In May of 2020, I discussed a rare and mysterious inflammatory condition that at the time had only been diagnosed in a few hundred children around the world. This Multisystem Inflammatory Syndrome in Children (MIS-C), which involves severe systemic inflammation and potential injury to numerous organs, in particular the heart, was ultimately linked to prior infection with the SARS-CoV-2 virus. As of March 28th of 2022, MIS-C has been diagnosed in almost 8,000 children in the United States alone, and there have been 66 known deaths.

The cases of COVID-19 that eventually result in MIS-C tend to be mild or even asymptomatic, a fact often ignored by people downplaying the potential harms of infection in young children. It also occurs in a mostly random pattern, meaning that any child who is infected with SARS-CoV-2 is at risk. Death is clearly not the only outcome of concern in kids, who are also not immune to the potential for lingering and potentially life-altering symptoms related to long-haul COVID.

Here we go again. Maybe. Well, probably not. Still…sheesh!

Last week, the CDC issued a health advisory via the CDC Health Alert Network to notify clinicians and public health authorities of a worrisome cluster of children diagnosed with severe inflammation of the liver, some of which ultimately required a liver transplant. They also warned of a possible link to a viral infection, though it doesn’t appear to be SARS-CoV-2 this time around. In this case, the most likely culprit is an adenovirus, specifically adenovirus serotype 41.

Back in 2018, I actually wrote about adenovirus infections after several children in a New Jersey nursing home died from severe respiratory disease during an outbreak of adenovirus serotype 7. I discussed the existence of a safe and effective vaccine that has historically only been available for military use but reasonably could, and probably should, be used in a focused manner in high-risk populations. Please check out that post for a more thorough primer on this fascinating family of viruses.

In a nutshell, however, adenoviruses are a well-known cause of febrile illnesses in children, but they can cause disease throughout the human lifespan. Typically when we think of adenoviruses, upper respiratory infections come to mind as they are primarily a cause of the common cold. But there are seven species of adenovirus that infect humans, with more than 60 serotypes between them, and exhibit a variety of clinical presentations. In addition to upper and lower respiratory infections (colds and pneumonia), adenoviruses can infect the GI tract (vomiting and diarrhea), the genitourinary tract (hemorrhagic cystitis), the eyes (pink eye), brain (meningitis and encephalitis), and heart (myocarditis). They can also cause disseminated disease, meaning that the virus gets pretty much everywhere.

Some of the specific clinical presentations seen with various adenovirus infections can provide clues as to the specific serotype involved. Serotypes 3 and 7 are associated with the combination of sore throat and pink eye while 11 and 21 are more likely to infect the bladder. 40 and 41 mostly cause diarrhea. Respiratory symptoms can be caused by many different serotypes, though severe disease is often the result of infection with 3, 4, 7, 14, and 21. Most adenoviral disease is mild and resolves with simple supportive care, but any serotype can cause severe, atypical, or even fatal disease in someone who can’t mount an effective immune response.

An unusual cluster of hepatitis cases

The first reported spike in cases of pediatric liver inflammation, known generally as hepatitis, came out of Alabama. In November of last year, a single hospital reported five children with severe liver injury, three of which would ultimately develop liver failure. All five of these children were found to have an adenoviral infection and all were negative for COVID-19.

A targeted search led to the discovery of four additional cases, bringing the total to nine children, all young (1-6 years) and previously healthy, from October 2021 through February 2022. These children had no identified common exposures or epidemiological link. Genetic sequencing revealed that seven of the nine cases were associated with adenovirus serotype 41, which is not a known cause of hepatitis except in patients who have a severely compromised immune system. Healthy children infected with adenovirus 41 normally develop respiratory symptoms, vomiting, and diarrhea.

Hepatitis isn’t an uncommon condition, even in children. And it is typically caused by a viral infection. Hepatitis caused by the hepatitis A virus, which is easily spread via the fecal-oral route, used to be common in the United States but has decreased by 95% thanks to a childhood vaccine that was added to the schedule in the mid-90s. The hepatitis B, C, D, and E viruses are also well-known causes of liver inflammation, though not particularly common in children, at least not here.

Cytomegalovirus, herpes simplex virus, varicella-zoster virus (chickenpox), various enteroviruses, rubella, parvovirus, and some adenoviruses are all potential causes of hepatitis as well. As a pediatric hospitalist closing in on twenty years of practice, I’ve seen several cases of hepatitis which have almost always been mild and associated with Epstein-Barr virus, which is more infamously known for causing infectious mononucleosis or “mono”. I’ve managed one teenage patient with chronic hepatitis B infection and also diagnosed one child with an autoimmune hepatitis. And I have taken care of a handful of patients with liver damage caused by an intentional acetaminophen overdose.

Severe hepatitis in kids, especially young children, is pretty darn uncommon. A cluster of nine such cases in one hospital over just a few months stands out as quite unusual, hence the CDC alert. And this was not the only cluster.

The United States is not the only country experiencing a spike in cases of severe pediatric hepatitis. The World Health Organization released a similar alert last as the number of regions involved quickly grew. In their April 23rd Disease Outbreak News publication, the WHO revealed that at least 169 cases had been reported from 11 countries in the European Region and one the Region of the Americas (that’s us). The United Kingdom and Ireland, were the first reports originated, had by far the most cases at 114.

Of the 169 total cases at that point, all involved children under the age of 17 years. 17 of these patients ended up requiring a liver transplant and at least one had died. Adenovirus was detected in at least 74 cases, 18 of which were further specified as serotype 41. 20 were positive for SARS-CoV-2 and 19 had co-infection with SARS-CoV-2 and adenovirus. The WHO says that common viral causes of hepatitis were ruled out in each case and that no particular risk factors, such as international travel, were identified.

Since the CDC and WHO alerts were issued last week, there have been additional cases reported in other states. Although not confirmed by the CDC, it appears that the first death related to this condition in the United States has now occurred in Wisconsin. Cases have also been reported in North Carolina. From a global perspective, Canada and Japan have also joined the list of countries reporting possible cases. There is good reason to worry that this is just the beginning, but cases are still thankfully rare.

What is going on and could it be related to COVID-19?

With everything that has happened over the past two years, it is understandable to try to make a connection between the SARS-CoV-2 pandemic, which again has already been causally linked to other unusual outcomes, and a surprising cluster of severe liver disease in kids. But so far, the leading hypothesis really is adenovirus serotype 41. The United Kingdom, where the bulk of these cases have been diagnosed, has seen a significant increase in community adenovirus infections and detection in wastewater compared to 2020 and 2021. It’s unlikely that this is a coincidence.

But adenovirus serotype 41, or really any adenovirus serotype, shouldn’t be causing severe hepatitis like this in children that are healthy. So what gives? Over the past two years, with the exception of COVID-19 children have largely been spared from viral infections in many regions because of increased caution, masks, school closures, etc. Thus there is a much larger than typical number of non-immune children at risk of adenovirus infections as things relax. With larger numbers of infected kids, the possibility of seeing even very rare potential complications increases.

It is possible that there has been a genetic mutation in adenovirus serotype 41 which has increased its virulence, or that co-infection with adenovirus serotype 41 and another virus, such as SARS-CoV-2, is causing atypical disease. One thing that is clear is that this is not a side effect of any COVID-19 vaccine because most of the cases have been seen in children too young to have received one. Ultimately, we need more data from detailed investigation into these and additional cases that pop up as surveillance increases, and we need to keep an open mind to a possible cause that nobody has even thought of yet.

Author

  • Clay Jones, M.D. is a pediatrician and a regular contributor to the Science-Based Medicine blog. He primarily cares for healthy newborns and hospitalized children, and devotes his full time to educating pediatric residents and medical students. Dr. Jones first became aware of and interested in the incursion of pseudoscience into his chosen profession while completing his pediatric residency at Vanderbilt Children’s Hospital a decade ago. He has since focused his efforts on teaching the application of critical thinking and scientific skepticism to the practice of pediatric medicine. Dr. Jones has no conflicts of interest to disclose and no ties to the pharmaceutical industry. He can be found on Twitter as @SBMPediatrics and is the co-host of The Prism Podcast with fellow SBM contributor Grant Ritchey. The comments expressed by Dr. Jones are his own and do not represent the views or opinions of Newton-Wellesley Hospital or its administration.

Posted by Clay Jones

Clay Jones, M.D. is a pediatrician and a regular contributor to the Science-Based Medicine blog. He primarily cares for healthy newborns and hospitalized children, and devotes his full time to educating pediatric residents and medical students. Dr. Jones first became aware of and interested in the incursion of pseudoscience into his chosen profession while completing his pediatric residency at Vanderbilt Children’s Hospital a decade ago. He has since focused his efforts on teaching the application of critical thinking and scientific skepticism to the practice of pediatric medicine. Dr. Jones has no conflicts of interest to disclose and no ties to the pharmaceutical industry. He can be found on Twitter as @SBMPediatrics and is the co-host of The Prism Podcast with fellow SBM contributor Grant Ritchey. The comments expressed by Dr. Jones are his own and do not represent the views or opinions of Newton-Wellesley Hospital or its administration.