Unexplained hepatitis: severe liver inflammation among young children

Uncharacterised and so far rare cases of unexplained severe liver inflammation among young children. These cases of unexplained hepatitis have been appearing in elevated numbers worldwide since November 2021. The most often-detected pathogen is a human adenovirus (HAdV) but work continues to ensure that isn’t just a coincidental finding as cases are identified in more countries.

What is hepatitis?

Hepatitis (Greek hêpar, “liver”) is inflammation of the liver which can result in a range of outcomes. If rapid onset (acute) and viral, signs and symptoms can range from mild to severe. Asymptomatic acute viral hepatitis is more common than symptomatic versions (detectable upon liver enzyme testing). And hepatitis also comes in a chronic form that can build from acute illness.

Symptoms can be indistinguishable among the different viral causes of hepatitis and can include fever, jaundice, malaise, fatigue, light stools, abdominal pain and diarrhoea.

Diagnosis can include the detection of specific genetic material, viral proteins (antigens) or detection of anti-virus IgM antibodies. The detection of elevated levels of alanine aminotransferase (ALT; found mostly in the liver) and aspartate aminotransferase (AST; found in several tissues) can flag some degree of liver cell damage, which has resulted in the release of these enzymes into the bloodstream where they are not normally elevated.

Viral causes of acute hepatitis

The most common causes are hepatitis viruses and they come in a range of colours and flavours. [4,5]

Hepatitis A virus (HAV)

A positive-sense RNA virus of the family Picornviridae, genus Hepatovirus, species Hepatovirus A, exists as multiple genotypes and is transmitted via a faecal-oral route. The virus replicates in the epithelial cells of the small intestine and in the liver cells of primates. They are not associated with chronic hepatitis

This is typically an acute self-limited illness in adults. The disease can be more severe if on top of chronic HBV or HCV. Vaccines and treatments are available.

Hepatitis B virus (HBV)

A double-stranded DNA virus of the family Hepadnaviridae, genus Orthohepadnavirus, species Hepatitis B virus, exists as multiple genotypes and is transmitted via entry of infected blood or body fluids into the bloodstream or open wounds, sexual contact, perinatal transmission from an infected mother and possible via “inapparent horizontal” transmission, particularly between children in low socio-economic settings.

 Schematic representation of a particle of hepatitis delta virus.
Image from Figure 1, Deltavirus page, ICTV.[6]

They are associated with chronic hepatitis which can lead to liver cirrhosis and hepatocellular carcinoma complications which can, in turn, lead to death. Chronic infection can follow perinatal infection. In adults, infection usually resolves in healthy people. Infant vaccines and treatments are available.

Hepatitis C virus (HCV)

A positive-sense RNA virus of the family Flaviviridae, genus Hepacivirus, species Hepacovirus C, exists as multiple genotypes and is transmitted via entry of infected blood, blood products and blood-contaminated objects into the bloodstream. The virus replicates in the liver cells and possible lymphocytes.

Hepacivirus genome organization (not to scale) and polyprotein processing.
Image from Figure 1, Hepacivirus page, ICTV.[7]

infection is often associated with chronic hepatitis following acute infection and without treatment can result in liver cirrhosis. Therapies are available.

Hepatitis D virus (HDV)

A negative-sense RNA satellite virus of the family Flaviviridae, genus Deltavirus, species Hepacovirus C, which requires envelope proteins from a helper virus, HBV (so cellular coinfection is required), to create more infectious particles.

The transmission, replication and outcome of infection of HDV are similar to that of HBV and they exist as multiple genotypes.

Hepatitis E virus (HEV)

A positive-sense RNA virus of the family Hepeviridae, genus Orthohepevirus, species Orthohepevirus A, exists as multiple genotypes and is transmitted via the faecal-oral route, and via contaminated water, raw/undercooked meats and rarely through blood transfusions. The virus replicates in the liver cells.


Negative contrast electron micrograph of hepatitis E virus virions from a case stool collected in Nepal. (A) virion and (B) empty capsid. The bar represents 100nm (photo from M. Purdy).
mage from Figure 1, Hepeviridae page, ICTV.[8]

Infection is usually self-limited in the healthy individual similar to that for HAV but can become a significant problem for the immunocompromised. Vaccines and treatments exist.

Disease in this new outbreak

In approximately 10% of the recent cases of this unexplained severe liver inflammation among young children, which are generally being noticed in younger children, inflammation was so severe that a liver transplant was required.[22] Symptoms have included jaundice, diarrhoea, vomiting and abdominal pain and raised AST or ALT (> 500 UI/L [2]). All of the originally described 13 cases were hospitalized and one required a liver transplant.[2]

Where has this round of unexplained hepatitis been noted so far?

Scotland, England, Ireland, The United States, Spain, Israel, Belgium, Denmark, France, Italy, the Netherlands, Norway and Romania have reported cases.[11] The list continues to grow. If these are all cases with the same cause, this supports an infectious agent’s role – in some way – rather than a more localised foodborne or chemical contamination event.

Scotland

The Scottish cases were recently written up and included the first documented instances from March 2022.[2] Scotland usually sees 7-8 cases of unexplained hepatitis cases over a year but it was notable that these 13 occurred over a shorter period and were severe.[13] Among these 13 cases, 5 (38%) tested positive for SARS-CoV-2 (2 that were 3 months before admission, 2 within 11 days of admission, and 1 point-of-care test positive upon admission, which was not confirmed by PCR) and 5 tested positive for an HAdV at the time (2 from throat swabs, 2 from blood samples and 1 by faeces).[2] The US subsequently identified cases from November 2021.[11,18]

United States, Alabama

In 9 immunocompetent children aged months to five years 9 months old.[18] None had documented SARS-CoV-2 infection but all had HAdV DNA (5 were genotyped as HAdV-41) detected in whole blood samples (plasma tested negative in 2 children) by real-time PCR. No viral inclusions were noted among the liver biopsies of 6 children. Two children required a liver transplant. All children recovered.[18]

Working case definitions to find cases

The WHO described the following:[14]

  • Confirmed: N/A at present.
  • Possible: A person presenting with an acute hepatitis (non hepA-E*) with serum transaminase >500 IU/L (AST or ALT), who is 16 years and younger, since 1 October 2021
  • Epi-linked: A person presenting with an acute hepatitis (non hepA-E*) of any age who is a close contact of a probable case, since 1 October 2021.

Sample sites for pathogen testing

Interestingly whole blood, a sample not normally tested for HAdV infections in otherwise healthy patients, has been increasingly shown to be one of the best samples to detect these viruses in this acute hepatitis outbreak – although viral loads have been low requiring sensitive tests to detect the viral DNA and as yet there is no signal supporting a change to any HAdV that wouel explain this emergent outbreak.[14,23]

Other samples to test include serum, urine, stool, and respiratory samples, as well as liver biopsy samples (if available), with further virus characterization including sequencing.[14]

What might be the cause?

There is still a lot to investigate.

None of the children, aged 1 month to 16 years, with this clinical syndrome have tested positive for any hepatitis virus.[14,23] The most commonly detected agent so far has been a human adenovirus (HAdV) found in 74 early cases, particularly HAdV-41 which was characterised in 18 (24%) of those 74 cases.[14] This is on a background of increased levels of HAdV- a very common virus normally – being detected in the community.[12,14] It’s also very noteworthy that 19 (26%) of those 74 cases tested positive for both an HAdV and SARS-CoV-2 as coinfections.[14]

interestingly, in England, among 118 cases, none were epidemiologically linked.[23]

We don’t yet have evidence of any virus in the liver cells of an ill child.

This graph from Pubic Health England highlights that the highest numbers of HAdV detections in the UK are among young children, but not at excessively high levels[16]

The adenoviruses

There are seven species of HAdV containing around 50 distinct human-infecting enveloped DNA viruses that are more often thought of as agents of the “common cold”. Transmission occurs from the throat, faeces, eye or urine, depending on the HAdV type.[12]

Most infections are mild or asymptomatic but some HAdVs have been associated with specific outcomes like adenoidal–pharyngeal conjunctivitis (types 3, 4, 7, 14), acute respiratory outbreaks (types 4, 7, 14, 21), epidemic keratoconjunctivitis (types 8, 19, 37, 53, 54) or venereal disease (HAdV-37). HAdV-40 and HAdV-41 can be isolated from the faeces of young children with acute gastroenteritis and are a major cause of infantile viral diarrhoea.[12]

When associated with hepatitis after in the immunocompromised children (a very different situation to the children in this new outbreak) HAdVs have been found in (see Twitter thread by Dr Farid Jalali) biopsied liver tissues as inclusions within the nucleus.[17]

Ways to stop the spread of adenoviruses

HAdVs have a history of surviving in a manufactured aerosolized state.[3] Ultraviolet light dramatically reduced very high loads of HAdV-2 in an aerosolized suspension, in a study from 1964.[3] This suggests measures to reduce viral loads in aerosols – the same that would work to reduce influenza virus, enterovirus and SARS-CoV-2 virus infections for example – should be hugely useful here as well. We should have already begun investing in this technology. Perhaps this serves as yet another reminder of why we should if we haven’t?

Handwashing also rates here as a lot of viruses and bacteria spread by contact with contaminated surfaces.

It may be simple, it may be complex

It may not be that any single virus is the cause though. Concurrent infection with another virus may create disease or an immune-mediated process due to prior infection by something, that could be at play. This means SARS-CoV-2 is worth consideration. Not as high a proportion of children have tested positive for the virus that causes COVID-19,[2] but that doesn’t rule it out. Nor have we yet ruled out anything entirely new, or specific evolution of HAdV-41 into something that has a direct liver-damaging outcome.

Misinformation and conspiracy

Some have of course jumped on the anti-virus bandwagon and blamed childhood COVID-19 vaccination. This is easily debunked as most children were too young for vaccination.

Direct causes and possible cofactors

Among the cases, many have tested positive for an HAdV, but it may not be that simple since there are often HAdVs circulating in the community. So we can’t yet rule out another factor entirely or interaction between multiple factors.[19,20]

Things being hypothesized as a cause of this rare hepatitis include:

  • Abnormal susceptibility to HAdV infection because of reduced or absent immunity due to lockdowns preventing infections
  • A novel (recent) variant of an HAdV or of SARS-CoV-2
  • An immune-mediated, post-infection inflammatory process
  • Coinfection between SARS-CoV-2 (recent or novel variant and/or an immune imprint left by it) + HAdV
  • A toxin, drug or other non-pathogen (environmental) exposure (perhaps exacerbated by a virus, or making a viral infection worse)
  • An entirely novel pathogen (substitute that into the list above as appropriate)

References

  1. Spike in child hepatitis cases linked to common virus
    https://www.bbc.com/news/health-61177329
  2. Investigation into cases of hepatitis of unknown aetiology among young children, Scotland, 1 January 2022 to 12 April 2022
    https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2022.27.15.2200318
  3. INACTIVATION OF AIRBORNE VIRUSES BY ULTRAVIOLET IRRADIATION
    https://pubmed.ncbi.nlm.nih.gov/14215971/
  4. International Committee on Taxonomy of Viruses (ICTV)
    https://talk.ictvonline.org/
  5. Principles and Practice of Infectious Diseases, 8th edition. Eds Bennet, Dolin, Blaser
  6. Deltavirus
    https://talk.ictvonline.org/ictv-reports/ictv_online_report/negative-sense-rna-viruses/w/deltavirus
  7. Hepacivirus
    https://talk.ictvonline.org/ictv-reports/ictv_online_report/positive-sense-rna-viruses/w/flaviviridae/362/genus-hepacivirus
  8. Hepeviridae
    https://talk.ictvonline.org/ictv-reports/ictv_online_report/positive-sense-rna-viruses/w/hepeviridae
  9. Acute hepatitis of unknown aetiology – the United Kingdom of Great Britain and Northern Ireland
    https://www.who.int/emergencies/disease-outbreak-news/item/acute-hepatitis-of-unknown-aetiology—the-united-kingdom-of-great-britain-and-northern-ireland
  10. Increase in acute hepatitis cases of unknown aetiology in children
    https://www.gov.uk/government/publications/hepatitis-increase-in-acute-cases-of-unknown-aetiology-in-children/increase-in-acute-hepatitis-cases-of-unknown-aetiology-in-children
  11. WHO says 12 countries have reported unusual cases of hepatitis in kids
    https://www.statnews.com/2022/04/23/who-says-12-countries-have-reported-unusual-cases-of-hepatitis-in-kids/
  12. Adenoviridae
    https://talk.ictvonline.org/ictv-reports/ictv_9th_report/dsdna-viruses-2011/w/dsdna_viruses/93/adenoviridae
  13. Eleven cases of hepatitis in children investigated in central belt
    https://www.bbc.com/news/uk-scotland-61013731
  14. Multi-Country – Acute, severe hepatitis of unknown origin in children
    https://www.who.int/emergencies/disease-outbreak-news/item/multi-country-acute-severe-hepatitis-of-unknown-origin-in-children
  15. Increase in acute hepatitis cases of unknown aetiology in children
    https://www.gov.uk/government/publications/hepatitis-increase-in-acute-cases-of-unknown-aetiology-in-children/increase-in-acute-hepatitis-cases-of-unknown-aetiology-in-children
  16. National flu and COVID-19 surveillance report: 21 April 2022 (week 16)
    https://www.gov.uk/government/statistics/national-flu-and-covid-19-surveillance-reports-2021-to-2022-season
  17. Adenovirus Hepatitis: Clinicopathologic Analysis of 12 Consecutive Cases From a Single Institution
    https://pubmed.ncbi.nlm.nih.gov/28296681/
  18. Acute Hepatitis and Adenovirus Infection Among Children — Alabama, October 2021–February 2022
    https://www.cdc.gov/mmwr/volumes/71/wr/mm7118e1.htm
  19. Mystery outbreak of severe acute hepatitis in children
    https://www.thelancet.com/journals/langas/article/PIIS2468-1253(22)00159-5/fulltext
  20. European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 23-26 April 2022, Lisbon, Portugal
    https://www.eccmid.org/scientific_programme/ and https://www.escmid.org/guidelines_publications/eccmid_2020_abstract_book/
  21. Slides tweeted by Dr Muge Cevkik from a Late breaker session at ECCMID 2022 on acute hepatitis cases of unknown origin in children
    https://twitter.com/mugecevik/status/1518505395689512962
  22. Severe hepatitis of unknown cause in 15 nations: Does pathology offer a clue?
    https://www.idsociety.org/science-speaks-blog/2022/severe-hepatitis-of-unknown-cause-in-15-nations-does-pathology-offer-a-clue/#/+/0/publishedDate_na_dt/desc/
  23. Investigation into acute hepatitis of unknown aetiology in children in England
    https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1073704/acute-hepatitis-technical-briefing-2.pdf

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