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 McKeonNicholas J. Ashton, Kaj W. Blenno, Henrik Zetterberg, Alessandro Padovani

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)E3019-E3026
JournalClinical Infectious Diseases
Issue number9
StatePublished - 2021


  • COVID-19
  • Cytokine storm syndrome
  • Encephalitis
  • SARS-CoV-2

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases


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