Cerebrospinal fluid cytokines and chemokines in children with Lyme neuroborreliosis; pattern and diagnostic utility.

BACKGROUND: Lyme neuroborreliosis (LNB) is characterized by cerebrospinal fluid (CSF) inflammation with several cytokines/chemokines and B-lymphocytes. Clinically, LNB in children may be difficult to discriminate from non-Lyme aseptic meningitis (NLAM). We aimed to identify CSF cytokine/chemokine patterns in children with LNB, NLAM and controls and elucidate the diagnostic value of these cytokines/chemokines alone or in combination to discriminate between LNB and NLAM. METHODS: Children with symptoms suggestive of LNB were included prospectively and categorized as LNB, NLAM or controls (no pleocytosis). Cytokines/chemokines in CSF were measured by multiplex bead assays and levels were compared between the three groups by nonparametric statistical tests. Previous results from the same children on the established biomarker, CXCL13, were included in the statistical analyses. The diagnostic properties of cytokines/chemokines to discriminate between LNB and NLAM were determined by receiver operating characteristic curve analyses with estimates of area under curve (AUC). To explore diagnostic properties of combinations of cytokines/chemokines, prediction models based on logistic regression were used. RESULTS: We included 195 children with LNB (n = 77), NLAM (n = 12) and controls (n = 106). Children with LNB had higher CSF levels of CCL19, CCL22 and CXCL13 compared to NLAM and controls, whereas INFγ was higher in NLAM than in LNB and controls. CXCL13 was the superior single cytokine/chemokine to discriminate LNB from NLAM (AUC 0.978). The combination CXCL13/CCL19 (AUC 0.992) may possibly improve the specificity for LNB, especially for children with moderate CXCL13 levels. CONCLUSIONS: The intrathecal immune reaction in LNB is characterized by B cell associated chemokines. Whether the combination CXCL13/CCL19 further improves discrimination between LNB and NLAM beyond the diagnostic improvements by CXCL13 alone needs to be tested in new studies.

The B-lymphocyte chemokine CXCL13 in the cerebrospinal fluid of children with Lyme neuroborreliosis: associations with clinical and laboratory variables.

Background: The B-lymphocyte chemokine CXCL13 is increasingly considered as a useful early phase diagnostic marker of Lyme neuroborreliosis (LNB). However, the large variation in level of CXCL13 in the cerebrospinal fluid (CSF) observed in LNB patients is still unexplained. We aimed to identify factors associated with the level of CXCL13 in children with LNB, possibly improving the interpretation of CXCL13 as a diagnostic marker of LNB. Methods: Children with confirmed and probable LNB were included in a prospective study on CXCL13 in CSF as a diagnostic marker of LNB. The variables age, sex, facial nerve palsy, generalized inflammation symptoms (fever, headache, neck-stiffness and/or fatigue), duration of symptoms, Borrelia antibodies in CSF, Borrelia antibody index (AI), CSF white blood cells (WBC), CSF protein and detection of the genospecies Borrelia garinii by PCR were included in simple and multivariable regression analyses to study the associations with the CXCL13 level. Results: We included 53 children with confirmed and 17 children with probable LNB. CXCL13 levels in CSF were positively associated with WBC, protein and Borrelia antibodies in CSF in both simple and multivariable analyses. We did not find any associations between CXCL13 and age, sex, clinical symptoms, duration of symptoms, AI or the detection of Borrelia garinii. Conclusions: High levels of CSF CXCL13 are present in the early phase of LNB and correlate with the level of CSF WBC and protein. Our results indicate that CSF CXCL13 in children evaluated for LNB can be interpreted independently of clinical features or duration of symptoms.

Direct Molecular Detection and Genotyping of Borrelia burgdorferi Sensu Lato in Cerebrospinal Fluid of Children with Lyme Neuroborreliosis.

The current diagnostic marker of Lyme neuroborreliosis (LNB), the Borrelia burgdorferisensu lato antibody index (AI) in the cerebrospinal fluid (CSF), has insufficient sensitivity in the early phase of LNB. We aimed to elucidate the diagnostic value of PCR for B. burgdorferisensu lato in CSF from children with symptoms suggestive of LNB and to explore B. burgdorferisensu lato genotypes associated with LNB in children. Children were prospectively included in predefined groups with a high or low likelihood of LNB based on diagnostic guidelines (LNB symptoms, CSF pleocytosis, and B. burgdorferisensu lato antibodies) or the detection of other causative agents. CSF samples were analyzed by two B. burgdorferisensu lato-specific real-time PCR assays and, if B. burgdorferisensu lato DNA was detected, were further analyzed by five singleplex real-time PCR assays for genotype determination. For children diagnosed as LNB patients (58 confirmed and 18 probable) (n = 76) or non-LNB controls (n = 28), the sensitivity and specificity of PCR for B. burgdorferisensu lato in CSF were 46% and 100%, respectively. B. burgdorferisensu lato DNA was detected in 26/58 (45%) children with AI-positive LNB and in 7/12 (58%) children with AI-negative LNB and symptoms of short duration. Among 36 children with detectable B. burgdorferisensu lato DNA, genotyping indicated Borrelia garinii (n = 27) and non-B. garinii (n = 1) genotypes, while 8 samples remained untyped. Children with LNB caused by B. garinii did not have a distinct clinical picture. The rate of detection of B. burgdorferisensu lato DNA in the CSF of children with LNB was higher than that reported previously. PCR for B. burgdorferisensu lato could be a useful supplemental diagnostic tool in unconfirmed LNB cases with symptoms of short duration. B. garinii was the predominant genotype in children with LNB.