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

Cates, Jordan; Baker, Julia M; Almendares, Olivia; Kambhampati, Anita; Burke, Rachel M; Balachandran, Neha; Burnett, Eleanor; Cubeñas-Potts, Caelin; Reagan‐Steiner, Sarah; Kirking, Hannah L.; Sugerman, David; Parashar, Umesh D.; Tate, Jacqueline E.

doi:10.15585/mmwr.mm7126e1

Cited by 26 publications

(36 citation statements)

References 8 publications

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“…Initial epidemiological investigation and molecular testing have found adenovirus in 45-90% of severe acute hepatitis cases 6,[8][9][10][11] . In the UK, 116 of 179 (64.8%) reported cases as of May 2022 have tested positive for adenovirus 1 .…”

Section: Discussionmentioning

confidence: 99%

“…Affected children were admitted to tertiary care hospitals in 6 states (Alabama, California, Florida, Illinois, North Carolina, and South Dakota) from October 1, 2021 to May 22, 2022 (Extended Data Table 1). Because many patients (12 of 16, 75%) were selected from those PUIs who tested positive for adenovirus and had samples submitted for adenovirus typing, PUIs with adenovirus infection may have been over-represented compared to the overall PUI population, of which adenovirus is detected in 45-90% 6,[8][9][10][11] . The median age of affected children was 3 years.…”

Section: Patient and Sample Characteristicsmentioning

confidence: 99%

“…Although previously reported as a severe and potentially fatal disease in immunocompromised patients 4,6 , hepatitis from adenovirus infection had been thought to be rare in immunocompetent children without underlying comorbidities 7 . In previous reports, adenoviruses, particularly adenovirus type 41 (HAdV-41), have been found in the blood from a majority of outbreak-associated cases of acute severe hepatitis from Scotland, the United Kingdom (UK), and the US 6,[8][9][10][11] , although it is unclear whether this virus is causative. AAVs have also been reported in children with severe acute hepatitis in a study of 9 patients from the United Kingdom (UK) 18 , often in association with adenovirus or human herpesvirus 6 (HHV-6 infection) 12 .…”

Section: Introductionmentioning

confidence: 99%

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Adeno-associated virus type 2 in children from the United States with acute severe hepatitis

Servellita

Sotomayor-González

Lamson

et al. 2022

Preprint

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As of August 2022, cases of acute severe hepatitis of unknown etiology in children have been reported from 35 countries, including the United States. Here we used PCR testing, viral enrichment based sequencing, and agnostic metagenomic sequencing to analyze 27 samples, including nasopharyngeal swab, stool, plasma, and/or whole blood, from 16 such cases from 6 states (Alabama, California, Florida, Illinois, North Carolina, and South Dakota) presenting from October 1, 2021 to May 22, 2022, in parallel with whole blood samples from 45 controls. Among the 13 cases for whom whole blood was available, adeno-associated virus 2 (AAV2) sequences were detected in 92% (12 of 13) (p<0.001), while adenovirus sequences were detected in 100%, of which 11 (84.6%) were genotyped as human adenovirus type 41 (HAdV-41), one as HAdV-40, and one as HAdV-2. Co-infections of herpesviruses, Epstein-Barr virus (EBV) or human herpesvirus 6 (HHV-6), and/or enterovirus A71 (EV-A71) were also detected in all 13 cases. In contrast, AAV2 and HAdV-41 were not detected in any control, and EBV, HHV-6, or EV-A71 were each only detected in one or two of 45 controls (p<0.001). Analysis of assembled AAV2 viral genome sequences identified 35 coding mutations relative to the AAV2 reference genome, predominantly located in the VP1 capsid and assembly-activating protein (AAP) proteins, and AAV2 genomes from cases clustered together by phylogenetic analysis. Our findings of a distinct AAV2 strain in nearly all cases of acute severe hepatitis of unknown etiology in conjunction with one or more infecting helper viruses suggest that disease pathogenesis and/or severity may be related to co-infection with AAV2.

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Section: Discussionmentioning

confidence: 99%

Section: Patient and Sample Characteristicsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Adeno-associated virus type 2 in children from the United States with acute severe hepatitis

Servellita

Sotomayor-González

Lamson

et al. 2022

Preprint

Self Cite

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“…Before publishing this article, the most recent study stated that clinical data are required to determine the underlying causes of these patients’ illnesses and to evaluate any possible associations with adenovirus. It also highlighted the SARS-CoV-2 infection both before and after the patient’s illness began ( Cates et al, 2022 ). At present, anti-COVID-19 and symptom-relieving hepatitis medications are the most effective means to treat both prevention and symptoms.…”

Section: Introductionmentioning

confidence: 99%

Potential protective benefits of Schisandrin B against severe acute hepatitis in children during the COVID-19 pandemic based on a network pharmacology analysis

et al. 2022

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Aims: Reports of hepatitis in children during the coronavirus disease 2019 (COVID-19) pandemic garnered worldwide attention. The most probable culprits are adenovirus and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). At present, the optimal symptomatic treatment consists of a combination of anti-COVID-19 and hepatitis symptom alleviators. Schisandrin B (SchB) has been known to have liver-protective properties for a long time, whereas anti-COVID-19 properties only recently have been discovered. In the case of COVID-19 with hepatitis of unknown origin, we used network pharmacology to explore the symptomatic therapy and protective effects of SchB.Main methods: The most probable protein targets of SchB were predicted in the SwissTargetPrediction database. The GeneCards, National Center for Biotechnology Information, and Online Mendelian Inheritance in Man databases were used to compile information on the diseases hepatitis, adenovirus, and SARS-CoV-2. Following the use of a Venn diagram viewer to identify intersection genes, we constructed a protein–protein interaction network and identified the core genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment, as well as molecular docking, were employed to highlight the mechanisms of SchB on hepatitis.Key findings: SchB contains 27 targets on adenovirus_hepatitis and 16 targets on SARS-CoV-2_hepatitis, with 12 shared genes. Both target populations clustered in viral infection and cancer pathways, as well as in processes such as kinase activity phosphatase, cell adhesion, and ATPase binding. These genes might be closely related to liver damage and membrane binding from adenovirus or SARS-CoV-2 infections. In addition, epidermal growth factor receptor, HSP90AA1, and MAPK1 were among the top five targets of both SchB SARS-CoV-2 hepatitis and SchB adenovirus hepatitis.Significance: SchB may target common protective targets and mechanisms against acute hepatitis caused by adenovirus or by SARS-CoV-2 in children during the COVID-19 pandemic. These findings indicate SchB’s potential as a treatment for hepatitis of unknown origin.

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“…analysis showed that 26% of 123 children with unexplained hepatitis in the United States had tested positive for COVID-19 before their liver illness 2 . The CDC is now collecting the samples it needs to test for antibodies against SARS-CoV-2, to find out if other children with hepatitis had had infections that went undetected, says David Sugerman, a medical officer in the Division of Viral Diseases at the CDC's National Center for Immunization and Respiratory Diseases in Atlanta, Georgia.…”

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confidence: 99%

Mysterious child hepatitis continues to vex researchers

Ledford¹

2022

Nature

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In the three months since UK physicians sounded the alarm about mysterious cases of hepatitis that seemed to be striking young children, researchers have been scrambling to determine the cause -and a possible connection to the coronavirus pandemic has been among the leading hypotheses.But on 17 June, researchers at the US Centers for Disease Control and Prevention (CDC) published data suggesting that -in the United States at least -rates of hepatitis, or liver inflammation, with an unknown cause had not changed since 2017 among children aged 11 or younger 1 . If true, the finding could confound the pandemic-link theory.Not everyone is convinced by the data, however, and it is unclear whether the same finding will emerge from other countries. "I can tell you, having worked in this country for 30 years as a liver doctor, we've had a huge number of cases in 2022," says Deirdre Kelly, a paediatric hepatologist at the University of Birmingham, UK. "And I think the United Kingdom's case ascertainment is extremely good."Despite the US results, the CDC continues to explore connections to the pandemic. A 24 June

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

Abstract: 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).

Cited by 26 publications

References 8 publications

Adeno-associated virus type 2 in children from the United States with acute severe hepatitis

Adeno-associated virus type 2 in children from the United States with acute severe hepatitis

Potential protective benefits of Schisandrin B against severe acute hepatitis in children during the COVID-19 pandemic based on a network pharmacology analysis

Mysterious child hepatitis continues to vex researchers

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