OVER a three week period in March, clinicians at Glasgow’s Royal Hospital for Children (RHC) noticed something very strange.
Five children, aged between three and five, were admitted to the hospital suffering from severe hepatitis - inflammation of the liver - but the cause was unknown.
In a typical year, medics would expect to see only four paediatric cases of what is officially described as “acute hepatitis of unknown aetiology” in the whole of Scotland.
All five had been vomiting, were jaundiced, and had “exceptionally high” levels of alanine aminotransferase - an enzyme used to screen for signs of liver damage.
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Three of the five children were transferred to paediatric liver units in England, and one subsequently required a transplant.
With alarm bells sounding, NHS Greater Glasgow and Clyde alerted Public Health Scotland (PHS) to the situation on March 31.
Scotland was the first country in the world to launch a formal investigation, but since then more than 130 cases involving very young children have been identified worldwide including in Spain, Ireland, Denmark, Israel, the Netherlands and the United States.
The UK accounts for the majority of known cases so far - 108 - and eight of these youngsters have required liver transplants.
No link has been found to any of the common hepatitis A, B, C and E viruses, nor to any environmental toxins, and there is no sign of geographical clustering of cases.
The first patient under 10 Scotland was identified on January 11, but the real flurry occurred in March as 12 cases were confirmed Scotland-wide between March 4 and April 7.
Since then, a further one has been identified.
None of these children had been vaccinated against Covid, but five of the 13 identified up to April 7 tested positive for adenovirus and five had current or recent Covid infections.
However, the very high community prevalence of the latter - compared to adenovirus - may suggest a more coincidental association.
On Thursday, Professor Susan Hopkins, the chief medical advisor at the UK Health Security Agency, said the “most likely trigger” is an adenovirus, with 77 per cent of the UK children affected having tested positive for some form of the virus, which normally causes cold-like symptoms, vomiting and diarrhoea.
US authorities are also investigating clusters of hepatitis and adenovirus in children.
Researchers, summarising Scotland’s investigation in the online journal ‘Eurosurveillance’, noted that adenovirus infection as a cause of severe hepatitis is “rare” in healthy (ie. non-immunosuppressed) children but “has been reported”.
Rates of adenovirus in the one to four age group were not unusually high at the beginning of 2022, but they had rebounded to levels last seen in pre-pandemic times.
The Eurosurveillance report, published on April 14, said the mysterious severity of paediatric hepatitis cases could be due to “a new variant [of adenovirus] with a distinct clinical syndrome or a routinely circulating variant that is more severely impacting younger children who are immunologically naïve”.
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This latter scenario “may be the result of restricted social mixing during the Covid-19 pandemic”, they added, but also stressed that Covid may have played a more direct role if infections with the Omicron BA.2 strain had triggered severe hepatitis.
Furthermore, they could not rule out a “novel or yet undetected virus” as the cause.
Maria Buti, a hepatology professor and chair of the European Association of the Study of the Liver’s public health committee, said: “This is still a very low number of cases, but they are children, that is the main concern. The other thing is the severity.”
Adenovirus is so prevalent normally that most children would be exposed as infants.
The theory goes that their immune systems, encountering the virus either for the first time - or after a long gap - aged two, three or older, are now over-reacting in a way that harms the liver.
Dr CJ Houldcroft, an expert virus evolution at Cambridge University, said: “It is increasingly likely a common adenovirus is the cause.
“We’ve altered the transmission patterns of many human viruses over the last two years, including RSV and (it seems) adenovirus in children. Large out of season peaks are not unexpected.”
The pandemic has certainly skewed patterns of infectious and respiratory diseases.
Cases of norovirus, which practically vanished in 2020, have rocketed in April and are now exceeding pre-pandemic levels as people return to workplaces, socialise more, and handwash less rigorously.
In August last year, unusual numbers of young children in Scotland were being hospitalised for Respiratory syncytial virus (RSV) - a virus which normally peaks in winter.
At the time, the out-of-season surge was put down to the effects of increased social mixing during summer following quasi-lockdown conditions which had stretched from December 2020 to April.
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Levels of rhinovirus - the main culprit behind the common cold - also surged well beyond pre-pandemic averages towards the end of 2021; rates parainfluenza were around eight times higher than normal in summer 2020; and the final weeks of 2021 saw rates of human metapneumovirus (HMPV), which causes cold-like illness, reach what PHS categorises as “extraordinary” levels.
The resurgence of adenovirus has been modest by comparison and rates remain normal for April.
Meanwhile, one of the few seasonal viruses not to make much of a comeback at all, surprisingly, was flu.
Cases - largely caused by an unidentified subtype of Influenza A - finally rose in mid-February but have plateaued well within the average for the time of year.
Strange patterns of hepatitis may not be the only viral legacy of the pandemic.
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