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CLB-09061; No.

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Clinical Biochemistry xxx (2015) xxxxxx

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Clinical Biochemistry

journal homepage: www.elsevier.com/locate/clinbiochem

Direct comparison of the diagnostic accuracy between blood and


cerebrospinal uid procalcitonin levels in patients with meningitis
Hong-Yuan Shen a,1, Wei Gao b,1, Juan-Juan Cheng a, Shi-Di Zhao a, Yi Sun c, Zhi-Jun Han a,, Jun Hua a,
a
Department of Laboratory Medicine, Wuxi Second People's Hospital of Nanjing Medical University, Wuxi, PR China
b
Department of Neurology, Wuxi New District Phoenix Hospital, Wuxi, PR China
c
Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai, PR China

a r t i c l e i n f o a b s t r a c t

Article history: Objective: To compare the clinical utility of serum and cerebrospinal uid (CSF) procalcitonin (PCT) for the
Received 6 May 2015 diagnosis of bacterial meningitis (BM) among patients with suspected meningitis.
Received in revised form 23 June 2015 Methods: Patients with meningitis-like symptoms (n = 120), admitted to the Second People's Hospital of
Accepted 24 June 2015 Wuxi or the Changhai Hospital of Shanghai between January 2011 and December 2013, were prospectively
Available online xxxx
and consecutively enrolled in this study. BM was nally diagnosed by CSF culture, Gram staining, quantitative po-
lymerase chain reaction (qPCR), and treatment response. The diagnostic accuracy of the serum and CSF PCT was
Keywords:
Meningitis
assessed by receiver operator characteristic (ROC) curve analysis. The relationship between CSF and serum PCT
PCT levels as well as the CSF leukocyte count and protein level was analyzed by Spearman's correlation analysis.
CSF Results: PCT level in both the serum and CSF was signicantly increased in the BM patients. The area under
Biomarker ROC curve of serum PCT for the diagnosis of BM was 0.96 (95% condence interval (CI): 0.931.00), signicantly
higher than that of CSF PCT (0.90, 95% CI: 0.830.96). Using 0.88 ng/mL as the threshold, the diagnostic sensitiv-
ity, specicity, and accuracy of serum PCT for the diagnosis of BM were 0.87 (95% CI, 0.730.95), 1.00 (95% CI,
0.951.00), and 95%, respectively. The serum PCT level was positively correlated with the CSF PCT level, leukocyte
count, and protein level.
Conclusion: Both the serum and CSF PCT had a high diagnostic value for BM among suspected meningitis pa-
tients, and serum PCT demonstrated a superior diagnostic value compared to CSF PCT.
2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

1. Introduction are not high enough to differentiate BM from viral meningitis, tubercu-
lous meningitis, or fungal meningitis [7,8]. Therefore, it is necessary to
Bacterial meningitis (BM) remains a common infectious disease identify more sensitive and specic biomarkers for the diagnosis of BM.
with high mortality and constitutes a major medical concern to public In recent decades, procalcitonin (PCT), a polypeptide of 116 amino
health worldwide [13]. To a large extent, clinical manifestations acids, has been reported to be an effective biomarker for bacterial infec-
among BM and viral meningitis, tuberculous meningitis, and fungal tion [9,10]. A meta-analysis showed that the sensitivity and specicity
meningitis are similar; however, different treatment approaches are re- of PCT for differentiating bacterial from viral infections were 0.92 and
quired for different pathogens. Thus, an early and accurate differential 0.86, respectively [11]. The PCT concentration in both serum and CSF
diagnosis is crucial [4,5]. Generally, the diagnosis of BM relies on micro- of BM patients is increased, and both can serve as diagnostic markers
biological tests and laboratory ndings. Identifying of pathogens by for BM detection [1215]. However, it is remains unknown whether
cerebrospinal uid (CSF) bacterial culture and Gram staining is highly serum or CSF PCT is better for the diagnosis of BM.
specic; however, the sensitivity of bacterial culture and staining tech- Therefore, the aim of the present study was to compare the diagnos-
niques is low as it has been reported that nearly half of BM patients tic accuracy between serum and CSF PCT determination in parallel. We
had negative microbiological ndings [6,7]. In addition, microbiological focused our investigations on whether serum and CSF PCT had a high
examination is time consuming, which makes an early diagnosis impos- diagnostic value for BM among suspected meningitis patients.
sible. Analysis of leukocyte count and protein level in CSF is an alterna-
tive method for diagnosing BM, although the sensitivity and specicity 2. Material and methods

2.1. Participants
Corresponding authors at: Department of Laboratory Medicine, Wuxi Second People's
Hospital of Nanjing Medical University, Wuxi, PR China.
E-mail addresses: zjhan1125@163.com (Z.-J. Han), huajun0308@sina.com (J. Hua). A total of 150 patients with meningitis-like manifestations, who
1
Both authors contributed equally to this work. were admitted to the Second People's Hospital of Wuxi or the Changhai

http://dx.doi.org/10.1016/j.clinbiochem.2015.06.017
0009-9120/ 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Please cite this article as: Shen H-Y, et al, Direct comparison of the diagnostic accuracy between blood and cerebrospinal uid procalcitonin levels
in patients with meningitis, Clin Biochem (2015), http://dx.doi.org/10.1016/j.clinbiochem.2015.06.017
2 H.-Y. Shen et al. / Clinical Biochemistry xxx (2015) xxxxxx

Hospital of Shanghai between January 2011 and December 2013, were were given an initial and a nal diagnoses. Of these subjects, 30 who
prospectively and consecutively enrolled in this study. The inclusion had a positive CSF or blood bacterial culture or Gram staining, but a neg-
criteria were as follows: 1) patients with two of the following symptoms ative PCR viral infection test, were initially diagnosed as BM. A total of
or signs: fever, confusion, headache, or nuchal rigidity; 2) older than 59 patients were categorized into the non-BM group because of positive
18 years old; 3) no determination of a meningitis pathogen on admis- PCR nding and negative CSF bacterial culture or Gram staining. For the
sion; and 4) CSF leukocyte count greater than 5 106/L [16]. Patients remaining subjects, antibiotic therapy was initiated and the responses
who were infected with bacteria and received antibiotic therapy during to the therapy were monitored. The nal diagnosis was based on the
the past two weeks were excluded. patients' CSF leukocyte count, protein and glucose determination, as
The present study was approved by the Ethics Committees of the well as their responses to antibiotic therapy. Conclusively, 45 subjects
Second People's Hospital of Wuxi and the Changhai Hospital of Shang- were categorized into BM and 75 were categorized into the non-BM
hai. Written informed consent was obtained from all patients included group. The clinical characteristics at baseline are shown in Table 1.
in this study. Among the 75 non-BM patients, 18 were diagnosed as Coxsackie
virus-induced meningitis, 17 were infected with the ECHO virus, 14
2.2. PCT test methods were infected with the herpes virus, 5 were infected with the EB virus,
3 were infected with the varicella zoster virus, 2 were infected with
The serum and CSF samples were drawn within 8 h after admission. the paramyxovirus, and 16 were infected with an unknown virus.
After completing routine bacterial and chemical analyses (e.g., CSF Among the BM group, 12 were infected with Streptococcus pneumoniae,
leukocyte count, protein level determination, and bacterial culture), 10 with Diplococcus intracellularis, 8 with Staphylococcus aureus, and 15
the serum and CSF samples were stored immediately at 80 C. In with unknown bacteria.
June 2014, all the serum and CSF samples were subjected to PCT concen-
tration determination by immunolumino-metric assay (LUMItest PCT, 3.2. Increased serum and CSF PCT levels in the bacterial meningitis patients
BRAHMS Diagnostica, Berlin, Germany). The laboratory technicians
were blinded to the clinical information of the subjects. As shown in Fig. 1, the median serum concentration of PCT in the BM
and non-BM patients was 4.22 ng/mL and 0.41 ng/mL, respectively. In
2.3. Diagnosis of BM addition, the CSF PCT concentration in the BM and non-BM patients
was 1.88 ng/mL and 0.34 ng/mL, respectively. Both the serum and CSF
Leukocyte count and protein level were determined in the CSF sam- PCT concentrations in the BM patients were signicantly higher than
ples from all admitted subjects. In addition, the blood and CSF samples those of the non-BM patients (P b 0.01 for both).
were subjected to bacterial culture and Gram staining. Finally, the CSF
samples were tested for viral infection, including CMV, ECHO, and 3.3. Relationship between the CSF and serum PCT levels in the BM and
HSV, by quantitative polymerase chain reaction (qPCR) to detect viral non-BM patients
infection. Patients with positive CSF bacterial culture or Gram staining,
but negative qPCR test, were diagnosed as BM, and antibiotic therapy As shown in Fig. 2, the serum PCT level was positively correlated
was initiated immediately. The patients who tested positive for viral in- with the CSF PCT level among all meningitis patients, resulting in a
fection according to the qPCR test, but had negative CSF bacterial culture correlation coefcient (R) of 0.64 (P b 0.01). We further analyzed the re-
and Gram staining, were diagnosed as viral meningitis. For the cases lationship between the serum and CSF PCT levels in the BM and non-BM
with negative bacterial culture, Gram staining and qPCR, experimental patients, respectively. A signicant positive correlation between the
therapy with antibiotics was introduced and the outcomes of the serum and CSF PCT levels (R = 0.69, P b 0.01) was observed in the BM
patients were documented [17]. The nal diagnosis was made by two patients but not in the non-BM patients.
experienced physicians using the CSF laboratory ndings and treatment In addition, we also analyzed the relationships between the PCT
response. level and the CSF leukocyte count as well as the CSF protein level. The
serum PCT level was positively correlated with the CSF leukocyte
2.4. Statistical analysis count (R = 0.36, P = 0.02) and with the protein level (R = 0.39, P =
0.01) in the BM patients but not in the non-BM patients.
For continuous variables, MannWhitney U test or Student's t-test
was used to assess whether the differences had statistical signicance. 3.4. Diagnostic accuracy of the serum and CSF PCT levels for BM patients
For categorical variables, 2 test was used. Spearman's rank correlation
coefcient was employed to analyze the relationship between two con- Fig. 3 shows the ROC curve of the serum and CSF PCT for the diagno-
tinuous variables. All continuous variables were reported as median (in- sis of BM. The AUC for serum and CSF PCT was 0.96 (95% CI: 0.931.00)
terquartile) or mean (SD) values. The diagnostic accuracy of PCT for BM
was analyzed by receiver operator characteristic (ROC) curve analysis.
Table 1
The cut-off value for the PCT level was established by seeking the max- Demographic and clinical characteristics of the subjects.
imum accuracy (the proportion of true positive to true negative results).
BM Non-BM P
The areas under ROC curve (AUCs) were compared by the method
developed by DeLong et al. [18]. P value of 0.05 or less was considered Number of patients 45 75
statistically signicant. All tests were two-sided, and all statistical Age (years) 50 18 47 19 0.34
Gender (male/female) 30/15 55/20 0.53
analyses were performed using SPSS version 17.0 (SPSS Inc., Chicago,
Clinical signs or symptoms
IL, USA) and SigmaPlot 11.0 for Windows. Median period between symptom 43 (25, 52) 43 (30, 54) 0.26
onset and admission (h)
3. Results Fever (yes/no) 45/0 60/15 b0.01
Headache (yes/no) 45/0 75/0 1.00
Nuchal rigidity (yes/no) 44/1 70/5 0.41
3.1. Demographic and clinical characteristics of the subjects Confusion (yes/no) 2/43 1/74 0.55
CSF laboratory ndings
Of the 150 patients who were initially included in this study, 13 were Leukocyte count (106/L) 3800 (620, 7500) 280 (58, 500) b0.01
returning patients and 17 had used antibiotics prior to admission. Final- Protein (g/L) 0.68 (0.40, 0.94) 0.39 (0.25, 0.56) b0.01

ly, 120 meningitis patients were eligible for nal analysis. All patients Note: Values are the median and quartile, where appropriate.

Please cite this article as: Shen H-Y, et al, Direct comparison of the diagnostic accuracy between blood and cerebrospinal uid procalcitonin levels
in patients with meningitis, Clin Biochem (2015), http://dx.doi.org/10.1016/j.clinbiochem.2015.06.017
H.-Y. Shen et al. / Clinical Biochemistry xxx (2015) xxxxxx 3

Fig. 1. Comparison of the serum and CSF PCT levels between the BM and non-BM patients. Note: Horizontal bars in the plots represent the mean values.

and 0.90 (95% CI: 0.830.96), respectively. The AUC for serum PCT was accuracy of both serum and CSF PCT by ROC curve analysis. A signi-
signicantly higher than that for CSF PCT (P = 0.03), indicating that cantly higher AUC was established using serum PCT. Therefore, we con-
the serum PCT exhibits a signicantly higher diagnostic accuracy than cluded that the overall diagnostic accuracy of serum PCT was superior to
that of the CSF PCT. CSF PCT in this cohort. Of note, the diagnostic accuracy of serum PCT
Table 2 shows the diagnostic sensitivity, specicity, and accuracy at a was 95% at cut-off of 0.88 ng/mL, implying that 95% of patients with
prespecied threshold (0.5 ng/mL) as well as the calculated threshold suspected meningitis can be correctly differentiated. At this cut-off
with maximum diagnostic accuracy. At the threshold of 0.88 ng/mL, value, the diagnostic specicity was 100%, implying that a patient with-
the serum PCT showed the highest diagnostic accuracy (95.0%), imply- out BM is very unlikely to have serum PCT level higher than 0.88 ng/mL.
ing that only 6 of the 120 meningitis patients were misdiagnosed. The Our data suggest that the serum PCT could be a reliable marker to distin-
highest diagnostic accuracy for CSF PCT was 83.3%, when a threshold guish BM from viral meningitis.
of 0.74 ng/mL was selected. A positive correlation between the serum and CSF PCT levels was ob-
served in our study, and this nding has not been reported previously
4. Discussion [15,21]. Such correlation may suggest that CSF PCT may originate from
serum, since the serum PCT level was higher than that of the CSF PCT
The purpose of this study was to determine relative efciency of level. During the pathogenic process of meningitis, the bloodbrain bar-
serum and CSF PCT for diagnosis of BM. We found that PCT level in rier is damaged by the inammatory response, and PCT in the blood is
both serum and CSF of BM patients was signicantly higher than that able to enter into the CSF. This process could explain why CSF PCT was
of non-BM patients. Our ndings were as expected [14], since PCT is a of high diagnostic accuracy for BM. We also found that the serum PCT
well-recognized marker for bacterial infection [12,13,19,20]. Thus, the level was signicantly and positively correlated with the CSF leukocyte
results from this study corroborate that PCT in serum and CSF is a poten- count and protein level. It is well established that the CSF leukocyte
tial diagnostic marker for BM. count and protein level are effective indices for the differential diagnosis
Previously, two studies have evaluated the diagnostic accuracy of of meningitis. Therefore, the detection of serum PCT is a valuable addi-
both serum and CSF PCT in the same cohorts [15,21]; however, the diag- tion to CSF leukocyte count and protein level determination; in addition,
nostic accuracy of serum and CSF PCT was not compared. To the best of it saves time and makes an early and accurate diagnosis of BM possible.
our knowledge, this study was the rst one to compare the diagnostic As the present study was limited by its small sample size, we were un-
accuracy of two PCTs in a head-to-head manner, thus eliminating able to use rigorous statistical models such as net reclassication or in-
potential variations at different settings. tegrated discrimination improvement [23] to determine whether serum
Unlike sensitivity and specicity, which can be greatly affected by PCT can improve the diagnostic accuracy of CSF leukocyte count and
the threshold chosen, the AUC is a global parameter that estimates the protein level, or the converse is true.
diagnostic accuracy of an index test [22]. We assessed the diagnostic One strength of the present study should be noted. To ensure that
the detected BM prevalence reected the clinical reality [24], all the sub-
jects in the present study were consecutively enrolled. That is why we

Fig. 2. Correlations between the serum and CSF PCT levels in all meningitis patients (BM
and non-BM). Note: Data were analyzed using the Spearman's correlation. Fig. 3. ROC curves of the serum and CSF PCT for the diagnosis of BM.

Please cite this article as: Shen H-Y, et al, Direct comparison of the diagnostic accuracy between blood and cerebrospinal uid procalcitonin levels
in patients with meningitis, Clin Biochem (2015), http://dx.doi.org/10.1016/j.clinbiochem.2015.06.017
4 H.-Y. Shen et al. / Clinical Biochemistry xxx (2015) xxxxxx

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did not exclude the subjects who did not have identiable microbio-
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logical ndings from the nal analysis. As reported, only 70%85% of [11] Simon L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J. Serum procalcitonin and
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In summary, we found that both serum and CSF PCT had high diag- [14] Li Y, Zhang G, Ma R, Du Y, Zhang L, Li F, et al. The diagnostic value of cerebrospinal
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[15] Jereb M, Muzlovic I, Hojker S, Strle F. Predictive value of serum and cerebrospinal
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[16] Schwarz S, Bertram M, Schwab S, Andrassy K, Hacke W. Serum procalcitonin levels
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Disclosures [17] Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, et al. Practice
guidelines for the management of bacterial meningitis. Clin Infect Dis 2004;39:
The authors declare no conict of interest. 126784.
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correlated receiver operating characteristic curves: a nonparametric approach. Bio-
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[19] Ray P, Badarou-Acossi G, Viallon A, Boutoille D, Arthaud M, Trystram D, et al.
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This work was supported by a grant from the National Natural rial meningitis, in case of negative gram-stained smear. Am J Emerg Med 2007;
Science Foundation of China (no. 81301503). 25:17984.
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Please cite this article as: Shen H-Y, et al, Direct comparison of the diagnostic accuracy between blood and cerebrospinal uid procalcitonin levels
in patients with meningitis, Clin Biochem (2015), http://dx.doi.org/10.1016/j.clinbiochem.2015.06.017

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