CSF inflammatory markers differ in gram-positive versus gram-negative shunt infections

Abstract

BackgroundCerebrospinal fluid (CSF) shunt placement is frequently complicated by bacterial infection. Shunt infection diagnosis relies on bacterial culture of CSF which can often produce false-negative results. Negative cultures present a conundrum for physicians as they are left to rely on other CSF indices, which can be unremarkable. New methods are needed to swiftly and accurately diagnose shunt infections. CSF chemokines and cytokines may prove useful as diagnostic biomarkers. The objective of this study was to evaluate the potential of systemic and CSF biomarkers for identification of CSF shunt infection.MethodsWe conducted a retrospective chart review of children with culture-confirmed CSF shunt infection at Children’s Hospital and Medical Center from July 2013 to December 2015. CSF cytokine analysis was performed for those patients with CSF in frozen storage from the same sample that was used for diagnostic culture.ResultsA total of 12 infections were included in this study. Patients with shunt infection had a median C-reactive protein (CRP) of 18.25 mg/dL. Median peripheral white blood cell count was 15.53 × 103 cells/mL. Those with shunt infection had a median CSF WBC of 332 cells/mL, median CSF protein level of 406 mg/dL, and median CSF glucose of 35.5 mg/dL. An interesting trend was observed with gram-positive infections having higher levels of the anti-inflammatory cytokine interleukin (IL)-10 as well as IL-17A and vascular endothelial growth factor (VEGF) compared to gram-negative infections, although these differences did not reach statistical significance. Conversely, gram-negative infections displayed higher levels of the pro-inflammatory cytokines IL-1β, fractalkine (CX3CL1), chemokine ligand 2 (CCL2), and chemokine ligand 3 (CCL3), although again these were not significantly different. CSF from gram-positive and gram-negative shunt infections had similar levels of interferon gamma (INF-γ), tumor necrosis factor alpha (TNF-α), IL-6, and IL-8.ConclusionsThis pilot study is the first to characterize the CSF cytokine profile in patients with CSF shunt infection and supports the distinction of chemokine and cytokine profiles between gram-negative and gram-positive infections. Additionally, it demonstrates the potential of CSF chemokines and cytokines as biomarkers for the diagnosis of shunt infection.

Identification of Potential Cerebrospinal Fluid Biomarkers To Discriminate between Infection and Sterile Inflammation in a Rat Model of Staphylococcus epidermidis Catheter Infection

“…The elevation of CSF IL-10 levels is consistent with data from our previous human study demonstrating increased levels of IL-10 in patients with Gram-positive shunt infections and the key role for IL-10 in regulating the inflammatory response in a murine model of S. epidermidis CNS catheter infection (19, 36). At day 1 postinfection, elevated IL-1β, CCL2, and CCL3 expression in the CSF mirrored that in the brain parenchyma.…”

“…epidermidis bacterial burden is significantly higher on the catheter than in surrounding brain tissue during acute infection, which is consistent with a murine model of catheter-associated biofilm infection, supporting its relevance as an in vivo model of human shunt infection (26). This is further supported by our CSF findings demonstrating a distinct CSF phenotype in infected versus sterile catheter placement, similar to human infection (6, 19).…”

“…epidermidis is the most common cause of CSF shunt infections, other bacteria are capable of causing disease. Our previous pilot study revealed that in human CSF, there were differences in CSF inflammatory mediator concentrations in Gram-positive versus Gram-negative infections, with higher levels of the proinflammatory cytokines IL-1β, CX 3 CL 1 , CCL2, and CCL3 seen in response to Gram-negative shunt infection (19). To the best of our knowledge, there are no other studies that have looked at biomarkers in response to Gram-negative or fungal CSF shunt infection; however, it is very likely that host biomarkers will vary based on the type of infecting organism (33).…”

“…However, this study examined cytokine levels not at the time of presentation of infection but rather at the time of initial shunt placement as a potential predictor of later infection (18). A report from our laboratory demonstrated that pediatric patients with Gram-positive shunt infection tended to have higher levels of the anti-inflammatory cytokine IL-10, while those with Gram-negative infection had higher levels of the proinflammatory mediators IL-1β, fractalkine (CX 3 CL 1 ), chemokine ligand 2 (CCL2), and CCL3 (19).…”

Neutrophil peptide-1 promotes the repair of sciatic nerve injury through the expression of proteins related to nerve regeneration

“…Expression at the site of injury may be the main factor affecting the infiltration of neutrophils [36], which are important effectors of acute inflammation [37]. Fractalkine is also an important chemokine [38] that participates in the migration and activation of lymphocytes and phagocytes and regulates proinflammatory factors in gram-negative bacterial infection-related diseases [39]. LIX is a chemokine, also known as CXCL5, that plays a regulatory role in inflammation and cancer cell growth caused by cancer Table 2.…”