PremiumJust when we thought that we had a little respite from the pandemic, there seems to be a new medical mystery on the horizon. In the United Kingdom, over 100 children—most under the age of five—have suffered from liver inflammation and damage (also known as hepatitis). The first cases in Scotland were detected in January where public health authorities noticed a spike in cases of young children with liver damage requiring hospitalization. Because of the unusual and serious nature of the causes, a health alert was put out in the UK. The World Health Organization (WHO) was informed in April, and additional cases were reported. These cases of hepatitis of unknown cause in children have now been reported in over 20 countries, including the US, Spain, Israel, Denmark and Indonesia.
At the time of writing, there were a few plausible theories on why these cases were occurring. However, no definitive cause had been established. Hepatitis is a response to liver injury. It is a non-specific response that can result from an infection or from other causes. Environmental factors such as toxic exposure and consumption of too much alcohol can also result in hepatitis. Tests for known viruses that cause hepatitis (hepatitis viruses A, B, C, D and E) have turned out negative. In fact, hepatitis in the absence of detectable hepatitis viruses is part of the probable case definition provided by the WHO.
The sick children show acute signs of liver inflammation with a detectable increase in liver enzymes. Many children have gastrointestinal symptoms such as abdominal pain, diarrhoea and vomiting. Fever has not been reported. But these symptoms can occur with many different illnesses that occur in children. The classic symptom of hepatitis is yellowing of the eyes or skin due to jaundice. Jaundice has also been detected in many children.
The WHO probable case definition is a person presenting with acute hepatitis (not caused by hepatitis virus A through E) with serum transaminase elevated greater than 500 IU/L. Serum transaminases are enzymes that are hallmarks of acute liver damage. To fit the probable case criteria, the patient must be 16 years and younger with acute hepatitis occurring on or after October 2021, which is when the first cases cropped up in a hospital in Alabama, US. Anyone of any age who reports acute hepatitis (not caused by hepatitis virus A-E) and who is in contact with a probable case is of epidemiological interest. However, it isn’t known if these cases of liver injury are caused by an infectious agent; international travel does not seem to be a factor.
Around 90% of the children who fit the case definition had to be hospitalized. Approximately 10% were sick enough to require liver transplants. These cases have occurred in children as young as one month old and as old as 16 years (which is the upper limit of the probable case definition). Tragically, a few children have died.
A new virus?
There is some speculation that an infection with a new virus or a virus that typically does not cause hepatitis is responsible for these cases. There are also theories that the serious hepatitis might be caused by a toxic agent. Both are plausible. However, with rising cases globally, experts have noted that a single source of toxin that is dispersed around the world in amounts that can cause severe damage in multiple children seems less likely. A toxic agent is more likely when cases are geographically clustered in one location. That said, seasonal differences in weather and pollution could be one predisposing factor that researchers might look at.
There are also a few theories that SARS-CoV-2, the causative agent of covid-19 might be indirectly responsible. Although covid-19 is associated with multiple different symptoms in people, hepatitis in children is not one of them. Post-infection hepatitis has not been observed in children in large numbers during two years of the pandemic in which time there were millions of SARS-CoV-2 infections.
Indeed, WHO has indicated that SARS-CoV-2 infection is not one of the probable case identification criteria. Further, most of the sick children did not have an active SARS-CoV-2 infection at the time of their hospitalization.
However, it is plausible that prior SARS-CoV-2 infection during the past two years reduced the ability of some children to deal with a second infection that led to hepatitis. Even after SARS-CoV-2 has been cleared, some people encountered damage to tissues inside their bodies. Quite often, this damage has resulted from the immune system attacking parts of the body. It is conceivable that such an aberrant immune response might be triggered in some children when they’re exposed to another virus. But this would also beg the question: why are only a few children suffering from hepatitis and why now?
It is also possible that social isolation during the past two years reduced exposure to many known and unknown viruses that children normally face. Hepatitis might be caused by a virus that typically would not lead to such severe symptoms and atypical presentation. Children under the age of five, who seem to be most affected, have come out of isolation and are facing a broad swathe of viruses in winter and spring in the northern hemisphere now. This might be leading to their immune systems responding in a way that is leading to liver damage. There could be a combination of factors that make some children susceptible to this kind of severe liver damage.
In the US, the Centers for Disease Control and Prevention is examining over 100 cases. In Alabama, four children had to be hospitalized with jaundice (an outcome of hepatitis) in a timespan of two weeks in October. Normally, the hospital would see that many cases in a year. None of these children tested positive for SARS-CoV-2 or the hepatitis viruses, but all tested positive for a kind of adenovirus.
The adenovirus play
This is one pattern researchers are noting, though whether there’s a causative association has not been established. Many of the sick children around the world are showing up with one particular kind of adenovirus.
Adenoviruses can cause respiratory and gastrointestinal symptoms, but infections are mild, and they typically get better on their own. Adenovirus infections spread from one person to another through surfaces, close contact and respiratory droplets. There are over 50 different kinds of adenoviruses that have been identified. The identified adenovirus (type 41) is a known virus that can cause diarrhoea, vomiting, fever. It’s present in a significant majority, but not all, cases of hepatitis of unknown cause in children.
The twist is that the adenovirus type that has been detected does not cause liver damage in otherwise healthy children (though it has been known to cause hepatitis in some immunocompromised children). Researchers are racing to sequence the genome of the virus that has been isolated from the children with hepatitis to see if it is markedly different from other adenoviruses. As we have seen with variants of SARS-CoV-2, mutations in genes that encode for different viral proteins can impact the ability of the virus to infect different people and different cell types in the body. Mutations can also alter the symptoms of a viral disease.
Adenoviruses are extremely common and an altered adenovirus was used as a vector for many covid-19 vaccines. But there is no cause for alarm that the hepatitis is an adverse effect of a covid-19 vaccine— a vast majority of the children who were identified with liver damage had not been vaccinated.
The presence of one kind of adenovirus in otherwise healthy children with hepatitis is one of the prime reasons that many researchers think there might be a secondary factor such as a weakened immune response, an environmental toxin, or perhaps even a second infectious agent that has not been identified. A new virus that causes hepatitis in conjunction with the identified adenovirus would ring alarm bells, but right now, there is no reason to suspect that we are dealing with an unknown infectious agent.
The WHO has observed in the UK “a significant increase in adenovirus infections in the community (particularly detected in faecal samples in children) following low levels of circulation earlier in the COVID-19 pandemic." It is still too early to say what the biological significance of this observation is. It could be that more testing is resulting in more cases of adenovirus being picked up.
Needed: Global surveillance
There is, after all, the matter of better surveillance. Some of the cases in children are being detected because we are looking for cases of hepatitis of unknown cause.
Yet, given the severe nature of hepatitis in otherwise healthy children, global surveillance is necessary. Most of the children being investigated are sick enough to require hospitalization. The good news is that in most cases, the liver recovers after hepatitis.
Could a rise in cases of hepatitis in children with no known cause also be reported from India? It is possible that there already are cases that have gone undetected since the presence of the known viruses that cause hepatitis have to be ruled out to fit the definition. It is easier to detect new cases of hepatitis (of no known cause) when the total number of cases every year is low, which may explain why cases were originally noticed in the UK and the US. However, a common thread in all the cases (apart from the lack of a known cause) is the severity of liver damage in otherwise healthy children. Now that a probable case definition has been provided by WHO, it certainly is possible that cases will be detected in India.
It may also be that some children are more susceptible than other others. If a type of adenovirus is implicated, then it may be that some children are better at clearing it without liver damage (perhaps due to prior exposure). But we need to first know what is causing hepatitis in these children. There may be one or several causes and they may be unrelated. We don’t know what the common characteristics are, if the patients have been exposed in the same way, and if the cause is an infectious agent. We don’t know how it is spread.
As of late April, the WHO was not even certain if the increase in cases was caused by something new or because of an increase in awareness of cases that normally would go undetected. In other words, some of the cases might have been identified because researchers were looking for them. In a normal year, there are some children who get very sick with liver damage with no underlying factors or cause identified.
The WHO also notes that adenovirus as a causative agent is a “possible hypothesis", but other possible infectious agents and non-infectious causes of hepatitis (such as toxin exposure) must be ruled out. Right now, it is important to be aware of the signs and symptoms, but there is no cause for panic. We are currently dealing with a nonspecific response due to an unidentified cause in a very small number of children spread across the globe. Clinical samples from some of the children are being examined. It is very likely that more cases will be reported before the cause is known. And until the cause is known, specific guidance on prevention is unlikely to be provided by public health authorities.
Anirban Mahapatra is a scientist by training and the author of a book on covid-19. These are his personal views.
