Interim Analysis of Acute Hepatitis of Unknown Etiology in Children Aged <10 Years — United States, October 2021–June 2022

Abstract

On June 24, 2022, this report was posted as an MMWR Early Release on the MMWR website (https://www.cdc.gov/mmwr). On April 21, 2022, CDC issued a health advisory † encouraging U.S. clinicians to report all patients aged <10 years with hepatitis of unknown etiology to public health authorities, after identification of similar cases in both the United States (1) and Europe. § A high proportion of initially reported patients had adenovirus detected in whole blood specimens, thus the health advisory encouraged clinicians to consider requesting adenovirus testing, preferentially on whole blood specimens. For patients meeting the criteria in the health advisory (patients under investigation [PUIs]), jurisdictional public health authorities abstracted medical charts and interviewed patient caregivers. As of June 15, 2022, a total of 296 PUIs with hepatitis onset on or after October 1, 2021, were reported from 42 U.S. jurisdictions. The median age of PUIs was 2 years, 2 months. Most PUIs were hospitalized (89.9%); 18 (6.1%) required a liver transplant, and 11 (3.7%) died. Adenovirus was detected in a respiratory, blood, or stool specimen of 100 (44.6%) of 224 patients. ¶ Current or past infection with SARS-CoV-2 (the virus that causes COVID-19) was reported in 10 of 98 (10.2%) and 32 of 123 (26.0%) patients, respectively. No common exposures (e.g., travel, food, or toxicants) were identified. This nationwide investigation is ongoing. Further clinical data are needed to understand the cause of hepatitis in these patients and to assess the potential association with adenovirus. Clinicians and health departments began retrospectively and prospectively identifying PUIs on April 21, 2022. A PUI was defined as a person aged <10 years with elevated (>500 U/L) aspartate aminotransferase (AST) or alanine aminotransferase (ALT), an unknown etiology for the hepatitis, and onset on or after October 1, 2021. Comprehensive investigations of PUIs included rapid reporting of preliminary information, medical chart abstractions, caregiver interviews, laboratory testing, and tissue specimen examination. Upon identification of a PUI, jurisdictional health departments sent preliminary information (basic demographic information, date of hepatitis * These authors contributed equally to this report. † https://emergency.cdc.gov/han/2022/han00462.asp § https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON368 ¶ Adenovirus-positive results on respiratory, blood, or stool specimen types but excluded PUIs with pending or unknown test results (test results might not have been available at the time of data collection). diagnosis, adenovirus testing results, and patient outcome) to CDC. Medical chart abstraction used standardized forms to collect information on demographic characteristics, signs and symptoms of illness, underlying health conditions, laboratory results (pathogen testing, biomarkers, and toxicology), radio-logic findings, tissue pathology findings, vaccination history, and diagnoses and treatment received. Patient caregiver interviews collected information on demographic characteristics, household structure, symptoms, health care use, medical and medication history, and potential exposures (e.g., close contacts , diet, and toxicants). Adenovirus nucleic acid amplification testing (e.g., polymerase chain reaction [PCR]) of blood, respiratory, or stool specimens or rectal swabs was requested at the discretion of the treating clinician and conducted at a diagnostic or reference laboratory.** Available specimens that yielded positive results for adenovirus were further characterized using Sanger sequencing of the six hypervariable regions of the hexon gene to determine adenovirus type (2). Formalin-fixed, paraffin-embedded (FFPE) liver biopsy, explant, or autopsy tissue specimens underwent routine evaluation at the clinical institutions, and residual FFPE tissue specimens were submitted to CDC for additional pathologic evaluation and diagnostic testing (3,4). This investigation was reviewed by CDC and conducted consistent with applicable federal law and CDC policy. † † Data were managed using REDCap electronic data tools hosted at CDC, § § and SAS (version 9.4; SAS Institute) was used to conduct all analyses. As of June 15, 2022, a total of 296 PUIs were reported from 42 U.S. jurisdictions. There was no apparent temporal clustering of hepatitis diagnoses among these children, although a peak in diagnoses coincided with the release of the health advisory (Figure 1). The median age at time of illness was 2 years, 2 months (range = 1 month-9 years, 8 months), and the largest percentage of PUIs (37.8%, 112) were Hispanic or Latino children, followed by White, non-Hispanic children (32.4%, 96) (Table). Among all reported PUIs, 266 (89.9%) required hospitalization, 18 (6.1%) required a liver transplant, and 11 (3.7%) died. Preliminary reports indicated that among ** https://www.cdc.gov/ncird/investigation/hepatitis-unknown-cause/ laboratories-testing-typing.html † † 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://projectredcap.org/