Has CXCL13 an Added Value in Diagnosis of Neurosyphilis?

Abstract

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...

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

“…The concentration of the chemokine has been found to be lower in HIV-positive/asymptomatic neurosyphilis than in HIV-negative/asymptomatic neurosyphilis, but the differences are not significant [54]. In patients without neurosyphilis, no significant differences between HIV-positive and HIV-negative infection have been revealed [52]. Furthermore, the odds of symptomatic neurosyphilis with HIV co-infection increase significantly with a rise in CSF CXCL13 levels, white blood cell count, detection of Treponema pallidum, and plasma HIV RNA.…”

“…However, patients with syphilis and HIV co-infection have been found to have higher CSF CXCL13 values than those with HIV infection only [49]. Moreover, CSF CXCL13 levels have been shown to be significantly higher in symptomatic and asymptomatic neurosyphilis in comparison to uncomplicated syphilis [52,53]. The concentration of the chemokine has been found to be lower in HIV-positive/asymptomatic neurosyphilis than in HIV-negative/asymptomatic neurosyphilis, but the differences are not significant [54].…”

“…Recent retrospective studies have revealed that CXCL13 levels are increased in the CSF and serum of patients with early and late neurosyphilis. Those patients were found to have higher CSF levels of the chemokine than individuals without neurological symptoms [6,[10][11][12][51][52][53][54][55][56]. Release of high levels of CXCL13 during the in vitro incubation of monocytes with Treponema pallidum may be evidence that CXCL13 could be a good diagnostic marker for nervous system infections caused by this particular spirochete [10].…”

“…Release of high levels of CXCL13 during the in vitro incubation of monocytes with Treponema pallidum may be evidence that CXCL13 could be a good diagnostic marker for nervous system infections caused by this particular spirochete [10]. As an example, to differentiate neurosyphilis from other neurological disorders, a cut-off point of 76.3 pg/mL of CXCL13 has been suggested with a sensitivity and specificity of 50% and 90%, respectively [52]. It is well known that the closer the AUC is to 1, the higher the sensitivity of the test is to identify disease presence.…”

“…Therefore, some authors have focused on patients who were co-infected with HIV and neurosyphilis and attempted to investigate CXCL13 levels in these patients. It has been demonstrated that patients with neurosyphilis and HIV co-infection have higher serum concentrations of CXCL13 than HIV-infected patients with syphilis, but without neurological symptoms [52,53]. Zeng et al suggested that serum CXCL13 levels are not useful in support of the diagnosis of neurosyphilis in HIV-negative patients, since serum CXCL13 concentrations are similar in neurosyphilis and other neurological viral or cryptococcal infections [11].…”