Public health officials in the US and internationally are actively investigating cases of severe, acute hepatitis without clear cause in children. Concerns were first escalated to WHO in early April based on reports of unusual cases across Scotland (1); as of mid-May, over 100 similar cases across roughly half of US states and territories have been identified, and over 200 probable cases have been identified globally (2). Though hepatitis is a disease that receives regular public health attention and research, this situation is notable for the severity and unknown etiology of cases, as well as the number of flagged cases (1, 2).
Hepatitis is inflammation of the liver (3, 4). It can impair the liver’s normal functioning, which is to process nutrients, filter blood, remove toxins, and fight infections (3). Hepatitis is most commonly caused by viral infection, of which there are five known types (A through E), but it can also be caused by toxins, some medications, heavy alcohol use, and autoimmune conditions (3, 4).
These cases warrant investigation due to their unusual nature. First, most affected children were previously healthy before falling ill. Second, cases drew the attention of specialists who then reported them to public health agencies due to their severity – around 90% of patients in the US required hospitalization, while around 15% required liver transplants, and 4% have died. Though hepatitis in general is not rare, this combination of healthy, young children falling so ill is extremely unusual (2). The liver is normally a relatively resilient organ – its regenerative ability is unique among solid organs, and liver failure is often a result of chronic conditions (5). Third, laboratory testing has excluded hepatitis virus as a cause, and so far, no etiology has been determined (1, 2). Reported symptoms include fatigue, loss of appetite, vomiting, diarrhea, abdominal pain, dark urine, light-colored stools, and jaundice (2). The working case definition used by WHO is someone presenting with “acute hepatitis (non-hepatitis viruses A, B, C, D, E) with aspartate transaminase (AST) or alanine transaminase (ALT) over 500 U/L, who is 10 years old and under, since 1 January 2022” (1).
After the initial alert by UK authorities, public health officials began investigating health records to find similar cases that may not have been drawn significant attention on their own. Possible cases were found in Ireland and Spain soon after (1). Similarly in the US, the CDC was first notified of a cluster of cases in Alabama; subsequent investigation identified possible cases in other areas (2).
Based on current data, the CDC is pursuing adenovirus as a leading possible cause. It is currently the only common factor that has been shared by public health agencies – many but not all of the identified children have tested positive for adenovirus (1, 2). Over 50 adenoviruses are known to be able to infect people, typically causing respiratory illness ranging from a cold to pneumonia and bronchitis, but sometimes causing inflammation in other organ systems (6). Genetic sequencing as a research tool for the cases with confirmed adenovirus infection has been limited by the fact that most samples did not have sufficient genetic material. The few cases that were partially or fully sequenced have all been adenovirus 41. However, this data point raises additional questions as adenovirus 41 has only been linked to hepatitis in immunocompromised children and never yet been linked to liver failure in otherwise healthy children (2). The majority of patients did not test positive for COVID-19 (1, 2).
Ongoing research efforts seek to elucidate the etiology behind these unusual cases of severe hepatitis in children. Though the cases under investigation share key similarities, they have so far not been classified as an outbreak, and the epidemiological risk is thought to be low.
- World Health Organization (15 April 2022). Disease Outbreak News; Acute hepatitis of unknown aetiology – the United Kingdom of Great Britain and Northern Ireland. Available at: https://www.who.int/emergencies/disease-outbreak-news/item/acute-hepatitis-of-unknown-aetiology—the-united-kingdom-of-great-britain-and-northern-ireland
- Brenda Goodman (6 May 2022). CDC investigating more than 100 cases of unexplained hepatitis in children, including 5 deaths. CNN. Available at: https://www.cnn.com/2022/05/06/health/hepatitis-kids-cdc-update/index.html
- Centers for Disease Control and Prevention (28 July 2020). What is Viral Hepatitis?. Available at: https://www.cdc.gov/hepatitis/abc/index.htm
- World Health Organization (n.d.). Hepatitis. Available at: https://www.who.int/health-topics/hepatitis
- Michalopoulos, G.K., Bhushan, B. (2021). Liver regeneration: biological and pathological mechanisms and implications. Nat Rev Gastroenterol Hepatol, 18, 40–55. https://doi.org/10.1038/s41575-020-0342-4
- Centers for Disease Control and Prevention (28 August 2019). Adenovirus. Available at: https://www.cdc.gov/adenovirus/index.html