Introduction by Croakey: An increasing number of cases of unexplained acute hepatitis in children globally highlights the need for governments to be ready to respond to emerging infectious diseases.
While no Australian children have been reported with the mysterious illness, the substantial increase in cases internationally in the past two months (from 74 cases in mid-April to 650 cases on 26 May), including nine deaths, mean it is imperative Australian governments monitor the situation.
Below, Croakey editor Meera Senthilingam reports from London that health authorities continue to be puzzled by the upsurge in cases, but investigations are shaping a number of theories around the adenovirus.
Meera Senthilingam writes:
Cases of severe hepatitis continue to be identified among young children worldwide and health agencies are still struggling to identify a clear cause for the mysterious outbreak.
A number of theories stem around an adenovirus playing a role.
Most of the hepatitis cases appear to be unrelated and are more severe than previously known outbreaks of hepatitis with an unknown origin, according to the World Health Organization (WHO), and a disproportionate number of the children affected are developing acute liver failure, which has not been seen before.
As of May 26, a total of 650 probable cases of acute hepatitis have been reported to the WHO from 33 countries and a further 99 were waiting to be classified. Among the cases, at least 38 needed a liver transplant and nine died. Most of the children were healthy before they became ill.
Among the numbers, the United Kingdom and United States stand out from the rest as they account for more than two-thirds of the global cases reported to date – the UK (222 cases) and the US (216 cases).
The outbreak first came to light in the UK, when 10 cases were reported in Scotland on 5 April and increased to 74 across the UK just three days later.
Professor Maria Buti, Chair of the Policy and Public Health Committee of the European Association for the Study of the Liver (EASL), suggested that this could be due to the UK having a particularly good surveillance system.
Experts at the European Centers for Disease Prevention and Control (ECDC) agreed, adding that because the UK was the first country to identify cases, it may also be ahead of other countries in detecting cases.
“But that´s still not a sufficient explanation,” Buti told Croakey. “It is rare that we have a hepatitis with a cluster of unknown causes concentrated in the UK.”
A number of theories were suggested when the outbreak first began, many of which have now been ruled out, including toxic substances, particular drugs, or any links to COVID-19 vaccinations given the majority of children affected had not received a vaccine.
However, “it is strongly suspected that an infectious agent underlies these cases,” ECDC told Croakey.
Potential causes
Hepatitis is the inflammation of the liver and it is typically caused by a viral infection such as hepatitis A, B, C or E, or other viruses such as parvovirus, EBV, and herpes viruses.
Environmental factors can sometimes be a cause, but it’s usually due to an infection and while hepatitis is known to affect children, it rarely becomes severe in this age group.
These viruses have all been ruled out, however, through investigations by multiple health agencies, including WHO. The frontrunning virus for some time has been the adenovirus.
Adenoviruses are a common group of viruses that spread from person to person and usually cause colds or flu-like symptoms, but can cause gastrointestinal problems like stomach upsets, vomiting and diarrhoea.
Multiple factors imply the adenovirus could be playing a role in the hepatitis outbreak, namely the fact that 75 percent of cases tested in the UK were found to be infected with adenovirus, according to WHO.
In addition, among cases from EU/EEA countries reported through the European Surveillance System (TESSy) as of 31 May, almost 60 percent of the cases tested for adenovirus were found to be positive. A common type of adenovirus (type 41F) was also identified among these cases, according to the ECDC.
Routine surveillance in a few countries, including the UK, has also shown increased community transmission of adenovirus.
But WHO spokesperson Tarik Jasarevic told Croakey that it is “very unusual for adenovirus to cause these types of severe symptoms”. He added that “the typical findings of an adenovirus infection in the liver were not observed in some of the liver samples that have been examined in detail.”
Crucially, adenoviruses were not found in all of the affected cases that were tested. Further investigations are therefore ongoing.
Buti explained that adenovirus, as well as other viruses, can cause mild elevations in liver enzymes, and that these elevations are usually transient, asymptomatic and often go undiagnosed.
But she added that severe cases like those seen in this outbreak are not usually associated solely with adenovirus alone and believes other factors may be playing a role and are being looked into, such as genetic predispositions or coinfections with other viruses.
“We are also investigating possible links to COVID-19 infection, either a current infection or a COVID infection the past,” said Jasarevic and the latest WHO summary states that another virus –Adenovirus associated virus 2 (AAV-2) – was also detected in a small number of cases in the United Kingdom.
Updated hypothesis
This has all led to a slightly updated theory now leading the way.
“The current leading hypothesis is that the disease is caused by a cofactor affecting young children having an adenovirus infection, that triggers either a more severe infection or an immune-mediated liver damage,” explained the ECDC in a statement provided in response to questions from Croakey.
“Some cofactors under investigation include SARS-CoV-2; Adeno-associated virus 2 (AAV-2) and other pathogens, chemicals or toxic substances.”
But the experts at the European agency also mentioned another “complimentary hypothesis” in which SARS-CoV-2 reservoirs persist in the gastrointestinal track of children over time and lead to “super-antigen mediated immune cell activation.” Superantigens are molecules that cause an excessive immune response, such as inflammation.
In a recent study, researchers at Imperial College London proposed SARS-CoV-2 that reservoirs in a child who is subsequently infected with adenovirus, could lead to this superantigen-mediated effect, in turn, leading to severe hepatitis.
“At ECDC we are working closely with affected countries and research groups to explore and test this hypothesis,” the agency’s experts told Croakey.
Multiple epidemiological studies are underway at WHO, ECDC and the UK Health Security Agency (UKHSA) to solve this puzzle.
“We are working with other countries who are also seeing new cases to share information and learn more about these infections,” Dr Sophia Makki, Incident Director at UKHSA told Croakey.
In addition to these studies, the impact of the Covid-19 pandemic and the resulting lockdowns is also being assessed through two hypotheses.
The first is whether a lack of exposure to viruses, including adenovirus, has led to abnormal susceptibility to the virus in children that allows infection to more easily lead to hepatitis.
The second is whether lockdowns have led to an exceptionally large wave of adenovirus infections, which would allow an otherwise rare complication like hepatitis to be more prominent.
Until comprehensive results are known it is impossible to draw any formal conclusions. More also needs to be known about the disease pathogenesis to find “the optimal treatment for these cases cannot be determined,” the ECDC said.
Signs of hepatitis
Ahead of these results, UKHSA’s Makki stressed the need to be aware of the signs of hepatitis, particularly in young children.
“We continue to remind everyone to be alert to the signs of hepatitis – particularly jaundice, look for a yellow tinge in the whites of the eyes – and contact your doctor if you are concerned.”
Since treatment is symptomatic, the earlier the diagnosis, the better, explained EASL’s Buti.
The ECDC added that the children affected have mostly presented with jaundice and often with preceding gastrointestinal symptoms, including vomiting, diarrhoea and abdominal pain.
They also reassured that while in a minority of cases the disease progressed to severe acute liver failure, the majority fully recovered after a few days of hospitalisation.
Local developments
While no cases have been reported in Australia, a spokesperson for the Department of Health told Croakey they are “monitoring the situation very closely” with the Communicable Diseases Network Australia (CDNA) and hospital-based paediatric networks.
Regarding a longstanding proposal for an Australian Centre for Disease Control and Prevention, Adjunct Professor Terry Slevin, CEO for the Public Health Association of Australia, told Croakey that they have been communicating with Health Minister Mark Butler’s office “but have had no specific advice yet on timing or process”.
In the meantime, the PHAA are undergoing consultation with members about features of a CDC.
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