{
  "abstract": "Background A rise in paediatric cases of acute hepatitis of unknown origin (AHUO) was observed in 2022, some requiring liver transplantation. A link to adeno-associated virus 2 infection and CD4 +T-cell mediated disease was reported in cohorts in the UK and USA but does not explain all cases.Objective To determine the intrahepatic immune cell interactions in the inflamed liver and a possible contribution of SARS-CoV-2 infection.Design Patients with acute non-A non-E hepatitis (10/12 AHUO, 2/12 subacute) during February 2022–December 2022 undergoing liver biopsy were recruited in a European patient cohort. Hepatological, virological, histopathological and highly multiplexed spatial and single-cell analyses of liver biopsies were performed.Results Patients were negative for adenoviral and SARS-CoV-2 PCR. Three patients had a positive adenoviral serology and 10/12 patients had a history or serological evidence of SARS-CoV-2 infection. Imaging mass cytometry identified significant intrahepatic immune infiltration with an enrichment of CD8 +T-cells. The highest CD8 infiltration and concomitant peripheral immune activation were observed in patients with the most severe hepatitis. CD8+T-cell infiltration was connected to histomorphological interface hepatitis and bridging necrosis. Cellular neighbourhood analysis indicated disease-associated microanatomic interactions between CX3CR1+ endothelial and myeloid cell populations, interacting with effector CD8+T-cells suggesting a pathogenic cellular triad. Of note, we detected intrahepatic SARS-CoV-2 antigens in ACE2-expressing cells in the areas with significant pathology in 11/12 samples using several different detection methods. 10/12 patients were treated with corticosteroid therapy and no liver transplantation was required.Conclusions We identified a possible manifestation of an immune-mediated postacute sequel to COVID-19 associated with a characteristic immune infiltrate in children with AHUO. COVID-19 testing should be considered in paediatric AHUO.",
  "authors": [
    {
      "affiliations": [
        "Clinic for Internal Medicine II, Freiburg University Medical Center, Freiburg im Breisgau, Germany"
      ],
      "name": "Felix Röttele"
    },
    {
      "affiliations": [
        "Division of Internal Medicine I, Gastroenterology, Hepatology Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria"
      ],
      "name": "Andreas Zollner"
    },
    {
      "affiliations": [
        "Institute of Pathology, School of Medicine and Health, Technical University of Munich, München, Germany"
      ],
      "name": "Carolin Mogler"
    },
    {
      "affiliations": [
        "Koc University School of Medicine, Pediatric GI and Hepatology Liver Transplantation Center, Koc Universitesi, Istanbul, Turkey"
      ],
      "name": "Muhammed Yuksel"
    },
    {
      "affiliations": [
        "Koc University School of Medicine, Pediatric GI and Hepatology Liver Transplantation Center, Koc Universitesi, Istanbul, Turkey"
      ],
      "name": "Cigdem Arikan"
    },
    {
      "affiliations": [
        "Clinic for Internal Medicine II, Freiburg University Medical Center, Freiburg im Breisgau, Germany"
      ],
      "name": "Vivien Karl"
    },
    {
      "affiliations": [
        "Center for Virology, Medical University of Vienna, Wien, Austria"
      ],
      "name": "Judith Helene Aberle"
    },
    {
      "affiliations": [
        "Center for Virology, Medical University of Vienna, Wien, Austria"
      ],
      "name": "Stephan W Aberle"
    },
    {
      "affiliations": [
        "Department of Pediatrics and Adolescent Medicine, St. Anna Children’s Hospital, Medical University Vienna, Vienna, Austria"
      ],
      "name": "Hubert Kogler"
    },
    {
      "affiliations": [
        "Department of Pediatrics and Adolescent Medicine, St. Anna Children’s Hospital, Medical University Vienna, Vienna, Austria"
      ],
      "name": "Andreas Vécsei"
    },
    {
      "affiliations": [
        "Department of Pediatrics and Adolescent Medicine, Division of Pediatric Pulmonology, Allergology and Endocrinology, Medical University of Vienna, Vienna, Austria"
      ],
      "name": "Julia Vodopiutz"
    },
    {
      "affiliations": [
        "Clinic for Internal Medicine II, Freiburg University Medical Center, Freiburg im Breisgau, Germany"
      ],
      "name": "Henrike Salié"
    },
    {
      "affiliations": [
        "Clinic for Internal Medicine II, Freiburg University Medical Center, Freiburg im Breisgau, Germany"
      ],
      "name": "Anne Gräser"
    },
    {
      "affiliations": [
        "Clinic for Internal Medicine II, Freiburg University Medical Center, Freiburg im Breisgau, Germany"
      ],
      "name": "Laurenz Krimmel"
    },
    {
      "affiliations": [
        "Clinic for Internal Medicine II, Freiburg University Medical Center, Freiburg im Breisgau, Germany"
      ],
      "name": "Pius Martin"
    },
    {
      "affiliations": [
        "Department of Pediatric Gastroenterology, Dr. von Hauner Children’s Hospital, University Hospital Munich, Munich, Germany"
      ],
      "name": "Eberhard Lurz"
    },
    {
      "affiliations": [
        "Department of Pediatric and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany"
      ],
      "name": "Felix Immanuel Maier"
    },
    {
      "affiliations": [
        "Department of Pediatric and Adolescent Medicine, Josefinum Hospital, Augsburg, Germany"
      ],
      "name": "Lena Woelfle"
    },
    {
      "affiliations": [
        "Department of Pediatrics, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal"
      ],
      "name": "Susana Nobre"
    },
    {
      "affiliations": [
        "Department of Pediatrics, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal"
      ],
      "name": "Isabel Goncalves"
    },
    {
      "affiliations": [
        "Institute of Virology, Freiburg University Medical Center, Freiburg im Breisgau, Germany"
      ],
      "name": "Lisa Kern"
    },
    {
      "affiliations": [
        "Institute of Virology, Freiburg University Medical Center, Freiburg im Breisgau, Germany"
      ],
      "name": "Martin Schwemmle"
    },
    {
      "affiliations": [
        "Clinic for Internal Medicine II, Freiburg University Medical Center, Freiburg im Breisgau, Germany"
      ],
      "name": "Tobias Boettler"
    },
    {
      "affiliations": [
        "Clinic for Internal Medicine II, Freiburg University Medical Center, Freiburg im Breisgau, Germany"
      ],
      "name": "Maike Hofmann"
    },
    {
      "affiliations": [
        "Clinic for Internal Medicine II, Freiburg University Medical Center, Freiburg im Breisgau, Germany"
      ],
      "name": "Peter Hasselblatt"
    },
    {
      "affiliations": [
        "Clinic for Internal Medicine II, Freiburg University Medical Center, Freiburg im Breisgau, Germany"
      ],
      "name": "Robert Thimme"
    },
    {
      "affiliations": [
        "Division of Internal Medicine I, Gastroenterology, Hepatology Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria"
      ],
      "name": "Herbert Tilg"
    },
    {
      "affiliations": [
        "Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria"
      ],
      "name": "Thomas Müller"
    },
    {
      "affiliations": [
        "Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria",
        "Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria"
      ],
      "name": "Georg Friedrich Vogel"
    },
    {
      "affiliations": [
        "Clinic for Internal Medicine II, Freiburg University Medical Center, Freiburg im Breisgau, Germany",
        "German Cancer Consortium (DKTK) Heidelberg, Germany, Partner Site Freiburg, Freiburg, Germany"
      ],
      "name": "Bertram Bengsch"
    }
  ],
  "title": "Characteristic immune cell interactions in livers of children with acute hepatitis revealed by spatial single-cell analysis identify a possible postacute sequel of COVID-19",
  "uid": "c4ed823f-536e-577f-b87b-6e2665d45c6b"
}