Cerebrospinal fluid CXCL13 in Lyme neuroborreliosis and asymptomatic HIV infection
Cerebrospinal fluid CXCL13 in Lyme neuroborreliosis and asymptomatic HIV infection
Daniel Bremell 0
Niklas Mattsson 2
Mikael Edsbagge 1
Kaj Blennow 2
Ulf Andreasson 2
Carsten Wikkels 1
Henrik Zetterberg 2 3
Lars Hagberg 0
0 Department of Infectious Medicine, Institute of Biomedicine, the Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
1 Hydrocephalus Research Unit, Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation, the Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
2 Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy, University of Gothenburg , Gothenburg and Molndal , Sweden
3 UCL Institute of Neurology , Queen Square, London WC1N 3BG , UK
Background: It has been suggested that cerebrospinal fluid (CSF) CXCL13 is a diagnostic marker of Lyme neuroborreliosis (LNB), as its levels have been shown to be significantly higher in LNB than in several other CNS infections. Levels have also been shown to decline after treatment with intravenous ceftriaxone, but levels after treatment with oral doxycycline have previously not been studied. Like Borrelia burgdorferi, HIV also has neurotropic properties. Elevated serum CXCL13 concentrations have been reported in HIV patients, but data on CSF levels are limited. Methods: We longitudinally analysed CSF CXCL13 concentrations in 25 LNB patients before and after oral doxycycline treatment. Furthermore, we analysed CSF CXCL13 concentrations in 16 untreated LNB patients, 27 asymptomatic untreated HIV-1 infected patients and 39 controls with no signs of infectious or inflammatory disease. Results: In the longitudinal LNB study, initially high CSF CXCL13 levels declined significantly after doxycycline treatment, which correlated to a decreased CSF mononuclear cell count. In the cross-sectional study, all the LNB patients had CSF CXCL13 levels elevated above the lowest standard point of the assay (7.8 pg/mL), with a median concentration of 500 pg/mL (range 34-11,678). Of the HIV patients, 52% had elevated CSF CXCL13 levels (median 10 pg/mL, range 0-498). There was a clear overlap in CSF CXCL13 concentrations between LNB patients and asymptomatic HIV patients. All but one of the 39 controls had CSF CXCL13 levels below 7.8 pg/mL. Conclusions: We confirm previous reports of highly elevated CSF CXCL13 levels in LNB patients and that these levels decline after oral doxycycline treatment. The same pattern is seen for CSF mononuclear cells. CSF CXCL13 levels are elevated in neurologically asymptomatic HIV patients and the levels overlap those of LNB patients. The diagnostic value of CSF CXCL13 in LNB remains to be established.
Lyme neuroborreliosis (LNB) is the most common
arthropod-borne CNS infection in Europe and the USA
. The diagnosis of LNB rests on a combination of
anamnestic, clinical and laboratory findings. For a definite
diagnosis, European guidelines require clinical
symptoms consistent with LNB, such as painful
meningoradiculitis, other diagnoses excluded, cerebrospinal fluid
(CSF) pleocytosis and intrathecal Borrelia burgdorferi
(Bb) antibody production [2,3]. There are some
limitations to this diagnostic procedure. CSF pleocytosis is not
specific to LNB but is seen in other infectious and
noninfectious diseases of the central nervous system.
Intrathecal antibody production may be absent for up to six
weeks after the onset of symptoms and intrathecally
produced antibodies are known to remain positive for years
after the initial disease [4,5].
In recent years, the chemokine CXCL13 (also known
as BLC B lymphocyte chemoattractant) in CSF has
been presented as a potential marker of LNB, more
specific than todays diagnostic approach . CXCL13 is a
potent attractor of B cells and CSF levels rise early in
the course of LNB and decline after treatment .
Significantly higher CSF CXCL13 concentrations are recorded in
LNB than in several other infectious and inflammatory
CNS diseases [6-8]. Cryptococcosis and neurosyphilis are
among the few other infectious diseases in which CSF
CXCL13 levels as high as those in LNB have been reported
Oral doxycycline and intravenous ceftriaxone are
considered equally effective for the treatment of LNB with
peripheral nervous system symptoms, while intravenous
ceftriaxone is still the preferred treatment of LNB with
central nervous system symptoms such as meningitis or
encephalitis in many centra .
HIV infects the central nervous system at the primary
infection or shortly thereafter, causing a chronic,
lowgrade inflammatory reaction in most clinically
asymptomatic patients [11,12]. In HIV patients, serum levels of
CXCL13 have been shown to be significantly elevated
when compared with controls . van Burgel et al.
described elevated CSF levels of CXCL13 in six patients
with HIV meningitis but low levels in seven patients
with HIV infection without intrathecal inflammation
. CSF levels of CXCL13 in a larger group of patients
with asymptomatic HIV infection have not been studied.
We analysed CSF levels of CXCL13 in patients with
LNB, HIV and controls, in order to assess whether the test
is specific for LNB even when compared with patients
with HIV infection. We have also studied how doxycycline
treatment of LNB affects CSF CXCL13 levels and the CSF
cell count by analysing a well-characterised set of LNB
patients before and after treatment.
We enrolled different study participants for the
longitudinal and the cross-sectional study. For the
longitudinal study, we analysed 25 LNB patients who had
undergone CSF sampling before and after treatment
between October 1995 and November 2005. All these
patients were treated with 200400 mg of oral
doxycycline daily for 1014 days, according to Swedish
recommendations . For the cross-sectional study,
we analysed three groups of patients: patients with
LNB, patients with HIV-1 infection and controls with
no infectious or inflammatory disease. The inclusion
criteria for LNB patients in the cross-sectional part of
the study were LNB diagnosed between January 2005
and June 2009 and CSF sampling before the start of
treatment. The inclusion criteria for HIV patients were: I.
Asymptomatic infection; II. No antiretroviral treatment;
III. No clinical signs of neurological disease; IV. A negative
test for syphilis. CSF sampling of the HIV patients was
undertaken between January 2005 and June 2009. The
control group included two subgroups. One subgroup
consisted of 18 patients with neurological symptoms such
as headache, vertigo and radiculitic pain, where an
underlying organic neurological disease had been ruled out and
where CSF sampling had been undertaken as part of the
investigations. The other subgroup consisted of 21
subjects with no neurological disease or symptoms who had
undergone lumbar puncture for CSF sampling as part of a
research project unrelated to this study . In
accordance with Swedish regulations, informed consent was
obtained from all participants prior to inclusion of their
CSF and blood samples into the biobank from which the
samples then were retrieved. The study was approved by
the regional ethical review board at the University of
LNB diagnostic criteria
The diagnostic criteria for LNB were: I. Symptoms
consistent with LNB and other diagnoses excluded; II. CSF
mononuclear pleocytosis with a mononuclear cell count
of > 5/L and erythrocytes of < 100/L; III. Bb-specific
antibodies in CSF above the upper reference level; IV. At
least one of the following: a) a positive antibody index
(AI), defined as the ratio of the CSF/serum quotient of
specific Bb antibodies to the corresponding CSF/serum
quotient of total immunoglobulins, where AI values
of 1.5 are considered positive, b) CSF cytological
examination consistent with LNB with activated plasma
All CSF samples were collected by lumbar puncture in
the L3/L4 or the L4/L5 inter-space. The first 512 mL
of CSF were collected in a polypropylene tube and
immediately transported to the local laboratory for
centrifugation. The supernatant was pipetted off, gently mixed
to avoid possible gradient effects and aliquoted in
polypropylene tubes that were stored at 80C pending
biochemical analyses, without being thawed and re-frozen.
CXCL13 was measured by ELISA (Human CXCL13/
BLC/BCA-1 Immunoassay, R&D Systems Inc., Abingdon,
United Kingdom), according to instructions from the
manufacturer. Based on measurements of duplicates of
the standard samples (concentrations 7.8-500 mg/L), the
average intra-assay CVs were 10%. Syphilis testing was
done with LIAISON Treponema Screen (Diasorin,
Saluggia, Italy). For the analysis of Bb antibodies in
serum and CSF, two different tests were used during
the study period. Until 26 June 2006, antibodies were
analysed using an enzyme-linked immunosorbent assay
(ELISA) kit for IgG and IgM antibodies (Dako Lyme
Borreliosis Kit, Dako Cytomation, Glostrup, Denmark).
Tests positive for IgM were further analysed with a
more specific test (IDEIA, Dako Cytomation, Glostrup,
Denmark). After 26 June 2006, Bb antibodies were
analysed using a sandwich chemiluminescence
immunoassay (CLIA) test kit (Diasorin, Saluggia, Italy). HIV
RNA in serum and CSF was determined using a
quantitative polymerase chain reaction (Amplicor, HIV-1
Monitor Test version 1.5, Roche Diagnostic Systems,
Hoffman-La Roche, Basel, Switzerland).
Statistical analysis was performed using GraphPad Prism
5.0 (GraphPad Software, San Diego, USA). Data are
presented as the median (range). CXCL13 values below the
detection limit of 7.8 ng/mL were assigned a value of
3.9 ng/mL for graphical purposes. Analyses were made
using non-parametric methods. In the longitudinal
study, differences before and after treatment were
analysed with the Wilcoxon matched pairs test.
Differences between groups in the cross-sectional study
were analysed with the Kruskal-Wallis test followed by
Dunns post test. Correlations were analysed using the
Spearman rank order correlation. P values of < 0.05
were considered significant.
Table 1 Baseline data, symptoms and routine CSF analyses
In the longitudinal part of the study, 25 LNB patients
were analysed. Baseline data, clinical symptoms and routine
CSF analyses are shown in Table 1. 23 of the patients had a
positive AI. One patient had an AI of 1.1 and for one
patient the AI could not be calculated due lack of data for
total immunoglobulins. The latter two patients had a CSF
cytological examination consistent with LNB with activated
plasma cells. The median time between CSF samplings was
45 days (3375). Before treatment, the median CSF
CXCL13 was 3,727 pg/mL (range 1143,746), >which
declined after treatment to 38 pg/mL (3.9-204) (P < 0.001)
(Figure 1). The decline in the CSF mononuclear cell count
after treatment was also significant: median 118 cells/L
(14590) before treatment, versus a median of 13 cells/L
(221) after treatment, P < 0.001 (Table 1 and Figure 1).
The quotients before and after treatment of CSF CXCL13
and CSF mononuclear cells were calculated as (CSF
CXCL13 before treatment)/(CSF CXCL13 after treatment)
Duration of symptoms (days)
radiculitis and facial palsy
radiculitis and other palsy
radiculits and sensibility disturbancies
CSF albumin (mg/L)
Baseline data, clinical symptoms and routine CSF analyses for the longitudinal and the cross-sectional study. Data are presented as median (range). LNB Lyme
neuroborrelios, na not applicable, other palsy palsy other than facial palsy.
Figure 1 CSF levels of CXCL13 and mononuclear cells before
and after treatment of Lyme neuroborreliosis. Pairwise
comparisons of CXCL13 and mononuclear cells in cerebrospinal fluid
before and after treatment of Lyme neuroborreliosis. P-values from
the Wilcoxon matched pairs test. BL baseline, FU follow-up,
Mono mononuclear cells. Median time between CSF samplings
was 45 days (range 3375).
and (CSF mononuclear cell before treatment)/(CSF
mononuclear cells after treatment). The quotients correlated
significantly (Spearman r = 0.37, P = 0.036) (Figure 2).
In the cross-sectional part of the study, 85 patients
were analysed; 16 with LNB, 27 with HIV infection and
39 controls without inflammatory CNS disease. Baseline
data, clinical symptoms and routine CSF analyses are
shown in Table 1. All 16 LNB patients had a positive AI
indicating intrathecal antibody production. For LNB
patients, the median duration of neurological symptoms
was 21 days (7120). For HIV patients, the median time
since diagnosis was 15 months (1180). There was no
significant difference in age between patients with LNB
and HIV infection (median 37 and 38 years respectively),
while the controls were significantly older, with a median age
of 64 years (P < 0.01). CSF levels of mononuclear cells
differed significantly between all three groups; they were
highest in LNB patients, with a median of 58 cells/L (8493),
followed by HIV patients at 4 cells/L (069) and controls at
1 cell/L (08) (P < 0.01).
CSF CXCL13 levels differed significantly between all
three groups of patients in the cross-sectional study
(Figure 3) (P < 0.01). All LNB patients had concentrations
above the lowest standard point of the assay, with a median
of 500 pg/mL (3411678). Fourteen of 27 HIV patients had
CXCL13 concentrations above the lowest standard point of
the assay. The median value of CXCL13 for the HIV
patients was 10 pg/mL (3.9-498). All but one of the 39
controls had CXCL13 concentrations below the lowest
standard point of the assay.
CSF mononuclear cells quotient
Figure 2 Quotients of CSF mononuclear cells and CSF CXCL13
before and after treatment. Quotients are calculated as (CSF
mononuclear cells before treatment)/(CSF mononuclear cells after
treatment) and (CSF CXCL13 before treatment)/(CSF CXCL13 after
treatment). Spearman r = 0.37, P = 0.036.
CSF CXCL13 levels between the LNB patients in the
longitudinal and the cross-sectional part of the study
differed (median 3727 pg/mL vs. 500 pg/mL) but the
difference was not statistically significant (P = 0.065).
Correlations between CSF mononuclear cells and CXCL13
were calculated. For the HIV patients there was a significant
correlation (Spearman r = 0.81, P < 0.001) (Figure 4A). For
the LNB patients, the correlation was significant both in the
cross-sectional study (Spearman r = 0.59, P = 0.016), and in
the pre-treatment part of the longitudinal study (Spearman
r = 0.40, P = 0.046). The combined analysis of the two groups
of untreated LNB patients produced a Spearman r = 0.55,
(P < 0.001) (Figure 4B).
For LNB patients, there was no significant correlation
between the duration of neurological symptoms and
CSF CXCL13 levels, either in the longitudinal study or
in the cross-sectional study (data not shown).
For the assessment of the diagnostic performance of
CSF CXCL13, we combined the data on LNB patients
from the cross-sectional study and the pre-treatment
part of the longitudinal study and analysed them against
the combined group of HIV patients and controls. A
receiver operating characteristic (ROC) curve is shown in
Figure 5. A CSF CXCL13 cut-off level of 61 pg/mL gives
a sensitivity of 90% and a specificity of 88% for the
diagnosis of LNB.
We confirm previous findings that CSF CXCL13 levels
are highly elevated in untreated LNB patients. We also
Figure 3 CSF levels of CXCL13 in patients with Lyme
neuroborreliosis, HIV infection and controls. CSF CXCL13 levels
in untreated, asymptomatic HIV patients, untreated LNB patients and
controls. Lines showing median and interquartile range for each
group. Dotted line at the lowest standard point of the assay
(7.8 pg/mL). Values below the detection limit were assigned a value of
3.9 pg/mL for graphical purposes. LNB Lyme neuroborreliosis.
show that CSF CXCL13 concentrations decline after
treatment with oral doxycycline and that the levels
before and after treatment differ by about a hundredfold.
This finding supports to the use of oral doxycycline for
the treatment of LNB. Oral treatment has the advantages
of being both cheaper and more convenient for the
patient compared with intravenous treatment.
Does CSF CXCL13 concentrations add any valuable
information to routine CSF analysis? Initially elevated
CSF mononuclear cell count also declines significantly
after treatment and the decline in levels of CSF
mononuclear cells and CXCL13 are correlated, as shown in
Figure 2. Even though the CSF cell count is unspecific, it
has the advantage of being a rapidly available, easily
performed test. As CSF mononuclear pleocytosis is one of
the diagnostic criteria for LNB, its clinical usefulness is
generally not assessed in studies of CSF CXCL13.
However, especially when evaluating treatment effect and in
diagnosing re-infection in patients with previous LNB,
the extra value of CSF CXCL13 determination over CSF
cell count is small, in our opinion. In spite of this, the
lack of detectable Bb-specific antibody production can
be seen in patients during the first few weeks of disease
and, in a small number of patients, CSF pleocytosis may
be absent for the first days of disease [17,18]. In this
group of patients, analysis of CSF CXCL13 may provide
additional information, as high CSF CXCL13
concentrations have been detected early in the infectious process,
as shown in this and other studies . A prospective
study would be needed to confirm the clinical usefulness
of CSF CXCL13 in this specific situation.
In the cross-sectional study, we chose to compare the
levels of CSF CXCL13 LNB patients with patients with
HIV infection for two reasons. Elevated serum CXCL13
levels have been described in HIV patients. Serum CXCL13
levels were higher in HIV patients with more advanced
disease and correlated moderately with viral load . In
addition, HIV is known to cause a chronic, low-grade CNS
infection in most asymptomatic patients, with a CSF
picture resembling that of LNB, with mononuclear pleocytosis
and oligoclonal IgG bands . Elevated CSF CXCL13
levels have been described in HIV patients with clinical
signs of CNS inflammation but not in asymptomatic HIV
patients . One inclusion criterion for HIV patients in
Figure 4 Correlation between CSF mononuclear cells and CSF CXCL13 in HIV and Lyme neuroborreliosis. A, Correlation between CSF
mononuclear cells and CSF CXCL13 in untreated, asymptomatic HIV patients. Dotted line at the lowest standard point of the assay (7.8 pg/mL).
(Spearman r = 0.81, P < 0.001). B, Correlation between CSF mononuclear cells and CSF CXCL13 in untreated Lyme neuroborreliosis
(Spearman r = 0.55, P < 0.001). Lyme neuroborreliosis patients from the cross-sectional study and the pre-treatment part of the longitudinal study.
100% - Specificity%
Figure 5 ROC curve analysis of CSF CXCL13 levels to
discriminate between Lyme neuroborreliosis patients and
controls. Lyme neuroborreliosis patients from the cross-sectional
study and the pre-treatment part of the longitudinal study. Controls
include asymptomatic HIV patients and study subjects with no CNS
infectious or inflammatory disease. Horizontal lines show different
suggested cut-off levels for CSF CXCL13 (Tjernberg et al. 142 pg/mL,
van Burgel et al. 250 pg/mL, and Schmidt et al. 1,229 pg/mL).
61 pg/mL was the chosen cut-off in this study.
this study was the absence of clinical signs of neurological
disease. Nevertheless, 14/27 patients had CSF CXCL13
above the detection limit and, even though the difference at
group level was significant, there was a clear overlap
between the LNB patients and HIV patients (Figure 3). As
highly elevated CSF CXCL13 concentrations has been
reported in cryptococcosis and moderately elevated
concentrations has been seen in African trypanosomiasis, the
high concentrations reported here in asymptomatic HIV
infection adds to the growing evidence that elevated CSF
CXCL13 concentrations can not be regarded as specific for
spirochetal CNS infections [10,20]. How this affects the
diagnostic potential of CSF CXCL13 in LNB remains to be
seen. Adding further to the problem is the fact that the
most common clinical finding in LNB, peripheral facial
palsy, is also reported among HIV patients [17,21].
The mechanism behind the previously reported
elevated serum CXCL13 concentrations in HIV patients
has not been determined. CXCL13 is known to be
produced by macrophages, but the direct stimulation of
macrophages and peripheral blood mononuclear cells by
HIV-1 failed to induce CXCL13 production in one study
. Cagigi et al. demonstrated CXCL13 production in
B cells from HIV patients but not in B cells from
uninfected controls . In this present study, we show a
significant correlation between CSF mononuclear cells and
CXCL13 (Figure 4A), but the correlation is not perfect
and elevated CSF CXCL13 levels are seen in HIV patients
without mononuclear pleocytosis. The exact mechanism
behind the elevated serum and CSF CXCL13
concentrations seen in HIV patients remains to be elucidated.
It is difficult to compare CSF CXCL13 results from
various studies. CSF CXCL13 has previously been
related to CSF protein (and presented as CSF CXCL13/
CSF protein, ng/g) to correlate with impaired blood
brain barrier function and possible leakage into the CSF
of CXCL13 . The fact that CXCL13 levels in LNB
patients are higher in CSF than in serum [23,24]
indicates that CSF CXCL13 is produced intrathecally and
absolute CSF CXCL13 values are therefore presented in
our study and other recent studies [10,23,25]. We
studied two separate groups of LNB patients. The median
CSF CXCL13 values differed between the longitudinal study
(3,727 pg/mL) and the cross-sectional study (500 pg/mL),
although the difference did not reach statistical significance
(P = 0.065). This cause of this difference is not clear. It could
be a random effect, or it could related to the difference
between the two groups in the CSF levels of mononuclear cells
(median 118 cells/L compared with median 58 cells/L), as
we show a significant correlation between CSF levels of
mononuclear cells and CXCL13 in Figure 4B. The median
value of 500 pg/mL in the cross-sectional study is lower
than in other reports, which could be considered a weakness
of this present study. However, two recent studies produced
such widely differing mean and median values for CSF
CXCL13 in LNB as 15,149 pg/mL (mean) and 1,183 pg/mL
(median). The latter study used the same analytic kit as the
one used in this study [10,23]. The differences between
studies might reflect inter-centre variability or variability
depending on the analytic kits used for measurements. Both
are known problems for research-grade biomarker kits and
kits for analyses for which certified reference methods and
materials for kit calibration are lacking [26,27].
Previous studies of CSF CXCL13 in LNB have
suggested optimal cut-off values, maximising sensitivity and
specificity, where the level of CSF CXCL13 should be
considered positive for LNB. Proposed cut-offs range
from 142 pg/mL to 1,229 pg/mL (Tjernberg et al.
142 pg/mL, Schmidt et al. 1,229 pg/mL and van Burgel
et al. 250 pg/mL) [10,23,25]. When these cut-off levels
are applied to our material, they all give sensitivity below
83%, making them less useful. A cut-off value at such a
low level as 61 pg/mL was needed to obtain acceptable
sensitivity, when LNB was compared with a mixed
population of non-infectious controls and asymptomatic HIV
patients in our study (Figure 5). If CSF CXCL13 is to be
used in clinical practice, the sensitivity and specificity
must be estimated against relevant control groups, i.e.
against populations with symptoms similar to those
caused by LNB. The great difference between the
suggested cut-off levels for CSF CXCL13 contrasts distinctly
with the analysis of CSF mononuclear cells, which
admittedly has a lower specificity for the diagnosis of LNB,
but has a high sensitivity and also have a universally
accepted cut-off level.
We confirm previous reports of highly elevated CSF
CXCL13 levels in LNB patients. CSF CXCL13
concentrations decline a hundredfold after treatment with oral
doxycycline, which support the efficacy of this regimen.
The same pattern is seen for CSF mononuclear cells. We
show that CSF CXCL13 levels are also elevated in
neurologically asymptomatic HIV patients and that the
levels overlap those of LNB patients. CSF CXCL13 levels
in LNB patients differ widely between studies. The
diagnostic value of CSF CXCL13 in LNB remains to be
NM has served on a scientific advisory board for Actelion Inc. LH has
participated in a scientific advisory board for Pfizer, Astra Zeneca and Meda.
The other authors report no competing interests.
DB, NM, HZ and LH came up with the idea for this study and participated in
its conception and design. DB and LH drafted the manuscript. KB and UA
participated in setting up the analyses. DB, ME, CW and LH recruited the
study participants. NM and HZ made important revisions to the manuscript.
All the authors read and approved the final manuscript.
This study was funded by grants from the Swedish Research Council,
Sahlgrenska University Hospital, the Sahlgrenska Academy, the Lundbeck
Foundation, Stiftelsen fr Gamla Tjnarinnor, Pfannenstills stiftelse, Thurus
stiftelse, the Swedish Association of Persons with Neurological Disabilities,
Alzheimers Association, the Dementia Foundation (Sweden), Uppsala
University (Medicinska fakultetens stiftelse fr psykiatrisk och neurologisk
forskning) and the Swedish Brain Foundation.
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