Clusters of Children with Severe Acute Hepatitis Reported Globally: Is Adenovirus F- 41 the Cause?

Clusters of Children with Severe Acute Hepatitis Reported Globally: Is Adenovirus F- 41 the Cause?

Dr. John W. Ward, Director of the Coalition for Global Hepatitis Elimination

The World Health Organization (WHO) reports, as of April 21, 2022, at least 169 cases of acute hepatitis of unknown origin in children one month to 16 years of age. Of these cases,17 children required liver transplantation, and one child died. Demographically, 160 were from 11 European countries, and nine were from the United States. No case has evidence of viral hepatitis A, B, C, D, or E. WHO reports detection of an adenovirus (HAdV) in at least 74 of these cases. 18 cases were identified as the adenovirus F type 41. The F type 41 type is a cause of gastrointestinal distress, which aligns with patient reports of symptoms.   

What are the data for HAdV as a cause of acute hepatitis before these recent cases?

HAdV hepatitis is relatively uncommon and is detected most frequently in immunosuppressed persons. Among those patients with adenovirus, rates of hepatitis range from  < 5% among persons with various causes of immunosuppression to 18% among adults receiving bone marrow transplants. The mortality rates of these immunosuppressed patients with HAdV hepatitis are approximately 50%.  HAdV hepatitis is rare among patients with no immune suppression. Indeed, studies of HAdV rarely reveal severe hepatitis in children with functional immunity. For example, in an earlier study of 78 hospitalized children who were immunocompetent with detection of adenovirus, 39 (50%) had hepatomegaly (enlarged liver), and 26 patients (45%) had elevated ALT levels, a marker of liver inflammation. Notably, none of these cases reported liver failure or liver-related mortality.

Searching for  answers

As the investigation continues, we will learn more. Perhaps viral detection, diagnosis, and/or reporting have improved, which seems likely given COVID-related investments in testing and surveillance. As a result, cases are clustered in time without representing an outbreak linked by a common cause of disease. Data also are needed regarding co-morbidities increasing the risk of severe forms of HAdV hepatitis. Of interest, SARS-CoV-2 was identified in 20 cases reported to WHO, including 19 with SARS-CoV-2 and adenovirus co-infection. Perhaps there are substantive genetic changes increasing HAdV virulence. The structure of adenovirus  F 41 was recently mapped. Also, other causes of acute hepatitis remain possibilities. The differential diagnosis of acute liver disease in children includes a range of infectious, metabolic, and other conditions. Indeed, many cases do not have specific diagnoses, yet liver failure and transplantation were rare before this outbreak.

Reports of additional cases will assist investigations. The US Centers for Disease Control and Prevention (CDC) requests reports of acute hepatitis, ALT> 500 U/L, of an unknown cause among children less than ten years of age. WHO advises Member States to investigate and report cases of persons 16 years or younger presenting with acute hepatitis (non-hep A-E), AST or ALT >500 IU/L, of unknown origin, and persons of any age with hepatitis who were in close contact with these pediatric cases.

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What is the most likely cause of acute hepatitis in these children? Are all the cases epidemiologically related? Are cases occurring in your area?