Study of the permeability of the blood-brain barrier and the intra-thecal inflammatory profile in patients with cerebral manifestations due to SARS-CoV-2

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Background: The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has had effects on the central nervous system in cases of acute neurological manifestations (ANM). Although cytokines, chemokines and immunoglobulins were investigated in patients with acute brain syndromes and SARS-CoV-2 infection, data on the integrity of the blood-brain barrier (BBB) and intrathecal production of these biomarkers in these patients are still scarce. Objective: To investigate whether patients with acute brain syndromes after exposure to SARS-CoV-2 have inflammatory BBB dysfunction. Methods: Experimental study, part of the NeuroCOVID study, funded by Fiocruz (nº VPPCB-005-FIO-20-2-22). Samples from 39 patients admitted in the neurology service of Hospital da Restauração, in Recife, were analyzed. The case series was selected according to three comparison groups: Exposed cases (acute central neurological syndrome and exposure to SARS-CoV-2), exposed controls (peripheral neurological syndrome and with exposure to SARS-CoV-2) and unexposed controls (without neurological syndrome and without exposure). Exposure was defined as positivity in the molecular test for SARS-CoV-2 in swab or serology (IgG or IgA anti-SARS-CoV-2) in serum or CSF. The neurological syndromes comprised acute brain manifestations and were confirmed by clinical-radiological evaluation by neurologists at the service. Inflammatory cytokines and chemokines were measured using CBA in a flow cytometer. The evaluation of the BBB function was evaluated through the protein profile by gel electrophoresis, with calculation of the CSF:serum coefficients and the reibergrams. Clinical and laboratory data were processed by GraphPad, R and CSF Software Tool software. Results: Of the 39 patients, 16 exposed cases (mean 59 years; 33-82), 17 exposed controls (mean 49 years; 26-68), and 7 unexposed controls (mean 37 years; 28-53) were included. When compared with controls exposed and not exposed to SARS-CoV-2, patients with acute neurological syndromes exposed to the virus had significantly (p<0.05) higher values of IL-6, CCL2, IL-8 and CXCL9 in both serum and CSF; also showed values of CXCL10 only in serum and CXCL5 in CSF. In the BBB integrity study, there were no significant differences in the values of total proteins and fractions (albumin and IgG) of exposed cases when compared with the other groups. The “reibergrams” indicated the absence of total intrathecal IgG production in the three groups. Conclusion: Patients with ANM associated with subclinical SARS-CoV-2 infections did not show signs of BBB breakdown or intrathecal production of immunoglobulins. Despite not presenting systemic manifestations of COVID-19, these patients presented increased values in both serum and CSF of some cytokines involved in the systemic inflammatory response. In turn, the highest CXCL5 values only in the CSF suggest that it may have a role in the neurological manifestations in our sample.

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