By Gary Evans, Medical Writer
Health officials are baffled as cases of hepatitis of unknown etiology in young children are being reported globally. Some, but not all, have adenovirus type 41, which previously had not been associated with pediatric liver disease.
“Adenovirus type 41 more commonly causes severe stomach illness,” Jay Butler, MD, deputy director for infectious diseases at the Centers for Disease Control and Prevention (CDC), said at a recent press conference. “[It commonly] occurs in immunocompromised patients and is not usually known as a cause of hepatitis in otherwise healthy children.”
As of May 5, 2022, the CDC was investigating 109 children with hepatitis of unknown origin across 25 states and territories. More than half of them have tested positive for adenovirus. More than 90% of the U.S. cases were hospitalized, 14% had liver transplants, and five died, the CDC reported in a health advisory alert.1
The CDC investigation began in November 2021 when the agency was apprised that nine children in Alabama had hepatitis and adenovirus infection. None were immunocompromised, nor were any of the typical spectrum of hepatitis viruses (A, B, C) detected. There was no identified epidemiological link between the nine children.
“A large children’s hospital in Alabama notified CDC of five pediatric patients with significant liver injury, including three with acute liver failure, who also tested positive for adenovirus,” the CDC reported.2 “All children were previously healthy. None had COVID-19. Case-finding efforts at this hospital identified four additional pediatric patients with hepatitis and adenovirus infection for a total of nine patients admitted from October 2021 through February 2022. All five that were sequenced had adenovirus type 41 infection identified. Two patients required liver transplant; no patients died.”
The investigation has become retrospective, looking back for similar cases that may have been missed. Symptoms of hepatitis include fever, fatigue, loss of appetite, nausea, vomiting, and abdominal pain. Adenovirus type 41 infections typically have diarrhea, vomiting, and fever, often accompanied by respiratory symptoms. Infection usually is self-limiting, and the virus is thought to spread primarily through the fecal-oral route.
Butler made a point of stressing that COVID-19 vaccination was not involved, and most of the children identified thus far are under 5 years of age and would not be indicated for immunization. There also are questions about whether the liver syndrome could be caused by COVID-19 infection.
“None of the nine children in Alabama had COVID-19 infection during their hospitalization or a documented history of COVID-19,” he said. “In addition, none of them had received COVID-19 vaccine prior to being hospitalized for hepatitis. COVID-19 vaccination is not the cause of these illnesses.”
A May 11, 2022, a CDC health alert recommended clinicians consider adenovirus testing in pediatric patients with hepatitis of unknown etiology. Because the link with adenovirus infection still is under investigation, clinicians should consider collecting a range of specimen types, including:
- Blood specimen collected in ethylenediaminetetraacetic acid (EDTA) (whole blood, plasma, or serum); whole blood is preferred to plasma and serum)
- Respiratory specimen (nasopharyngeal swab, sputum, or bronchioalveolar lavage [BAL])
- Stool specimen preferred to a rectal swab
- Liver tissue, if a biopsy was clinically indicated, or tissue from native liver explant or autopsy. This includes formalin-fixed, paraffin-embedded (FFPE) liver tissue and fresh liver tissue, frozen on dry ice or liquid nitrogen immediately or as soon as possible, and stored at -70°C or below.
Nucleic acid amplification testing (NAAT) is preferred for adenovirus detection, although it currently is not available for FFPE liver biopsy or native liver explant. “Testing whole blood by PCR [polymerase chain reaction] is more sensitive to and is preferred over testing plasma by PCR,” the CDC reported. “Where possible, clinical specimens should be tested locally to ensure timely results for patient care.”
Global Cases
The World Health Organization (WHO) reported at a May 10, 2022, press conference that there were 348 “probable cases” globally of the severe pediatric liver syndrome.3 Another 70 cases still were under investigation. These latter cases either are still ruling out common hepatitis viruses or awaiting verification of findings from national health officials, explained Phillipa Easterbrook, MD, MPH, a senior scientist with the WHO.
“These 70 [cases] are in addition to the 348,” she said. “Overall, there are 20 countries that have reported probable cases, and then an additional 13 where these other ongoing cases are being investigated.”
Only six countries have reported more than five cases, which includes the United States with 109 cases and the United Kingdom with 163 cases. In addition to the CDC investigation, which includes international collaboration, U.K. scientists are doing a “comprehensive series of investigations looking at the genetics of the children, their immune response, the viruses, and [conducting] further epidemiological studies,” Easterbrook said.
“The cases that have been reported include a mixture of new cases and retrospective or historic cases,” she said. “That is the nature of the surveillance that has been set up. The numbers are, of course, changing as we verify and establish, at country level, the cases.”
Approximately 70% of the cases have tested positive for adenovirus, using primarily blood assays.
“The leading hypotheses remain those which involve adenovirus, but I think it is still important to consider, the role of COVID as well — either as a co-infection or as a past infection,” she said. “Further typing of the adenovirus confirms again that those that have been tested have identified subtype 41 as prevalent. Over the last week there has also been some more histological examination looking at the tissue samples, liver samples, and biopsies. None of these [cases] show any of the typical features you might expect with a liver inflammation due to adenovirus.”
U.K. researchers are conducting a case control study comparing the prevalence of adenovirus in the liver patients compared to other hospitalized children in general.
“That will really help hone down whether adenovirus is just an incidental infection that has been detected, or there is a causal or likely causal link,” Easterbrook said.
- Centers for Disease Control and Prevention. Updated recommendations for adenovirus testing and reporting of children with acute hepatitis of unknown etiology. Published May 11, 2022. https://emergency.cdc.gov/han/2022/han00465.asp
- Centers for Disease Control and Prevention. Recommendations for adenovirus testing and reporting of children with acute hepatitis of unknown etiology. Published April 21, 2022. https://emergency.cdc.gov/han/2022/han00462.asp
- World Health Organization. WHO press conference on COVID-19, Ukraine and other global health issues. Published May 10, 2022. https://www.who.int/multi-media/details/who-press-conference-on-covid-19--ukraine-and-other-global-health-issues---10-may-2022#
