OVER a two week period in March, clinicians at Glasgow’s Royal Hospital for Children noticed something very strange.

Four children, all aged between three and five, were admitted suffering from acute inflammation of the liver - hepatitis - but the cause was unknown.

All four had been vomiting, were jaundiced, and had “exceptionally high” levels of alanine aminotransferase - an enzyme used to screen for signs of liver damage - yet there was nothing to link the youngsters, either geographically or physiologically.

The Herald: Since doctors in Scotland first raised the alarm in March, hundreds of cases have been reported worldwideSince doctors in Scotland first raised the alarm in March, hundreds of cases have been reported worldwide

These were previously healthy children now on the brink of potential liver failure, but who were all negative for the common hepatitis viruses associated with the disease and had no evidence of exposure to environmental or chemical toxins.

When one of the children’s siblings presented with identical symptoms in week three, alarm bells sounded.

“I cover the whole of the west of Scotland for paediatric liver disease, and normally we would see between two and four cases a year in that area,” said Dr Rachel Taylor, a consultant in paediatric gastroenterology at the RHC.

“But they would normally be spread out. We wouldn’t expect to see them together, and you wouldn’t expect them to be the same type of patients - the same age, the same kind of presentation.

“Then a sibling came in of one of the patients. And again, you wouldn’t normally expect to see that.

“They are the only sibling group in the whole of the UK, so at that point we thought ‘this isn’t quite right, we should look at speaking to public health about this’.”

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After consulting historic UK-wide paediatric surveys which had tracked the annual incidence per 100,000 of what is clinically known as ‘acute paediatric hepatitis of unknown aetiology’ (ie. cause), the medics at RHC realised “this is way more than we would normally see”, said Dr Taylor.

“And they just kept coming in,” she added.

“They were all the same age, very high levels of inflammation in the liver - incredibly high levels - so that was the other thing that really made them stand out.”

Several children were transferred to the specialist paediatric liver unit in Leeds, although to date only one child from Scotland has required a liver transplant - none from the west region.

Amid mounting concern, Dr Taylor called her counterparts for paediatric liver disease in the East and North Scotland regions.

They too had similar cases: two in Edinburgh, and one in Aberdeen who had already been sent to Leeds.

The Herald: Royal Hospital for Children, GlasgowRoyal Hospital for Children, Glasgow

Dr Taylor said it was these networks close working relationships which meant that doctors in Scotland were the first in the UK to realise something was wrong.

She said: “Individually, the [East and North networks] wouldn’t necessarily have thought anything of it, but because we all communicate so closely and quite regularly we were able to quite quickly say across Scotland, ‘this is an issue and a problem’.

“We also knew that all the patients would be referred into us, whereas the paediatric liver transplant unit in England would only see the tip of the iceberg - the really, really sick ones, not the tens of others that we were seeing.

“I absolutely think that that’s why, in Scotland, it was quickly picked up.”

The Herald: Age distribution of cases globally (Source: World Health Organisation)Age distribution of cases globally (Source: World Health Organisation)

When the RHC team alerted Public Health Scotland (PHS) on March 31, they were also first clinicians in the world to identify a phenomenon which has gone on to baffle scientists and sicken more than 900 children in 33 countries worldwide, including Japan, Israel, Mexico, and Spain.

According to the most recent update from the World Health Organisation, issued on Friday, at least 45 children have required liver transplants, and 18 have died.

The UK - along with the US - has reported the highest number of cases, with 267 to date, including 35 in Scotland. Almost all are under five.

The most recent admission to the RHC occurred within the last two weeks, although Dr Taylor stresses that the peak appears be over.

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“Cases have definitely stopped coming as quickly now,” she said.

The children still being monitored are improving, and unlikely to require liver transplants, she added.

One of the most confusing aspects of the illness for parents is that youngsters don’t appear particularly ill.

Dr Taylor said: “Up until the point where their liver has stopped working they’ve all been very well.

"A bit tired, and they’ve gone yellow, but you wouldn’t know that there’s anything wrong - that’s the other thing that families found quite difficult.

"You’re telling them their child is seriously unwell, and they’re bouncing around the room.”

The only way to monitor liver function is through blood tests, which at times had to be carried out multiple times a day “because that’s how quickly the liver can deteriorate”.

The Herald: After peaking in late March, the number of new cases associated with the paediatric hepatitis outbreak have steadily declined across the UKAfter peaking in late March, the number of new cases associated with the paediatric hepatitis outbreak have steadily declined across the UK

Even the existence of paediatric hepatitis stunned parents who had only ever heard of the disease associated with alcohol or drug addiction in adults, said Dr Taylor.

An additional obstacle was the impact of misinformation as false claims that the outbreak had been caused by Covid vaccinations spread on social media, despite the vast majority of patients being under five and ineligible for the jag.

Dr Taylor said: “I know some of the families have been targeted by people on social media saying ‘you have secretly vaccinated your children and that’s why this has happened’, which is just appalling.

“We knew very early on that it was nothing to do with the vaccine. That was a message put out very early on but it didn’t stop people spreading it.

"I’m very keen that that message gets out there: none of them had had it.”

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Three months on, scientists - including those at PHS - are still trying to unravel the mystery.

Currently, the leading hypotheses link the outbreak to a spike in the adenovirus 41F strain, which has been found in significant numbers among the children, or to a combination of adenovirus plus something called adeno-associated virus 2 (AAV2) which is “activated” in the presence of adenovirus.

Dr Nick Phin, who leads on public health protection for PHS, said: “AAV2 is what we call a ‘bystander’: it’s there, circulating, people have acquired it, and then acquire adenovirus and the these two things together reactivate the pathogen, and that may play a part in the presentation of hepatitis.

“We don’t think there’s a novel adenovirus variant out there that’s causing the problem.

"Adenovirus 41F - that’s one of the subtypes that has been found in a number of the children - may be a factor, but why that should suddenly create a problem at this point, given that it has been circulating in the past, we’re not sure.”

The Herald: Data up to mid-May from the UKHSA shows that around two thirds of the children were positive for adenovirus where test results were available compared to around 10 per cent who were positive for CovidData up to mid-May from the UKHSA shows that around two thirds of the children were positive for adenovirus where test results were available compared to around 10 per cent who were positive for Covid

One widely-touted theory is that the children’s immune systems have overreacted as a result of a lack of exposure to respiratory viruses during the pandemic, when lockdown restrictions largely stamped them out.

Dr Phin believes the answer may be more mundane.

He thinks cases of acute paediatric hepatitis caused by adenovirus or AAV2 have probably been occurring a low levels, steadily, for years; the only difference this year is that the ending of all Covid restrictions triggered a sudden spike in these viruses at the same time that a large population of young children with no immunity from prior infection began mixing again unhindered.

That created a cluster of cases in short period of time.

He said: “We had two years where children won’t have been exposed to the same level of circulating viruses as would normally be the case, and suddenly they’re ‘released into the community’.

“Suddenly you’ve got very large numbers of people circulating, and very large numbers of people who may be suddenly exposed to a virus that they haven’t seen before.

“This might have been happening in the background for years - unnoticed, undetected - but it’s only because so many people are non-immune and circulating at the same time, that you have this abnormal surge.

“A good example would be the Covid vaccine. Let’s say we’ve got an underlying adverse incident that occurs in one in half a million people.

“Now normally, with vaccines, it might take you 12 or 18 months to vaccinate half a million people; if suddenly you’re vaccinating 40 million people over a six week period you’ll see about 100 cases in a fairly short period of time.

“It’s not that the finding is real; it’s an artefact caused by large numbers of people being exposed in a relatively compressed period of time, and you’re only detecting it because so many people are presenting.”

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Scientists in Scotland are also investigating whether any of the children had an undetected genetic predisposition to hepatitis.

Their results will feed into the case-control study being led by the UK Health Security Agency, which  is trying to understand what distinguishes these patients from their healthy peers.

The findings are expected to be published within the next three weeks.

It comes against a backdrop of online speculation that the real cause could be Covid.

One widely shared recent study from Israel found that five children with mild Covid went on to develop hepatitis, with two - aged three months and five months - requiring liver transplants.



However, clinicians have cautioned that the sample size is too small to draw conclusions.

Dr Phin said: “In January and March, Covid circulation was very high. It’s inevitable that even if there was no association whatsoever, you would be picking up children who were Covid positive.

“It’s the age old chestnut: association does not necessarily imply causation.

“We can’t completely discount the possibility of Covid as a potential cause - but it’s not our top candidate.”