Cerebrospinal fluid chemokine CXCL13 in the diagnosis of neuroborreliosis in children

Sillanpää, Heidi; Skogman, Barbro H.; Sarvas, Heikki; Seppälä, Ilkka; Lahdenne, Pekka

doi:10.3109/00365548.2013.776700

Cited by 32 publications

(24 citation statements)

References 21 publications

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“…However, Bremell et al showed that CSF CXCL13 was not increased in HIV-infected patients (15), and we did not observe elevated CSF CXCL13 concentrations in the HIV-and T. pallidum-coinfected control group with a negative CSF-RPR result. Even though the effect of HIV alone was not proven in our study, Bremell et al (15) data may suggests that there is an added CSF CXCL13 release in neurosyphilis patients coinfected with HIV, 16 (16) hence the observed added benefit of CSF CXCL13 in HIV-infected patients in diagnosing neurosyphilis. However, we cannot strictly exclude other causes for high or detectable CXCL13.…”

Section: Discussioncontrasting

confidence: 59%

“…Even though CSF CXCL13 concentration is not a confirmatory test, we assume on the basis of serological syphilis and pathogenesis of CXCL13 that CSF CXCL13 concentration can contribute to the diagnosis of neurosyphilis. Furthermore, the use of CSF CXCL13 concentration for the diagnosis of neurological infections with spirochetes, such as neuroborreliosis and also neurosyphilis, has been shown before (13,16). However, the current study demonstrates an added value of CXCL13 concentration as a marker in the diagnosis of neurosyphilis, which increases in HIV-infected patients.…”

Section: Discussionmentioning

confidence: 57%

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Has CXCL13 an Added Value in Diagnosis of Neurosyphilis?

et al. 2015

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eIn patients with syphilis, central nervous system (CNS) involvement is often difficult to determine. In patients who also are infected with human immunodeficiency virus (HIV), this is even more challenging, as cerebrospinal fluid (CSF) pleocytosis can be attributed to HIV, syphilis, or both. Hence, this study investigated (i) CSF chemokine (C-X-C motif) ligand 13 (CXCL13) as a potential marker to diagnose neurosyphilis in HIV-infected individuals and (ii) the added value of CSF CXCL13 to conventional CSF biomarkers, such as the rapid plasma reagin test (RPR), in diagnosing neurosyphilis. We included 103 syphilis patients from two centers in The Netherlands: 47 non-HIV-infected patients and 56 HIV-infected patients. A positive CSF-RPR was regarded as the gold standard for neurosyphilis. CSF CXCL13 levels were significantly higher in neurosyphilis patients when neurosyphilis was diagnosed by CSF-RPR (P ‫؍‬ 0.0002) than in the syphilis control group. The sensitivity and specificity of CSF CXCL13 (cutoff of 76.3 pg/ml) to diagnose neurosyphilis by using positive CSF-RPR as the gold standard were 50% and 90%, respectively. CSF CXCL13 had an added value to CSF-RPR positivity in 70% of HIV-positive patients and in 33% of HIV-negative patients. Our data show that CSF CXCL13 might be a potential additional marker in neurosyphilis when other markers are not conclusive. The added value of CSF CXCL13 measurement to the current neurosyphilis gold standard appears to benefit HIV-positive patients more than HIV-negative patients. In 2007, the World Health Organization estimated an incidence of 12 million new infections with Treponema pallidum each year worldwide (1). Invasion of the central nervous system (CNS) by T. pallidum may occur during any disease stage of syphilis, leading to the development of neurosyphilis in some patients (2, 3). When dual infections with HIV and syphilis exist, the diagnostic challenge increases. A positive cerebrospinal fluid (CSF) Venereal Disease Research Laboratory test (VDRL) is generally considered the gold standard for neurosyphilis (4); however, several studies have clearly shown that a positive CSF rapid plasma reagin test (RPR) is an alternative to CSF-VDRL (5, 6), and RPR is also recommended by 2014 European guidelines (IUSTI-2014) (7). When the CSF-RPR or CSF-VDRL is negative, the diagnosis relies on other markers, like CSF pleocytosis, the CSF T. pallidum particle agglutination (TPPA) index, and clinical signs and symptoms.As the laboratory diagnosis of neurosyphilis is difficult, new markers are needed, and CSF B cell chemoattractant chemokine (C-X-C motif) ligand 13 (CXCL13) is currently forwarded as an interesting marker. CXCL13 has been demonstrated to be elevated in B lymphocyte-rich CSF (8, 9). CSF CXCL13 has a higher sensitivity than the established diagnostic markers for neuroborreliosis, such as CSF pleocytosis and Borrelia-specific antibodies (10). High numbers of B lymphocytes have also been observed in CSF from patients with syphilitic meningitis (11). CXCL13 dictates homi...

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Section: Discussioncontrasting

confidence: 59%

Section: Discussionmentioning

confidence: 57%

Has CXCL13 an Added Value in Diagnosis of Neurosyphilis?

et al. 2015

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“…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 . 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.…”

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confidence: 98%

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

Henningsson

Gyllemark

Lager

et al. 2016

APMIS

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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...

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“…However just as in neurosyphilis, since active infection is almost always accompanied by a CSF pleocytosis, elevated CSF protein or both, these non-specific markers can be used to judge whether infection is currently active. Some studies further suggest that measurement of CSF CXCL13, though not necessarily specific for Lyme disease [26], may provide an additional useful marker of disease activity [27][28][29].…”

Section: Diagnosismentioning

confidence: 99%

Nervous system Lyme disease, chronic Lyme disease, and none of the above

Halperin

2015

Acta Neurol Belg

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Lyme borreliosis, infection with the tick-borne spirochete Borrelia burgdorferi sensu lato, causes nervous system involvement in 10-15 % of identified infected individuals. Not unlike the other well-known spirochetosis, syphilis, infection can be protracted, but is microbiologically curable in virtually all patients, regardless of disease duration. Diagnosis relies on 2-tier serologic testing, which after the first 4-6 weeks of infection is both highly sensitive and specific. After this early, acute phase, serologic testing should rely only on IgG reactivity. Nervous system involvement most commonly presents with meningitis, cranial neuritis and radiculoneuritis, but can also present with a broader array of peripheral nervous system manifestations. Central nervous system infection typically elicits a cerebrospinal fluid pleocytosis and, often, intrathecal production of specific antibody, findings that should not be expected in disease not affecting the CNS. Treatment with recommended courses of oral or, when necessary, parenteral antibiotics is highly effective. The attribution of chronic, non-specific symptoms to "chronic Lyme disease", in the absence of specific evidence of ongoing B. burgdorferi infection, is inappropriate and unfortunate, leading not only to unneeded treatment and its associated complications, but also to missed opportunities for more appropriate management of patients' often disabling symptoms.

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Cerebrospinal fluid chemokine CXCL13 in the diagnosis of neuroborreliosis in children

Abstract: In LNB, the production of CXCL13 in CSF seems to precede antibody production. Assessment of CSF CXCL13 may improve the diagnostics for children with possible LNB.

Cited by 32 publications

References 21 publications

Has CXCL13 an Added Value in Diagnosis of Neurosyphilis?

Has CXCL13 an Added Value in Diagnosis of Neurosyphilis?

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

Nervous system Lyme disease, chronic Lyme disease, and none of the above

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