In a typical year, few children need a liver transplant, and it is usually because they previously had a disease that lowered their immunity. For example, in Spain about 120 child transplants are performed each year, including all organs. And each case is a small tragedy for the families involved.

So when the numbers go out of the norm, the matter is serious. That is why in the medical community, starting with the United Kingdom and continuing with Israel and the USA, alarms have been raised in the face of a sudden and strange outbreak of childhood hepatitis of unknown origin, of which 450 cases are currently known.

Of these, 14% in the US and 10% in the UK have required a liver transplant. In Europe, 232 cases have been recorded, including Spain, with 26 cases so far.

Hepatitis is an inflammation of the liver usually caused by a virus. When it is not treated in time, it may end up being necessary to perform a liver transplant. In children, this type of surgery involves lifelong immunosuppressive medications. Which is not trivial: we all know from the covid pandemic that this predisposes the individual to suffer from infectious diseases with special severity. Another aspect that complicates the issue is that, in order to function well in the long term, the liver to be transplanted must come from another child and not from an adult.

Faced with the new outbreak, it is essential to determine the cause, because it conditions the treatment to be used. Let's not forget that early treatment can prevent liver transplantation.

From the first moment, different hypotheses have been used:

-The first and most obvious was that it was one of the hepatitis viruses, which are five, marked with letters from A to E. This hypothesis was quickly ruled out, since none of the children were positive for these five viruses.

-The next candidate was an adenovirus, since a high percentage of children were positive for adenovirus in blood samples. But there are two problems with this hypothesis. The first is that adenoviruses very rarely cause hepatitis in previously healthy children. And the second, that the liver samples have been negative for adenovirus.

-Another hypothesis that has been considered is that children are especially susceptible to adenoviruses because they have not been in contact with them before due to confinements and school closures. But this hypothesis is not supported either, since some of the children who have suffered from hepatitis are relatively older and had had time to be in contact with adenovirus before the pandemic.

-It has even been postulated that the cause could be pets, such as dogs, but it has not been demonstrated either.

Given the difficulty of finding a simple explanation, the concurrence of several factors is being analyzed, such as, for example, the combination of two viruses. Because SARS-CoV-2 is a new virus that also produces multi-organ sequelae in all types of patients, including children, its involvement has always remained a possibility. And now a new hypothesis has emerged that could definitively link them.

A few days ago, an article was published in The Lancet launching a daring hypothesis that could explain the phenomenon of hepatitis. The first thing to keep in mind is that many of the children affected by this new hepatitis had recently had covid (for example, in Israel it happened in 11 of 12 cases).

It must also be understood that the disease caused by SARS-CoV-2 occurs differently in children compared to adults. For example, in children, traces of the virus are detected in the intestine for a much longer period than in adults (Figure 1). The good aspect of these differences is that in children the disease is usually much milder; the bad, which is sometimes complicated by a multi-organ inflammatory process called MIS-C.

This syndrome appears in a small percentage of children some time (between a few weeks and a few months) after the child has had the disease, even if it has been mild. And it is usually quite serious, to the point of requiring hospitalization.

The liver is one of the most frequently affected organs. In fact, 43% of MIS-C cases result in hepatitis. It is thought that the cause is a deterioration of the intestinal barrier, with traces of the virus entering the bloodstream, which would cause inflammation.

Well, the other piece that is added to this puzzle is the presence in the Spike protein of SARS-CoV-2 of a sequence that resembles another that appears in a toxin from the bacterium Staphylococcus aureus, called enterotoxin B. This sequence it corresponds to what is called a "superantigen", that is, a part of a protein that the immune system perceives as a high danger signal, triggering a very fast and powerful inflammatory reaction. It is thought that a recent mutation that appeared in Europe could increase the similarity.

To add fuel to the fire, it is known that, in mice, an adenovirus infection can generate hypersensitivity against enterotoxin B. With this, we would already have all the pieces of the puzzle. It would be a concatenation of two circumstances:

-A SARS-CoV-2 infection with accumulation of virus in the intestine and release of virus proteins into the bloodstream due to increased intestinal permeability;

-An adenovirus infection that would sensitize the immune system and cause an excessive reaction with the subsequent inflammation of the liver.

This hypothesis at the moment is just that, a hypothesis. It is quite convoluted and it is not going to be trivial to show that it is true. But if proven, children could be treated with steroids early, avoiding liver damage and preventing transplantation. This therapy has already been shown to be effective in some cases in Israel and in another case of a 3-year-old girl in Cincinatti (USA).

On the contrary, if it is verified that the damage to the liver is caused directly by a virus, it would be necessary to continue refining the antiviral treatments.

The lesson we draw from all this is that, in such a complex situation, one must keep an open mind to all possible explanations. And that, unfortunately, not always the simplest is the correct one.

This article has been published in 'The conversation'.