Diagnostic relevance of the chemokine CXCL13 and anti-C6 peptide antibodies in patients with neuroborreliosis

Česká verzia

Authors: D. Pícha; L. Moravcová; D. Smíšková
Authors place of work: Klinika infekčních nemocí, Univerzita Karlova, 2. lékařská fakulta a Nemocnice Na Bulovce, Praha
Published in the journal: Epidemiol. Mikrobiol. Imunol. 66, 2017, č. 2, s. 80-85
Category: Původní práce

Summary

Aim of the study:
The study was focused on testing the diagnostic value of detection of the chemokine CXCL13 (B lymphocyte chemoattractant) and anti-C6 peptide (synthetic peptide derived from B. burdorferi VlsE protein) antibodies in patients with neuroborreliosis (NB).

Material and methods:
One hundred and twenty-nine patients with clinical suspicion of neuroinfection were included in the study. Eighty patients with NB (positive for antibodies in serum and CSF) were subdivided into four groups (A1–A4) based on positivity/negativity of the antibody index (AI) and pleocytosis. The control group was composed of 49 patients with a negative AI and absence of CSF pleocytosis. Chemokine CXCL13 and anti-C6 antibodies were examined by commercial kits (Human CXCL13/BLC/BCA-1 Immunoassay, R&D Systems, INC, USA and C6 B. burgdorferi (Lyme) ELISA, Immunetics Inc. USA). The CXCL13 cut-off values were set to ≥ 130 pg/ml for the CSF and ≥ 62 pg/ml for the serum.

Results:
The highest CSF levels of CXCL13 chemokine were found in group A1 (pleocytosis, AI positive), and they were significantly higher (p < 0.001) comparing with other groups except A3 (pleocytosis, AI negative; p = 0.04). Group A3 also showed significantly higher levels of CXCL13 than groups A2 (without pleocytosis, AI positive; p = 0.005), A4 (without pleocytosis, AI negative), and B (p < 0.001). The differences in the serum CXCL13 levels between groups were non-significant.

The serum anti-C6 antibodies were detected in all NB groups and the positivity rates did not differ between groups (92%) except for A3 where 55% of the patients were positive. In the CSF, the highest anti-C6 sensitivity was found in the patients with a positive AI (A1 88.6%; A2 76.9%) while in the groups with a negative AI, it was low (A3 25%; A4 0%). In group B, anti-C6 antibodies were not detected.

Conclusion:
The highest CSF CXCL13 levels were found in early stage NB. Elevated CXCL13 concentrations correlate better with pleocytosis than with AI positivity; however, there exist some patients with a positive AI who have low CXCL13 levels. These patients are most probably those in the late – subacute stage of neuroinfection. The CXCL13 testing seems to be the most diagnostically helpful in the acute stage of NB where AI is still negative. The clinical sensitivity of the C6 ELISA test appears to be insufficient for CSF examination under our conditions. On the contrary, the specificity of this test was proven high, because none of the controls tested positive.

KEYWORDS:
neuroborreliosis – anti-C6 peptide antibodies – CXCL13 chemokine– diagnostics

Zdroje

1. Sanchez E, Vannier E, Gary P, et al. Diagnosis, treatment, and prevention of Lyme disease, human granulotic anaplasmosis, and babesiosis. JAMA, 2016; 315 (16): 1767–1777.

2. Halperin JJ. Nervous system Lyme disease. Clin Lab Med, 2015; 35 (4): 779–795.

3. Hammers-Berggren S, Hansen K, Lebech AM, et al. Borrelia burgdorferi-specific intrathecal antibody production in neuroborreliosis: a folow-up study. Neurology, 1993; 43 (1): 169–175.

4. Ljøstad U, Mygland A. CSF B – lymphocyte chemoattractant (CXCL13) in the early diagnosis of acute Lyme neuroborreliosis. J Neurol, 2008; 255 (5): 732–737.

5. Rupprecht TA, Pfister HW, Angele B, et al. The chemokine CXCL13 (BLC): A putative diagnostic marker for neuroborreliosis. Neurology, 2005; 65(3); 448–450.

6. van Burgel ND, Branderburg A, Gerritsen HJ, et al. High sensitivity and specificity of the C6-peptide ELISA on cerebrospinal fluid in Lyme neuroborreliosis patients. Clin Microbiol Infect, 2011; 17 (10): 1495–1500.

7. Skarpaas T, Ljøstad U, Søbye M, et al. Sensitivity and specificity of a commercial C6 peptide enzyme immuno assay in diagnosis of acute Lyme neuroborreliosis. Eur J Clin Microbiol Infect Dis, 2007; 26 (9): 675–677.

8. Mygland A, Ljøstad U, Fingerle V, et al. EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis. Eur J Neurol, 2010; 17 (1): 8–16.

9. Hytönen J, Kortela E, Waris M, et al. CXCL13 and neopterin concentrations in cerebrospinal fluid of patients with Lyme neuroborreliosis and other diseases that cause neuroinflammantion. J Neuroinflamm, 2014; 11:103. doi: 10. 1186/1742-2094-11-103.

10. Kowarik MC. Cepok S, Sellner J, et al. CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation. J Neuroinflamm, 2012; 9: 93. doi: 10. 1186/1742-2094-9-93.

11. Rupprecht TA, Plate A, Adam M, et al. The chemokine CXCL13 is a key regulator of B cell recruitment to the cerebrospinal fluid in acute Lyme neuroborreliosis. J Neuroinflamm, 2009; 6:42. doi: 10.1186/1742-2094-6-42.

12. Dersch R, Hottenrott T, Senel M, et al. The chemokine CYXCL13 is elevated in cerebrospinal fluid of patients with neurosyphilis. Fluids Barriers CNS, 2015; 12:12. doi: 10.1186/sl2987-015-0008-8.

13. Wutte N, Berghold A, Löffler S, et al. CXCL13 in pediatric and adult neuroborreliosis. Acta Neurol Scand, 2011; 124 (5): 321–328.

14. Tjernberg I, Henningsson AJ, Eliasson I, et al. Diagnostic performance of cerebrospinal fluid chemokine CXCL13 and antibodies to C6-peptide in Lyme neuroborreliosis. J Infect, 2011; 62 (2): 149–158.

15. Pícha D, Moravcová L, Smíšková D. Prospective study on the chemokine CXCL13 in neuroborreliosis and other aseptic neuroinfections. J Neurol Sci, 2016; 15; 368: 214–20. doi: 10.1016/j.jns.2016.05.059.

16. Wutte N, Berghold A, Krainberg I, et al. Serum CXCL13 chemokine is not a marker for active Lyme borreliosis. Acta Derm Venerol, 2011; 91 (6): 724–724.

17. Vermeesch P, Resseler S, Nackers E, et al. The C6 Lyme antibody test has low sensitivity for antibody detection in cerebrospinal fluid. Diagn Microbiol Infect Dis, 2009; 64 (3): 347–349.

18. Leeflang MMG, Ang CW, Berkhout J, et al. The diagnostic accurancy of serological tests for Lyme borreliosis in Europe: a systematic review and meta-analysis. BMC Infect Dis, 2016; 16:140 doi: 10.1186/s12879-016-1468-4.

19. Tjernberg I, Schön T, Ernerudh J, et al. C6-peptide serology as diagnostic tool in neuroborreliosis. APMIS, 2008; 116 (5): 393–399.