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

Bjørn Barstad; Anna J Henningsson; Dag Tveitnes; Anastasia Ushakova; Sølvi Noraas; Ingvild S Ask; Franziskus J Bosse; Knut Øymar

doi:10.1016/j.cyto.2020.155023

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

Cytokine. 2020 Mar 18:130:155023. doi: 10.1016/j.cyto.2020.155023. Online ahead of print.

Authors

Bjørn Barstad¹, Anna J Henningsson², Dag Tveitnes³, Anastasia Ushakova⁴, Sølvi Noraas⁵, Ingvild S Ask⁶, Franziskus J Bosse⁷, Knut Øymar⁸

Affiliations

¹ Department of Pediatric and Adolescent Medicine, Stavanger University Hospital, Stavanger, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway. Electronic address: bjorn.barstad@sus.no.
² Division of Clinical Microbiology, Laboratory Medicine, Jönköping Region Jönköping County, Sweden; Department of Clinical and Experimental Medicine, Linköping University, Sweden; Division of Clinical Microbiology, Department of Clinical and Experimental Medicine, Linköping University Hospital, Linköping, Sweden. Electronic address: anna.jonsson.henningsson@rjl.se.
³ Department of Pediatric and Adolescent Medicine, Stavanger University Hospital, Stavanger, Norway. Electronic address: dag.tveitnes@sus.no.
⁴ Department of Research, Section of Biostatistics, Stavanger University Hospital, Stavanger, Norway. Electronic address: anastasia.ushakova@sus.no.
⁵ Department of Medical Microbiology, Hospital of Southern Norway Trust, Kristiansand, Norway. Electronic address: solvi.noraas@sshf.no.
⁶ Department of Pediatric and Adolescent Medicine, Hospital of Southern Norway Trust, Kristiansand, Norway. Electronic address: ingvild.s.ask@gmail.com.
⁷ Department of Pediatric and Adolescent Medicine, Haukeland University Hospital, Bergen, Norway. Electronic address: franziskus.johannes.bosse@helse-bergen.no.
⁸ Department of Pediatric and Adolescent Medicine, Stavanger University Hospital, Stavanger, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway. Electronic address: knut.oymar@sus.no.

PMID: 32199247
DOI: 10.1016/j.cyto.2020.155023

Abstract

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.

Keywords: Chemokine; Cytokine; Diagnosis; Meningitis; Neuroborreliosis; Neuroinflammation.