Pediatric Hepatitis of Unknown Etiology
As of May 6, 2022, The Centers for Disease Control and Prevention (CDC) has received 109 reports of unexplained hepatitis in young children from 24 states and Puerto Rico. Ninety percent of the children have been hospitalized and 14% have required liver transplants. Five children have died. Most of the children have recovered, though some were still hospitalized. More than half of the children have had confirmed adenovirus infections. Some of the cases were further typed as adenovirus type 41. All of the patients have tested negative for hepatitis viruses A, B, C, D and E.
The United Kingdom has also reported 163 cases of pediatric hepatitis, of which eleven required liver transplants. None of their children had died. Adenovirus was identified in 75% of the cases. Four cases had coinfections with adenovirus and SARS-CoV-2.
The European Centre for Disease Prevention and Control (ECDC) has received at least 300 reports of pediatric hepatitis, including 145 from the United Kingdom, 95 from the rest of Europe, and 60 outside of Europe.
Most of the children with severe acute hepatitis did not have active SARS-CoV-2 infection and were unvaccinated. However, between 75 and 95% of cases in the US and UK have tested positive for SARS-CoV-2 antibodies. One hypothesis is that fragments of SARS-CoV-2 linger in the GI tract for months after acute infection. Subsequent infection with an adenovirus could prompt an exaggerated immune reaction that causes severe hepatitis.
Adenoviruses are doubled-stranded DNA viruses that spread by close personal contact, respiratory droplets, and fomites. There are more than 50 types of immunologically distinct adenoviruses that can cause infections in humans. Adenoviruses most commonly cause respiratory illness but depending on the adenovirus type they can cause other illnesses such as gastroenteritis, conjunctivitis, cystitis, and, less commonly, neurological disease.
Adenovirus type 41 commonly causes pediatric acute gastroenteritis, which typically presents as diarrhea, vomiting, and fever. It can be accompanied by respiratory symptoms. While there have been some case reports of hepatitis associated with adenovirus type 41infection in immunocompromised children, it has not been reported to cause hepatitis in otherwise healthy children.
On May 11, CDC issued a Health Alert Network (HAN) Health Update to provide clinicians and public health authorities with updated information about their epidemiologic investigation of pediatric cases of hepatitis of unknown etiology in the United States. This investigation focuses on collecting information to describe the epidemiology, etiology, clinical presentation, severity, and risk factors related to illness and to identify any relationship between adenovirus infection or other factors and hepatitis.
The recommendations for clinicians included:
- Clinicians should continue to follow standard practice for evaluating and managing patients with hepatitis of known and unknown etiology.
- Clinicians are recommended to consider adenovirus testing for patients with hepatitis of unknown etiology and to report such cases to their state or jurisdictional public health authorities.
- Because the potential relationship between adenovirus infection and hepatitis is still under investigation, clinicians should consider collecting the following specimen types if available from pediatric patients with hepatitis of unknown cause for adenovirus detection:
- Blood specimen collected in ethylenediaminetetraacetic Acid (EDTA) (whole blood, plasma, or serum but whole blood is preferred)
- Respiratory specimen (nasopharyngeal swab, sputum, or bronchioalveolar lavage [BAL])
- Stool specimen or rectal swab; stool specimen is preferred to a rectal swab
- Liver tissue, if a biopsy was clinically indicated, or if tissue from native liver explant or autopsy is available:
- Formalin-fixed, paraffin embedded (FFPE) liver tissue
- Fresh liver tissue, frozen on dry ice or liquid nitrogen immediately or as soon as possible, and stored at ≤ -70°C
Nucleic acid amplification testing (NAAT), such as polymerase chain reaction (PCR), is preferred for adenovirus detection. Testing whole blood by PCR is more sensitive to and is preferred over testing plasma by PCR.
Where possible, clinical specimens should be tested locally to ensure timely results for patient care. For any diagnostic testing needs beyond the local capacity, CDC recommends that clinicians contact their state public health laboratory.
References
Schnirring L. Probe of unexplained hepatitis in kids expands to 24 states, Puerto Rico, CIDRAP News, May 6, 2022.
CDC Health Alert Network, Updated Recommendations for Adenovirus Testing and Reporting of Children with Acute Hepatitis of Unknown Etiology, May 11, 2022, HAN Archive - 00465 | Health Alert Network (HAN) (cdc.gov)
UK Health Security Agency, Investigation into acute hepatitis of unknown aetiology in children in England, Technical briefing, April 25, 2022.
Kansas Department of Health and Environment, Kansas Health Alert, Recommendations for Adenovirus Testing and Reporting of Children with Acute Hepatitis of Unknown Etiology.
Munoz FM, Piedra PA, Demmler GJ. Disseminated Adenovirus Disease in Immunocompromised and Immunocompetent Children. Clin Infect Dis. 1998. Nov;27(5):1194-200. https://doi.org/10.1086/514978
Peled N, Nakar C, Huberman H, Scherf E, Samra Z, Finkelstein Y, et al. Adenovirus Infection in Hospitalized Immunocompetent Children. Clin Pediatr (Phila). 2004 Apr;43(3):223–9. https://doi.org/10.1177/000992280404300303
Kendall EK et al. Elevated liver enzymes and bilirubin following SARS-CoV-2 infection in children under 10. MedRxiv, posted May 14, 2022, doi: https://doi.org/10.1101/2022.05.10.22274866
