Dr. Matt Binnicker, an expert in the diagnosis of infectious diseases, provides an update on the global outbreak of hepatitis in young children, and discusses the possible causes being investigated by scientists around the world, including the potential role of Covid-19.
During the fall of 2021, physicians in Alabama began to observe an unusual increase in the number of young children diagnosed with hepatitis - inflammation of the liver that may become a serious, life-threatening disease. At first, 5 children were admitted to Children’s of Alabama with symptoms of hepatitis, including yellowing of the eyes, jaundice, and an enlarged liver. Over the next 3 months, 4 more children were diagnosed, but each from a different part of the state and with no apparent epidemiologic link. The only common thread was most had experienced a gastrointestinal or upper respiratory illness in the days preceding their hospital admission, and each of the patients tested positive for adenovirus.
Fast-forward to May 2022, and the number of pediatric hepatitis cases has risen to 450 globally. Eleven children have died. In the United States alone, 109 cases across 25 states have been reported, with more than 90% of children requiring hospitalization, 14% requiring liver transplant, and 5 dying. While the exact cause remains a mystery, more than 50% of children have tested positive for adenovirus, raising suspicion that this common viral infection may be linked to the outbreak. But researchers are also investigating other potential causes, like Covid-19, or the possibility that Covid-19 precautions have decreased natural immunity to common viruses, such as adenovirus.
What is Adenovirus?
Adenoviruses are named from the tissue from which they were first isolated - the adenoids, which is the tonsil and lymphatic tissue where the nose and throat meet. There are more than 50 different types of adenoviruses that can cause disease in humans, and infection with one or multiple types is extremely common. Infection usually results from direct contact with respiratory droplets – coughing or sneezing – or through the fecal-oral route (touching your mouth with unwashed, contaminated hands). In those with a normal immune system, infection generally results in a mild or asymptomatic disease course, with common symptoms including a respiratory illness (cough, sore throat, runny nose), conjunctivitis (eye infection), or gastroenteritis (diarrhea, vomiting). Historically, adenovirus infection in otherwise healthy people has not been associated with liver inflammation.
Is Adenovirus causing a global outbreak of hepatitis in children?
Because many of the early cases of hepatitis occurred in children who had recently experienced a respiratory or gastrointestinal illness, specific testing for adenovirus was performed and the virus was identified in the blood of these patients. Of the 450 total cases to date, approximately 70% have tested positive for adenovirus, and additional studies have shown the majority of these to be adenovirus serotype 41, which is commonly associated with diarrhea and vomiting in infected individuals. Although these results seem to strongly suggest an association between adenovirus and hepatitis, liver biopsies performed in a subset of cases have not shown evidence of adenovirus infection, thereby prolonging the mystery as to the cause of the outbreak.
Could Covid-19 be behind the outbreak of child hepatitis?
Due to the lack of documented adenovirus infection in all reported child hepatitis cases, a significant amount of effort is focused on investigating other potential causes. One possibility is that Covid-19, along with infection by another common virus – like adenovirus – may result in liver disease. In some patients, Covid-19 may hyper-stimulate the immune system and increase the odds that a subsequent viral infection could trigger damaging inflammation.
A second possibility is that Covid-19 alone may be behind the rise in child hepatitis cases. Covid-19 has been associated with a condition called multisystem inflammatory syndrome in children (MIS-C), and a recent study found that children with Covid-19 are at increased risk for liver disease. However, only 18% of the child hepatitis cases have shown laboratory evidence of active SARS-CoV-2 infection. Ongoing studies are investigating whether the children have Covid-19 antibodies, which would suggest prior infection and strengthen the case that Covid-19 may be a contributor.
A third hypothesis is that the significant reduction in adenoviral infections during the Covid-19 pandemic due to precautionary measures such as masking, distancing, and lockdowns has resulted in decreased natural immunity in young children, increasing their susceptibility to infection – and potentially more severe disease. Although possible, this hypothesis seems unlikely, as cases have occurred in children up to the age of 16. Older children are much more likely to have been exposed to adenoviruses, and therefore, possess a level of natural immunity.
Over the next several weeks, new data from a case-controlled study in Britain should provide clearer insight into whether adenovirus infection is an incidental finding or has a causal relationship with child hepatitis. Until then, parents and caregivers should be on the lookout for signs and symptoms of hepatitis in young children, including fever, abdominal pain, and yellowing of the eyes and skin.
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