Encephalopathies associated with severe COVID-19 present specific neurovascular unit alterations without evidence of strong neuroinflammation

ABSTRACTObjectiveCoronavirus disease (COVID-19) has been associated with a large variety of neurological disorders. However the mechanisms underlying these neurological complications remain elusive. In this study we aimed at determining whether neurological symptoms were caused by SARS-CoV-2 direct infection or by either systemic or local pro-inflammatory mediators.MethodsWe checked for SARS-CoV-2 RNA by RT-qPCR, SARS-CoV-2-specific antibodies and for 49 cytokines/chemokines/growth factors (by Luminex) in the cerebrospinal fluids (CSF) +/-sera of a cohort of 22 COVID-19 patients with neurological presentation and 55 neurological control patients (inflammatory [IND], non-inflammatory [NIND], multiple sclerosis [MS]).ResultsWe detected SARS-CoV-2 RNA and virus-specific antibodies in the CSF of 0/22 and 10/21 COVID-19 patients, respectively. Of the four categories of tested patients, the CSF of IND exhibited the highest level of cytokines, chemokines and growth factors. In contrast, COVID-19 patients did not present overall upregulation of inflammatory mediators in the CSF. However, the CSF of patients with severe COVID-19 (ICU patients) exhibited higher concentrations of CCL2, CXCL8, and VEGF-A in the CSF than patients with a milder form of COVID-19. In addition, we could show that intrathecal CXCL8 synthesis was linked to an elevated barrier index and correlated to the increase of peripheral inflammation (serum HGF and CXCL10).ConclusionOur results point at an absence of massive SARS-CoV-2 infection or inflammation of the central nervous system, but highlight a specific impairment of the neurovascular unit linked to intrathecal production of CXCL8.</jats:sec

Encephalopathies Associated With Severe COVID-19 Present Neurovascular Unit Alterations Without Evidence for Strong Neuroinflammation

ObjectiveCoronavirus disease (COVID-19) has been associated with a large variety of neurologic disorders. However, the mechanisms underlying these neurologic complications remain elusive. In this study, we aimed at determining whether neurologic symptoms were caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) direct infection or by either systemic or local proinflammatory mediators.MethodsIn this cross-sectional study, we checked for SARS-CoV-2 RNA by quantitative reverse transcription PCR, SARS-CoV-2–specific antibodies, and 49 cytokines/chemokines/growth factors (by Luminex) in the CSF +/− sera of a cohort of 22 COVID-19 patients with neurologic presentation and 55 neurologic control patients (inflammatory neurologic disorder [IND], noninflammatory neurologic disorder, and MS).ResultsWe detected anti–SARS-CoV-2 immunoglobulin G in patients with severe COVID-19 with signs of intrathecal synthesis for some of them. Of the 4 categories of tested patients, the CSF of IND exhibited the highest level of cytokines, chemokines, and growth factors. By contrast, patients with COVID-19 did not present overall upregulation of inflammatory mediators in the CSF. However, patients with severe COVID-19 (intensive care unit patients) exhibited higher concentrations of CCL2, CXCL8, and vascular endothelium growth factor A (VEGF-A) in the CSF than patients with a milder form of COVID-19. In addition, we could show that intrathecal CXCL8 synthesis was linked to an elevated albumin ratio and correlated with the increase of peripheral inflammation (serum hepatocyte growth factor [HGF] and CXCL10).ConclusionsOur results do not indicate active replication of SARS-CoV-2 in the CSF or signs of massive inflammation in the CSF compartment but highlight a specific impairment of the neurovascular unit linked to intrathecal production of CXCL8.</jats:sec

CD177, a specific marker of neutrophil activation, is associated with coronavirus disease 2019 severity and death

International audienceThe identification of patients with coronavirus disease 2019 and high risk of severe disease is a challenge in routine care. We performed cell phenotypic, serum, and RNA sequencing gene expression analyses in severe hospitalized patients (n = 61). Relative to healthy donors, results showed abnormalities of 27 cell populations and an elevation of 42 cytokines, neutrophil chemo-attractants, and inflammatory components in patients. Supervised and unsupervised analyses revealed a high abundance of CD177, a specific neutrophil activation marker, contributing to the clustering of severe patients. Gene abundance correlated with high serum levels of CD177 in severe patients. Higher levels were confirmed in a second cohort and in intensive care unit (ICU) than non-ICU patients (P < 0.001). Longitudinal measurements discriminated between patients with the worst prognosis, leading to death, and those who recovered (P = 0.01). These results highlight neutrophil activation as a hallmark of severe disease and CD177 assessment as a reliable prognostic marker for routine care

CD177, a specific marker of neutrophil activation, is a hallmark of COVID-19 severity and death

AbstractCOVID-19 SARS-CoV-2 infection exhibits wide inter-individual clinical variability, from silent infection to severe disease and death. The identification of high-risk patients is a continuing challenge in routine care. We aimed to identify factors that influence clinical worsening. We analyzed 52 cell populations, 71 analytes, and RNA-seq gene expression in the blood of severe patients from the French COVID cohort upon hospitalization (n = 61). COVID-19 patients showed severe abnormalities of 27 cell populations relative to healthy donors (HDs). Forty-two cytokines, neutrophil chemo-attractants, and inflammatory components were elevated in COVID-19 patients. Supervised gene expression analyses showed differential expression of genes for neutrophil activation, interferon signaling, T- and B-cell receptors, EIF2 signaling, and ICOS-ICOSL pathways in COVID-19 patients. Unsupervised analysis confirmed the prominent role of neutrophil activation, with a high abundance of CD177, a specific neutrophil activation marker. CD177 was the most highly differentially-expressed gene contributing to the clustering of severe patients and its abundance correlated with CD177 protein serum levels. CD177 levels were higher in COVID-19 patients from both the French and “confirmatory” Swiss cohort (n = 203) than in HDs (P&lt; 0.01) and in ICU than non-ICU patients (P&lt; 0.001), correlating with the time to symptoms onset (P = 0.002). Longitudinal measurements showed sustained levels of serum CD177 to discriminate between patients with the worst prognosis, leading to death, and those who recovered (P = 0.01). These results highlight neutrophil activation as a hallmark of severe disease and CD177 assessment as a reliable prognostic marker for routine care.</jats:p