Neurologic complications in herpes simplex encephalitis: clinical, immunological and genetic studies.
Por:
Armangue-Salvador T, Olivé-Cirera G, Martínez-Hernandez E, Rodes M, Peris-Sempere V, Guasp M, Ruiz R, Palou E, González A, Marcos MÁ, Erro ME, Bataller L, Corral-Corral Í, Planagumà J, Caballero E, Vlagea A, Chen J, Bastard P, Materna M, Marchal A, Abel L, Cobat A, Alsina L, Fortuny-Guasch C, Saiz A, Mignot E, Vanderver A, Casanova JL, Zhang SY and Dalmau J
Publicada:
3 oct 2023
Ahead of Print:
15 jul 2023
Resumen:
Patients with herpes simplex virus (HSV) encephalitis (HSE) often develop neuronal autoantibody-associated encephalitis (AE) post-infection. Risk factors of AE are unknown. We tested the hypotheses that predisposition for AE post-HSE may be involved, including genetic variants at specific loci, human leucocyte (HLA) haplotypes, or the blood innate immune response against HSV, including type I interferon (IFN) immunity. Patients of all ages with HSE diagnosed between 1 January 2014 and 31 December 2021 were included in one of two cohorts depending on whether the recruitment was at HSE onset (Spanish Cohort A) or by the time of new neurological manifestations (international Cohort B). Patients were assessed for the type of neurological syndromes; HLA haplotypes; blood type I-IFN signature [RNA quantification of 6 or 28 IFN-response genes (IRG)] and toll-like receptor (TLR3)-type I IFN-related gene mutations. Overall, 190 patients (52% male) were recruited, 93 in Cohort A and 97 in Cohort B. Thirty-nine (42%) patients from Cohort A developed neuronal autoantibodies, and 21 (54%) of them developed AE. Three syndromes (choreoathetosis, anti-NMDAR-like encephalitis and behavioural-psychiatric) showed a high (=95% cases) association with neuronal autoantibodies. Patients who developed AE post-HSE were less likely to carry the allele HLA-A*02 (4/21, 19%) than those who did not develop AE (42/65, 65%, P = 0.0003) or the Spanish general population (2005/4335, 46%, P = 0.0145). Blood IFN signatures using 6 or 28 IRG were positive in 19/21 (91%) and 18/21 (86%) patients at HSE onset, and rapidly decreased during follow-up. At Day 21 after HSE onset, patients who later developed AE had higher median IFN signature compared with those who did not develop AE [median Zs-6-IRG 1.4 (0.6; 2.0) versus 0.2 (-0.4; 0.8), P = 0.03]. However, a very high median Zs-6-IRG (>4) or persistently increased IFN signature associated with uncontrolled viral infection. Whole exome sequencing showed that the percentage of TLR3-IFN-related mutations in patients who developed AE was not different from those who did not develop AE [3/37 (8%) versus 2/57 (4%), P = 0.379]. Multivariate logistic regression showed that a moderate increase of the blood IFN signature at Day 21 (median Zs-6-IRG >1.5 but <4) was the most important predictor of AE post-HSE [odds ratio 34.8, interquartile ratio (1.7-691.9)]. Altogether, these findings show that most AE post-HSE manifest with three distinct syndromes, and HLA-A*02, but not TLR3-IFN-related mutations, confer protection from developing AE. In addition to neuronal autoantibodies, the blood IFN signature in the context of HSE may be potentially useful for the diagnosis and monitoring of HSE complications.
Filiaciones:
Armangue-Salvador T:
Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain
Pediatric Neuroimmunology Unit, Neurology Department, Sant Joan de Déu Children's Hospital, University of Barcelona, 08950 Esplugues de Llobregat, Barcelona, Spain
Olivé-Cirera G:
Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain
Pediatric Neurology Unit, Parc Taulí Hospital Universitari, 08208 Sabadell, Barcelona, Spain
Martínez-Hernandez E:
Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain
Service of Neurology, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain
Neuroimmunology Unit, Service of Neurology, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain
Rodes M:
Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain
Peris-Sempere V:
Center for Sleep Science and Medicine, Stanford University, Stanford, CA 94304, USA
Guasp M:
Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain
Service of Neurology, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain
Neuroimmunology Unit, Service of Neurology, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain
Ruiz R:
Immunology Department, Hospital Clínic, Centre de Diagnòstic Biomèdic, 08036 Barcelona, Spain
Palou E:
Immunology Department, Hospital Clínic, Centre de Diagnòstic Biomèdic, 08036 Barcelona, Spain
González A:
Immunology Department, Hospital Clínic, Centre de Diagnòstic Biomèdic, 08036 Barcelona, Spain
Marcos MÁ:
Service of Microbiology, Hospital Clínic, Centre de Diagnòstic Biomèdic, 08036 Barcelona, Spain
ISGlobal Barcelona Institute for Global Health, 08036 Barcelona, Spain
CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28222 Madrid, Spain
Erro ME:
Department of Neurology, Hospital Universitario de Navarra, 31008 Pamplona, Spain
Bataller L:
Department of Neurology, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain
Corral-Corral Í:
Hospital Universitario Ramon y Cajal, 28034 Madrid, Spain
Department of Neurology, Hospital Universitario Ramon y Cajal, 28034 Madrid, Spain
Planagumà J:
Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain
Caballero E:
Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain
Vlagea A:
Immunology Department, Hospital Clínic, Centre de Diagnòstic Biomèdic, 08036 Barcelona, Spain
Chen J:
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
Bastard P:
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Necker Hospital for Sick Children, 75015 Paris, France
Paris City University, Imagine Institute, 75015 Paris, France
Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France
Materna M:
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Necker Hospital for Sick Children, 75015 Paris, France
Paris City University, Imagine Institute, 75015 Paris, France
Marchal A:
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Necker Hospital for Sick Children, 75015 Paris, France
Paris City University, Imagine Institute, 75015 Paris, France
Abel L:
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Necker Hospital for Sick Children, 75015 Paris, France
Paris City University, Imagine Institute, 75015 Paris, France
Cobat A:
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Necker Hospital for Sick Children, 75015 Paris, France
Paris City University, Imagine Institute, 75015 Paris, France
Alsina L:
Clinical Immunology and Primary Immunodeficiencies Unit. Pediatric Allergy and Clinical Immunology Department. Hospital Sant Joan de Déu, 08950 Barcelona, Spain
Department of Pediatrics, Universitat de Barcelona, 08036 Barcelona, Spain
Study Group for Immune Disfunction Diseases in Children. Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Barcelona, Spain
Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, 08950 Barcelona, Spain
Study Group for Immune Disfunction Diseases in Children, Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Esplugues de Llobregat, Barcelona, Spain
Fortuny-Guasch C:
Department of Pediatrics, Universitat de Barcelona, 08036 Barcelona, Spain
Infectious Diseases Department, Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Barcelona Spain
Infectious Diseases Department, Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Esplugues de Llobregat, Barcelona, Spain
Saiz A:
Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain
Service of Neurology, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain
Neuroimmunology Unit, Service of Neurology, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain
Mignot E:
Center for Sleep Science and Medicine, Stanford University, Stanford, CA 94304, USA
Vanderver A:
Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Casanova JL:
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Necker Hospital for Sick Children, 75015 Paris, France
Paris City University, Imagine Institute, 75015 Paris, France
Howard Hughes Medical Institute, Rockefeller University, New York, NY 10065, USA
Zhang SY:
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Necker Hospital for Sick Children, 75015 Paris, France
Paris City University, Imagine Institute, 75015 Paris, France
Howard Hughes Medical Institute, Rockefeller University, New York, NY 10065, USA
Dalmau J:
Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain
Pediatric Neuroimmunology Unit, Neurology Department, Sant Joan de Déu Children's Hospital, University of Barcelona, 08950 Esplugues de Llobregat, Barcelona, Spain
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Catalan Institute for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain
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