Evaluation of two assays for CXCL13 analysis in cerebrospinal fluid for laboratory diagnosis of Lyme neuroborreliosis

Abstract

Henningsson AJ, Gyllemark P, Lager M, Skogman BH, Tjernberg I. Evaluation of two assays for CXCL13 analysis in cerebrospinal fluid for laboratory diagnosis of Lyme neuroborreliosis. APMIS 2016; 124: 985-990 We evaluated the diagnostic performance of two assays, one bead-based assay and one enzyme-linked immunosorbent assay (ELISA), for the determination of CXCL13 levels in cerebrospinal fluid (CSF) from patients with suspected Lyme neuroborreliosis (LNB). Patients investigated for LNB were retrospectively included (n = 132): 35 with definite LNB, 8 with possible LNB with CSF pleocytosis but normal antibody index (AI), 6 with possible LNB with elevated AI but no CSF pleocytosis and 83 non-LNB patients. CSF samples had been drawn before antibiotic treatment and were analysed for CXCL13 by Quantikine ELISA (R&D Systems) and recomBead (Mikrogen). Receiver operating characteristic analyses based on the definite LNB and non-LNB groups revealed a best performance cut-off of 56 pg/mL for Quantikine and 158 pg/mL for recomBead (sensitivity and specificity 100% for both assays). When applying these cut-off levels on the study groups, the two assays performed equally well regarding sensitivity and specificity. In the group of patients with pleocytosis but negative AI, the majority of whom were children with short symptom duration, the CXCL13 analysis supported the LNB diagnosis in half of the cases. We consider CSF-CXCL13 analysis a useful diagnostic tool, in addition to Borrelia-specific AI, in laboratory diagnostics of LNB.Key words: Lyme neuroborreliosis; cerebrospinal fluid; CXCL13; sensitivity; specificity. Anna J. Henningsson, Clinical Microbiology, Division of Medical Services, Region J€ onk€ oping County, S-551 85 J€ onk€ oping, Sweden. e-mail: anna.jonsson.henningsson@rjl.se AJH and PG contributed equally to this work.Lyme neuroborreliosis (LNB) is the most common form of disseminated Lyme borreliosis in Sweden as well as in other parts of Europe (1, 2). According to European guidelines, the diagnosis of definite LNB requires neurological symptoms, pleocytosis in the cerebrospinal fluid (CSF) and intrathecal production of Borrelia-specific antibodies (positive antibody index, AI) (3). Patients fulfilling only two of the three criteria may be diagnosed with possible LNB. However, in very early disease, the sensitivity of antibody tests may be low, and a positive AI may also persist for a long time after a passed LNB (4, 5).The B-cell-attracting chemokine CXCL13 has in previous studies been shown to be reliably elevated in the CSF of patients with early LNB, and furthermore, to decrease rapidly after antibiotic treatment (6-9). Thus, analysis of CXCL13 in the CSF may be helpful in AI-negative patients with possible early LNB, as well as a marker for active disease and in control of therapeutic response in AI-positive patients. Furthermore, CXCL13 has been proven to be useful for discriminating acute LNB from other CNS disorders (10-12). However, the This is an open access article under the terms of the Creative C...

The chemokine CXCL13 in cerebrospinal fluid in children with Lyme neuroborreliosis

“…These results are consistent with those observed in several previous studies [ 18 – 20 , 22 , 28 , 29 ], all supporting the hypothesis that elevated concentrations of CXCL13 in CSF can be used as a marker for LNB. However, the overall sensitivity (88%) and overall specificity (89%) observed in our study were moderate, compared to previous studies on CXCL13 in CSF with sensitivities ranging between 88 and 100% and specificities between 89 and 100% [ 18 , 19 , 22 , 25 , 29 , 30 ]. The variation in diagnostic performances between these studies may partly be explained by differences in classification of LNB patients and controls, the use of different laboratory methods with different intra-assay variability, and variations in cut-off levels for CXCL13 (ranging between 55 and 415 pg/mL) [ 18 , 19 , 25 , 29 ].…”

“…It has also been suggested that CXCL13 in the CSF may be a marker for disease duration [ 21 ]. Different methods and cut-off levels have been suggested in different studies [ 18 , 19 , 22 – 25 ], but no consensus has been established so far.…”

Chemokine Ligand 13 (CXCL13) in Neuroborreliosis and Neurosyphilis as Selected Spirochetal Neurological Diseases: A Review of Its Diagnostic Significance

“…However, most studies measuring CXCL13 using ELISA and lateral flow (LFA) methods have shown elevated CXCL13 circulation levels in the CSF of patients with acute neuroborreliosis compared to other tested groups. Results of the available studies suggest its very high diagnostic value and report its high sensitivity and specificity [5][6][7][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46]. These studies are in agreement with a meta-analysis performed by Yang J. et al, who confirmed that CXCL13 has a high sensitivity and specificity for diagnosing neuroborreliosis [68].…”

“…It also may indicate that CXCL13 correlates better with pleocytosis than with the CSF-specific antibodies index. Such results also suggest that CXCL13 levels can be helpful in distinguishing the activity and acuteness of the current infection from previous infections [5,34,[37][38][39][40]. Levels of the chemokine in possible neuroborreliosis with negative specific antibodies has been found not to differ from other neurological conditions, e.g., multiple sclerosis, viral meningitis, neurosyphilis, or lupus [41].…”

“…Neuroborreliosis CSF CXCL13 levels are highly elevated in NB compared to healthy and other non-inflammatory CNS diseases [5][6][7][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] CSF CXCL13 levels are significantly elevated in NB in comparison to NS [9,10,12] CSF CXCL13 concentrations are elevated in acute and possible NB with positive specific antibodies against Borrelia burgdorferi [5,34,[37][38][39][40] CSF CXCL13 concentrations correlate with WBC count and disease activity [41,42] CSF CXCL13 concentrations correlate better with pleocytosis than with CSF-specific antibodies [5,34,[37][38][39][40] CSF CXCL13 levels are highly elevated in NB patients with shorter disease duration [41,42] CSF CXCL13 levels are markedly elevated before treatment compared to after treatment [7,28,32,…”