Hepatitis in children of unknown etiology occurs in many countries, and the latest reports from the United Kingdom and the United States provide detailed analysis

▎ WuXi AppTec content team editor

Recently, many countries around the world have reported cases of acute severe hepatitis in children of unknown origin. The World Health Organization (WHO) has also issued a circular reminding health agencies around the world to focus on severe cases of hepatitis in children and to help identify the cause of the case. Today, the UK Health Security Agency released a report on cases of acute hepatitis in the UK, providing a detailed analysis of these cases and working hypothesis that are being tested. Click "Read more" at the end of the article to download the full report.

Characteristics of patients with acute hepatitis

As of 3 May 2022, a total of 163 children with acute hepatitis (younger than 16 years of age) have been identified in the UK. Their hepatitis was not caused by the hepatitis A-E virus. The most common symptom in patients is jaundice, followed by vomiting, and light stool color is also a common symptom. Histologically, current samples show varying degrees of liver damage, ranging from mild hepatocyte damage to severe liver necrosis. A clear cause of histopathological results has not been found. Of these, 11 patients require liver transplants, no patients have died so far, and 54% of patients have fully recovered or been discharged from the hospital.

At present, new cases are still being detected, and while the number of confirmed cases in the UK has decreased in the past two weeks, the number of cases to be confirmed is still so high that it cannot be asserted that the number of new cases is beginning to decrease.

Prognostic outcomes for child cases of acute hepatitis in the UK (Image source: Reference[1])

Related pathogen studies

Detection of pathogens in patients found that the most common pathogen was adenovirus, in 163 patients, adenovirus was found in the blood of 91 patients, 35 patients tested negative for adenovirus, 4 patient results have not been released, and 33 patients had no adenovirus testing information. The study found that the sensitivity of adenovirus testing was also different for different types of samples. The highest proportion of adenoviruses was detected in blood samples, while adenovirus was detected in stool and respiratory samples. A review of patients with negative adenovirus test results found that some patients received only stool or respiratory samples, and because these tests were not sensitive, it could not be ruled out that patients with negative tests also carried adenovirus.

Of the 33 patients who were able to confirm the virus subtype, 18 had a viral subtype of 41 and 41 of the 6 patients who received liver transplantation had an adenovirus subtype.

Of the cases detected in the UK, 24 patients tested positive for COVID-19 (nucleic acid or antibody testing), accounting for 18% of the total number of patients with test information (132).

▲The type of virus found in the body of a child case of acute hepatitis in the United Kingdom (Image source: Reference[1])

The UK has not recommended COVID-19 vaccination for children under 5 years of age, and no record of COVID-19 vaccination has been found in cases under 5 years of age. This group accounts for more than 75% of acute hepatitis cases. Fewer than 5 cases were vaccinated against COVID-19 before the onset of hepatitis in a patient population over 5 years of age. The report notes that there is no evidence that the COVID-19 vaccine is associated with acute hepatitis in children.

Epidemiological and toxicological studies of the patients did not find a common link between them or the presence of toxins in the body that cause hepatitis.

Hypothesis of the cause of acute hepatitis

The report says the current main hypothesis is that acute hepatitis in children is caused by common adenovirus infection, although adenovirus does not usually cause such severe symptoms of the disease. Causes of severe symptoms may include:

The patient's own abnormal susceptibility or host response makes adenovirus infection more likely to progress to hepatitis

Very large adenovirus infections in the UK have led to an increased frequency of complications that were previously very rare or undetected

Patients have developed an abnormal susceptibility to adenovirus or host responses due to other previous infections, including the coronavirus

Because of concomitant infection with the new crown virus or other infections, there is an abnormal susceptibility to adenovirus or host response

Abnormal susceptibility to adenovirus or host response due to toxins, drugs, and environmental factors

Researchers are also exploring other possible causes of the disease, including the emergence of new variants of adenovirus; post-covid-19 syndromes; drugs, toxins, or environmental factors; entirely new pathogens; and new variants of the coronavirus.

Image credit: 123RF

Today, the US CDC also reported research progress on unexplained cases of acute childhood hepatitis in the United States. There are currently 109 patients being surveyed in the United States, of which more than 90 percent require hospitalization, 14 percent require a liver transplant, and more than half confirmed to have an adenovirus infection. Adenoviruses were found in the blood of all 9 patients initially identified in Alabama, and the adenovirus subtypes of all 5 patients who were able to identify subtypes were 41. None of the nine patients were found to be infected with the new coronavirus during the onset of illness or vaccinated against COVID-19. It is worth mentioning that the presence of adenovirus is not found in hepatocytes, both in the United States and the United Kingdom, and in the liver tissue obtained from patients. So even though adenovirus is the causative agent of acute hepatitis, the mechanism by which it triggers inflammation and damage to the liver remains unanswered.

At present, researchers are conducting research on epidemiology, symptom monitoring of liver disease in children, liver damage mechanisms, pathogen tracking, and patient characterization. It is expected that they will determine the cause of the disease as soon as possible and formulate more effective prevention and treatment plans.

Resources:

[1] Investigation into acute hepatitis of unknown aetiology in children in England, Technical briefing 2. Retrieved May 6, 2022, from https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1073704/acute-hepatitis-technical-briefing-2.pdf#page6

[2] With usual suspects ruled out, disease detectives try to crack mystery of viral hepatitis cases in kids. Retrieved May 6, 2022, from https://www.statnews.com/2022/05/04/with-usual-suspects-ruled-out-disease-detectives-try-to-crack-mystery-of-viral-hepatitis-cases-in-kids/

[3] https://www.statnews.com/2022/05/06/cdc-looking-at-cases-of-109-children-in-suspected-hepatitis-outbreak/

[4] CDC investigating more than 100 cases of unexplained hepatitis in children, including 5 deaths. Retrieved May 6, 2022, from https://www.cnn.com/2022/05/06/health/hepatitis-kids-cdc-update/index.html

[4] Acute Hepatitis and Adenovirus Infection Among Children — Alabama, October 2021–February 2022. Retrieved May 6, 2022, from https://www.cdc.gov/mmwr/volumes/71/wr/mm7118e1.htm

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