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

Andrea Pilotto; Stefano Masciocchi; Irene Volonghi; Valeria De Giuli; Francesca Caprioli; Sara Mariotto; Sergio Ferrari; Silvia Bozzetti; Alberto Imarisio; Barbara Risi; Enrico Premi; Alberto Benussi; Emanuele Focà; Francesco Castelli; Gianluigi Zanusso; Salvatore Monaco; Paola Stefanelli; Roberto Gasparotti; Anastasia Zekeridou; Andrew McKeon; Nicholas J Ashton; Kaj BlennoW; Henrik Zetterberg; Alessandro Padovani

doi:10.1093/cid/ciaa1933

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

Clin Infect Dis. 2021 Nov 2;73(9):e3019-e3026. doi: 10.1093/cid/ciaa1933.

Authors

Andrea Pilotto^{1

2}, Stefano Masciocchi¹, Irene Volonghi¹, Valeria De Giuli³, Francesca Caprioli³, Sara Mariotto⁴, Sergio Ferrari⁴, Silvia Bozzetti⁴, Alberto Imarisio¹, Barbara Risi¹, Enrico Premi¹, Alberto Benussi¹, Emanuele Focà⁵, Francesco Castelli⁵, Gianluigi Zanusso⁴, Salvatore Monaco⁴, Paola Stefanelli⁶, Roberto Gasparotti⁷, Anastasia Zekeridou⁸, Andrew McKeon⁸, Nicholas J Ashton^{9

10

11

12}, Kaj BlennoW^{9

13}, Henrik Zetterberg^{9

13

14

15}, Alessandro Padovani¹

Affiliations

¹ Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
² Parkinson's Disease Rehabilitation Centre, FERB ONLUS-S. Isidoro Hospital, Trescore Balneario (BG), Italy.
³ Neurology Unit, Istituti Ospedalieri, ASST Cremona, Cremona, Italy.
⁴ Neurology Unit, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
⁵ University Division of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili Hospital, Brescia, Italy.
⁶ Department of Infectious Diseases, Italian National Public Health Institute, Rome, Italy.
⁷ Neuroradiology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia and ASST Spedali Civili Hospital, Brescia, Italy.
⁸ Departments of Laboratory Medicine and Pathology, and Neurology, Mayo Clinic, Rochester, Minnesota, USA.
⁹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
¹⁰ Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
¹¹ King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute, London, United Kingdom.
¹² NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, United Kingdom.
¹³ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Molndal, Sweden.
¹⁴ Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, London, United Kingdom.
¹⁵ UK Dementia Research Institute at UCL, London, United Kingdom.

Abstract

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.

Keywords: COVID-19; ICANS; SARS-CoV-2; cytokine storm syndrome; encephalitis.

Publication types

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

MeSH terms

COVID-19*
Cytokine Release Syndrome
Encephalitis*
Glial Fibrillary Acidic Protein
Humans
SARS-CoV-2

Substances

Glial Fibrillary Acidic Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding