Tuesday, April 26, 2022

UK Technical Briefing: Investigation Into Acute Hepatitis of Unknown Aetiology in Children in England




#16,714

Three weeks ago the UK Health Security Agency raised the alarm over a large number of young children presenting to hospitals with acute hepatitis of unknown etiology. A few of the children were sick enough to require liver transplants (see UK HSA: Investigating An Unusual Increase In Hepatitis In Children).
Since then we've seen scores of reports from Europe, the United States - and most recently from Japan - of suspected or confirmed cases. 
Most of the cases involved young children - many under the age of 5 - who have tested negative for the common viral (A-E) causes of hepatitis, and who share no common exposures. Although investigators are looking at a potential viral cause (e.g. adenovirus, COVID, novel virus, etc.), these cases remain a medical mystery.

Late yesterday the UKHSA published a lengthy (41-page) and highly detailed technical briefing on what is currently known about cases from England, and current avenues of investigation. 

First we have a brief update from the UKHSA, followed by a link and some excerpts from the technical briefing. You will, however, want to follow the link to read the report in its entirety.  I'll have a postscript after the break. 

Increase in hepatitis (liver inflammation) cases in children under investigation
Regular UKHSA updates on the ongoing investigation into higher than usual rates of liver inflammation (hepatitis) in children across the UK.

From:UK Health Security Agency Last updated 25 April 2022 

Today, the UK Heath Security Agency (UKHSA) published a detailed technical briefing on the investigations into a rise in cases of sudden onset hepatitis (liver inflammation) in children, with data and findings on cases resident in England, up to 20 April 2022.

UKHSA, working with Public Health Scotland, Public Health Wales and the Public Health Agency, are continuing to investigate the cases in children aged 10 and under that have occurred since January 2022. The usual viruses that cause infectious hepatitis (hepatitis A to E) have not been detected. The cases are predominantly in children under 5 years old who showed initial symptoms of gastroenteritis illness (diarrhoea and nausea) followed by the onset of jaundice.

Active case finding investigations have identified a further 3 confirmed cases since the last update on 21 April, bringing the total number of cases to 111. Of the confirmed cases, 81 are resident in England, 14 are in Scotland, 11 are in Wales and 5 are in Northern Ireland.

Of these cases, 10 children have received a liver transplant. No UK cases have died. A small number of children over the age of 10 are being investigated.

There is no link to the coronavirus (COVID-19) vaccine. None of the currently confirmed cases in under 10 year olds in the UK is known to have been vaccinated.

Information gathered through the investigations increasingly suggests that the rise in severe cases of hepatitis may be linked to adenovirus infection but other causes are still being actively investigated. Adenovirus was the most common pathogen detected in 40 of 53 (75%) confirmed cases tested. Sixteen per cent of cases were positive for SARS-CoV-2 at admission between January and April but there was a high background rate of COVID-19 during the investigation period, so this is not unexpected.

Routine NHS and laboratory data show that common viruses circulating in children are currently higher than in previous years and there is a marked increase of adenovirus, particular in the 1 to 4 age group.

Dr Meera Chand, Director of Clinical and Emerging Infections at UKHSA, said:

  • Information gathered through our investigations increasingly suggests that this rise in sudden onset hepatitis in children is linked to adenovirus infection. However, we are thoroughly investigating other potential causes.
  • Parents and guardians should be alert to the signs of hepatitis (including jaundice) and to contact a healthcare professional if they are concerned. Normal hygiene measures such as thorough handwashing (including supervising children) and good thorough respiratory hygiene, help to reduce the spread of many common infections, including adenovirus.
  • Children experiencing symptoms of a gastrointestinal infection including vomiting and diarrhoea should stay at home and not return to school or nursery until 48 hours after the symptoms have stopped.
  • We are working with partners to further investigate the link between adenovirus and these cases.

Hepatitis symptoms include:
  • yellowing of the white part of the eyes or skin (jaundice)
  • dark urine
  • pale, grey-coloured faeces (poo)
  • itchy skin
  • muscle and joint pain
  • a high temperature
  • feeling and being sick
  • feeling unusually tired all the time
  • loss of appetite
  • tummy pain


Due to its length, I've only reproduced the summary and one chart from the 41-page technical document. 



Summary

As of 20 April 2022, there have been 111 cases of acute non-A-E hepatitis with serum transaminases greater than 500 iu/l identified in children aged under 16 years old, since 1 January 2022. This is the result of an active case finding investigation in April which identified prospective as well as retrospective cases. No cases resident in the United Kingdom (UK) have died. 

Eighty-one cases are resident in England, and the rest of the investigation data concerns cases from England only. This briefing is produced to share data useful to other public health investigators and academic partners. Although a detailed clinical case review is also taking place, that data is not shared here as, given the small number of cases, there are some risks to confidentiality. 

The cases are predominantly under 5 years old. The clinical syndrome often begins with gastroenteritis-type symptoms, followed by the onset of jaundice. From the information available, 43 cases resident in England have recovered. Seven cases have received a transplant. Trawling questionnaires have not revealed any obvious common exposures. Detailed clinical case review is underway. 

Fifty-three cases have been tested for adenovirus of which 40 have adenovirus detected. SARS-CoV-2 has been detected in 10 of 60 patients and other pathogens are detected at lower levels. The detection of SARS-CoV-2 at this level is not unexpected given the community prevalence across the period of the investigation and based on the limited available information there is no evidence implicating a new variant of SARS-CoV-2. 

Preliminary typing of the adenovirus has been consistent with type 41F where data is available from blood samples, however other adenovirus types have also been identified in non-blood samples. Whole genome sequencing from multiple cases is essential before the  characterisation of the virus can be confirmed. This is in process although the low level of adenovirus present in blood means that data quality has been challenging. 

There is also a marked exceedance of adenovirus in routine laboratory data, primarily driven by enteric samples and the 1 to 4 year old age group, although there are also exceedances seen in many other common gastrointestinal and respiratory viral infections at present, likely due to behavioural change and population susceptibility after a period of low incidence during the pandemic. 

The leading hypothesis at present is that the hepatitis is linked to adenovirus. The mechanism of liver injury may be virally mediated or may be an immunopathology. 

There may be a cofactor causing a normal adenovirus to produce a more severe clinical presentation in young children, such as increased susceptibility due to reduced exposure during the pandemic, prior SARS-CoV-2 or other infection, or a yet undiscovered coinfection or toxin. Alternatively, there may have been emergence of a novel adenovirus strain with altered characteristics. 

UKHSA has convened an expert group of NHS and academic partners to steer a comprehensive investigation. Rapid pathogen, toxicology and host investigations are underway, including in partnership with the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) Clinical Characterisation Protocol for those investigations where a research framework is appropriate.


One (of many) charts included shows the marked drop off of adenovirus infections detected in the UK during the opening year of the pandemic and much of 2021. Its rebound, which began in the fall of 2021, corresponds with the gradual lessening of NPI (non-pharmaceutical interventions) late last year. 



This distinctive epi curve is not unlike what we've seen with influenza, RSV, and scarlet fever (see chart below) in the UK, and around the world during the pandemic.  The precautions (social distancing, face covers, etc.) taken to prevent COVID severely dampened the transmission of other, common viral infections. 


As a result, our community immunity to a variety of infections - particularly among very young children - is believed to be lower than normal.  Whether that has any direct bearing on these acute hepatitis cases remains to be seen. 

But the potential for seeing unusual `epidemics' or unseasonable outbreaks from non-COVID infections - like influenza, RSV, Scarlet Fever, Enteroviruses, and adenoviruses -  as COVID precautions are removed, has been a frequent topic of conversation over the past 2 years.

A few (of many) examples include:

EID Journal Perspective: Viral Interference Between Respiratory Viruses




Much as the SARS-Cov-2 virus (and our attempts to contain it) have disrupted our lives and economies, this COVID pandemic has also disrupted the spread - and evolution - of numerous competing viruses.  

There are reports suggesting that the Yamagata lineage of Influenza B may have gone extinct over the past 2 years, we are seeing growing antigenic diversity among H1N1 flu viruses, and we've seen frequent out-of-season RSV outbreaks around the world. 

We may also see COVID coinfections (with Influenza, RSV, Adenovirus, etc.) - which have been shown to produce significantly higher mortality (see The Lancet: SARS-CoV-2 Co-infection With Influenza Viruses, RSV, or Adenoviruses) - worsen flu seasons for years to come.

Also on the list of potential changes coming to our world as a result of COVID :
The long-term impacts of this pandemic are many, varied, and largely unpredictable.  And just as  importantly, they are likely to continue to emerge for years to come.  

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