Potential role of CSF cytokine profiles in discriminating infectious from non-infectious CNS disorders

Abstract

Current laboratory testing of cerebrospinal fluid (CSF) does not consistently discriminate between different central nervous system (CNS) disease states. Rapidly distinguishing CNS infections from other brain and spinal cord disorders that share a similar clinical presentation is critical. New approaches focusing on aspects of disease biology, such as immune response profiles that can have stimulus-specific attributes, may be helpful. We undertook this preliminary proof-of-concept study using multiplex ELISA to measure CSF cytokine levels in various CNS disorders (infections, autoimmune/demyelinating diseases, lymphomas, and gliomas) to determine the potential utility of cytokine patterns in differentiating CNS infections from other CNS diseases. Both agglomerative hierarchical clustering and mixture discriminant analyses revealed grouping of CNS disease types based on cytokine expression. To further investigate the ability of CSF cytokine levels to distinguish various CNS disease states, non-parametric statistical analysis was performed. Mann-Whitney test analysis demonstrated that CNS infections are characterized by significantly higher CSF lP-10/CXCL10 levels than the pooled non-infectious CNS disorders (p = 0.0001). Within the infection group, elevated levels of MDC/CCL22 distinguished non-viral from viral infections (p = 0.0048). Each disease group of the non-infectious CNS disorders independently showed IP-10/CXCL10 levels that are significantly lower than the infection group [(autoimmune /demyelinating disorders (p = 0.0005), lymphomas (p = 0.0487), gliomas (p = 0.0294), and controls (p = 0.0001)]. Additionally, of the non-infectious diseases, gliomas can be distinguished from lymphomas by higher levels of GRO/CXCL1 (p = 0.0476), IL-7 (p = 0.0119), and IL-8 (p = 0.0460). Gliomas can also be distinguished from autoimmune/demyelinating disorders by higher levels of GRO/CXCL1 (p = 0.0044), IL-7 (p = 0.0035) and IL-8 (p = 0.0176). Elevated CSF levels of PDGF-AA distinguish lymphomas from autoimmune/demyelinating cases (p = 0.0130). Interrogation of the above comparisons using receiver operator characteristic analysis demonstrated area under the curve (AUC) values (ranging from 0.8636–1.0) that signify good to excellent utility as potential diagnostic discriminators. In conclusion, our work indicates that upon formal validation, measurement of CSF cytokine levels may have clinical utility in both identifying a CNS disorder as infectious in etiology and, furthermore, in distinguishing viral from non-viral CNS infections.

Intrathecal immunoreactivity in people with or without previous infectious mononucleosis

“…[24][25][26] At that stage, also CSF oligoclonal IgG bands and kappa light chains predict the evolution to MS. 26,27 Microglia secrete a number of the selected cytokines or chemokines, and PET studies revealed extensive microglia activation in normal-appearing white matter in MS. infections. 32 The authors correlated it with the treatment response in chronic hepatitis C infections. 33 Furthermore, the IP-10 level was elevated in both the sera and CSF from patients with relapsing-remitting and secondary progressive MS. 34 IP-10 levels predicted MS activity at different time points, and it was higher in patients that converted from CIS to MS than in those that did not convert.…”

Phenol-Soluble Modulin-Mediated Aggregation of Community-Associated Methicillin-Resistant Staphylococcus Aureus in Human Cerebrospinal Fluid

“…To investigate the role of PSMs in human CSF and prepare for the potential increases in CNS CA-MRSA infection, it is necessary to study the MRSA growth characteristics that are exclusively present in the CNS environment. CSF is the best representative for pathological CNS changes owing to its close anatomical relationship with critical CNS structures [15]. Thus, the MRSA culture characteristics observed in CSF would be almost identical to those shown in the CNS environment.…”

“…The proximity of CSF to the CNS makes it a good target for studying the pathophysiology of CNS diseases. Because CSF serves as a conduit for inflammatory mediators and signaling proteins released during changes in the CNS environment, CSF analysis provides crucial information in the diagnosis of CNS diseases [15,[21][22][23]. Many compounds do not distribute homogeneously in the CSF space and this non-uniform distribution of compounds within the CSF space has clinical significance because the ratio of bacterial cell aggregation varies with the different CSF compartments [24].…”

A Contemporary Review of Neurological Sequelae of COVID-19

“…The cerebrospinal fluid (CSF) is a bodily fluid that surrounds the brain and serves an array of functions ranging from acting as a shock absorber from neurological trauma to circulating nutrients around the CNS. Its role in homeostasis and neurological metabolism has made it a great reporter of the neurological environment; therefore, it can be clinically used to detect infectious agents and diseases (25). Furthermore, viral implications on the immune system could induce indirect effects on the CNS.…”