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The predictive value of CXCL13 in suspected Lyme neuroborreliosis: a retrospective cross-sectional study

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Abstract

The role of CXCL13 as a marker of Lyme neuroborreliosis (LNB) is under investigation, and CXCL13 is not part of routine diagnostics in suspicion of LNB. Our aim was to find the optimal cut-off value of CXCL13 for LNB in a Danish population and to investigate the role of CXCL13 both in early LNB and as a discriminatory marker between LNB and other neuroinflammatory disorders. We conducted a retrospective cross-sectional study including all patients with a cerebrospinal CXCL13 test performed at the Department of Clinical Immunology, Odense University Hospital, Denmark, between 1 January 2015 and 31 December 2018. We included 619 patients, of which 51 had definite LNB, 14 patients had possible LNB with neurological symptoms suggestive of LNB and pleocytosis but no intrathecal Borrelia antibodies, eight patients had prior LNB and 546 had no LNB. With an optimal CXCL13 cut-off of 49 ng/L we found a sensitivity of 100% and specificity of 94% (AUC 0.988, 95% CI 0.980–0.996) when patients treated with antibiotics prior to lumbar puncture were excluded (n = 130). All patients with possible LNB had a CXCL13 value above the cut-off value; 18/546 patients (3.3%) without LNB had a CXCL13 value ≥ 50 ng/L. While CXCL13 cannot be used as a stand-alone test, it can be used as a reliable additional marker in treatment-naive patients suspected of LNB. CXCL13 can be used to monitor treatment response in LNB patients.

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Data availability

The dataset generated and analysed during the current study is not publicly available due to the Danish Data Protection Law in accordance with approval by the Danish Data Protection Agency (j.nr.19/4365). It is available from the corresponding author on reasonable request.

References

  1. Mygland A, Ljostad U, Fingerle V, Rupprecht T, Schmutzhard E, Steiner I, European Federation of Neurological S (2010) EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis. Eur J Neurol 17(1):8–16, e11-14. https://doi.org/10.1111/j.1468-1331.2009.02862.x

    Article  CAS  PubMed  Google Scholar 

  2. Stanek G, Wormser GP, Gray J, Strle F (2012) Lyme borreliosis. Lancet 379(9814):461–473. https://doi.org/10.1016/s0140-6736(11)60103-7

    Article  PubMed  Google Scholar 

  3. Halperin JJ (2011) Neurologic manifestations of Lyme disease. Curr Infect Dis Rep 13(4):360–366. https://doi.org/10.1007/s11908-011-0184-x

    Article  PubMed  Google Scholar 

  4. Djukic M, Schmidt-Samoa C, Lange P, Spreer A, Neubieser K, Eiffert H, Nau R, Schmidt H (2012) Cerebrospinal fluid findings in adults with acute Lyme neuroborreliosis. J Neurol 259(4):630–636. https://doi.org/10.1007/s00415-011-6221-8

    Article  CAS  PubMed  Google Scholar 

  5. Borde JP, Meier S, Fingerle V, Klier C, Hubner J, Kern WV (2012) CXCL13 may improve diagnosis in early neuroborreliosis with atypical laboratory findings. BMC Infect Dis 12:344. https://doi.org/10.1186/1471-2334-12-344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Blanc F, Jaulhac B, Fleury M, de Seze J, de Martino SJ, Remy V, Blaison G, Hansmann Y, Christmann D, Tranchant C (2007) Relevance of the antibody index to diagnose Lyme neuroborreliosis among seropositive patients. Neurology 69(10):953–958. https://doi.org/10.1212/01.wnl.0000269672.17807.e0

    Article  CAS  PubMed  Google Scholar 

  7. Ljostad U, Skarpaas T, Mygland A (2007) Clinical usefulness of intrathecal antibody testing in acute Lyme neuroborreliosis. Eur J Neurol 14(8):873–876. https://doi.org/10.1111/j.1468-1331.2007.01799.x

    Article  CAS  PubMed  Google Scholar 

  8. Rupprecht TA, Manz KM, Fingerle V, Lechner C, Klein M, Pfirrmann M, Koedel U (2018) Diagnostic value of cerebrospinal fluid CXCL13 for acute Lyme neuroborreliosis. A systematic review and meta-analysis. Clin Microbiol Infect 24(12):1234–1240. https://doi.org/10.1016/j.cmi.2018.04.007

    Article  CAS  PubMed  Google Scholar 

  9. Wagner JN, Weis S, Kubasta C, Panholzer J, von Oertzen TJ (2018) CXCL13 as a diagnostic marker of neuroborreliosis and other neuroinflammatory disorders in an unselected group of patients. J Neurol 265(1):74–81. https://doi.org/10.1007/s00415-017-8669-7

    Article  CAS  PubMed  Google Scholar 

  10. Tjernberg I, Henningsson AJ, Eliasson I, Forsberg P, Ernerudh J (2011) Diagnostic performance of cerebrospinal fluid chemokine CXCL13 and antibodies to the C6-peptide in Lyme neuroborreliosis. J Infect 62(2):149–158. https://doi.org/10.1016/j.jinf.2010.11.005

    Article  PubMed  Google Scholar 

  11. Hytonen J, Kortela E, Waris M, Puustinen J, Salo J, Oksi J (2014) CXCL13 and neopterin concentrations in cerebrospinal fluid of patients with Lyme neuroborreliosis and other diseases that cause neuroinflammation. J Neuroinflammation 11:103. https://doi.org/10.1186/1742-2094-11-103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gyllemark P, Forsberg P, Ernerudh J, Henningsson AJ (2017) Intrathecal Th17- and B cell-associated cytokine and chemokine responses in relation to clinical outcome in Lyme neuroborreliosis: a large retrospective study. J Neuroinflammation 14(1):27. https://doi.org/10.1186/s12974-017-0789-6

    Article  PubMed  PubMed Central  Google Scholar 

  13. Yang J, Han X, Liu A, Bao F, Peng Y, Tao L, Ma M, Bai R, Dai X (2017) Chemokine CXC ligand 13 in cerebrospinal fluid can be used as an early diagnostic biomarker for Lyme neuroborreliosis: a meta-analysis. J Interf Cytokine Res 37(10):433–439. https://doi.org/10.1089/jir.2016.0101

    Article  CAS  Google Scholar 

  14. Barstad B, Tveitnes D, Noraas S, Selvik Ask I, Saeed M, Bosse F, Vigemyr G, Huber I, Oymar K (2017) Cerebrospinal fluid B-lymphocyte chemoattractant CXCL13 in the diagnosis of acute Lyme neuroborreliosis in children. Pediatr Infect Dis J 36(12):e286–e292. https://doi.org/10.1097/inf.0000000000001669

    Article  PubMed  Google Scholar 

  15. Henningsson AJ, Lager M, Brannstrom R, Tjernberg I, Skogman BH (2018) The chemokine CXCL13 in cerebrospinal fluid in children with Lyme neuroborreliosis. Eur J Clin Microbiol Infect Dis 37(10):1983–1991. https://doi.org/10.1007/s10096-018-3334-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rupprecht TA, Lechner C, Tumani H, Fingerle V (2014) CXCL13: a biomarker for acute Lyme neuroborreliosis: investigation of the predictive value in the clinical routine. Nervenarzt 85(4):459–464. https://doi.org/10.1007/s00115-014-4020-z

    Article  CAS  PubMed  Google Scholar 

  17. Denmark S StatBank Denmark: population at the first day of the quarter by region and time. https://statistikbanken.dk/statbank5a/default.asp?w=1440. Accessed 27-05-2019

  18. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig L, Lijmer JG, Moher D, Rennie D, de Vet HC, Kressel HY, Rifai N, Golub RM, Altman DG, Hooft L, Korevaar DA, Cohen JF (2015) STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies. BMJ 351:h5527. https://doi.org/10.1136/bmj.h5527

    Article  PubMed  PubMed Central  Google Scholar 

  19. Markowicz M, Schotta AM, Kundi M, Bogovic P, Ogrinc K, Strle F, Stanek G (2018) CXCL13 concentrations in cerebrospinal fluid of patients with Lyme neuroborreliosis and other neurological disorders determined by Luminex and ELISA. Ticks Tick Borne Dis 9(5):1137–1142. https://doi.org/10.1016/j.ttbdis.2018.04.008

    Article  PubMed  Google Scholar 

  20. Remy MM, Schobi N, Kottanattu L, Pfister S, Duppenthaler A, Suter-Riniker F (2017) Cerebrospinal fluid CXCL13 as a diagnostic marker of neuroborreliosis in children: a retrospective case-control study. J Neuroinflammation 14(1):173. https://doi.org/10.1186/s12974-017-0948-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Picha D, Moravcova L, Smiskova D (2016) Prospective study on the chemokine CXCL13 in neuroborreliosis and other aseptic neuroinfections. J Neurol Sci 368:214–220. https://doi.org/10.1016/j.jns.2016.05.059

    Article  CAS  PubMed  Google Scholar 

  22. Schmidt C, Plate A, Angele B, Pfister HW, Wick M, Koedel U, Rupprecht TA (2011) A prospective study on the role of CXCL13 in Lyme neuroborreliosis. Neurology 76(12):1051–1058. https://doi.org/10.1212/WNL.0b013e318211c39a

    Article  CAS  PubMed  Google Scholar 

  23. Henningsson AJ, Gyllemark P, Lager M, Skogman BH, Tjernberg I (2016) Evaluation of two assays for CXCL13 analysis in cerebrospinal fluid for laboratory diagnosis of Lyme neuroborreliosis. APMIS 124(11):985–990. https://doi.org/10.1111/apm.12596

    Article  CAS  PubMed  Google Scholar 

  24. Ljostad U, Mygland A (2008) CSF B--lymphocyte chemoattractant (CXCL13) in the early diagnosis of acute Lyme neuroborreliosis. J Neurol 255(5):732–737. https://doi.org/10.1007/s00415-008-0785-y

    Article  CAS  PubMed  Google Scholar 

  25. Pietikainen A, Maksimow M, Kauko T, Hurme S, Salmi M, Hytonen J (2016) Cerebrospinal fluid cytokines in Lyme neuroborreliosis. J Neuroinflammation 13(1):273. https://doi.org/10.1186/s12974-016-0745-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bremell D, Mattsson N, Edsbagge M, Blennow K, Andreasson U, Wikkelso C, Zetterberg H, Hagberg L (2013) Cerebrospinal fluid CXCL13 in Lyme neuroborreliosis and asymptomatic HIV infection. BMC Neurol 13:2. https://doi.org/10.1186/1471-2377-13-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Karrasch M, Fingerle V, Boden K, Darr A, Baier M, Straube E, Nenadic I (2018) Neuroborreliosis and acute encephalopathy: the use of CXCL13 as a biomarker in CNS manifestations of Lyme borreliosis. Ticks Tick Borne Dis 9(2):415–417. https://doi.org/10.1016/j.ttbdis.2017.12.008

    Article  PubMed  Google Scholar 

  28. van Burgel ND, Bakels F, Kroes AC, van Dam AP (2011) Discriminating Lyme neuroborreliosis from other neuroinflammatory diseases by levels of CXCL13 in cerebrospinal fluid. J Clin Microbiol 49(5):2027–2030. https://doi.org/10.1128/jcm.00084-11

    Article  PubMed  PubMed Central  Google Scholar 

  29. Dersch R, Hottenrott T, Senel M, Lehmensiek V, Tumani H, Rauer S, Stich O (2015) The chemokine CXCL13 is elevated in the cerebrospinal fluid of patients with neurosyphilis. Fluids Barriers CNS 12:12. https://doi.org/10.1186/s12987-015-0008-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rubenstein JL, Wong VS, Kadoch C, Gao HX, Barajas R, Chen L, Josephson SA, Scott B, Douglas V, Maiti M, Kaplan LD, Treseler PA, Cha S, Hwang JH, Cinque P, Cyster JG, Lowell C (2013) CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma. Blood 121(23):4740–4748. https://doi.org/10.1182/blood-2013-01-476333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Marra CM, Tantalo LC, Sahi SK, Maxwell CL, Lukehart SA (2010) CXCL13 as a cerebrospinal fluid marker for neurosyphilis in HIV-infected patients with syphilis. Sex Transm Dis 37(5):283–287. https://doi.org/10.1097/OLQ.0b013e3181d877a1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yu Q, Cheng Y, Wang Y, Wang C, Lu H, Guan Z, Huang J, Gong W, Shi M, Ni L, Wu J, Peng R, Zhou P (2017) Aberrant humoral immune responses in neurosyphilis: CXCL13/CXCR5 play a pivotal role for B-cell recruitment to the cerebrospinal fluid. J Infect Dis 216(5):534–544. https://doi.org/10.1093/infdis/jix233

    Article  CAS  PubMed  Google Scholar 

  33. Wang C, Wu K, Yu Q, Zhang S, Gao Z, Liu Y, Ni L, Cheng Y, Guan Z, Shi M, Lu H, Lou Y, Zhou P (2016) CXCL13, CXCL10 and CXCL8 as potential biomarkers for the diagnosis of neurosyphilis patients. Sci Rep 6:33569. https://doi.org/10.1038/srep33569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Huber AK, Irani DN (2015) Targeting CXCL13 during neuroinflammation. Adv Neuroimmune Biol 6(1):1–8. https://doi.org/10.3233/nib-150101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank the technicians at the Autoimmune Laboratory at the Department of Clinical Immunology, Odense University Hospital, for performing all CXCL13 analyses.

Funding

This work was supported by the University of Southern Denmark, the Region of Southern Denmark (J.nr. 18/50638/73), Oestifterne (J.nr.19-063) and A. J. Andersen og hustrus fond (J.nr. 01737-0005/JEB). JWH was supported by the EU Interreg program as part of the NorthTick project.

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Authors and Affiliations

  1. Clinical Center of Emerging and Vector-borne Infections (CCEVI), Department of Infectious Diseases, Odense University Hospital, J.B.Winsloews vej 4, 5000, Odense C, Denmark

    Fredrikke Christie Knudtzen & Sigurdur Skarphedinsson

  2. Clinical Institute, Research Unit for Infectious Diseases, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark

    Fredrikke Christie Knudtzen & Sigurdur Skarphedinsson

  3. Department of Clinical Immunology, Odense University Hospital, Odense, Denmark

    Anna Christine Nilsson

  4. Center for Experimental and Molecular Medicine, Amsterdam Multidisciplinary Lyme Borreliosis Center, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The Netherlands

    Joppe W. Hovius

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  1. Fredrikke Christie Knudtzen
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Contributions

Conceptualization: Fredrikke C. Knudtzen, Anna Christine Nilsson, Joppe W. Hovius and Sigurdur Skarphedinsson. Data curation: Fredrikke C. Knudtzen and Anna Christine Nilsson. Formal analysis: Fredrikke C. Knudtzen. Funding acquisition: Fredrikke C. Knudtzen and Sigurdur Skarphedinsson. Investigation: Fredrikke C. Knudtzen and Anna Christine Nilsson. Methodology: Fredrikke C. Knudtzen. Project administration: Fredrikke C. Knudtzen and Sigurdur Skarphedinsson. Resources: Anna Christine Nilsson. Supervision: Anna Christine Nilsson, Joppe W. Hovius and Sigurdur Skarphedinsson. Visualization: Fredrikke C. Knudtzen and Sigurdur Skarphedinsson. Writing—original draft: Fredrikke C. Knudtzen. Writing—review and editing: Fredrikke C. Knudtzen, Anna Christine Nilsson, Joppe W. Hovius and Sigurdur Skarphedinsson.

Corresponding author

Correspondence to Fredrikke Christie Knudtzen.

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ICMJE forms for all authors are attached.

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethics approval

The study was approved by the Danish Data Protection Agency (j.nr.19/4365) and as a quality development project at Odense University Hospital (j.nr.18/6688). The Danish National Committee on Health Research Ethics stated that no approval was required therefrom (j.nr.2019-2000-12).

Informed consent

As this was a retrospective study, no individual patient consent was required. This was stated at approval by the Danish Data Protection Agency (j.nr.19/4365) and Odense University Hospital (j.nr.18/6688).

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Knudtzen, F.C., Nilsson, A.C., Hovius, J.W. et al. The predictive value of CXCL13 in suspected Lyme neuroborreliosis: a retrospective cross-sectional study. Eur J Clin Microbiol Infect Dis 39, 1461–1470 (2020). https://doi.org/10.1007/s10096-020-03861-4

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