Characteristic immune cell interactions in livers of children with acute hepatitis revealed by spatial single-cell analysis…, 2025, Röttele+

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
Felix Röttele; Andreas Zollner; Carolin Mogler; Muhammed Yuksel; Cigdem Arikan; Vivien Karl; Judith Helene Aberle; Stephan W Aberle; Hubert Kogler; Andreas Vécsei; Julia Vodopiutz; Henrike Salié; Anne Gräser; Laurenz Krimmel; Pius Martin; Eberhard Lurz; Felix Immanuel Maier; Lena Woelfle; Susana Nobre; Isabel Goncalves; Lisa Kern; Martin Schwemmle; Tobias Boettler; Maike Hofmann; Peter Hasselblatt; Robert Thimme; Herbert Tilg; Thomas Müller; Georg Friedrich Vogel; Bertram Bengsch

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.


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