Almost 350 children in 20 countries have fallen ill with a mysterious inflammation of the liver in recent months. Some of them got so severe with hepatitis that they needed a liver transplant, and even children died from it in the US.
The World Health Organization is now also investigating possible causes – including Sars-CoV-2. In an interview, Guido Engelmann, chief physician at the clinic for children and adolescents at the Rheinland Klinikum Lukaskrankenhaus Neuss, explains why it is so difficult to find out the cause of the disease – and why many experts suspect an adenovirus.
Spektrum.de: How many more cases of hepatitis are there in children compared to normal years?
Guido Engelmann: There is very good data from Scotland on this. The British NHS has published a report according to which there are as many as seven to eight cases of adenovirus hepatitis (inflammation of the liver caused by various adenoviruses, editor’s note) in Scotland in a normal year. It’s already nine this year and it’s only May.
This means that the occurrence is at least twice as common. In Germany there was a comparable survey at German liver centers; this has so far not shown that there would be an accumulation in this country. But the survey is still ongoing.
Why do you have better information in England at the moment?
In Great Britain the system is extremely centralised, with only one unit for the whole country in Birmingham, King’s College in London and Leeds. Therefore they have a much better overview than we do.
But Great Britain is not perfect either: it started with the fact that such cases appeared in Scotland, and only then did people ask the other centres. At that moment it turned out that there were actually more patients with acute hepatitis. The definition of a case is relatively strict. The point is that the value for transaminases must be over 500.
This is definitely a value where you start to worry. A few of these kids ended up having liver transplants. So that was real acute liver failure.
Why is it so difficult to find out the cause of hepatitis? Why can so many different causes all cause exactly the same clinical picture?
Hepatitis is a disease of the liver cells. If the immune system attacks the liver cells in an autoimmune disease, a virus enters the liver cells and the immune system then destroys them, or a toxin or copper builds up in the liver cells as in Wilson’s disease, it always produces the same effect.
The affected liver cells dissolve, many at once. This then shows the increased liver values in the blood: the more cells dissolve, the more markers such as transaminases are released.
If a large number of liver cells are damaged, then at some point the substances that are actually broken down by the liver cells, such as bile acids, bilirubin or ammonia, also increase.
And the values that are built by the liver cells, such as proteins or components of blood clotting, drop. The first effect you see is usually that the bilirubin is not broken down as quickly. Then the skin turns yellow.
Most of the patients eventually transplanted turned very yellow. This shows that an extremely large number of liver cells have been lost. The system stopped working. And without a liver, you can only survive a few days.
And how do you find out what exactly is the cause of hepatitis now?
A standard panel is used in acute liver failure. It records viral infections, autoimmune diseases and a few metabolic diseases that can trigger such a clinical picture. In the case of viral infections, a PCR test is carried out in the blood to detect certain pathogens. An adenovirus in the blood is therefore not bad at first; That’s why we have our immune system.
In many of the affected patients, however, a very specific adenovirus subtype was noticed in the PCR test: 41F. This virus is one of the few adenoviruses that make people sick.
Because there are many more adenovirus subtypes: According to an overview published in the Bulletin of the RKI in 2019, there are eight species and in each of these species up to twelve types, which is an enormous number. Many of these do nothing, but 40F, 41F, and 52G can cause gastrointestinal infections.
So far, however, the virus has only been detected in half of those affected. Why do you still think that there is a connection with 41F?
Such adenovirus infections can actually cause liver damage in children. It’s rare, but it happens. Unfortunately, there is no sensible data collection, at least in Germany. But if you look at the registers, every now and then you’ll find adenovirus as a trigger. That is why, in the case of liver failure, in addition to Epstein-Barr virus, cytomegalovirus and hepatitis A to E viruses, it is standard practice to test whether an adenovirus infection is present.
On the other hand, such an analysis does not initially look at subtypes, but only checks the question “adenovirus yes/no”. In England, the exact subtype was then determined again in many cases and the high number of 41F adenoviruses was found. But so far it has not been possible to determine the exact subtype in all patients.
Adenovirus infections in children are quite common. Can the coincidence also be coincidence?
The high number of infections with 41F is quite impressive. It could be coincidence, that’s true. But there are various considerations as to why there are more cases of hepatitis caused by adenoviruses right now. The most plausible explanation for me is that we have hardly seen any infections in the last two years due to the pandemic measures. And hardly any adenovirus infections.
There are certain viral infections that are very closely monitored in Germany and worldwide, an example is RSV. In the penultimate RSV season there were practically no infections with it, in Germany maybe a handful, while we usually have tens of thousands. The accumulation of adenoviruses may also be due to the fact that children are now coming into contact with this adenovirus in large numbers again for the first time.
This would of course increase the number of cases in which children react highly pathologically to the actually banal infection. It would therefore no longer be children suffering from hepatitis, but only all the cases that would otherwise have been spread over the last two years.
This is a variant. A second theory is that co-infections with Sars-CoV-2 somehow play a role. That is unclear, but it is of course conceivable that a reinforcement or whatever will take place. We do not know that, yet. There is no good data on this yet. It is of course the case that many children are currently infected with Sars-CoV-2. So it may mean nothing at all that the virus is found in those affected.
And yet another variant would be that Covid-19 may itself be the cause, and adenoviruses are found quite coincidentally in those affected. All of these are currently unanswered questions. Various organizations such as the NHS in Great Britain and the Robert Koch Institute, but also the German Society for Pediatric Infectious Diseases are now in the process of finding out.
Is it now reasonably safe to assume that a virus is responsible? For example, would poisoning still be an option?
Interestingly, that was actually a possible explanation at the beginning. The first cases have appeared in Great Britain. And one of the most common reasons for liver failure there is actually acetaminophen poisoning.
Paracetamol causes liver damage above a certain dose, and severe hepatitis develops from around 200 milligrams per kilogram of body weight. Since you can buy very large amounts of paracetamol freely in Great Britain – which is not possible in Germany – such poisonings are more common there.
As a result, the patients were checked toxicologically: not just for paracetamol, but in general. However, there was no evidence that environmental toxins would suddenly be released.
If it were now a case of viral hepatitis caused by adenoviruses or Sars-CoV-2, there would still be very few affected children compared to the total number of infected children. Why is it that some children become seriously ill while most others do not?
That’s a good question that no one can answer right now. One can only say Solomonic: It is either the patient or the virus. As with many other things, there may be immunological or other factors in the patient that are causing them to react unusually violently to something that might seem mundane. There are certainly examples of this, and it is generally known in the case of allergies.
Another example is meningococci. About ten percent of us have meningococci on the tonsils, but very rarely does this lead to serious illness. This is probably due to the pathogenicity factors of the meningococci and probably also to factors in the patient’s immune system.
What is the next step in analyzing and researching the cases of hepatitis?
The first step is an assessment of the situation, i.e. the inquiry from the Robert Koch Institute on the situation in Germany on April 29. So this is still going on. The RKI retrospectively asked about cases from January 1, 2022. I suspect that this year we will wait and see whether there are more cases of hepatitis and whether this might even become a big wave.
According to what is known so far, there is no problem in Germany at the moment. Although cases of acute liver failure do occur from time to time, nothing above the normal frequency has been noticed so far.
Attempts will also be made to determine the pathogenicity factors of the viruses involved. But that’s not easy in virology. It’s a little easier with bacteria because they’re easier to grow in culture.
We currently know that there is a clearly over-random cluster in the UK and US, it may just be the result of increased attention in the wake of the pandemic. This is also described in the publications of the NHS. The greater attention to potential corona consequences could lead to finding more things that would not have been noticed before.
What does that mean for parents now? Do you have to worry about the hepatitis cases?
No, we are still talking about individual cases. And even if there are already several isolated cases, I see no reason for concern. Anyway, I’m not worried about my kids.
The original of this article “Adenovirus triggers hepatitis: A chief physician explains what’s behind it” comes from Spektrum.de.