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

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 probably underestimated figure, but already well above the usual averages, which questions the medical profession. How to explain such a phenomenon? What are the traces mentioned as to the origin of these hepatitis, and possibly those that should be excluded from the beginning? 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 a blockage of the bile ducts, such as a painful stone in the gallbladder. It can also be the result of direct destruction of liver cells, called hepatic cytolysis, which sometimes requires a liver transplant.

The causes of cytolytic hepatitis are toxic, viral or immunological: a hepatotoxic substance – alcohol in the first place, but also drugs such as paracetamol in high overdoses; a virus, first of all the so-called hepatitis A, B, C, D or E viruses, 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 requires first 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 functional enough, a transplant may be necessary. In children, acute hepatitis such as those recently reported is very rare. Eleven children died from it and thirty-one needed an emergency liver transplant.

The police hit (or almost)

Since 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, the cause. Cause that, in the current context of pandemic, is even less easy to determine.

The first step is to exclude the most obvious ones by looking for similarities between affected children and performing initial biological tests.
Today, several causes could be excluded.

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

For most cases, therefore, we cannot blame an immune reaction that has occurred as a result of the injection of a Covid vaccine 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 rest of those known to cause viral hepatitis, have also been eliminated after systematic testing of all children affected by these liver lesions of unknown origin.

Adenovirus, first suspect

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

The first hypothesis that was raised was that of adenovirus, since in the first series (British) 72% of the children tested were seropositive for adenovirus. But it is a category of virus that is very commonly found in children (by age 4, 85% of children have developed immunity against enteric-type adenovirus), which is transmitted by air and indirectly, such as conjunctivitis contracted in the pool.

Indian study shows hepatitis cases rise when covid infections rise

In a healthy child, they usually cause relatively mild disorders: pharyngitis, conjunctivitis, gastroenteritis (with diarrhoea, vomiting and fever). But they are not known to cause hepatitis, let alone severe hepatitis. If this hypothesis remains on the table, however, it is difficult to be convinced that adenoviruses 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 also have accomplices!). Various possibilities are available to us. Hepatitis could, for example, complete the clinical picture of Covid-19 and could not have been described until then because it would be due to Omicron or one of its recent subvariants, but not to earlier strains.

Some children with hepatitis have tested positive for Covid-19. More a little like for the adenovirus, now that I was infected by SARS-CoV-2 is assez peu spécifique during this period allant de janvier 2022 aujourd’hui, puisque de très nombreux enfants (sans atteinte hépatique) l’ont eux aussi Summer. However, an Indian study shows that hepatitis cases rise as covid infections rise and fall with incidence. Once again, this hypothesis cannot be rejected.

What if there were multiple culprits?

Hepatitis could also be related to a post-infection immune reaction, a bit on the model of PIMS (Pediatric Multisystem Inflammatory Syndrome, for “Pediatric Multisystem Inflammatory Syndrome”), commonly described in Covid-positive children and occurring at a distance. of the acute phase of infection But equally, given the considerable number of infections, especially in children, in all the countries that have reported cases, a positive serology alone cannot substitute for a causal explanation.

What could argue in favor of the SARS-CoV-2 causal hypothesis is the number of publications since 2020 establishing a link between Covid-19 and post-Covid acute hepatitis. The cases are rare but real, and given that many children were affected by Covid during the winter of 2022, this hypothesis is reinforced although, at present, the difficulty of the experts in confusing the culprits is seen.

About this plural, let’s not forget the accomplices. Because it is also possible that these hepatitis are the result of multiple 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 superantigens whose specific mechanisms, however, remain to be clarified.

Presence of dogs, paracetamol…

Finally, there are assumptions that are considered “outlandish”. Actually, in these stories, as long as the culprit is still at large, nothing should be considered “crazy,” hence the caution in our quotation marks.

Thus, the British – who have reported the largest series of cases in the world, with 197 cases of hepatitis of unknown origin occurring in children reported until May 16 – have confirmed the presence of a dog in the home of 70% of the cases notified. Another fact, 75% of children with hepatitis had taken paracetamol to treat symptoms, although we know that the drug is hepatotoxic when consumed in high doses. However, many Brits have dogs, and the doses of paracetamol were not high in any case…

In short, we wanted to take stock with you, although we are not very advanced, as you can read. However, we are quite confident that the investigation carried out in the countries where these hepatitis have been reported will ultimately be successful and that the culprit(s) 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 only point out that these are sometimes serious events, but very rare. In addition, hepatitis requiring liver transplantation in children is so rare that it cannot be imagined that the exact number is greatly underestimated in developed countries. Business to follow…

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