Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses

Abstract

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

Keywords: COVID-19; autoantibodies; brain injury; neuroinflammation.

Figure 1

Serum brain injury biomarker concentrations in patients with COVID-19. (A–C) Dot plots showing the effect of COVID-19 disease severity on brain injury biomarkers at the acute, subacute and convalescent time points; representative levels from five patients with acute severe traumatic brain injury (TBI) included as a reference for magnitude of elevation. Maroon dashed line denotes the functional lower limit of quantification. (D) Temporal changes in serum GFAP, NfL and tau concentrations. (E) Elevated serum total tau concentrations at the convalescent time point in COVID-19. HC = healthy controls; nCOV = COVID-19; TBI = traumatic brain injury; CNS = central nervous system complication; PNS = peripheral nervous system complication. Multiple group comparisons are by Kruskal-Wallis test with post hoc Dunn’s multiple comparison test; two-group unpaired comparisons are by Mann-Whitney U-test, and paired by Wilcoxon matched-pairs signed rank test; correlations are by Spearman’s rank.

Figure 2

Immune profiling in COVID-19. (A and B) Volcano plots of groupwise comparisons in autoantibody profiles between COVID-19 patients and controls. (C) Relationship between disease severity and anti-SFTPA1 IgG autoantibodies. (D and E) Temporal profiles of IgG and IgM autoantibody responses. (F and G) Effect of disease severity on number of IgG and IgM autoantibody ‘hits’. (H) Top 10 most frequently detected autoantibodies across all samples. (I) Comparison of cytokine profiles at the subacute and convalescent time points, with normal range shown by hatching. (J) Correlation matrix between measured subacute cytokines. (K) Loadings plot from principal component analysis demonstrating the contributions of proinflammatory cytokines to PC1. (L) Comparison in subacute proinflammatory cytokine response between mild and moderate/severe disease (‘Inflammatory Load’ = the inverse of cytokine PC1). Volcano plots use multiple Mann-Whitney U-tests with an FDR rate set to 1%; multiple group comparisons are by Kruskal-Wallis test with post hoc Dunn’s multiple comparison test; two-group unpaired comparisons are by Mann-Whitney U-test, correlation matrix is by Spearman’s rank.

Figure 3

Relationship between serum brain injury biomarkers and autoantibody profiles. (A and B) Correlation between number of IgG hits and serum GFAP and NfL concentrations at the subacute time point. (C) Correlation between number of IgG hits and serum NfL concentrations at the convalescent time point. (D) Correlation between number of IgM hits and serum total tau concentrations at the convalescent time point. (E) Comparison of convalescent serum brain injury biomarker concentrations between patients with high IgM responses (>3 IgM hits Z > 3) versus those with low IgM responses (<3 IgM hits Z > 3). Two-group unpaired comparisons are by Mann-Whitney U-test, correlations are by Spearman’s rank.