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Acute, Severe Hepatitis of Unknown Origin in Children - the State of Play

Child Hepatitis
Photo: Janko Ferlic via Unsplash

[This text has been written by Jeffrey Lazarus, head of the Health Systems Research Group at ISGlobal, and Meaghan Kall, epidemiologist at the UK Health Security Agency]

Since an outbreak of acute non-A-E hepatitis affecting children in the United Kingdom was announced this past April, more than 650 cases occurring over the last seven months in several European countries, the United States, Israel, and Southeast Asia have been identified. Acute hepatitis (sudden inflammation of the liver) can be caused by infections, medications, excessive alcohol intake, environmental toxins, and autoimmune disorders, among other possibilities. However, most known causes of hepatitis have been ruled out in this outbreak. The underlying cause of acute hepatitis in these cases remains a mystery, and many potential explanations are being pursued. As additional pre-existing and new cases are identified, researchers rush to find a plausible culprit and an in-depth understanding of the mechanism of illness in order to prevent it from affecting more children.

What is Known?

Reports of children with acute hepatitis are increasing, with the majority of cases being identified in the United Kingdom (222 as of 25 May 2022) and in the United States (180 as of 5 May 2022). Most of those affected were previously healthy and aged between one month and 16 years of age, with the majority being under the age of ten and in Europe 75% under the age of five. A small, but nonetheless relevant, number (38 as of 27 May 2022) have required liver transplantation, and at least nine deaths have been reported. Most children presented to care with gastroenteritis (diarrhoea, nausea, vomiting) and jaundice (yellowing of the skin and whites of the eyes). Other reported symptoms are listed as dark-coloured urine, pale and/or gray-coloured stools, itchy skin, a high temperature or fever, muscle and joint pain, loss of appetite, stomach pain or general discomfort.

As of now, the most common causes of acute hepatitis have been eliminated. No common exposure to drugs/medication, toxins or other environmental factors has been identified among the affected children, and researchers have ruled out viruses that most commonly cause hepatitis (such as hepatitis A, B, C, D and E). This has narrowed the possible causes to a handful of hypotheses which are actively being investigated.

Michael Mims via Unsplash.

The Adenovirus Hypotheses

One leading hypothesis is that adenovirus (a common virus that causes mild cold or flu symptoms) may play a role. Adenovirus has been the most commonly detected infectious agent in these mysterious cases in children (found in nearly half of children in the US and two-thirds of cases in the UK). This hypothesis is further supported by the fact that approximately 25% of the cases had the same adenovirus serotype, known as adenovirus F41 and that many of the youngest children may not have been exposed to adenovirus previously when infection rates were at an all time low during the COVID-19 pandemic.

However, before this outbreak, adenovirus F41 was not known to cause acute hepatitis in healthy children. Instead, it was associated with mild gastrointestinal illness and more severe disease in children with deficient immune systems. Moreover, not all cases in this outbreak have tested positive for this virus, and the specific mechanisms as to why it would cause liver damage now is not known. Maybe our improved laboratory technology and enhanced surveillance activities are allowing us to detect a disease that was previously going unnoticed, or maybe there is an interplay between adenovirus infection and some other, still unknown, factor. Some of the factors that are being considered include an abnormally large wave of normal adenovirus infections and increased susceptibility after decreased exposure to adenovirus during the COVID-19 pandemic.

Other Working Hypothesis

While the adenovirus hypothesis is investigated, other infectious and/or non-infectious etiologies along with novel variants of adenovirus and SARS-CoV-2 (particularly the Omicron variant) continue to be explored. Active or recent SARS-CoV-2 infection has been detected in only 15% of children affected in the UK, but serologic studies to determine the prevalence of past infection will provide important information regarding the possibility of a post-infectious SARS-CoV-2 syndrome. One possibility is that previous or current SARS-CoV-2 infection is interacting with adenovirus or another infection to cause a severe inflammatory immune reaction. In Europe, of 19 cases with serology reports for SARS-CoV-2, 74% were positive. However, serological data will be difficult to interpret given the high infection rate, particularly during the Omicron wave. No connection to the COVID-19 vaccine is possible as nearly all affected children were too young to be eligible for vaccination.

CDC via Unsplash.

Finally, research teams are conducting a range of tests to definitively rule out potential exposures to environmental toxins, like those produced by some fungi, and medications such as paracetamol and fluconazole, which are used for pain relief and treatment of fungal infections, respectively. 

While there is evidence to support that adenovirus is a possible cause, it appears unlikely to fully explain the severity of the illness. According to WHO and the European Centre for Disease Prevention and Control (ECDC), the aetiology and pathogenetic mechanisms of this hepatitis outbreak remain unknown.


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