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Adenovirus-Associated Hepatitis in Children: An Emerging Infectious Disease?

“While severe hepatitis with acute liver failure is rare in healthy children and the odds are greatly in your child’s favor should they get hepatitis, your best defense right now against the current, rare cases is information.”

- Amanda Loudin, American freelance writer


“These kids just looked yellow; eyes, skin, everything. They looked like a jaundice newborn, and that is really concerning for liver disease.”

- Markus Buchefellner, M.D., University of Alabama, pediatric infectious diseases fellow sounding the alarm on adenovirus-associated hepatitis in children



It appears another emerging infection is rearing its ugly head, and we should all be paying close attention. On May 3, the World Health Organization (WHO) reported that the number of cases of a new and mysterious form of childhood hepatitis had jumped to at least 228 cases in 20 countries, including more than 20 children in 10 states in the U.S. Researchers are currently calling the illness “hepatitis of unknown origin,” but mounting evidence points to an exceedingly rare cause of severe hepatitis—adenovirus type 41. In this Germ Gems post, I provide a brief overview of viral hepatitis and then put this new emerging infection in perspective.

What is hepatitis and what causes it? Hepatitis refers to inflammation of the liver. While it can be caused by a variety of toxins and some medications, the most common cause of hepatitis by far is a viral infection of the liver. A multitude of viral pathogens can target the liver where they provoke an inflammatory reaction. The most common are hepatitis A, B, C, D, and E, but herpes group viruses (cytomegalovirus, Epstein-Barr virus, and herpes simplex virus), yellow fever virus, and, rarely, other types of viruses, including one named adenovirus, can infect the liver.


Typical symptoms of acute hepatitis are fever, fatigue, loss of appetite, abdominal pain, nausea, and vomiting. Dark urine and a yellow discoloration of the skin and/or eyes (jaundice)—consequences of an elevated serum bilirubin—can point to the diagnosis. Characteristic of the disease are very high blood levels of enzymes called transaminases that are made in the liver as well as bilirubin. While most cases are mild and self-limited, severe cases of acute hepatitis may progress rapidly to liver failure marked by poor hepatic synthetic function reflected by an elevation of blood prothrombin time (PT), a blood clotting factor made by the liver.


Hepatitis A (also called infectious hepatitis) is acquired by the fecal-oral route; it is very common in areas of the world where good hygiene isn’t practiced. Hepatitis B (or serum hepatitis) is acquired by the sharing of infected needles by drug users or sexual exposure. This is also the case with hepatitis C.


About 1.5 million people die from viral hepatitis annually, most of them in East Asia due to hepatitis B and C. Hepatitis B infections result in more than 1 million deaths per year worldwide, and hepatitis C virus kills about 300,000 a year. Chronic liver disease is a sequela of both hepatitis B and C as is cancer of the liver. Effective vaccines are routinely given to children to prevent hepatitis A and B, and virologists are working on a vaccine for hepatitis C.


“Hepatitis of unknown origin” in children: what parents should know. The WHO’s recent report of the outbreak of severe hepatitis in children involved children between the ages of 1 month and 16 years. The first cases were concentrated in the U.K., with additional cases appearing in Spain, Israel, the U.S., Denmark, Ireland, the Netherlands, Italy, Norway, France, Romania, Belgium, and Asia.


Most of the children presented with gastrointestinal symptoms such as vomiting, diarrhea, and abdominal pain, followed by development of jaundice. Interestingly, fever was an uncommon symptom. Of note, all the children were previously healthy and had no contacts in common. The most striking aspect of the disease is its severity—at least 17 of these children required liver transplantation.


Clinicians began looking for the cause of this “hepatitis of unknown origin” by ruling out the common viruses associated with acute viral hepatitis—hepatitis A, B, C, D, and E. But in at least 74 cases, they identified an unusual pathogen of liver disease—adenovirus type 41.

Adenovirus belongs to a class of common viruses that typically cause self-limiting infections of the gastrointestinal and respiratory tracts in humans. (Scientists first isolated adenovirus from adenoid tissue, thus its name.) There are more than 50 adenovirus types that can infect humans. Of the “hepatitis of unknown origin” cases that were subjected to molecular testing, scientists found 18 cases that involved adenovirus type 41. Adenovirus type 41 has never before been closely linked with severe hepatitis; it most often causes diarrhea and vomiting. According to the WHO, “While there have been case reports of hepatitis in immunocompromised children with adenovirus infection, adenovirus type 41 is not known to be a cause of hepatitis in otherwise healthy children.”


The WHO is also investigating connections between this hepatitis outbreak and COVID-19, which was identified in 20 cases. But the role of SARS-CoV-2 in this outbreak of hepatitis in children is currently unknown.


The Center for Disease Control and Prevention (CDC) reported that the first confirmed cases in the U.S. were nine children in a pediatric hospital in Alabama admitted between October 2021 and February 2022. By May 6, 2022, the CDC was investigating 109 cases in 25 states. The median age was two years. The hepatitis was considered severe in more than 90% of the cases; 14% underwent liver transplantation, and five children died.


The CDC is considering adenovirus as a possible contributing factor in the U.S cases. (Adenovirus was recovered from more than half of the patients.) In an analysis of the nine Alabama cases, scientists detected adenovirus in the blood samples of all nine children. Five of the nine tested positive for adenovirus type 41. None of the children tested positive for COVID-19 or had a documented history of previous COVID-19 infection. According to the CDC, “while the growing consensus among experts is that adenovirus could be behind these severe cases, there are many unanswered questions, such as why this strain of adenovirus causes such severe hepatitis.”


Adenovirus type 41 acute hepatitis in children—yet another “emerging infectious disease?” Even though adenovirus type 41 has not as yet been established as the cause of these cases of “severe hepatitis of unknown cause in children,” it is certainly the prime suspect. If its etiologic role is confirmed, the discovery of what appears to be a new infectious disease shouldn’t come as a surprise given the numerous emerging infectious diseases epidemics that we have faced during the last 50 years. But what can be learned from these earlier emerging infectious diseases that might be relevant to understanding the new outbreak of acute hepatitis in children, due presumptively to adenovirus type 41?


While the WHO and CDC are still investigating the source(s) of adenovirus type 41 infections, we do know that the biggest contributor to the extraordinary acceleration of emerging infections is transportation of people and food by planes. There is almost no better way to spread germs as far and wide, or as rapidly as by air transportation. The recent cases of severe hepatitis in children quickly cropped up around the world, and it’s possible that adenovirus type 41 hitched a ride in infected airline travelers, or possibly in contaminated food products.


We also know that more than 60% of the estimated 140 emerging infections in humans in the last 50 years were transmitted to us from animals. So far, a zoonotic (animal to human) source hasn’t surfaced in this recent hepatitis outbreak, but the potential role of animals will almost certainly be investigated.

What can parents do? Parents should be aware of the symptoms of acute hepatitis and should contact their primary care provider with any questions or concerns should their child develop symptoms. It is important to get medical care quickly to diagnose and treat the condition.


There is, however, no specific treatment for acute hepatitis. Instead, treatment, in general, is mainly supportive, e.g., intravenous fluids if dehydration is a problem. Liver transplantation is rarely needed with acute hepatitis but when it is, it can be lifesaving. The good news is the liver is capable of complete healing, and long-term effects after recovery from hepatitis are not expected.


In the meantime, until more is learned about how adenovirus 41 is transmitted, thorough handwashing with soap and water is highly recommended. But as the Institute of Medicine warned in its landmark book published 30 years ago, Emerging Infections: Microbial Threats to Health in the United States, “washing our hands” of “emerging infectious diseases” is much easier said than done.

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Main Page images courtesy of Shuxian Hu, MD. Dr. Hu is a scientist in the Neuroimmunology Research Laboratory at the University of Minnesota.

 

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