Late-onset enteric virus infection associated with hepatitis (EVAH) in transplanted SCID patients

Quentin Riller; Jacques Fourgeaud; Julie Bruneau; Suk See De Ravin; Grace Smith; Mathieu Fusaro; Samy Meriem; Aude Magerus; Marine Luka; Ghaith Abdessalem; Ludovic Lhermitte; Anne Jamet; Emmanuelle Six; Alessandra Magnani; Martin Castelle; Romain Lévy; Mathilde M Lecuit; Benjamin Fournier; Sarah Winter; Michaela Semeraro; Graziella Pinto; Hanène Abid; Nizar Mahlaoui; Nathalie Cheikh; Benoit Florkin; Pierre Frange; Eric Jeziorski; Felipe Suarez; Françoise Sarrot-Reynauld; Dalila Nouar; Dominique Debray; Florence Lacaille; Capucine Picard; Philippe Pérot; Béatrice Regnault; Nicolas Da Rocha; Camille de Cevins; Laure Delage; Brieuc P Pérot; Angélique Vinit; Francesco Carbone; Camille Brunaud; Manon Marchais; Marie-Claude Stolzenberg; Vahid Asnafi; Thierry Molina; Frédéric Rieux-Laucat; Luigi D Notarangelo; Stefania Pittaluga; Jean Philippe Jais; Despina Moshous; Stephane Blanche; Harry Malech; Marc Eloit; Marina Cavazzana; Alain Fischer; Mickaël M Ménager; Bénédicte Neven

doi:10.1016/j.jaci.2022.12.822

Late-onset enteric virus infection associated with hepatitis (EVAH) in transplanted SCID patients

J Allergy Clin Immunol. 2023 Jun;151(6):1634-1645. doi: 10.1016/j.jaci.2022.12.822. Epub 2023 Jan 10.

Authors

Quentin Riller¹, Jacques Fourgeaud², Julie Bruneau³, Suk See De Ravin⁴, Grace Smith⁵, Mathieu Fusaro⁶, Samy Meriem⁷, Aude Magerus¹, Marine Luka⁸, Ghaith Abdessalem⁸, Ludovic Lhermitte⁹, Anne Jamet¹⁰, Emmanuelle Six¹¹, Alessandra Magnani¹², Martin Castelle¹³, Romain Lévy¹⁴, Mathilde M Lecuit¹³, Benjamin Fournier¹⁵, Sarah Winter¹⁵, Michaela Semeraro¹⁶, Graziella Pinto¹⁷, Hanène Abid¹⁸, Nizar Mahlaoui¹³, Nathalie Cheikh¹⁹, Benoit Florkin²⁰, Pierre Frange²¹, Eric Jeziorski²², Felipe Suarez²³, Françoise Sarrot-Reynauld²⁴, Dalila Nouar²⁵, Dominique Debray²⁶, Florence Lacaille²⁷, Capucine Picard²⁸, Philippe Pérot²⁹, Béatrice Regnault²⁹, Nicolas Da Rocha²⁹, Camille de Cevins³⁰, Laure Delage¹, Brieuc P Pérot³¹, Angélique Vinit³², Francesco Carbone³³, Camille Brunaud¹, Manon Marchais¹, Marie-Claude Stolzenberg¹, Vahid Asnafi⁹, Thierry Molina³⁴, Frédéric Rieux-Laucat¹, Luigi D Notarangelo⁴, Stefania Pittaluga³⁵, Jean Philippe Jais³⁶, Despina Moshous³⁷, Stephane Blanche¹⁵, Harry Malech⁴, Marc Eloit³⁸, Marina Cavazzana³⁹, Alain Fischer⁴⁰, Mickaël M Ménager³³, Bénédicte Neven⁴¹

Affiliations

¹ University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France.
² University of Paris Cité, Paris, France; Microbiology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Pathogen Discovery Laboratory, Institut Pasteur, Université de Paris, Paris, France; Prise en Charge des Anomalies Congénitales et leur Traitement, Unit 7328, Imagine Institute, University of Paris Cité, Paris, France.
³ University of Paris Cité, Paris, France; Pathology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Imagine Institute, INSERM UMR 1163, Laboratory of Molecular Mechanisms of Hematologic Disorders and Therapeutic Implications, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
⁴ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
⁵ Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md.
⁶ Study Center for Primary Immunodeficiencies, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
⁷ Laboratory of Biostatistics, University of Paris Cité, Paris, France.
⁸ Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, Paris, France.
⁹ University of Paris Cité, Paris, France; Laboratory of Onco-Haematology, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; the Institut Necker-Enfants Malades (INEM), INSERM UMR 1151, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁰ University of Paris Cité, Paris, France; Microbiology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; the Institut Necker-Enfants Malades (INEM), INSERM UMR 1151, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹¹ University of Paris Cité, Paris, France; Laboratory of Human Lympho-Hematopoiesis, Imagine Institute, INSERM UMR 1163, Paris, France.
¹² Department of Biotherapy, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹³ Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁴ University of Paris Cité, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁵ University of Paris Cité, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁶ University of Paris Cité, Paris, France; Clinical Investigation Center, Clinical Research Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁷ Pediatric Endocrinology, Gynecology, Diabetology, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁸ University of Paris Cité, Paris, France; Microbiology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁹ Pediatric Hematology Oncology Unit, University Hospital of Besançon, Besançon, France.
²⁰ Immuno-Hémato-Rhumatologie Pédiatrique, Service de Pédiatrie, CHR Citadelle, Liege, Belgium.
²¹ University of Paris Cité, Paris, France; Microbiology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
²² Department of Pediatrics, Infectious Diseases, and Immunology, University of Montpellier, CHU Montpellier, Montpellier, France.
²³ University of Paris Cité, Paris, France; Imagine Institute, INSERM UMR 1163, Laboratory of Molecular Mechanisms of Hematologic Disorders and Therapeutic Implications, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Hematology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
²⁴ Service de Médecine Interne, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France.
²⁵ Service d'Immunologie Clinique et d'Allergologie, Centre Hospitalier Régional Universitaire, Tours, France.
²⁶ Pediatric Liver Unit, National Reference Center for Rare Diseases, Biliary Atresia and Genetic Cholestasis, Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare Liver, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
²⁷ Gastroenterology-Hepatology-Nutrition Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
²⁸ Study Center for Primary Immunodeficiencies, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Imagine Institute, INSERM UMR 1163, Paris, France.
²⁹ Pathogen Discovery Laboratory, Institut Pasteur, Université de Paris, Paris, France; OIE Collaborating Center for the Detection and Identification in Humans of Emerging Animal Pathogens, Institut Pasteur, Paris, France.
³⁰ University of Paris Cité, Paris, France; Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, Imagine Institute, INSERM UMR 1163, Paris, France; Artificial Intelligence & Deep Analytics (AIDA) Group, Data & Data Science (DDS), Sanofi R&D, Chilly-Mazarin, France.
³¹ University of Paris Cité, Paris, France; Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, Imagine Institute, INSERM UMR 1163, Paris, France.
³² Sorbonne Université, UMS037, PASS, Plateforme de Cytométrie de la Pitié-Salpêtrière CyPS, Paris, France.
³³ University of Paris Cité, Paris, France; Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, Paris, France; Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, Imagine Institute, INSERM UMR 1163, Paris, France.
³⁴ University of Paris Cité, Paris, France; Pathology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
³⁵ National Cancer Institute, National Institutes of Health, Bethesda, Md.
³⁶ University of Paris Cité, Paris, France; Laboratory of Biostatistics, University of Paris Cité, Paris, France.
³⁷ University of Paris Cité, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée Ligue contre le Cancer, Imagine Institute, INSERM UMR 1163, Paris, France.
³⁸ Pathogen Discovery Laboratory, Institut Pasteur, Université de Paris, Paris, France; OIE Collaborating Center for the Detection and Identification in Humans of Emerging Animal Pathogens, Institut Pasteur, Paris, France; Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France.
³⁹ University of Paris Cité, Paris, France; Laboratory of Onco-Haematology, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory of Human Lympho-Hematopoiesis, Imagine Institute, INSERM UMR 1163, Paris, France.
⁴⁰ Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Collège de France, Paris, France.
⁴¹ University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address: benedicte.neven@aphp.fr.

Abstract

Background: Allogenic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) are potentially curative treatments for severe combined immunodeficiency (SCID). Late-onset posttreatment manifestations (such as persistent hepatitis) are not uncommon.

Objective: We sought to characterize the prevalence and pathophysiology of persistent hepatitis in transplanted SCID patients (SCIDH+) and to evaluate risk factors and treatments.

Methods: We used various techniques (including pathology assessments, metagenomics, single-cell transcriptomics, and cytometry by time of flight) to perform an in-depth study of different tissues from patients in the SCIDH+ group and corresponding asymptomatic similarly transplanted SCID patients without hepatitis (SCIDH-).

Results: Eleven patients developed persistent hepatitis (median of 6 years after HSCT or GT). This condition was associated with the chronic detection of enteric viruses (human Aichi virus, norovirus, and sapovirus) in liver and/or stools, which were not found in stools from the SCIDH- group (n = 12). Multiomics analysis identified an expansion of effector memory CD8⁺ T cells with high type I and II interferon signatures. Hepatitis was associated with absence of myeloablation during conditioning, split chimerism, and defective B-cell function, representing 25% of the 44 patients with SCID having these characteristics. Partially myeloablative retransplantation or GT of patients with this condition (which we have named as "enteric virus infection associated with hepatitis") led to the reconstitution of T- and B-cell immunity and remission of hepatitis in 5 patients, concomitantly with viral clearance.

Conclusions: Enteric virus infection associated with hepatitis is related to chronic enteric viral infection and immune dysregulation and is an important risk for transplanted SCID patients with defective B-cell function.

Keywords: B-cell function; CD8(+) T cells; SCID; enteric virus; gene therapy; interferon; transplantation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes
Enterovirus Infections*
Hematopoietic Stem Cell Transplantation* / adverse effects
Hematopoietic Stem Cell Transplantation* / methods
Hepatitis* / etiology
Humans
Severe Combined Immunodeficiency* / etiology
Severe Combined Immunodeficiency* / therapy
Virus Diseases* / etiology

Grants and funding

ZIA AI001222/ImNIH/Intramural NIH HHS/United States