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

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

doi:10.1093/cid/ciaa1933

Cited by 151 publications

(179 citation statements)

References 31 publications

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“…Furthermore, cognitive impairment with prominent decline in executive functions has been reported in COVID-19 patients, either in the acute phase, or at discharge, and correlates with COVID-19 disease severity and use of mechanical ventilation [2,5,6]. Presence of inflammatory markers in serum and/or cerebrospinal fluid (CSF), such as increased interleukin 6 (IL-6), IL-8, or oligoclonal bands, have been reported by several groups in association to this clinical phenotype [2][3][4]7]. Frontal abnormalities on electroencephalography (EEG), including slowwaves and slowing-down of the background rhythm or epileptiform discharges, are present in one-third of COVID-19 patients and have been proposed as an EEG biomarker for COVID-19 encephalopathy [8].…”

Section: Clinical Evidencementioning

confidence: 97%

“…Indeed, the pattern of activated microglia seems reminiscent of autoimmune encephalitis rather than direct central nervous system (CNS) damage caused by the virus [18]. An inflammatory process could be in keeping with increased levels of glial markers, including fibrillary acidic protein (GFAP), sTREM-2, and YKL-40, found in COVID-19 patients in plasma and in the brain [7,18,24]. COVID-19 encephalitis presenting as Acute Disseminated Encephalomyelitis (ADEM) or limbic encephalitis have also been reported, suggesting a possible, though rarer, autoimmune mechanism [25][26][27].…”

Section: Pathophysiological Theoriesmentioning

confidence: 99%

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Is the Frontal Lobe the Primary Target of SARS-CoV-2?

Toniolo

Lorenzo

Scarioni

et al. 2021

JAD

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Acute delirium and other neuropsychiatric symptoms have frequently been reported in COVID-19 patients and are variably referred to as acute encephalopathy, COVID-19 encephalopathy, SARS-CoV-2 encephalitis, or steroid-responsive encephalitis. COVID-19 specific biomarkers of cognitive impairment are currently lacking, but there is some evidence that SARS-CoV-2 could preferentially and directly target the frontal lobes, as suggested by behavioral and dysexecutive symptoms, fronto-temporal hypoperfusion on MRI, EEG slowing in frontal regions, and frontal hypometabolism on 18F-FDG-PET imaging. We suggest that an inflammatory parainfectious process targeting preferentially the frontal lobes (and/or frontal networks) could be the underlying cause of these shared clinical, neurophysiological, and imaging findings in COVID-19 patients. We explore the biological mechanisms and the clinical biomarkers that might underlie such disruption of frontal circuits and highlight the need of standardized diagnostic procedures to be applied when investigating patients with these clinical findings. We also suggest the use of a unique label, to increase comparability across studies.

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Section: Clinical Evidencementioning

confidence: 97%

Section: Pathophysiological Theoriesmentioning

confidence: 99%

Is the Frontal Lobe the Primary Target of SARS-CoV-2?

Toniolo

Lorenzo

Scarioni

et al. 2021

JAD

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“…3,9 Additionally, CSF analysis, neuroimaging, and neuropathological findings, as well as the clinical response to various immunotherapies, are not consistent with an infectious disease targeting the brain but rather with an immune-mediated pathogenesis. 4,[9][10][11] Therefore, a cytokine-mediated neuroinflammatory process, associated with cytokine storm, has been suggested as the underlying pathogenic mechanism. 5,10,[12][13][14] Chimeric antigen receptor T-cell (CAR-T) therapy is a novel and highly effective treatment for refractory hematological malignancies, whose most common complication is cytokine release syndrome, a cytokine storm disorder.…”

Section: Introductionmentioning

confidence: 99%

Brain dysfunction in COVID‐19 and CAR‐T therapy: cytokine storm‐associated encephalopathy

Pensato

Muccioli

Cani

et al. 2021

Ann Clin Transl Neurol

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Objective Many neurological manifestations are associated with COVID‐19, including a distinct form of encephalopathy related to cytokine storm, the acute systemic inflammatory syndrome present in a subgroup of COVID‐19 patients. Cytokine storm is also associated with immune effector cell‐associated neurotoxicity syndrome (ICANS), a complication of chimeric antigen receptor T‐cell (CAR‐T) therapy, a highly effective treatment for refractory hematological malignancies. We investigated whether COVID‐19‐related encephalopathy, ICANS, and other encephalopathies associated with cytokine storm, share clinical and investigative findings. Methods Narrative literature review. Results Comparisons between COVID‐19‐related encephalopathy and ICANS revealed several overlapping features. Clinically, these included dysexecutive syndrome, language disturbances, akinetic mutism and delirium. EEG showed a prevalence of frontal abnormalities. Brain MRI was often unrevealing. CSF elevated cytokine levels have been reported. A direct correlation between cytokine storm intensity and severity of neurological manifestations has been shown for both conditions. Clinical recovery occurred spontaneously or following immunotherapies in most of the patients. Similar clinical and investigative features were also reported in other encephalopathies associated with cytokine storm, such as hemophagocytic lymphohistiocytosis, sepsis, and febrile infection‐associated encephalopathies. Interpretation COVID‐19‐related encephalopathy and ICANS are characterized by a predominant electro‐clinical frontal lobe dysfunction and share several features with other encephalopathies associated with cytokine storm, which may represent the common denominator of a clinical spectrum of neurological disorders. Therefore, we propose a unifying definition of cytokine storm‐associated encephalopathy (CySE), and its diagnostic criteria.

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“…In line with our report, two recent studies observed vascular leakage and peri-vascular immune infiltration in the brain of COVID-19 patients, but without the crucial link to ACE2 expression by, and infection of, pericytes 27, 28 . However, it is still an outstanding question whether SARS-CoV-2 is overtly neurotropic or if the neurological symptoms associated with COVID-19 are secondary to events related to the systemic host response 29 . Although solely based on the comparable abundance of GFAP in the tissues, our observations do not provide support for the hypothesis of a cytokine storm.…”

Section: Discussionmentioning

confidence: 99%

Infection of brain pericytes underlying neuropathology of COVID-19 patients

Bocci

Oudenaarden

Sàenz-Sardà

et al. 2021

Preprint

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A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69,5 years; and n = 7 control, median age = 68 years), and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in peri-vascular cells. Viral particles were identified in the vascular wall and paralleled by peri-vascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from an additional 16 individuals (n = 8 COVID-19, median age = 67 years; and n = 8 control, median age = 69,5 years) exhibited significantly lower levels of the pericyte marker PDGFRβ in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to peri-vascular inflammation and a locally compromised blood-brain barrier.

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

Cited by 151 publications

References 31 publications

Is the Frontal Lobe the Primary Target of SARS-CoV-2?

Is the Frontal Lobe the Primary Target of SARS-CoV-2?

Brain dysfunction in COVID‐19 and CAR‐T therapy: cytokine storm‐associated encephalopathy

Infection of brain pericytes underlying neuropathology of COVID-19 patients

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