Pediatric hepatitis of unknown origin: what emerges from the first investigations

As of May 11, some 450 children with unexplained hepatitis had been reported to health security agencies around the world. A figure probably underestimated, but already well above the usual averages, which questions the medical profession. How to explain such a phenomenon? What are the tracks mentioned as to the origin of these hepatitis – and those to be excluded from the outset, possibly? Let’s take stock of what we know and what we don’t know today.

Let’s start with some information about what hepatitis is. This is liver damage. It can be caused by an obstruction of the bile ducts, such as a painful gallbladder stone. It can also be the result of direct destruction of liver cells, called hepatic cytolysis – sometimes requiring a liver transplant.

The causes of cytolytic hepatitis are toxic, viral or immune: a hepatotoxic substance – alcohol in the first place, but also drugs such as paracetamol in high overdose; a virus, first of all those designated as hepatitis A, B, C, D, or E virus, or other “non-alphabetic” ones, such as herpes virus or cytomegalovirus; a post-infectious immune reaction or an autoimmune disorder.

Symptoms are nausea, vomiting, abdominal pain, dark urine, pale stools, sometimes jaundice, fever and fatigue. There are vaccines to prevent hepatitis A and B and effective antivirals to treat hepatitis C.

Toxic hepatitis first requires the cessation of exposure to the toxic substance, then the initiation of symptomatic treatments that are known to be more or less effective. In a small minority of cases, when the liver is no longer sufficiently functional, a transplant may be required. In children, acute hepatitis such as those reported recently are very rare. Eleven children died of it and thirty-one needed an emergency liver transplant.

Police beat (or almost)

From the moment when several series of cases are reported around the world, health security agencies embark on an investigation that resembles a police battle. We must understand what is happening, identify the suspects and identify the culprit, that is to say the cause. Cause which, in the current pandemic context, is even less easy to determine.

The first step is to exclude the most obvious by noting the similarities between the affected children and by carrying out initial biological tests.
Today, various causes could be excluded.

Vaccines against Covid, first of all. Indeed, the vast majority of children who developed acute hepatitis were between 0 and 5 years old and were therefore not eligible for vaccination. Over 65% of children with severe hepatitis of unknown cause in the UK and over 80% of children in Europe were unvaccinated.

For the majority of cases, we cannot therefore blame an immune reaction that has occurred as a result of the injection of a vaccine against Covid or evoke hepatotoxicity of the vaccine or one of its components. This is already reassuring news in the midst of a global vaccination campaign, and at a time when we are thinking of extending it to younger children.

No toxic cause – alcohol, drugs, plants, chemicals or other environmental factors – has been found to date.
Viruses A, B, C, D and E, like the others known to cause viral hepatitis, have also been eliminated following systematic tests on all children affected by these liver damage of unknown origin.

Adenovirus, first suspect

So what could it be, if the vaccine against Covid-19 as well as the most common causes of acute hepatitis are excluded? Here we come to the stage of hypotheses.

The first hypothesis put forward was that of the adenovirus, because in the first (British) series, 72% of the children tested were seropositive for the adenovirus. But it is a category of virus very frequently encountered in children (by the age of 4, 85% of children have developed immunity against enteric-type adenovirus), which is transmitted by air and indirectly – as with conjunctivitis caught at the swimming pool.

Indian study shows hepatitis cases rise when Covid infections rise

In a healthy child, they tend to cause relatively mild disorders: pharyngitis, conjunctivitis, gastroenteritis (with diarrhea, vomiting and fever). But they are not known to cause hepatitis, let alone severe hepatitis. If this hypothesis remains on the table, it is nevertheless difficult to be convinced that it would be the adenoviruses which would be directly responsible for this global epidemic.

Of course, there is the question of whether SARS-CoV-2 could be responsible or even co-responsible (because the culprit may have accomplices, here too!). Several possibilities are available to us. Hepatitis could, for example, complete the clinical picture of Covid-19 and might not have been described until then because it would be due to Omicron or one of its recent subvariants, but not to previous strains.

Some children with hepatitis have tested positive for Covid-19. But a bit like for the adenovirus, having been infected with SARS-CoV-2 is not very specific during this period from January 2022 to today, since a very large number of children (without liver damage) also have it. summer. However, an Indian study shows that cases of hepatitis increase when Covid infections are on the rise, and decrease with incidence. Again, this hypothesis cannot be rejected.

What if there were multiple culprits?

Hepatitis could also be linked to a post-infection immune reaction – somewhat on the model of PIMS (Paediatric inflammatory multisystem syndrome, for “pediatric multisystem inflammatory syndrome”), commonly described in Covid-positive children and occurring at a distance from the acute phase of infection. But in the same way, given the considerable number of infections, especially in children, in all the countries that have reported cases, a positive serology alone cannot take the place of a causal explanation.

What could argue for the causal hypothesis of SARS-CoV-2 is the number of publications since 2020 that establish a link between Covid-19 and post-Covid acute hepatitis. The cases are rare but real, and since very many children were affected by the Covid during the winter of 2022, this hypothesis is reinforced even if, at the present time, you see the difficulty of the experts in confusing the or the culprits.

About this plural, let’s not forget the accomplices. Because it is also possible that these hepatitises are the result of several attackers combining their packages. An adenovirus and a coronavirus for example. It would then be an activation of the immune cells mediated by the two viruses, which would then play the role of super-antigens whose specific mechanisms nevertheless remain to be clarified.

Presence of dogs, paracetamol…

Finally, there are assumptions that are thought to be “outlandish”. In reality, in these stories, as long as the culprit is still at large, nothing should be considered “wacky”, hence the caution of our quotation marks.

Thus, the British – who have reported the world’s largest series of cases, with 197 cases of hepatitis of unknown origin occurring in children reported as of May 16 – have found the presence of a dog in the home of 70% of the reported cases. Another data, 75% of children with hepatitis had taken paracetamol to treat symptoms, while we know the drug is hepatotoxic when consumed in high doses. However, many British people own dogs, and the doses of paracetamol were not high in any case…

In short, we wanted to take stock with you, even if we are not very advanced, as you can read. However, we are rather confident that the research carried out in the countries where these hepatitises have been reported will eventually succeed and that the culprit or culprits will soon be identified.

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At the moment, it is not even possible to issue specific recommendations aimed at protecting children. We can just note that these are sometimes serious events, but very rare. Moreover, hepatitis requiring a liver transplant in children is so exceptional that one cannot think that in developed countries the exact number would be greatly underestimated. To be continued…

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