Could Mysterious Hepatitis Cases be Triggered by COVID-19?
Children are routinely vaccinated against hepatitis.

More than 100 mysterious cases of hepatitis in children under the age of 10 around the world are raising a red flag among the medical community, with some doctors and scientists starting to hypothesise that the cases could be triggered by a new strain of adenovirus or even COVID-19.

“Severe hepatitis in children is very rare and we don’t yet know what’s causing this highly unusual rise in cases,” according to Conor Meehan, a senior lecturer in Microbiology at Nottingham Trent University. “The leading theory is that it’s some kind of viral infection, perhaps even SARS-CoV-2, the coronavirus that causes COVID-19.”

Hepatitis is inflammation of the liver. Adenovirus is a common virus that generally causes cold-like symptoms, such as fever, sore throat and diarrhoea. It is super-common in children, and nearly every child has at least one adenovirus infection before the age of 10.

Are adenoviruses to blame?

“Adenovirus can cause hepatitis,” Meehan said.

He told Health Policy Watch that several of the children diagnosed in his area have had adenovirus, though the number of hepatitis cases is unusually high. “There could be a new variant that is increasing the chance of developing hepatitis or it could be that these children have something else in common that makes them more susceptible to developing hepatitis from adenovirus. It is still early to peg the cause directly on this.”

In total, 91 children in the United States and Europe have now been reported to be confirmed or suspected ill with hepatitis of unknown aetiology since January, according to the World Health Organization (WHO) and American health reports. This includes nine children in Alabama, three in Spain and at least 74 in England, Scotland and Northern Ireland. There were also 12 cases reported in Israel, the country’s Health Ministry said, and a handful of others in the Republic of Ireland, according to WHO’s latest report.

At least six children in the UK have undergone transplants of liver lobes donated by their parents so far and another two children in Israel. No one has died.

WHO said Friday that Hepatitis viruses (A, B, C, E, and D where applicable) have been excluded after laboratory testing, bewildering medical personnel who are now investigating an alternate cause. The organisation said that given the increasing number of cases reported over the past month, and that it has now called on paediatricians and other doctors to keep an eye out for children experiencing hepatitis from an unknown cause, it expects that the number of cases will rise in the coming days.

In Israel, seven cases were managed at Schneider Children’s Medical Center in Petah Tikva and five at Shaare Zedek Medical Center in Jerusalem.

Prof Eyal Shteyer, director of the Paediatric Liver Unit at Shaare Zedek, told Health Policy Watch that the sick children came from across Israel and were not of the same ethnicity or religious affiliation. But what most of them did have in common is that they had been infected with SARS-CoV-2.

Almost all the kids had COVID-19

“Ninety-nine percent of the children had COVID,” said Shteyer, who treated the children who came to his hospital with steroids and the children recovered quickly, in most cases within days.

“I think COVID did trigger the immune system to injure the liver in some cases, but other viruses can do this as well,” he said. “Since we see so much COVID, I think that is what is happening here.”

Meehan confirmed that there have been suggestions that COVID could be behind these cases of hepatitis, as SARS-CoV-2 has been detected in some of the children.

“Isolated cases of hepatitis have been reported in COVID patients, but this is even rarer than autoimmune hepatitis, and has mostly been observed in adults with severe COVID,” Meehan cautioned in an article he wrote for The Conversation. “If this was the case, we would have expected to see hepatitis in immunocompromised adults as well, not just these children, and that is why it seems less likely.

“I would not rule it out, but I would not put most of my money there,” he said.

Instead, he said, another possibility is that this is a new symptom resulting from the interaction between the two viruses – adenovirus and COVID – which could both infect children at the same time. Or that the hepatitis is being caused by a totally different virus that hasn’t been detected yet.

Unusual scenarios

“As the COVID pandemic continues, we must routinely consider coronavirus as a possible cause for unusual healthcare scenarios. At the same time, we shouldn’t assume there’s always necessarily a link. Such thinking carries the risk of blinding us to what’s really going on,” Meehan wrote.

WHO said that both COVID-19 and/or adenovirus had been detected in several cases and added that the UK has recently observed an increase in adenovirus activity, which is co-circulating with COVID.

“The role of these viruses in the pathogenesis (mechanism by which disease develops) is not yet clear,” WHO said.

The Alabama Department of Public Health said its analyses have revealed a possible association of this hepatitis with Adenovirus 41.

“To date, nine children less than 10 years old have been identified as positive for adenovirus and two have required liver transplants,” it said in a statement.

“The affected children were from throughout the state of Alabama, and an epidemiological linkage among them has not been determined. None of these children has had any underlying health conditions of note.”

None of the children was known to have been vaccinated against COVID-19, ruling out any tie to the vaccine.

Liver inflammation under a microscope

Data-sharing is key to solving the mystery

Shteyer explained that hepatitis is a generic name for inflammation of the liver and does not indicate anything about the cause, which can range from viral, autoimmune to genetic. What has raised the flag here is not hepatitis but that there “has been a dramatic increase in the last four to six months in those children coming to the hospital with acute elevation of liver enzymes and we did not find a proper diagnosis”.

He said in 70% of cases before now doctors were able to find a cause.

Moreover, he added, that usually children who develop viral hepatitis see their liver enzymes elevated to around 300 U/L or 400 U/L, but in these cases, the levels were in the 1,000s.

“That signals to us that there is severe injury to the liver,” he said.

One of the challenges of this is tied to the fact that adenoviruses or coronaviruses only stay in children’s systems for a finite period of time, and in some cases, parents do not even know that their children have had the viruses.

“Think about a PCR test, after a few weeks this is going to be negative,” Meehan said. “If the infection was months ago and this is a delayed system, it is difficult to identify.”

He said that more sophisticated testing is usually conducted at hospitals could be required to develop the case definition. In Israel, hospitals have been asked to send blood samples from the infected cases to the Central Virology Lab at Sheba Medical Center for a more in-depth analysis.

Meehan said the next step will be to do novel virus testing, meaning to do more of a broad search for a cause using genome sequencing and looking for anything that looks like a virus or bacteria in these children’s blood samples.

“This could hint at a new variant of a virus that we normally would not think causes hepatitis and may have been inadvertently ruled out or even a new virus,” Meehan said.

And, of course, he said data sharing is key.

“As we see cases in Spain and the US it is about determining if and how they may be connected,” he told Health Policy Watch.

What should parents watch for?

The general symptoms of hepatitis are dark urine, grey-coloured faeces and yellowing of the skin and eyes, as well as fever.

“I think if your child looks even a little yellow, I would go fast to the hospital and do a blood test,” Meehan said.

Adenovirus and COVID-19 are not necessarily preventable, but the risks can be minimised by good hygiene, most importantly hand washing.

“As kids go back into the world, we should try to reduce their chances of infection in general and this will help reduce adenovirus infections too,” Meehan said.

Image Credits:, UNICEF South Africa/2013/Hearfield, PIXNIO.

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