The mystery of the surging child hepatitis cases

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In late March, doctors at Glasgow’s Royal Hospital for Children already had a sinking feeling that something was wrong. In just three weeks, five previously healthy young children had arrived with severe hepatitis. Usually, it’s rare to see so many cases in a year.

The infants, aged between three and five, were vomiting and lethargic. In a sure sign of liver damage their skin was jaundiced, the yellow tinge gradually spreading from their eyes.

The severity of disease, paediatricians later recalled in a rapid situation report, was “unfortunately remarkable”. Three of the children were transferred to specialist units in England, where doctors determined that one was in need of an urgent liver transplant.

The unusual cluster of cases set alarm bells ringing and, on March 31, the team notified Public Health Scotland. Soon, as concern and curiosity rippled across the “epidemiological grapevine”, it emerged that this phenomenon was not unique to Scotland.

The World Health Organization said on Saturday that at least one child death had been reported following an increase of acute hepatitis of unknown origin in children, and that at least 169 cases had been reported in children in 12 countries. The WHO issued the figures as health authorities around the world investigate a mysterious increase in severe cases of hepatitis – inflammation of the liver – in young children.

The WHO said that as of April 21 acute cases of hepatitis of unknown origin had been reported in the United Kingdom, the United States, Spain, Israel, Denmark, Ireland, the Netherlands, Italy, Norway, France, Romania and Belgium.

The cases reported were in children aged from one month to 16 years, and 17 had required liver transplantation, it said. It gave no details of the death that it said had been reported, and did not say where it occurred.

The WHO said a common cold virus known as an adenovirus had been detected in at least 74 cases. COVID-19 infection was identified in 20 of those tested and 19 cases were detected with a COVID-19 and adenovirus co-infection, it said.

The WHO said it was closely monitoring the situation and working with British health authorities, other member states and partners.

U.S. health officials have sent out a nationwide alert warning doctors to be on the lookout for symptoms of pediatric hepatitis, possibly linked with a cold virus, as part of a wider probe into unexplained cases of severe liver inflammation in young children.

In Alabama, paediatricians noticed five children under 10 with unusual hepatitis back in November – they’ve since reported another four, plus two in North Carolina. Cases across the UK now stand at 108, according to the UK Health Security Agency (UKHSA), including 79 in England and 14 in Scotland since January.

Meanwhile Israel has detected 12 cases and in Europe, nine countries have so far reported roughly 30 cases – including in Ireland, Spain and Denmark. Of these, four children have required transplants, and most have needed hospitalisation. The youngest was only one month old.

“I felt like I was watching my little girl die before my eyes,” Alan Raine, who’s three-year-old daughter Lola-Rose developed hepatitis six weeks ago, told The Telegraph yesterday. She is currently recovering from an urgent transplant at King’s College Hospital in London, after Mr Raine donated part of his liver to save her life two weeks ago.

“I don’t think we’ve processed it yet, it all happened so quickly. One day she was a bubbly child, then she was admitted to hospital and a week and a half later she was in a coma with acute liver failure,” he said. “I just cried when I found out I was a donor match – this was her chance at life.”

Now, investigators across the globe are rushing to explain the mystery behind these cases, hunting for potential infections and analysing the children’s immune systems, genetics, diets and recent movements. In the Eurosurveillance report describing Scotland’s early cases, published on April 14, no specific characteristics stand out – just over half were female, all were white and there was not a “discernible geographic pattern”.

Further reports from UKHSA labs are expected next week but, for now, firm answers elude scientists to two big questions: what is causing this spate of hepatitis, and how far might it spread?

WADING THROUGH THE ‘FOG OF WAR’

Hepatitis – a broad term used to describe liver inflammation – can be caused by a range of issues, including a virus, toxins, fungi or even damage caused by drinking alcohol. In up to 20 per cent of cases, no cause is identified.

But the scale of the current outbreak, combined with a complete absence of the “usual suspects”, is baffling scientists. None of the patients tested positive for hepatitis A, B, C, D or E, nor other likely culprits – such as cytomegalovirus (CMV), which causes cold sores and chickenpox, and Epstein-Barr virus, which causes glandular fever.

Prof Deirdre Kelly, an expert in paediatric hepatology at Birmingham Women’s & Children’s Hospital, helped set up Britain’s liver transplant network some three decades ago. In early April, while on holiday in France, she got a call from the UKHSA that set her mind running. She didn’t have to look far to realise there was an issue.

“We do normally see, every year, some children with severe hepatitis for which we don’t know the cause, with a peak in spring suggesting it’s linked to a virus,” she said. “But this year is a big jump. In 2018, we saw six such cases between January and April in Birmingham. This year we’ve had 40.”

Currently, experts suspect an adenovirus is the culprit. So far, 77 per cent of cases in the UK tested positive for an active adenovirus infection, plus five of the nine cases in Alabama.

These infections are incredibly common – especially among children – but they usually cause cold symptoms, sometimes pneumonia. Only in rare cases in immunocompromised patients have they been known to cause hepatitis.

“That gives rise to the possibility that this might be an unusual or mutated adenovirus,” said Prof Kelly. “Although so far, it doesn’t look abnormal.”

Another, related theory is that the virus’s impact has been amplified by a lack of exposure to common adenoviruses during lockdowns.

But it’s not a slam dunk. In Denmark, where four cases have been confirmed, no children have tested positive, said Prof Anders Koch, infectious disease specialist at Denmark’s Statens Serum Institut.

“We haven’t seen the same signal with the adenovirus, but we have looked,” he told The Daily Telegraph. “So what you are seeing in England may be different from what you see in Denmark.”

According to the European Centre for Disease Prevention and Control (ECDC), only seven of the 30 cases detected on the continent have tested positive for an adenovirus, while three children had Covid. A few also tested positive for other viruses like rotavirus and influenza.

“The situation across the EU has unfolded since Easter,” said Erika Duffell, principal expert in hepatitis at the ECDC. “We’re updating our information on an hourly basis.” But experts warned we’re still in the “fog of war” – figures are murky as patients may not have all been tested for all viruses in the same way.

Some believe another, as-yet-unidentified infection may be to blame. “One possibility is there is a completely new infectious agent that we have not come across before,” said Prof Will Irving, a professor of virology at the University of Nottingham.

Or, suggested Prof Kelly, “we might find there is more than one virus behind it”.

“It’s hugely important to have an open mind that an adenovirus might not be the only factor here,” she said. “It may be too obvious – I hate to say that, but there may be more behind it.”

A side effect from coronavirus vaccines has also been ruled out, as none of the children affected in the UK have received a jab. While the case definition applies to children under 10, most in the UK are actually younger than five, so not yet eligible to receive a vaccine.

‘A MYRIAD OF SYMPTOMS’

In the meantime, paediatricians are focused on treating the children who end up on a hospital ward.

Doctors stress that most cases are relatively mild and self-resolve. They suspect that many cases have gone unnoticed, with children recovering without medical intervention. But, while no one has yet died, for some the prognosis is serious.

Dr Tassos Grammatikopoulos, a consultant in paediatric hepatology, works at King’s College Hospital in London – one of three specialist liver units in England, alongside Birmingham and Leeds. Since January, he’s treated a handful of the hepatitis patients.

“We’ve seen a myriad of symptoms,” he said. “It can start with a high temperature, feeling unwell and/or not drinking well and experiencing abdominal pain. You may see that they start developing a yellow tinge, usually it starts from the eyes and then gradually spreads over the skin.”

Treatment for these milder cases is usually supportive. Intravenous fluids are provided to manage the kidney function, antibiotics to ensure no subsequent infections occur and vitamins to ensure good nutrition. Antivirals and antifungals are also given, to cover unknown elements, or treat the adenovirus where a patient has tested positive.

But if the condition deteriorates and the liver damage is extensive, a child will be referred for urgent assessment at a transplant centre and may receive a transplant. So far eight children in the UK have been through this process, with one on a waiting list.

At King’s campus in south-east London, where Dr Grammatikopoulos performs around 50 transplants a year, three of his young hepatitis patients have required surgery. All are now “making a good recovery,” he said.

“This is just an extraordinary event, I wouldn’t like to place a bet on what the cause will be,” added Prof Irving. “We have to hope it doesn’t take off in the way an epidemic does. But it is equally possible that the cases start to fade away, possibly without us ever knowing why.”

With additional reporting from Reuters

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