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Updates on severe hepatitis of unknown etiology

Daniel R. Lucey, MD, MPH, FIDSA
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While the cause(s) of acute, severe hepatitis of unknown etiology remain uncertain, several key updates are cited below from the past week, May 5-12.

Whole genome sequencing has not been reported yet for the adenovirus 41 found in the majority of patients (in whole blood much more often than stool or respiratory samples). Low viral loads of this adenovirus 41 are making whole genome sequencing  difficult. (See page 20 of the U.K. Health Security Agency’s May 6 technical briefing.)

Liver histopathology on biopsy and explanted livers also has not been reported to show any direct evidence of adenovirus infection. Surprisingly, no immunologic analyses have been reported yet on any of these livers, e.g., including lymphocyte subsets, cytokines or activation markers.

From page 14 of the May 6 U.K. technical briefing: “The overall pattern seen is non-specific and there is no clear identifiable cause from the histopathology results. On hematoxylin and eosin (H and E) staining, the inflammatory response was variable throughout the specimens reviewed. Further immunohistochemistry for lymphocytic subpopulations is planned.”

On May 11, the European CDC reported a total of 449 probable cases in 27 nations including from Europe, the Americas (North, Central and South), Asia and the Middle East. The highest numbers of cases so far are: U.K. (163), USA (109), Italy (35), Spain (22), Brazil (16), Indonesia (15), Israel (12),  Sweden (nine), Argentina (eight), Japan (seven) and Canada (seven).

According to the European CDC’s report, “In EU/EEA countries, approximately 105 cases have been identified in 13 EU/EEA countries as of 10 May 2022.” (See Table 1 for nations listed in alphabetical order. Of these 13 countries, Italy has reported 35 cases, Spain 22 cases and Sweden nine cases.)

United Kingdom: As of May 3, the U.K. Health Security Agency had identified a total of 163 children, aged under 16 years, with acute hepatitis of unknown etiology. Of these cases, 11 children have received a liver transplant. A second detailed technical briefing on the investigations among the U.K. cases was published by the agency on May 6.

Outside of the European Union/European Economic Area and the U.K.: As of May 10, there are at least 181 cases of acute hepatitis among children. Cases have been reported by Argentina (eight), Brazil (16), Canada (seven), Costa Rica (two), Indonesia (15), Israel (12), Japan (7), Panama (one), Palestine* (one), Serbia (one), Singapore (one), South Korea (one) and the United States (at least 109).

Also on May 11, the U.S. CDC issued an update via its Health Alert Network, “Updated Recommendations for Adenovirus Testing and Reporting of Children with Acute Hepatitis of Unknown Etiology”: “As of May 5, 2022, CDC and state partners are investigating 109 children with hepatitis of unknown origin across 25 states and territories, more than half of whom have tested positive for adenovirus with more than 90% hospitalized, 14% with liver transplants, and five deaths under investigation.”  

These U.S. data on the 109 children in 25 states and territories were first presented May 6 at a CDC media telebriefing with Jay Butler, MD, and Umesh Parashar, MD.

Further information can be anticipated each week, including on Fridays from the U.K. Health Security Agency, U.S. CDC, WHO and European CDC, among an increasing number of others around the world.  

Of note: If an infectious disease etiology is found, then predictable urgent questions should be anticipated. Effective, clear and trustworthy communication and messaging should be ready on Day 1 for, e.g., diagnostic tests (for severe and nonsevere hepatitis in children and adults), infection prevention and control measures, antiviral drugs, polyclonal (immune survivors) and rapid development of monoclonal antibodies and vaccines, among other key issues.

Potential questions as to the origin of any such potential infectious disease etiology are certain. Whether the new WHO Scientific Advisory Group on Origins will be convened is another question that could be anticipated. By coincidence, the annual World Health Assembly will meet later this month, May 22-28. Looking at the agenda, the USA has proposed some amendments to the International Health Regulations that could be seen as relevant to identifying outbreaks and their potential origin.



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