Health authorities around the world are continuing to investigate an outbreak of severe and unexplained hepatitis in children, with about 450 cases now reported worldwide.
Hepatitis is an inflammation of the liver, often caused by a viral infection and generally rare in healthy children.
The spate of unusual cases first came to global attention in April when UK health authorities reported higher than average rates of liver inflammation in children where the typical causes — hepatitis viruses A, B, C, D and E — were not detected.
Such cases, though not unheard of, are generally rare, says Melbourne gastroenterologist Winita Hardikar.
"We would probably see five or six cases of severe, non A-E hepatitis in children each year, and one or two would need a transplant," said Professor Hardikar, head of the liver and intestinal transplantation unit at the Royal Children's Hospital in Melbourne.
While most children recover from hepatitis, the severity of recent cases — most of which have occurred in children under the age of 5 — has concerned experts.
Most children have reported gastrointestinal symptoms including abdominal pain, diarrhoea and vomiting, before developing jaundice, a condition in which the skin and whites of the eyes turn yellow.
In roughly 10 per cent of cases, children have required liver transplants, and according to the European Centre for Disease Prevention and Control, 11 children have died.
Cases have been identified in more than 20 countries, including in the United States, Israel, Indonesia and Japan.
"We haven't seen it yet [in Australia] … but obviously we've been alerted and we'll be on the lookout for it," Professor Hardikar said.
What could be behind the unusual hepatitis?
After health authorities failed to find any evidence of the hepatitis viruses that most commonly cause liver inflammation, they began to look for common environmental exposures and toxins that might explain the outbreak.
So far, none have been identified, but it's early days and "everything is still on the table", virologist Ian Mackay says.
"At the moment, the leading hypothesis is that it's something likely to be infectious," said Dr Mackay from the University of Queensland.
"The hardest thing is that there is no link epidemiologically to these cases — nothing to suggest they're being infected in the same household or same school.
But health authorities in the UK have identified a number of clues and begun to narrow their focus.
"The leading hypotheses remain those which involve adenovirus," they wrote in their most recent technical briefing.
"However, we continue to investigate the potential role of SARS-CoV-2 and to work on ruling out any toxicological component."
What is adenovirus and why does it matter?
Adenovirus refers to a large family of common viruses that typically cause mild cold- and flu-like illnesses, as well as gastroenteritis and conjunctivitis.
It's currently at the top of the suspect list because, in the UK at least, 72 per cent of children affected by the outbreak have also tested positive for an adenovirus.
UK researchers have hypothesised that some children may have become more susceptible to adenovirus infections during the COVID-19 pandemic because public health measures and lockdowns have limited their exposure to viruses.
They've also speculated that an "exceptionally large wave of normal adenovirus infections" may have unearthed a "very rare or under-recognised complication".
But several experts, including Dr Mackay, have pointed out that adenovirus could just be a red herring.
"Most fingers are pointing to adenovirus simply because there have been a lot of adenovirus-positive samples … but it might be a bit misleading because adenovirus is quite a common virus," Dr Mackay said.
"It's worth remembering that a lot of these viruses have circulated even during lockdown."
Adenovirus also doesn't "fully explain the severity of the clinical picture", according to the World Health Organization (WHO).
Further analysis of adenovirus-positive cases found they were consistent with adenovirus subtype 41, which is associated with symptoms such as diarrhoea, vomiting, and abdominal pain — not severe liver disease.
Although adenoviruses have been known to cause rare cases of hepatitis in immunocompromised patients, they are not usually associated with liver problems in healthy children, Professor Hardikar said.
"Adenovirus is really not identified as a major cause of acute liver failure, so it's hard to make a link," she said.
"Unless it's a super potent virus, it's more likely that there is some other co-factor like an aberrant immune response or some other susceptibility."
Researchers look at other factors including COVID-19
Another working theory, as Professor Hardikar notes, is that a "cofactor" — such as a prior or existing infection with another virus like SARS-CoV-2 — may have primed some children to have a more severe reaction or abnormal immune response to adenovirus infection.
According to UK health authorities, studies of the immune system are underway "to determine if changes in susceptibility or the effect of prior or concurrent infections" could be contributing factors.
"That might be a cofactor that relates to the child … a genetic predisposition, so that when they meet adenovirus 41, they're more likely to develop severe illness," said infectious disease physician and hepatitis researcher Andrew Lloyd of the Kirby Institute.
"It might be a cofactor in the form of another virus that is co-occurring, or it might be some other environmental factor … that sets up the risk for disease."
To date, only a small subset of children with hepatitis have tested positive for COVID-19, but more testing is underway to find out what proportion have antibodies to SARS-CoV-2 and have been infected in the past.
Health authorities are also investigating the possibility of "a post-infectious SARS-CoV-2 syndrome".
Professor Lloyd said he wasn't convinced the hepatitis cases were solely a complication of COVID-19, but post-viral phenomena — including abnormal immune responses — should be considered more broadly.
Another possibility is that the outbreak is being driven by an entirely new virus, or a mutated version of adenovirus that hasn't been seen before.
But Dr Mackay said low viral loads in the collected samples meant investigators hadn't yet managed to sequence a whole virus.
"So far, and it may just be because those analyses haven't been completed, nothing points to there being a brand new type of adenovirus," he said.
"But if we can't get those sequences, we can't be sure."
What is clear is that there is no evidence of a link between hepatitis cases and COVID-19 vaccines.
"The majority of cases are under 5 years old, and are too young to have received the vaccine," investigators said.
Will the outbreak reach Australia?
Given the global nature of the outbreak, Dr Mackay said he expected Australia to see cases at some point.
But Professor Hardikar stressed that cases remain rare — even in countries like the UK — and that liver specialists had experience treating atypical hepatitis in children.
"We know about it, we haven't seen this yet, but it's reassuring that since last year, we haven't transplanted any child for this," she said.
It's important for parents to be aware of the signs of hepatitis — particularly jaundice, dark urine, and light-coloured stools, as well as "ongoing nausea and vomiting", Professor Lloyd said.
He added that it was also a good idea to keep up good hand and respiratory hygiene to reduce the spread of infections.
"Particularly in families where there are young kids, or venues where there are young kids, that means good hand washing and disinfecting surfaces in the bathroom and food-preparation areas in the kitchen."
