Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Encephalitis Is a Cytokine Release Syndrome: Evidences From Cerebrospinal Fluid Analyses.

COVID-19 Cytokine Release Syndrome Encephalitis Glial Fibrillary Acidic Protein Humans SARS-CoV-2
COVID-19 ICANS SARS-CoV-2 cytokine storm syndrome encephalitis

Journal

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
ISSN: 1537-6591
Titre abrégé: Clin Infect Dis
Pays: United States
ID NLM: 9203213

Informations de publication

Date de publication:
02 11 2021
Historique:
received: 01 11 2020
pubmed: 5 1 2021
medline: 9 11 2021
entrez: 4 1 2021
Statut: ppublish

Résumé

Recent findings indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related neurological manifestations involve cytokine release syndrome along with endothelial activation, blood brain barrier dysfunction, and immune-mediated mechanisms. Very few studies have fully investigated the cerebrospinal fluid (CSF) correlates of SARS-CoV-2 encephalitis. Patients with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection and encephalitis (COV-Enc), encephalitis without SARS-CoV-2 infection (ENC), and healthy controls (HC) underwent an extended panel of CSF neuronal (neurofilament light chain [NfL], T-tau), glial (glial fibrillary acidic protein [GFAP], soluble triggering receptor expressed on myeloid cells 2 [sTREM2], chitinase-3-like protein 1 [YKL-40]) and inflammatory biomarkers (interleukin [IL]-1β, IL-6, Il-8, tumor necrosis factor [TNF] α, CXCL-13, and β2-microglobulin). Thirteen COV-Enc, 21 ENC, and 18 HC entered the study. In COV-Enc cases, CSF was negative for SARS-CoV-2 real-time PCR but exhibited increased IL-8 levels independently from presence of pleocytosis/hyperproteinorracchia. COV-Enc patients showed increased IL-6, TNF- α, and β2-microglobulin and glial markers (GFAP, sTREM2, YKL-40) levels similar to ENC but normal CXCL13 levels. Neuronal markers NfL and T-tau were abnormal only in severe cases. SARS-CoV-2-related encephalitis were associated with prominent glial activation and neuroinflammatory markers, whereas neuronal markers were increased in severe cases only. The pattern of CSF alterations suggested a cytokine-release syndrome as the main inflammatory mechanism of SARS-CoV-2-related encephalitis.

Sections du résumé

BACKGROUND
Recent findings indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related neurological manifestations involve cytokine release syndrome along with endothelial activation, blood brain barrier dysfunction, and immune-mediated mechanisms. Very few studies have fully investigated the cerebrospinal fluid (CSF) correlates of SARS-CoV-2 encephalitis.
METHODS
Patients with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection and encephalitis (COV-Enc), encephalitis without SARS-CoV-2 infection (ENC), and healthy controls (HC) underwent an extended panel of CSF neuronal (neurofilament light chain [NfL], T-tau), glial (glial fibrillary acidic protein [GFAP], soluble triggering receptor expressed on myeloid cells 2 [sTREM2], chitinase-3-like protein 1 [YKL-40]) and inflammatory biomarkers (interleukin [IL]-1β, IL-6, Il-8, tumor necrosis factor [TNF] α, CXCL-13, and β2-microglobulin).
RESULTS
Thirteen COV-Enc, 21 ENC, and 18 HC entered the study. In COV-Enc cases, CSF was negative for SARS-CoV-2 real-time PCR but exhibited increased IL-8 levels independently from presence of pleocytosis/hyperproteinorracchia. COV-Enc patients showed increased IL-6, TNF- α, and β2-microglobulin and glial markers (GFAP, sTREM2, YKL-40) levels similar to ENC but normal CXCL13 levels. Neuronal markers NfL and T-tau were abnormal only in severe cases.
CONCLUSIONS
SARS-CoV-2-related encephalitis were associated with prominent glial activation and neuroinflammatory markers, whereas neuronal markers were increased in severe cases only. The pattern of CSF alterations suggested a cytokine-release syndrome as the main inflammatory mechanism of SARS-CoV-2-related encephalitis.

Identifiants

DOI: 10.1093/cid/ciaa1933 PMID: 33395482 PMC: PMC7799260
pubmed: 33395482
pii: 6062486
doi: 10.1093/cid/ciaa1933
pmc: PMC7799260
doi:

Substances chimiques

Glial Fibrillary Acidic Protein 0

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

e3019-e3026

Subventions

Organisme : Swedish Alzheimer Foundation
ID : grant number AF-742881
Organisme : Italian Ministry of Health
Organisme : Swedish Research Council
ID : 2017-00915
Organisme : Hjärnfonden, Sweden
ID : FO2017-0243
Organisme : European Research Council
ID : 681712
Pays : International
Organisme : Alzheimer Drug Discovery Foundation
ID : RDAPB-201809-2016615

Commentaires et corrections

Type : CommentIn

Informations de copyright

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Auteurs

Andrea Pilotto (A)

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
Parkinson's Disease Rehabilitation Centre, FERB ONLUS-S. Isidoro Hospital, Trescore Balneario (BG), Italy.

Stefano Masciocchi (S)

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Irene Volonghi (I)

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Valeria De Giuli (V)

Neurology Unit, Istituti Ospedalieri, ASST Cremona, Cremona, Italy.

Francesca Caprioli (F)

Neurology Unit, Istituti Ospedalieri, ASST Cremona, Cremona, Italy.

Sara Mariotto (S)

Neurology Unit, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Sergio Ferrari (S)

Neurology Unit, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Silvia Bozzetti (S)

Neurology Unit, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Alberto Imarisio (A)

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Barbara Risi (B)

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Enrico Premi (E)

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Alberto Benussi (A)

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Emanuele Focà (E)

University Division of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili Hospital, Brescia, Italy.

Francesco Castelli (F)

University Division of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili Hospital, Brescia, Italy.

Gianluigi Zanusso (G)

Neurology Unit, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Salvatore Monaco (S)

Neurology Unit, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Paola Stefanelli (P)

Department of Infectious Diseases, Italian National Public Health Institute, Rome, Italy.

Roberto Gasparotti (R)

Neuroradiology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia and ASST Spedali Civili Hospital, Brescia, Italy.

Anastasia Zekeridou (A)

Departments of Laboratory Medicine and Pathology, and Neurology, Mayo Clinic, Rochester, Minnesota, USA.

Andrew McKeon (A)

Departments of Laboratory Medicine and Pathology, and Neurology, Mayo Clinic, Rochester, Minnesota, USA.

Nicholas J Ashton (NJ)

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute, London, United Kingdom.
NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, United Kingdom.

Kaj BlennoW (K)

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Molndal, Sweden.

Henrik Zetterberg (H)

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Molndal, Sweden.
Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, London, United Kingdom.
UK Dementia Research Institute at UCL, London, United Kingdom.

Alessandro Padovani (A)

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

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Classifications MeSH

questionsmedicales.fr › Maladies de l'appareil respiratoire › Infections de l'appareil respiratoire › Pneumopathie infectieuse › Pneumopathie virale › COVID-19 › Severe Acute Respiratory Syndrome Coronavirus...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Choc › Syndrome de réponse inflammatoire généralisée › Syndrome de libération de cytokines › Severe Acute Respiratory Syndrome Coronavirus...
questionsmedicales.fr › Maladies du système nerveux › Encéphalite › Severe Acute Respiratory Syndrome Coronavirus...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines du cytosquelette › Protéines de filaments intermédiaires › Protéine gliofibrillaire acide › Severe Acute Respiratory Syndrome Coronavirus...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Severe Acute Respiratory Syndrome Coronavirus...
questionsmedicales.fr › Virus › Virus à ARN › Virus à ARN à brin positif › Nidovirales › Coronaviridae › Coronavirus › Betacoronavirus › Virus du SRAS › SARS-CoV-2 › Severe Acute Respiratory Syndrome Coronavirus...