Outbreaks, Alerts and Hot Topics

A Case of Whodunit: Hepatitis

Author: Megan Hamner, MD | Pediatric Infectious Diseases Fellow

Column Editor: Angela Myers, MD, MPH | Director, Division of Infectious Diseases | Professor of Pediatrics, UMKC School of Medicine | Medical Editor, The Link Newsletter

What is going on?

The World Health Organization is tracking severe acute hepatitis cases of unknown etiology in pediatric patients worldwide.¹ This outbreak was first identified in April 2022. As of June 22, 2022, 920 probable cases have been reported from 33 countries, with the majority reported from the United Kingdom (267 cases) and the United States (296 cases).^1,2 Seventy-five percent of cases have occurred in children <5 years of age. Etiology remains unknown and under investigation. However, a proposed etiology has focused on adenovirus; of the 181 cases that were tested for adenovirus, 110 (60.8%) tested positive.¹

In late April 2022, the Centers for Disease Control and Prevention (CDC) issued a Health Advisory that recommended adenovirus testing and reporting in children with acute hepatitis of unknown etiology.^3,4 This recommendation responded to a cluster of children identified in Alabama with severe hepatitis who tested positive for adenovirus. Efforts to locate cases identified nine previously healthy patients admitted for hepatitis and concomitant adenovirus infection between October 2021 and February 2022. In five of these patients, additional sequencing identified infection with adenovirus type 41. Two patients received liver transplants. All patients recovered.

How did these patients present?

Vomiting and diarrhea were the most common presenting complaints, occurring in seven and six of the nine patients respectively. Upper respiratory symptoms occurred in three patients. Findings at the time of admission included scleral icterus (eight), hepatomegaly (seven), jaundice (six), and encephalopathy (one).³ All patients had significantly elevated transaminases. Results of viral hepatitis testing as well as testing for additional causes of hepatitis were negative. Adenovirus PCR results from whole blood specimens were positive for all nine patients.

What do we know about adenovirus?

Adenoviruses are double-stranded DNA viruses that cause a variety of infectious symptoms.⁴ There are currently over 100 types of adenoviruses. Transmission can occur through respiratory tract secretions, by the fecal-oral route or by fomites. Infection can occur in all age groups; peak incidence is between the ages of 6 months and 5 years.⁴ Adenovirus type 41 most commonly presents as a gastroenteritis syndrome with accompanying diarrhea, vomiting and fever. Although adenovirus is associated with hepatitis in cases of disseminated disease or in immunocompromised hosts, it is not known to be a common cause of hepatitis in otherwise healthy children.^5,6

What does this mean?

Acute hepatitis of unknown etiology and adenovirus type 41 infections are not reportable in the U.S. However, trends in hepatitis-associated emergency department visits and hospitalizations, liver transplants, and adenovirus stool testing results were reviewed from October 2021 to March 2022 and compared to pre-COVID-19 pandemic baselines.⁷ Currently, there is no evidence of an increase in pediatric hepatitis or adenovirus types 40/41 above baseline levels. Ongoing surveillance will be important to monitor for changes in incidence over time.

What should clinicians do?

The CDC recommends clinicians consider adenovirus testing in pediatric patients with hepatitis of unknown etiology. PCR is preferable and can be performed on respiratory specimens, stool or blood. The CDC is also requesting notification of children <10 years of age with elevated AST or ALT (>500 U/L) who have an unknown etiology for their hepatitis (with or without any adenovirus testing results, independent of test results) since Oct. 1, 2021.⁴

Figure 1. Patients under investigation for pediatric hepatitis of unknown etiology* reported to CDC (N = 296), by week of hepatitis presentation and stratified by results of preliminary adenovirus testing using whole blood — United States, October 2021–June 2022

* https://emergency.cdc.gov/han/2022/han00462.asp

Source: Reference 2. All material in the MMWR series is in the public domain and may be used and reprinted without special permission.

Special thanks to Dr. Megan Hamner for writing the Outbreaks, Alerts and Hot Topics column for the July 2022 edition of The Link. Megan is graduating from Pediatric Infectious Diseases fellowship and taking on her first faculty position at the University of Mississippi Medical Center and Children’s Hospital of Mississippi. We are so proud of all she has accomplished during her fellowship at Children’s Mercy.

References: 

1. World Health Organization. Disease Outbreak News. Acute hepatitis of unknown aetiology in children-multi-country. June 24, 2022.
2. Cates J, Baker JM, Almendares O, et al. Interim analysis of acute hepatitis of unknown etiology in children aged <10 Years-United States, October 2021-June 2022. MMWR Morb Mortal Wkly Rep. Published online June 24, 2022.
3. Baker JM, Buchfellner M, Britt W, et al. Acute hepatitis and adenovirus infection among children-Alabama, October 2021-February 2022. MMWR Morb Mortal Wkly Rep. 2022;71:638-640.
4. Centers for Disease Control and Prevention. CDC Health Advisory. Recommendations for adenovirus testing and reporting of children with acute hepatitis of unknown etiology. April 21, 2022. https://emergency.cdc.gov/han/2022/pdf/CDC_HAN_462.pdf
5. Long SS, Prober CG, Fischer M, eds. Principles and Practice of Pediatric Infectious Diseases. 5th ed. Elsevier, 2018.
6. Munoz FM, Piedra PA, Demmler GJ. Disseminated adenovirus disease in immunocompromised and immunocompetent children. Clin Infect Dis. 1998;27(5):1104-1200.
7. Kambhampati AK, Burke RM, Dietz S, et al. Trends in acute hepatitis of unspecified etiology and adenovirus stool testing results in children-United States, 2017-2022. MMWR Morb Mortal Wkly Rep. 2022;71:797-802.