Acute Hepatitis and Adenovirus Infection... (2023)

On April 29, 2022, this report was posted online as an MMWR Early Release.

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)

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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.

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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 (46), 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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(Video) Doctor warns parents about hepatitis outbreak in young kids | ABC7 Chicago

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

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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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TABLE. Demographics, clinical characteristics, laboratory testing results, and clinical outcomes in a cluster of pediatric patients with acute hepatitis and adenovirus infection (N = 9) — Alabama, October 2021–February 2022
DemographicNo.
Age at admission, yrs
0–25
3–41
5–63
Sex
Female7
Male2
Race
White9
Other0
Ethnicity
Hispanic6
Non-Hispanic3
Initial sign/symptom
Vomiting7
Diarrhea6
Fever5
Upper respiratory symptoms*3
Initial physical exam
Scleral icterus8
Hepatomegaly7
Jaundice6
Hepatic encephalopathy1
Splenomegaly1
Ascites0
Liver function testing on admission, median (range)
ALT (U/L)1,724 (603–4,696)
AST (U/L)1,963 (447–4,000)
Total bilirubin (mg/dL)7 (0.23–13.5)
Pathogen testing performed
Blood viral PCR9
Hepatitis A/B/C9
Epstein-Barr Virus, blood viral PCR9
Epstein-Barr Virus, IgM8
Respiratory panel testing§8
Blood culture4
Urine culture4
Stool culture1
Pathogen testing result, no. positive/total no.
Adenovirus (whole blood)9/9
EBV6/9
Enterovirus/Rhinovirus4/8
Metapneumovirus1/8
Respiratory syncytial virus1/8
Human coronavirus OC431/8
SARS-CoV-2**0/9
Hepatitis A/B/C0/9
Outcome
Recovered without transplant7
Required transplant and recovered2
Died0

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; EBV = Epstein-Barr virus; IgM = immunoglobulin M; PCR = polymerase chain reaction.
* Upper respiratory symptoms were identified when taking the patient’s history and conducting an initial physical exam. Upper respiratory symptoms can include nasal congestion, nasal discharge, cough, sore throat, wheezing, and dyspnea, among other symptoms.
Normal ranges are ALT = 9–25 U/L; AST = 21–44 U/L; total bilirubin = 0.1–1.0 mg/dL.
§ The respiratory viral panels (ePlex Respiratory Pathogen Panel [GenMark] or BioFire Respiratory Panel [Biomérieux]) were used to test for adenovirus, coronavirus 229E, coronavirus HKU1, coronavirus NL63, coronavirus OC43, human metapneumovirus, human rhinovirus/enterovirus, influenza A, influenza A/H1, influenza A/H1–2009, influenza A/H3, influenza B, parainfluenza 1, parainfluenza 2, parainfluenza 3, parainfluenza 4, respiratory syncytial virus A, respiratory syncytial virus B, Chlamydia pneumoniae, Mycoplasma pneumoniae, Bordetella parapertussis (BioFire only), and Bordetella pertussis (BioFire only).
Positive EBV test results were based on PCR testing, but all patients received negative test results for EBV IgM antibodies (except one patient who did not have IgM testing) suggesting that infections were likely not acute but rather potential low-level reactivation of previous infections.
** All patients received testing for SARS-CoV-2 using nucleic acid amplification tests.

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Suggested citation for this article: 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. DOI: http://dx.doi.org/10.15585/mmwr.mm7118e1external icon.

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FAQs

What type of hepatitis is caused by adenovirus? ›

Adenoviruses are common viral pathogens in childhood; however, they can cause serious disease in an immunocompromised host. Fulminant hepatitis is a rare complication of adenoviral infection.

Which viruses cause acute hepatitis? ›

The hepatitis A virus is the most common cause of acute hepatitis, followed by the hepatitis B virus. (mono). Engaging in certain activities, such as getting a tattoo or body piercing, sharing needles to inject drugs, or having multiple sex partners, increases the risk of developing hepatitis.

Can adenovirus cause hepatitis in adults? ›

Respiratory-viral-panel came positive for adenovirus. With supportive treatment, symptoms and LFT trended down, thus, liver biopsy decision was deferred. We believe this is the first reported case of adenovirus hepatitis in an immunocompetent adult.

Which is a common infection of adenovirus? ›

Most adenovirus infections cause mild respiratory illness, such as the common cold. Some infections can cause other illnesses, such as bronchitis (inflammation of the windpipe and main airways), pneumonia (inflammation of the lungs), skin rash, conjunctivitis (pink eye), bladder infection, or bowel infection.

How is adenovirus hepatitis treated? ›

Treatment. There is no specific treatment for people with adenovirus infection. Most adenovirus infections are mild and may require only care to help relieve symptoms, such as over-the-counter pain medicines or fever reducers.

What causes acute hepatitis? ›

The hepatitis A virus is the most common cause of acute hepatitis, followed by the hepatitis B virus. (mono). Engaging in certain activities, such as getting a tattoo or body piercing, sharing needles to inject drugs, or having multiple sex partners, increases the risk of developing hepatitis.

What are the symptoms of adenovirus? ›

Symptoms
  • common cold or flu-like symptoms.
  • fever.
  • sore throat.
  • acute bronchitis (inflammation of the airways of the lungs, sometimes called a “chest cold”)
  • pneumonia (infection of the lungs)
  • pink eye (conjunctivitis)

Is acute hepatitis serious? ›

Hepatitis A usually passes within a few months, although it can occasionally be severe and even life threatening. There's no specific treatment for it, other than to relieve symptoms like pain, nausea and itching.

Is acute viral hepatitis contagious? ›

Hepatitis A can be spread from close, personal contact with an infected person, such as through certain types of sexual contact (like oral-anal sex), caring for someone who is ill, or using drugs with others. Hepatitis A is very contagious, and people can even spread the virus before they feel sick.

Is hepatitis adenovirus contagious? ›

Adenovirus can cause mild to severe illness and is spread from infected individuals to others by close personal contact, through the air when someone coughs or sneezes and touching infected objects and then touching your mouth, nose or eyes. Symptoms can range from a few days to a few weeks.

How is adenovirus hepatitis spread? ›

Some adenoviruses can spread through an infected person's stool, for example, during diaper changing. Adenovirus can also spread through the water, such as swimming pools, but this is less common.

Is adenovirus the same as hepatitis in dogs? ›

Hepatitis is defined as inflammation of the liver. As a specific disease, infectious canine hepatitis (ICH) is a viral infection caused by a member of the adenovirus family. Other members of the dog family (e.g., foxes), as well as otters and bears, can be infected, but the ICH virus is harmless to people. "...

What is acute hepatitis? ›

Acute hepatitis is a term used to describe a wide variety of conditions characterized by acute inflammation of the hepatic parenchyma or injury to hepatocytes resulting in elevated liver function indices.

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