Q&A: ‘The search for answers continues,’ expert says about hepatitis outbreak in children
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As the WHO continues its investigation into an outbreak of severe, acute hepatitis of unknown origin in children aged 1 month to 16 years, more questions than answers remain.
Healio spoke with John W. Ward, MD, director of the Coalition for Global Hepatitis Elimination, a program launched in 2019 by the Task Force for Global Health, about the outbreak and emerging data on adenovirus, which has been cited as a potential cause.
Healio: What do hepatologists need to be aware of and what symptoms should parents and physicians be looking out for?
Ward: This cluster of cases has been reported from European countries and the United States. A case was recently reported from Israel. It is not unusual for young children to get mild forms of hepatitis. However, in this cluster of cases, it is the severity of the hepatitis leading to liver transplant and one case, unfortunately, to mortality that is raising concern. At the moment, the number of cases globally is not large. However, clinicians should be aware of these reports, be vigilant for signs/symptoms of hepatitis and, when evident, test for the serologic markers of liver inflammation or hepatitis.
Similarly, parents and caregivers can be on the lookout symptoms such as fever, fatigue, loss of appetite or nausea, diarrhea and vomiting. Signs of hepatitis include tenderness in upper right area of the abdomen, yellowing of the eyes and skin, dark urine and clay-colored stools. If those symptoms and signs appear, parents and caregivers should take a child for further clinical evaluation.
Healio: What do we know about the outbreak?
Ward: The search for answers continues. What is causing these cases is the big question for researchers and public health officials responsible for these investigations. A particular family of viruses known as adenoviruses is a suspected cause. These viruses circulate quite commonly, particularly in the spring, causing cold-like and gastrointestinal symptoms. These diseases are typical and resolve on their own, particularly in children without any immune defects or immunosuppression.
There is one strain of virus, adenovirus F 41, that is a cause of gastrointestinal illness that has been isolated among a good number of these cases, raising suspicion that this viral strain is the cause of hepatitis in these children. Previous studies have found this strain of virus can cause severe hepatitis in persons who have immunosuppression; however, this virus has not caused severe hepatitis among children with normal immune systems. That is the real puzzle.
What is causing this severe hepatitis? You really have to think about a variety of possibilities. First, are there now detection and reporting systems in place to find rare cases of severe hepatitis in children that previously went unrecognized? For example, the response to COVID-19 could have improved viral detection systems. It is best to think of these as clusters of cases rather than an outbreak linked to a common exposure or infection.
Second, is there a certain cofactor or comorbidity with some other disease that is coming together with the adenovirus infection, making the viral infection more severe? It is interesting that there are a good number of cases with SARS-CoV-2, the cause of COVID-19, and adenovirus. It will be interesting to see if the investigations reveal cofactors increasing severity of illness in these children.
Third, has the adenovirus itself changed or mutated and, as a result, the cause of more severe liver disease? Also, we are in the springtime and that is when adenovirus circulates widely. Investigators are mindful that the adenovirus could be an innocent bystander with the real cause of the hepatitis some other agent yet unidentified.
Even though we have early suggestive evidence of adenovirus, other agents could be playing a role or could actually be the cause. Toxins are a possibility, but there is no data on possible exposures to toxins, such as in a medication, vitamins or food.
Hepatitis is not infrequent in children, but it is just not as severe as in these cases. The known causes of hepatitis in children remain possibilities. The early evidence implicates an adenovirus, but additional evidence is required for a definitive answer. Is an adenovirus a new cause of severe hepatitis in children or are there other cofactors or infectious causes agents yet to be identified? This is the open question.
Healio: Can you speak to the SARS-CoV-2/adenovirus co-infection found in 19 children thus far?
Ward: COVID-19 on its own does not cause severe hepatitis in children. It is definitely up in the air whether these two viruses are coming together. We need to look at whether SARS-CoV-2 and adenovirus cause greater insult and damage to the liver together than they do individually.
Visit the CDC or WHO for information on the ongoing investigation and how to report cases.
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Clusters of Children with Severe Acute Hepatitis Reported Globally: Is Adenovirus F- 41 the Cause? https://www.globalhep.org/news/clusters-children-severe-acute-hepatitis-reported-globally-adenovirus-f-41-cause. Published April 25, 2022. Accessed April 26, 2022.
Healio Interview
Multi-Country – Acute, severe hepatitis of unknown origin in children. https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON376. Published April 23, 2022. Accessed April 26, 2022.
Mystery outbreak of severe hepatitis in children prompts worldwide surveillance. https://www.healio.com/news/gastroenterology/20220426/mystery-outbreak-of-severe-hepatitis-in-children-prompts-worldwide-surveillance. Published April 26, 2022.
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