Scientists and healthcare professionals around the world are continuing to investigate a sudden increase in hepatitis cases in children.
An unexpected increase in hepatitis cases among young, previously healthy children was first reported in the United Kingdom in late March. As of 10 May, the World Health Organization (WHO) estimates that there are 348 cases globally. So far, one death has been reported and an estimated 18 liver transplants have been carried out globally.
Scientists and healthcare professionals around the world are working together to understand the cause of the outbreak. Initial findings suggest that an adenovirus – a common type of virus that causes a range of symptoms and illnesses – could be linked to these cases. However, several different theories are currently being explored.
We spoke to experts from Imperial College London’s Faculty of Medicine about what we know so far and the questions that still need to be answered:
- Professor Graham Cooke, Professor of Infectious Diseases (GC)
- Professor Wendy Barclay, Action Medical Research Chair Virology and Head of Department (WB)
- Dr Elizabeth Whittaker, Honorary Clinical Senior Lecturer and Consultant in Paediatric Infectious Diseases and Immunology at Imperial College Healthcare NHS Trust (EW)
- Professor Petter Brodin, Garfield Weston Chair of Neonatology and Professor of Paediatric Immunology (PB)
What is hepatitis?
GC: Hepatitis is a general term that refers to inflammation in the liver, and this can be caused by a range of things. There are several viruses that can infect the liver, the best-known being hepatitis A, B, C, D and E. These viruses are all quite different – some of them can be prevented by vaccination and some can be treated with antiviral therapies. However, drugs, environmental exposures and other factors can also cause hepatitis.
In children, mild hepatitis is quite common. Even mild illness can cause low-level inflammation of the liver. However, what we’re currently seeing is something very different. There are at least ten children here in the UK who have required a liver transplant because the level of inflammation is so high.
How and where were the first cases of this outbreak identified?
EW: The first cases were reported towards the end of March 2022 in Scotland, where a group of 14 children had unusual and severe hepatitis, which wasn’t caused by the usual viruses.
Since then, other countries have identified cases retrospectively – in particular, a group of children in Alabama in the USA indicate that cases might go back to November 2021. But, as we don't know what this hepatitis is caused by yet, it's very difficult to be certain that the cases are linked.
Are hepatitis outbreaks common and do they usually affect only children?
GC: There are well-documented outbreaks of viral hepatitis. Viruses like hepatitis A can spread through faecal-oral contamination, typically through contaminated water. This doesn’t happen often in the UK, but it is fairly common in other parts of the world. However, this is obviously something quite different. The viruses that commonly cause hepatitis have not been detected in these cases.
One important consequence of this is that the vaccines we have will not be effective at preventing these cases. Unfortunately, current treatments are also not very effective, so trying to find these cases and diagnose them early is essential.
PB: Hepatologists do see cases of unexplained hepatitis on and off all the time, but this is quite out of the ordinary because there are spots of cases around the world and there’s a dramatic increase in numbers of cases.
Obviously, because we don’t know the cause of these cases, we still don't know if all of them are the same condition, but it's definitely suspicious.
EW: What's also unusual here is that it's all happened quite acutely over a couple of months and that it's predominantly been in children under the age of five.
There are several reasons why these cases are only affecting children, and if we’re honest, we’re still trying to understand it.
Some possibilities include that young children have different responses to new viruses compared to older children and adults. This is because your immune system matures as you get bigger, so, because it's the first time young children have been exposed to something, their immune systems can behave in a slightly different fashion.
Another theory is that this is due to exposure to a certain toxin in a substance that only young children encounter, but this doesn’t seem to be true based on the children that researchers have studied so far.
What could be causing the outbreak?
GC: At the moment, the evidence appears to suggest that the most probable cause is a particular type of adenovirus, called subtype 41. This subtype hasn’t previously been associated with severe liver disease, so it’s unclear as to how it could now be causing hepatitis. One possibility is that this adenovirus subtype may have changed in some way and work is going on to sequence the viruses to understand this.
WB: Adenovirus has been detected in a high proportion of cases, and it seems to be a specific serotype. However, it is important to keep an open mind about whether the adenovirus is itself the root cause, or if there are other, combined factors at play.
I think there may be a combination of factors underlying these cases – the unusual epidemiological circumstances due to the pandemic, the virus itself or perhaps some kind of co-infection.
PB: My personal hypothesis, which is not validated by data yet because we need to do detailed research, is that this is due to a co-infection. I think that the SARS-CoV-2 virus stays in these children, normally without causing any problems. But when they get another virus – whether it’s an adenovirus or something else – the pair become a bad combination triggering the immune system to overreact which causes this hepatitis.
What are adenoviruses? Have they previously been linked to hepatitis?
WB: There are many different types of adenoviruses, and they are common in humans and animals. Human adenoviruses cause a variety of diseases but are probably responsible for a fair proportion of common colds. Adenoviruses can be spread through respiratory means and cause respiratory infections that are typically mild. However, adenoviruses can also be spread via faecal-oral transmission and cause things like diarrhoea. In most healthy people, adenoviruses aren’t associated with severe disease.
Adenoviruses have previously been reported to cause hepatitis in immunocompromised people. However, there hasn't really been any detailed molecular virology or analysis to suggest that there are particular serotypes of adenovirus which do this more often than others. So, at the moment, we don’t know if there are serotypes that are more likely to cause hepatitis – there could be.
Are COVID-19, vaccines, or lockdowns behind this?
"It's really important that we explore all theories. We’re coming into this with an open mind as we don't know what's causing it, so let's ask all the questions and make sure we explore all the avenues." Dr Elizabeth Whittaker
EW: These questions are very interesting and I think it's really important that we explore all theories. We’re coming into this with an open mind as we don't know what's causing it, so let's ask all the questions and make sure we explore all the avenues.
I would be surprised if these cases were directly caused by SARS-CoV-2 infections because COVID-19 has been around for two years and 95 per cent of kids have antibodies against it, so we would expect to have seen an effect of that kind sooner than this. However, it is possible that there is an indirect effect of co-infection with SARS-CoV-2 and an adenovirus, or another virus.
With COVID-19 vaccines, these have not been given to any of the 114 children who have had hepatitis in England or the UK. And with vaccine uptake in children being quite low, it seems unlikely that there is an effect that is directly related to the vaccine.
PB: I don't think vaccines are behind this. I think, if anything, vaccines should protect from this. Most of the cases that are happening are actually in unvaccinated young children.
WB: From an epidemiological point of view, we are living in unusual times. Because of the pandemic lockdowns, we have a cohort of children whose exposure to infectious diseases has been very different to those of children in previous years.
The preliminary data seems to show that there is a peak in the incidence of this hepatitis in children who are around three years old. That would support the idea that these are children who were born during the pandemic and whose first years have coincided with the reduced transmission of many different bugs due to lockdowns and restrictions. It may be that, as a result, these children are being exposed to this virus for the first time now and their immune systems are in some ways more vulnerable.
GC: One possibility being explored is that the easing of social restrictions has caused increased circulation of adenoviruses, and that’s why we're seeing a higher incidence of something that was previously a rare complication that was not recognised.
What should parents be looking out for?
EW: These children have usually been presenting with vomiting, tummy pain and diarrhoea over a two-week period, then becoming unwell with yellow eyes or skin – which is what we call jaundice. A few cases have other symptoms like headaches and sore throats, and a very small proportion have a fever.
The tricky thing is that children get gastrointestinal symptoms all the time, so it’s difficult and we don’t want every parent who has a child who vomits worrying that something serious is going on.
Although there have been a number of these cases, it’s still a tiny proportion of the entire population of children. So, what we’d say is that it would be normal to have a vomiting or diarrhoea illness for a few days and then to settle, but anybody having persistent symptoms after more than three to four days should seek medical attention. And, of course, parents should seek help from a doctor before that time if their child is drowsy, unresponsive or irritable, or they're not managing to keep any water down.
Should parents be worried?
I think the most important thing is that parents should understand this is very, very rare and we are trying to get on top of things to understand it and treat it. Professor Petter Brodin
PB: I think the most important thing is that parents should understand this is very, very rare and we are trying to get on top of things to understand it and treat it.
It's important not to panic – children have to live their lives and isolating them in the home isn’t helpful.
If this condition is due to a co-infection with SARS-CoV-2 and another virus, we should have very effective treatments in the same way we do for other childhood inflammatory syndromes related to COVID-19. However, we need to fully understand the causes of these cases of hepatitis before any treatments will become available.
What research can be done to shed more light on these cases?
"We’re living in an era when it is quite tempting to point the finger at a virus. However, there are several different theories and possible causes." Professor Wendy Barclay
WB: I think that ongoing sequencing work will be key to understanding the underlying cause. For this kind of virus, it’s quite difficult to develop lab-based models to study what is happening, which is why looking at and sequencing primary samples such as liver biopsies will be vital.
Taking a detailed look at the clinical case histories of these children will also be really important. We’re living in an era when it is quite tempting to point the finger at a virus. However, there are several different theories and possible causes.
Sometimes hepatitis can be the result of a ‘hit-and-run' infection, where damage to the liver appears several weeks afterwards. If you can’t detect the pathogen itself, it is possible to look at blood samples for evidence of a recent infection, and then see if this is something these cases have in common.
EW: The UK Health Security Agency (UKHSA) is involved with public health issues like this, and they perform a comprehensive investigation to try to understand the problem. To do this, they’re examining the trends – the epidemiology – but also bringing in experts in infectious diseases, viruses, and the liver, alongside immunologists and rheumatologists to consider immune and inflammation responses. They’re also consulting with pharmacists who can help look at whether this is caused by a toxin but can also think about possible treatments for these children. Infectious disease consultants, like me, are also involved because we are experienced in doing investigations of unusual presentations like this – we're sort of like Sherlock Holmes.
With those people together in the room, we share ideas of what could be behind the outbreak and discuss how we can investigate our theories. It's really important that we explore all of the hypotheses in as much detail as we can.
The World Health Organization (WHO) is also pulling together as many people as possible to join in a kind of ‘bring your heads together and think about how we can address this' approach. The European and American Centres for Disease Control (CDC) are doing a similar thing and they work closely with the WHO as well – everybody always collaborates when something like this happens because you only have a small number of cases in each country, which means it’s quite hard to put the jigsaw together. However, if you put all the smaller case reports together, you're more likely to get an answer as to what's going on.
Article text (excluding photos or graphics) © Imperial College London.
Photos and graphics subject to third party copyright used with permission or © Imperial College London.
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