"Over the past week, there's been some important progress with the further investigations and some refinements of the working hypotheses," said Philippa Easterbrook, from the WHO's global hepatitis programme, last week.
"At present, the leading hypotheses remain those which involve adenovirus ― with also still an important consideration about the role of Covid as well, either as a co-infection or a past infection," Ms Easterbrook said.
Experts said the cause is still speculative and research is continuing.
Dr Bharat Pankhania, a senior consultant in communicable disease control and senior lecturer at the University of Exeter in the UK, said “it could well be” that two factors are causing the hepatitis cases in children.
“A sensitised immune system with Covid, and that immune system acts exuberantly and causes hepatitis,” he said. “At this moment we don’t know for sure.
“Could it be triggered by an infectious agent? Your immune system is perked up, and another infection comes along, and the two infections together make the situation a lot worse.
“We’re exploring that second hypothesis. It could be a complex cascade of immune responses causing it.”
Prof Ian Jones, a professor of virology at the University of Reading in the UK, said the hypothesis involving Covid-19 “seems plausible”. However, he added it was unclear why the children have suffered hepatitis specifically, rather than wider symptoms caused by over-activation of the immune system.
“I would have thought if you had hyperactivity, you would’ve had a range of symptoms,” he said.
“Why are you seeing the focus on the liver, why aren’t there general inflammatory [symptoms affecting] other organs like the skin or kidney or even the lungs?”
Prof Eskild Petersen, of Aarhus University Hospital in Denmark and chairperson of the European Society of Clinical Microbiology and Infectious Diseases, said suggested links between the adenovirus and the hepatitis cases were “highly speculative” because the adenovirus had not been detected in the affected children’s liver tissue.
“I don’t think the evidence of the adenovirus connection is very strong," he said. "It’s the same with legacy Covid. Nobody has demonstrated these children have virus in their liver cells."
Prof Petersen, who is editor of the International Journal of Infectious Diseases, said the cases could, however, have some link to Covid-19, with the virus causing an elevated reaction by the immune system in certain people.
“I still think maybe because of a certain genetic background, Covid could prime them for autoimmune hepatitis, but at present, it’s all based on guesses,” he said.
A British scientist investigating a mysterious global hepatitis outbreak that has infected hundreds of children globally told The National recently she believes researchers are getting closer to identifying its cause.
Judith Breuer, professor of virology and director of the pathogen genomics unit at University College London, said Omicron's role is a "big question", but added "we don't have the answer".
Although many of the children have tested positive for Covid, metagenomic tests have seemed to play down an adverse reaction to Omicron as the main cause, she said.
"We haven't found Omicron in our tests as a whole, but it has certainly has been found in some children," Prof Breuer said. "We haven't found it from our metagenomics, for example. So at the moment, it remains uncertain what role it might have in the genesis of this problem".
Children receive Covid vaccinations - in pictures
