By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
SYNOPSIS: Cases of acute hepatitis in children, tentatively ascribed to adenovirus 41 infection, while first reported from a single hospital in Alabama, are being seen internationally.
SOURCE: 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.
In November 2021, five children with acute hepatitis associated with viremia due to adenovirus were identified at a children’s hospital in Alabama, leading to a comprehensive investigation and to identification of an additional four cases. Despite issuance of a statewide advisory, no further cases were identified.
The median age of the patients was 2 years, 11 months; seven of the nine patients were female. None were immunocompromised or had significant comorbidities, and no epidemiological link between the cases was identified. Symptoms included vomiting in seven patients, diarrhea in six patients, and upper respiratory infection in three patients. Eight children had scleral icterus, seven had hepatomegaly, and one was encephalopathic. All had elevated serum transaminase concentrations with alanine aminotransferase (ALT) 603 U/L to 4,696 IU/L and aspartate aminotransferase (AST) 447 IU/L to 4,000 IU/L, while serum bilirubin ranged from 0.23 mg/dL to 13.5 mg/dL.
Three patients developed acute hepatic failure, and two, who were treated with cidofovir and corticosteroids, underwent liver transplantation. All nine patients had recovered or were recovering at the time of the Centers for Disease Control and Prevention (CDC) report.
Adenovirus deoxyribonucleic acid (DNA) was detected in whole blood specimens of each at concentrations of 991 copies/mL to 70,680 copies/mL on initial testing. Sequencing was performed on the polymerase chain reaction (PCR) product in five cases, and adenovirus type 41 was identified in each. Subsequent testing of plasma samples in two cases was negative, while repeat testing of whole blood remained positive. Examination of liver biopsy specimens from six patients found evidence of hepatitis but did not find viral inclusions or immunohistochemistry evidence of adenovirus, and no viral particles were found on electron microscopy.
All tests for hepatitis A, B, and C, as well as a variety of other causes of acute hepatitis, were negative. Respiratory viruses were present in several patients. In addition, Epstein-Barr virus DNA was detected in the blood of six of the nine patients, but immunoglobulin M (IgM) antibody to this virus was negative in all five patients in whom the test was performed, suggesting this was the result of reactivated viral replication of latent infection.
COMMENTARY
This problem is not limited to a single Alabama hospital, and the number of cases continues to grow. On May 6, 2022, the CDC stated that they were investigating 109 possible cases in 24 states and Puerto Rico.1
On April 26, 2022, the World Health Organization (WHO) announced at a press conference that “at least 169 cases of acute hepatitis have been reported from 11 countries in Europe, and in the United States, in children aged from 1 month to 16 years.”2 Thus, in the United Kingdom alone, 163 cases of acute hepatitis of unknown cause in children without an identified etiology had been identified as of May 3, 2022, with 11 patients undergoing liver transplantation.1 Then the European CDC has reported that, as of May 10, 2022, there were at least 181 cases outside of Europe and the United Kingdom, with a total number of cases worldwide of approximately 450. Adenovirus has been detected in many of the cases in which its presence has been sought.
The association with adenovirus 41 seems relatively strong, although with some caveats. Of particular concern is the lack of morphologic, PCR, or electron microscopy (EM) evidence of virus in liver biopsy specimens. From a diagnostic standpoint, the need to test whole blood rather than plasma by PCR is unusual. These findings have led to suggestions that, while adenovirus is necessary to cause this illness, it is insufficient, and one or more cofactors are required.
First recovered from adenoidal tissue (hence its name) in 1953, there now are 88 known serotypes and seven species (A-G) of adenovirus. Adenovirus 41, along with adenovirus 40, which together comprise species F, most commonly causes diarrhea in children. Adenovirus is an uncommon cause of hepatitis, with most reported cases occurring in small infants with disseminated disease or in immunocompromised patients, with very few occurring in immunocompetent children.3 The diagnosis is confirmed by testing of hepatic tissue by PCR, immunohistochemistry, or thin section EM — each of which was negative in all the Alabama cases.
REFERENCES
- ProMed. Hepatitis undefined, global (11): ECDC, USA, children, possible adenovirus, 2021-2022. May 11, 2022. http://www.promedmail.org
- World Health Organization. Acute hepatitis of unknown aetiology – the United Kingdom of Great Britain and Northern Ireland. April 15, 2022. https://www.who.int/emergencies/disease-outbreak-news/item/acute-hepatitis-of-unknown-aetiology---the-united-kingdom-of-great-britain-and-northern-ireland
- Shieh WJ. Human adenovirus infections in pediatric population — An update on clinico-pathologic correlation. Biomed J 2021;S2319-4170(21)00109-8. doi: 10.1016/j.bj.2021.08.009. [Online ahead of print].
Cases of acute hepatitis in children, tentatively ascribed to adenovirus 41 infection, while first reported from a single hospital in Alabama, are being seen internationally.
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