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Acute Hepatitis and Adenovirus Infection Among Children — Alabama, October 2021–February 2022
Early Release / April 29, 2022 / 71
Julia M. Baker, PhD1,2; Markus Buchfellner, MD3; William Britt, MD3; Veronica Sanchez, PhD3; Jennifer L. Potter, MPH3; L. Amanda Ingram, MPH4; Henry Shiau, MD5,6; Luz Helena Gutierrez Sanchez, MD5,6; Stephanie Saaybi, MD5; David Kelly, MD6,7; Xiaoyan Lu, MS1; Everardo M. Vega, PhD1; Stephanie Ayers-Millsap, MPH8; Wesley G. Willeford, MD8; Negar Rassaei, MD9; Hannah Bullock, PhD9,10; Sarah Reagan-Steiner, MD9; Ali Martin4; Elizabeth A. Moulton, MD, PhD11,12; Daryl M. Lamson13; Kirsten St. George, PhD13,14; Umesh D. Parashar, MD, MBBS1; Aron J. Hall, DVM1; Adam MacNeil, PhD1; Jacqueline E. Tate, PhD1; Hannah L. Kirking, MD1 (View author affiliations)
During October–November 2021, clinicians at a children’s hospital in Alabama identified five pediatric patients with severe hepatitis and adenovirus viremia upon admission. In November 2021, hospital clinicians, the Alabama Department of Public Health, the Jefferson County Department of Health, and CDC began an investigation. This activity was reviewed by CDC and conducted consistent with applicable federal law and CDC policy.*
Clinical records from the hospital were reviewed to identify patients seen on or after October 1, 2021, with hepatitis and an adenovirus infection, detected via real-time polymerase chain reaction (PCR) testing on whole blood specimens, and no other known cause for hepatitis. An additional four children were identified, for a total of nine patients with hepatitis of unknown etiology and concomitant adenovirus infection during October 2021–February 2022. On February 1, 2022, a statewide health advisory† was disseminated to aid in the identification of cases at other facilities in Alabama; no additional patients were identified.
All nine children were patients at Children’s of Alabama. These patients were from geographically distinct parts of the state; no epidemiologic links among patients were identified. The median age at admission was 2 years, 11 months (IQR = 1 year, 8 months to 5 years, 9 months) and seven patients were female (Table). All patients were immunocompetent with no clinically significant medical comorbidities.
Before admission, among the nine patients, vomiting, diarrhea, and upper respiratory symptoms were reported by seven, six, and three patients, respectively. At admission, eight patients had scleral icterus, seven had hepatomegaly, six had jaundice, and one had encephalopathy (Table). Elevated transaminases were detected among all patients§ (alanine aminotransferase [ALT] range = 603–4,696 U/L; aspartate aminotransferase [AST] range = 447–4,000 U/L); total bilirubin ranged from normal to elevated (range = 0.23–13.5 mg/dL, elevated in eight patients). All patients received negative test results for hepatitis viruses A, B, and C, and several other causes of pediatric hepatitis and infections were ruled out including autoimmune hepatitis, Wilson disease, bacteremia, urinary tract infections, and SARS-CoV-2 infection. None of the children had documented history of previous SARS-CoV-2 infection.
Adenovirus was detected in whole blood specimens from all patients by real-time PCR testing (initial viral load range = 991–70,680 copies/mL). Hexon gene hypervariable region sequencing was performed on specimens from five patients, and adenovirus type 41 was detected in all five specimens. Low viral loads precluded sequencing among three patients, and residual specimens were not available for sequencing for one patient. Seven patients were coinfected with other viral pathogens (Table). Six received positive test results for Epstein-Barr virus (EBV) by PCR testing but negative test results for EBV immunoglobulin M (IgM) antibodies (one patient did not have IgM testing), suggesting that these were likely not acute infections but rather low-level reactivation of previous infections. Other detected viruses included enterovirus/rhinovirus, metapneumovirus, respiratory syncytial virus, and human coronavirus OC43.
Liver biopsies from six patients demonstrated various degrees of hepatitis with no viral inclusions observed, no immunohistochemical evidence of adenovirus, or no viral particles identified by electron microscopy. Three patients developed acute liver failure, two of whom were treated with cidofovir (off-label use) and steroids, and were transferred to a different medical facility where they underwent liver transplantation. Plasma specimens from these two patients were negative for adenovirus by real-time PCR testing upon arrival at the receiving medical facility, but both patients received positive test results when retested by the same real-time PCR test using a whole blood specimen. All patients have recovered or are recovering, including the two transplant recipients.
Adenovirus type 41 is primarily spread via the fecal-oral route and predominantly affects the gut. It is a common cause of pediatric acute gastroenteritis typically with diarrhea, vomiting and fever, often accompanied by respiratory symptoms (1). Adenovirus is recognized as a cause of hepatitis among immunocompromised children (2). It might be an underrecognized contributor to liver injury among healthy children (3); however, the magnitude of this relationship remains under investigation.
This cluster, along with recently identified possible cases in Europe (4–6), suggests that adenovirus should be considered in the differential diagnosis of acute hepatitis of unknown etiology among children. Clinicians and laboratorians should be aware of possible differences in adenovirus test sensitivity for different specimen types; tests using whole blood might be more sensitive than those using plasma. CDC is monitoring the situation closely to understand the possible cause of illness and identify potential efforts to prevent or mitigate illness. Enhanced surveillance is underway in coordination with jurisdictional public health partners. Clinicians are encouraged to report possible cases of pediatric hepatitis with unknown etiology occurring on or after October 1, 2021, to public health authorities for further investigation.¶
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Acknowledgments
Paige A. Armstrong, Julu Bhatnagar, Neil Gupta, Senad Handanagic, Megan Hofmeister, Philip Spradling, CDC; James J. Dunn, Texas Children’s Hospital, Houston, Texas; Advanced Technology and Genomics Core, Wadsworth Center, New York Department of Health, Albany New York.
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Corresponding author: Julia M. Baker, ncirddvdgast@cdc.gov.
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1Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, CDC; 2Epidemic Intelligence Service, CDC; 3Department of Pediatrics, Division of Pediatric Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama; 4Alabama Department of Public Health; 5Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Alabama at Birmingham, Birmingham, Alabama; 6Children’s of Alabama, Birmingham, Alabama; 7Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; 8Jefferson County Department of Health, Birmingham, Alabama; 9Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, CDC; 10Synergy America, Inc., Duluth, Georgia; 11Department of Pediatrics, Division of Pediatric Infectious Diseases, Baylor College of Medicine, Houston, Texas; 12Texas Children’s Hospital, Houston, Texas; 13Wadsworth Center, New York State Department of Health; 14Department of Biomedical Sciences, University at Albany, Albany, New York.
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All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. William Britt reports consulting fees from Hookipa Pharma and stocks from Kroger Care, First Energy Corporation, MDU Resources Group, and PG&E Corporation. Elizabeth A. Moulton serves as a coinvestigator for Pfizer SARS-CoV-2 vaccine trials in healthy and immunocompromised pediatric patients with payment made to her institution. Kirsten St. George reports receipt of research support for her institution through equipment and materials from Thermo Fisher, and royalties from ZeptoMetrix Corporation paid to her institution. No other potential conflicts of interest were disclosed.
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* 45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501 et seq.
† https://www.alabamapublichealth.gov/bcd/assets/adph_han_report_adenovirus_020122.pdfpdf iconexternal icon
§ Normal ranges are ALT = 9–25 U/L; AST = 21–44 U/L; total bilirubin = 0.1–1.0 mg/dL.
¶ https://emergency.cdc.gov/han/2022/pdf/CDC_HAN_462.pdfpdf icon
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References
- Kang G. Viral diarrhea. In: Quah SR, ed. International encyclopedia of public health. 2nd ed. Cambridge, MA: Elsevier; 2017:360–7. https://www.sciencedirect.com/referencework/9780128037089/international-encyclopedia-of-public-healthexternal icon
- Hierholzer JC. Adenoviruses in the immunocompromised host. Clin Microbiol Rev 1992;5:262–74. https://doi.org/10.1128/CMR.5.3.262external icon PMID:1323383external icon
- Munoz FM, Piedra PA, Demmler GJ. Disseminated adenovirus disease in immunocompromised and immunocompetent children. Clin Infect Dis 1998;27:1194–200. https://doi.org/10.1086/514978external icon PMID:9827268external icon
- UK Health Security Agency. Increase in acute hepatitis cases of unknown aetiology in children. London, United Kingdom: Department of Health and Social Care, UK Health Security Agency; 2022. https://www.gov.uk/government/publications/hepatitis-increase-in-acute-cases-of-unknown-aetiology-in-children/increase-in-acute-hepatitis-cases-of-unknown-aetiology-in-childrenexternal icon
- Marsh K, Tayler R, Pollock L, et al. Investigation into cases of hepatitis of unknown aetiology among young children, Scotland, 1 January 2022 to 12 April 2022. Euro Surveill 2022;27. https://doi.org/10.2807/1560-7917.ES.2022.27.15.2200318external icon PMID:35426362external icon
- World Health Organization. Multi-Country – acute, severe hepatitis of unknown origin in children. Geneva, Switzerland: World Health Organization; 2022. Accessed April 23, 2022. https://www.who.int/emergencies/disease-outbreak-news/item/multi-country-acute-severe-hepatitis-of-unknown-origin-in-childrenexternal icon
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https://www.cdc.gov/mmwr/volumes/71/...cid=mm7118e1_x
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Media Statement
EMBARGOED FOR 1PM ET Friday, April 29, 2022
Contact: CDC Media Relations (404) 639-3286
MMWR on children with acute hepatitis and adenovirus infection in Alabama A new study published by the Centers for Disease Control and Prevention (CDC) today, “Acute Hepatitis and Adenovirus Infection Among Children — Alabama, October 2021–February 2022” provides additional clinical and epidemiologic information from an ongoing investigation involving children in Alabama with hepatitis (inflammation of the liver) of unknown cause. These findings build on previous information shared about the cluster of nine cases currently under investigation by CDC and the Alabama Department of Public Health. In the fall of 2021, clinicians at a children’s hospital in Alabama identified five patients with severe hepatitis and adenovirus infection, including some with acute liver failure. A review of hospital clinical records identified four additional cases, all of whom had liver injury and adenovirus infection. All were previously healthy, ranged in age from about 1 to 6-years-old, and had no significant underlying conditions. Among the findings in the MMWR: two of the pediatric patients in Alabama required liver transplants, and three developed liver failure, but all have since recovered or are recovering. Prior to hospitalization, most of the children experienced vomiting and diarrhea, while some experienced upper respiratory symptoms. During hospitalization, most had yellowing eyes, yellowing skin (or jaundice), and an enlarged liver. All nine patients tested positive for adenovirus, and six tested positive for Epstein-Barr Virus but did not have antibodies, which implies an earlier, not active infection. Laboratory tests identified that some of these children had adenovirus type 41, which more commonly causes pediatric acute gastroenteritis. Additionally, some showed a history of other viruses including enterovirus/rhinovirus, metapneumovirus, respiratory syntactical virus, and human coronavirus OC43.
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