CLB-08884; No. of pages: 5; 4C: Clinical Biochemistry xxx (2014) xxx–xxx
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The diagnostic value of cerebrospinal fluids procalcitonin and lactate for the differential diagnosis of post-neurosurgical bacterial meningitis and aseptic meningitis☆ Youran Li a, Guojun Zhang a,b,⁎, Ruimin Ma a, Yamei Du a, Limin Zhang a, Fangqiang Li a, Fang Fang a, Hong Lv a, Qian Wang a, Yan Zhang a, Xixiong Kang a,b a b
Department of Clinical Laboratory, Beijing Tiantan Hospital, Capital Medical University, Beijing, China China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
a r t i c l e
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Article history: Received 21 August 2014 Accepted 22 October 2014 Available online xxxx Keywords: Procalcitonin Lactate CSF Bacterial meningitis
a b s t r a c t Objectives: Distinguishing between post-neurosurgical bacterial meningitis (PNBM) and aseptic meningitis is difficult. This study aims to evaluate the combined diagnostic value of CSF procalcitonin and lactate as novel PNBM markers in hospitalized post-neurosurgery patients. Design and methods: This study was performed using CSF samples, collected by lumbar puncture, from 178 PNBM-suspected patients enrolled in a retrospective clinical study. The levels of CSF procalcitonin and lactate were appropriately assayed and the combined diagnostic value of these markers was assessed using receiver operating characteristic (ROC) curves, a two by two table, and non-parametric tests. Results: Fifty of the 178 patients were diagnosed with PNBM, based on the clinical symptoms and laboratory results. These PNBM patients showed significantly elevated levels of CSF procalcitonin and CSF lactate compared with the non-PNBM group (p b 0.001 for both). It was revealed that the cut-off values for the diagnosis of PNBM were: 0.075 ng/mL (sensitivity, 68%; specificity, 73%) for procalcitonin and 3.45 mmol/L (sensitivity, 90%; specificity, 85%) for lactate. A serial test combining the levels of these two markers showed decreased sensitivity (64%) and increased specificity (91%), compared with either marker alone. In contrast, a parallel test combining the levels of these both markers showed increased sensitivity (96%) and decreased specificity (65%), compared with either marker alone. Conclusion: Our study shows that the combined use of CSF procalcitonin and lactate can reliably distinguish between PNBM and non-PNBM and can be included in the design of diagnostic approaches to circumvent the shortcomings of conventional methods. © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Introduction Bacterial meningitis after neurosurgical procedures is relatively uncommon with a low incidence of about 0.3%–1.5% [1], but it is a severe and life threatening infection with a high mortality that ranges from 20 to 50% [2]. At present, post-neurosurgery bacterial meningitis Abbreviations: PNBM, post-neurosurgery bacterial meningitis; CSF, cerebrospinal fluid; WBC, white blood cell; ROC, receiver operator curve; AUC, area under curve; PPV, positive predictive value; NPV, the negative predictive value; PLR, the positive likelihood ratio; NLR, the negative likelihood ratio. ☆ This work was supported by the Natural Science Foundation of Beijing (7142051), the High Level Technical Talent Development of Beijing Health System (2013-3-052), the State Science and Technology Support Program—Application Evaluation of Basic Biological and Chemical Equipment (3013BAI17B04) and the National Key Technology Research and Development Program of the Ministry of Science and Technology of the People's Republic of China (2013BAI09B03). ⁎ Corresponding author at: Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing 100050, China. E-mail address: [email protected] (G. Zhang).
(PNBM) is diagnosed based on the criteria proposed by the Center for Disease Control and Prevention (CDC) [3], the Massachusetts General Hospital (MGH) [4], the Infectious Diseases Society of America (IDSA) and our local criteria. Our criteria included clinical symptoms, various biochemical parameters of the cerebrospinal fluid (CSF) and the blood, and the CSF bacterial culture, which constitutes the golden standard for the diagnosis of bacterial meningitis. However, the low level of the various blood and CSF biochemical parameters does not always rule out bacterial meningitis and should be used with caution. Actually, PNBM and aseptic meningitis share some clinical symptoms and physical signs, including headache, fever, neck stiffness, and vomiting [5]. In addition, hemorrhage, surgical procedure, trauma, and bone dust all appear to trigger an inflammatory response that mimics the bacterial meningitis CSF changes and fail to demonstrate a high diagnostic accuracy [5,6]. Moreover, the time-consuming nature and propensity to contamination of the CSF bacterial culture contribute to the low detection rate of positive culture, reported to be about 6–9% [7–9]. Given all these influencing factors, it is necessary to introduce novel diagnostic
http://dx.doi.org/10.1016/j.clinbiochem.2014.10.007 0009-9120/© 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Please cite this article as: Li Y, et al, The diagnostic value of cerebrospinal fluids procalcitonin and lactate for the differential diagnosis of postneurosurgical bacter..., Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.10.007
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Y. Li et al. / Clinical Biochemistry xxx (2014) xxx–xxx
markers to assist in the diagnosis of PNBM in order to offer more diagnostic options and to evaluate the utility of antibiotic drugs. It has been established that the production of the CSF lactate by the astrocytes is triggered by bacterial infection. Recently, the CSF lactate has been shown to be correlated with bacterial infection and was suggested as a potential marker for distinguishing between infection and inflammation, as well as a biomarker for PNBM for its excellent discriminatory power [10,11]. Serum procalcitonin has also been proposed as a novel biomarker with high sensitivity and specificity for both diagnostic and prognostic values in various severe infections [12–14]. Although this biomarker has been studied as an aid to classify infections according to severity and to guide therapy durations the clinical value of CSF procalcitonin in the differential diagnosis of PNBM is rarely investigated. Thus, whether the combined use of CSF procalcitonin and lactate as biomarkers could improve the diagnostic efficacy is still unclear. Method Patients The current study retrospectively analyzed 178 patients who underwent neurosurgery at our institute between October 2013 and March 2014. This study was approved by our Institutional Review Board and written informed consent was obtained from all the patients enrolled. Patients who showed clinical symptoms of bacterial meningitis such as fever, headache, neck stiffness, and disturbance of consciousness, within 48 to 72 h after surgery were subjected to lumbar puncture in order to collect CSF samples for diagnostic analysis, which included protein content, glucose, chloride, WBC count, etc. The residual CSF samples were used to assay levels of procalcitonin and lactate. The diagnosis of bacterial meningitis was based on the following criteria [15]: 1) clinical symptoms including headache, fever (N38.5 °C), meningeal irritation sign, and disturbance of consciousness; 2) positive bacterial CSF culture or Gram stain; 3) CSF WBC count ≥ 1000/μL and polykaryocyte percentage ≥ 75%; and 4) CSF glucose b2.5 mmol/L or when the ratio of CSF glucose to blood glucose was lower than 0.4. Patients who did not meet the above criteria and with a WBC count b 500/μL were classified into the non-PNBM group. Measurements After CSF samples were collected the levels of glucose, protein, chloride, procalcitonin, lactate, as well as the WBC count, and polykaryocyte percentage were determined immediately. The procalcitonin concentration was measured using a commercially available enzyme-linked fluorescent assay (VIDAS® B.R.A.H.M.S procalcitonin, Berlin, Germany), which has a lower detection limit of 0.05 ng/mL; when the CSF procalcitonin level of the patients was below this detection limit we regarded it as 0 ng/mL. The lactate concentration in the CSF was measured using a VITROS chemistry products lactate slides (Ortho-Clinical Diagnostics, Inc., New York, USA), which has a lower detection limit of 0.50 mmol/L. The CSF lactate and other biomarkers, including polykaryocyte percentage, WBC count, CSF protein, CSF chloride, and CSF glucose were assessed quantitatively on the VITROS 5,1 FS Automatic Chemistry Analyzer device using the velocity method. The positive result of the serial test was confirmed when all the included sub-tests were positive. While the positive result of the parallel test was defined as that in which at least one sub-test was positive. Statistical analysis Since neither the procalcitonin nor the lactate data followed a normal distribution (Kolmogorov–Smirnov, p b 0.05), the non-parametric test (Mann–Whitney test) was used to compare the medians of the CSF procalcitonin and lactate levels to ascertain whether there was a
relevant relationship between the PNBM and non-PNBM groups. The optimal cut-off value was calculated using the receiver operator curve (ROC) analysis for procalcitonin and lactate in CSF. Two-by-two tables were created based on the cut-off values and were used to calculate the positive and negative predictive values, the positive and negative likelihood ratio, the accuracy, and the diagnostic index. Subsequently, the serial and parallel tests were applied to determine the diagnostic accuracy of the combined procalcitonin and lactate levels in CSF. All the analyses were done using IBM SPSS Statistics, version 19.0 (IBM, Armonk, NY, USA). Results The 178 patients enrolled in this study were divided into 50 patients to the PNBM group and 128 to the non-PNBM group. The values for each of the various parameters were not normally distributed when examined by category. The medians of the parameters for diagnosis (age, sex, CSF procalcitonin, CSF lactate, CSF WBC count and polykaryocyte percentage, CSF protein, CSF chloride, and CSF glucose) were compared and the comparison results are given in Table 1. In the PNBM group, the median of the CSF procalcitonin levels was 0.2 ng/mL, ranging from 0 ng/mL to 3.1 ng/mL, and the median of the CSF lactate levels was 5.3 mmol/L, ranging from 2.2 mmol/L to 10.6 mmol/L. The performance of the procalcitonin and the lactate tests in the diagnosis of PNBM is summarized in Table 2. The difference in the CSF procalcitonin levels between the PNBM and the non-PNBM groups was statistically significant (p b 0.001) (Fig. 1). Similarly the CSF lactate levels for the PNBM and the non-PNBM groups also showed significant difference (p b 0.001) (Fig. 2). The ROC curve analysis of the CSF procalcitonin and lactate data revealed that the cut-off values were: 0.075 ng/mL (AUC = 0.746, p b 0.001, sensitivity, 68.0%; specificity, 72.7%) for the CSF procalcitonin; and 3.45 mmol/L (AUC = 0.943, p b 0.001, sensitivity, 90.0%; specificity, 84.4%) for the CSF lactate (Fig. 3). Together these ROC curve analysis results suggest that CSF lactate and procalcitonin hold significant diagnostic value for PNBM. In addition, the accuracy, the diagnostic index, the positive predictive value (PPV), the negative predictive value (NPV), the positive likelihood ratio (PLR), and the negative likelihood ratio (NLR) of CSF procalcitonin, CSF lactate, serial test and parallel test of CSF procalcitonin and lactate were determined. The diagnostic power of the CSF procalcitonin plus lactate was also determined by using the serial and the parallel tests. When combined for the diagnosis of PNBM, the diagnostic criteria of the CSF procalcitonin and lactate, together, showed lower sensitivity (64.0%) and higher specificity (91.4%) compared with the result of either marker alone. When the parallel test of the CSF procalcitonin and lactate was applied, there was a higher sensitivity (96.0%) and a lower specificity (64.8%) in comparison with the result of either marker alone. The relationship between procalcitonin, lactate and conventional laboratory indicators including polykaryocyte percent, WBC count, protein level and glucose level is shown in Table 3. When the values of conventional indicators were classified by the diagnostic threshold value (0.075 ng/mL) of procalcitonin estimated above, the variation trend of procalcitonin was consistent with that of the conventional markers; a Table 1 CSF data of all patients. Parameters
PNBM
Non-PNBM
Age (yrs, range) Sex (M/F) WBC/μL Polykaryocyte percent CSF protein (mg/dL) CSF chloride (mmol/L) CSF glucose (mmol/L) Procalcitonin (ng/mL) Lactate (mmol/L)
42 (21–67) 23/27 2237 (1000–18,757) 90.4% (75.1–99.4%) 148.7 (64.3–587.5) 113.0 (102.7–129.0) 2.1 (0.3–4.3) 0.2 (0–3.1) 5.3 (2.2–10.6)
42 (17–69) 49/79 98 (1–2567) 41.9% (0–97.7%) 72.4 (19.6–305.8) 114.0 (48.7–132.6) 3.3 (1.0–9.0) 0 (0–0.5) 2.3 (1.2–5.4)
Please cite this article as: Li Y, et al, The diagnostic value of cerebrospinal fluids procalcitonin and lactate for the differential diagnosis of postneurosurgical bacter..., Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.10.007
Y. Li et al. / Clinical Biochemistry xxx (2014) xxx–xxx
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Table 2 The diagnostic efficacy evaluation of CSF procalcitonin and lactate for PNBM. Procalcitonin Lactate Procalcitonin + lactate Procalcitonin/ lactate AUC 0.746 Cut-off point 0.075 p value b0.001 Sensitivity (%) 68.0 Specificity (%) 72.7 Accuracy (%) 71.3 Diagnostic index 1.4 PPV (%) 49.3 NPV (%) 85.3 PLR (%) 2.49 NLR (%) 0.44
0.943 3.450 b0.001 90.0 84.4 86 1.7 69.2 95.6 5.77 0.12
– – – 64.0 91.4 83.7 1.6 74.4 86.7 7.44 0.39
– – – 96.0 64.8 73.6 1.6 51.6 97.6 2.73 0.06
AUC: area under the curve; PPV: positive predictive value; NPV: negative predictive value; PLR: positive likelihood ratio; NLR: negative likelihood ratio.
Fig. 2. Lactate level in CSF for the PNBM and the non-PNBM groups showing significant difference (Mann–Whitney, p b 0.001).
similar tendency was also observed for the lactate threshold value (3.45 mmol/L). When the data of the CSF procalcitonin and lactate were combined, an increased trend for the conventional markers was revealed in both the serial and the parallel tests. Furthermore, it was established that the serial test was more suitable for the diagnosis of PNBM since all the conventional indicators for the definite diagnosis of PNBM were higher than the thresholds under the circumstance.
and to establish a novel diagnostic method which offers more sensitivity and specificity in the diagnosis of PNBM, we combined the CSF procalcitonin and lactate data to test the diagnostic efficacy of this new approach. Our results demonstrated that the combined CSF procalcitonin and lactate levels in the patients with bacterial meningitis are significantly higher than those in the aseptic meningitis patients. The ROC analysis results revealed that the CSF lactate assay exhibited a high sensitivity and specificity in distinguishing between PNBM and aseptic meningitis, even in patients under antibiotic treatment [25,26]. Combining the CSF procalcitonin and lactate data results in a higher sensitivity and specificity compared with the CSF lactate alone, indicating that the combined biomarker method is more powerful for the diagnosis of PNBM. The use of the CSF lactate level as another useful biomarker in diagnosing bacterial meningitis has been suggested in many previous reports. Indeed, it is well known that the production of lactate by the astrocytes in the CSF is triggered by bacterial infection, and that the lactate in CSF is rarely affected by serum lactate; and thus can reflect the intracranial infection accurately [27–29]. Several meta-analyses demonstrated that the CSF lactate level served as a better marker for bacterial meningitis than conventional markers such as CSF glucose, CSF protein, and CSF cell count [25-30]. In addition, Leib et al. [2] considered that the determination of the CSF lactate value is a quick, sensitive, and specific test to identify patients with bacterial meningitis after neurosurgery. In their study, the CSF lactate values (cut-off, 4 mmol/L), in comparison with the CSF/blood glucose ratios (cut-off, 0.4), were associated with higher sensitivity (0.88 vs. 0.77), specificity (0.98 vs. 0.87), and positive (0.96 vs. 0.77) and negative (0.94 vs. 0.87) predictive values. Our study shows that the CSF lactate is a reliable marker to distinguish between PNBM and aseptic meningitis. High sensitivity and negative predictive values were achieved with a cut-off value of 3.45 mmol/L (sensitivity,
Discussion Conventional laboratory biomarkers are always applied to the diagnosis of PNBM, including the CSF bacterial culture, polymerase chain reaction (PCR) testing of CSF bacteria, WBC count, protein, glucose, and chloride in the CSF [16]. Although the CSF bacterial culture remains the golden standard, the percent positive results are only about 10% due to a variety of reasons, including the low amount and contamination of CSF sample, time constraints, and antibiotic drug administration [7,9]. Incidentally, in our cohort study the percent of CSF culture positive results was about 6–8%. Another consideration is the limitations of PCR testing, including a high false positive rate due to sample contamination during the lumbar puncture and the interaction between the gene probes and other unrelated germ, resulting in a low specificity of the technique [17–20]. Moreover, the high cost and the complexity of the procedure also limit the wide clinical application of PCR testing [21,22]. Although the sensitivity and specificity of the CSF WBC count appear very high, many factors can affect its diagnostic accuracy for PNBM, such as the considerable inter-observer variation, poor repeatability and specificity, and problematic standardization [23]. The diagnostic efficacy of other biomarkers including the CSF protein content, glucose and chloride levels also has limitations [24]. In order to circumvent the potential shortcomings of the current diagnostic parameters
Fig. 1. The difference in procalcitonin level in CSF between the PNBM and the non-PNBM groups showed statistical significance (Mann-Whitney, p b0.001).
Fig. 3. ROC analysis illustrating that the CSF procalcitonin and the CSF lactate are significant predictors of the PNBM (AUC = 0.746, p b 0.001, and AUC = 0.943, p b 0.001, respectively).
Please cite this article as: Li Y, et al, The diagnostic value of cerebrospinal fluids procalcitonin and lactate for the differential diagnosis of postneurosurgical bacter..., Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.10.007
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Y. Li et al. / Clinical Biochemistry xxx (2014) xxx–xxx
Table 3 The relationship between the procalcitonin, the lactate and the conventional laboratory indicators. Procalcitonin (ng/mL)
LA (mmol/L)
b0.075 ≥0.075 – – b0.075 b0.075 ≥0.075 ≥0.075
– b3.45 ≥3.45 b3.45 ≥3.45 b3.45 ≥3.45
Polykaryocyte percent (%) (mean ± SD)
WBC (/μL) (mean ± SD)
Protein (mg/dL) (mean ± SD)
Glucose (mmol/L) (mean ± SD)
44.7 71.9 40.1 81.5 43.9 64.0 72.0 76.5
590.4 1829.5 119.5 2593.1 566.2 1368.7 1829.5 2021.0
88.2 152.7 81.3 167.7 88.1 117.5 152.7 162.3
3.3 2.9 3.6 2.4 3.3 2.9 2.9 2.9
± ± ± ± ± ± ± ±
36.8 30.4 35.6 21.0 36.7 33.2 30.4 26.4
90.0%; specificity, 84.6%). However, some of the indicators of the CSF lactate were not powerful enough for the accurate diagnosis of PNBM, including the specificity, PPV, PLR and even the NLR, which would increase the possibility of misdiagnosis or false negative results. Serum procalcitonin has been studied extensively as a novel biomarker for the diagnosis of bacterial meningitis with a satisfactory sensitivity and specificity in various severe infections [12]. Calcitonin is primarily produced by the C cells of the thyroid gland and is the product of the calcitonin-related polypeptide alpha (CALCA) gene. It is thought that bacterial endotoxins and cytokines produced during the immune response blunt the final step in the synthesis of calcitonin, creating an abundance of the precursor hormone, procalcitonin [12]. However, the usefulness of CSF procalcitonin in the diagnosis of intracranial infection has not been well investigated. We investigated the efficacy of the CSF procalcitonin level in diagnosing PNBM by ROC curve analysis and demonstrated that the CSF procalcitonin level was higher in the PNBM group than that in the non-PNBM group (p b 0.001). Indeed, the results show the usefulness of the CSF procalcitonin as a diagnostic biomarker for bacterial meningitis with a cut-off value of 0.075 ng/mL (AUC = 0.746; sensitivity, 68.0%; specificity 72.7%, p b 0.001). Nevertheless, the reference values of the CSF procalcitonin, such as the sensitivity, specificity, PPV, and PLR were even more unsatisfactory and seemed to be inadequate for the clinical demands of the PNBM diagnosis. As discussed previously, although the CSF lactate appeared to be a good detective factor for the PNBM diagnosis with a relatively high sensitivity and specificity, some of the indicators of CSF lactate were not powerful enough to guarantee the accurate diagnosis of PNBM in the current study. Accordingly, we combined the CSF procalcitonin and the CSF lactate to determine the diagnosis usefulness (diagnostic accuracy, diagnostic index, PPV, NPV, PLR and NLR) of the serial and the parallel tests, aiming at identifying a novel combined diagnosis indicator whose use in the diagnosis of PNBM was clinically feasible. The serial and the parallel tests with the combined procalcitonin and the lactate data demonstrated an increased specificity and sensitivity compared with the level of either marker alone. For all the potential PNBM patients with a CSF lactate level higher than the diagnostic threshold, the percent of actual PNBM patients was reflected by the PPV. Although the CSF lactate has a PPV of 69.2%, a higher PPV of 74.4% was observed in the serial test when combined with the CSF procalcitonin, indicating that this method is better suited to accurately diagnose PNBM. Similarly, for all the potential non-PNBM patients with a CSF lactate level lower than the diagnostic threshold, the percent of actual non-PNBM patients was reflected by the NPV. Although the CSF lactate has a PPV of 95.6%, a higher NPV of 97.6% was also shown in the parallel test when combined with the CSF procalcitonin, indicating that this test method is more suitable to discriminate the non-PNBM patients. Unlike PPV and NPV, the accuracy of PLR and NLR was not affected by the morbidity and can be used to evaluate the diagnostic test more effectively. A higher PLR and a lower NPV indicate an enhanced diagnostic efficacy of a certain test. Although CSF lactate showed a relatively high PLR and a low NLR, the serial and the parallel tests of the combined CSF lactate and procalcitonin demonstrated a more favorable PLR and NLR compared to lactate alone. However, when we combined lactate with procalcitonin, the diagnostic
± ± ± ± ± ± ± ±
1978.2 2389.0 298.2 3123.4 1974.2 3198.8 2389.0 2470.8
± ± ± ± ± ± ± ±
54.8 102.9 49.0 100.6 55.2 63.4 103.0 105.0
± ± ± ± ± ± ± ±
1.1 1.4 1.1 1.2 1.1 1.3 1.4 1.5
index of both the serial and the parallel tests did not show a satisfactory result. So, the selection and application of the various testing methods rely on the purpose of clinical diagnosis. For instance, when we need to screen patients with suspected PNBM, we can choose the parallel test of the combined CSF lactate and procalcitonin with higher sensitivity, NPV and lower NLR. Whereas, if we want to confirm the patients with PNBM, we can choose the serial test with a higher specificity, PPV and PLR. In order to confirm the diagnostic efficacy of CSF procalcitonin, CSF lactate, and the combined indicator, we categorized the conventional markers based on the CSF procalcitonin and lactate thresholds in our study. The CSF procalcitonin and lactate both demonstrated their elevated trend, as conventional markers showed in PNBM patients, which suggests that the CSF procalcitonin and lactate could be potential markers for the diagnosis of PNBM. Under the circumstance of the combined indicators, a potential interaction between CSF procalcitonin and lactate may exist. The procalcitonin was more sensitive than the lactate in monitoring the alternation of conventional indicators in patients with PNBM. Nevertheless, this study has several limitations. First, patients' information was retrospectively collected from a single institution, which may not reflect an appropriate definition for PNBM. Second, the diagnostic criteria we used to discriminate PNBM from non-PNBM were based on the study by Gray and Fedorko [15] two decades ago, which may not reflect recent progress in the study of PNBM. Third, the study was not designated to have the CSF lactate differentiate between those with proven and presumed PNBM. In conclusion, our study shows that CSF procalcitonin and lactate are reliable markers to distinguish between PNBM and non-PNBM, and current sensitivity and negative predictive values are achieved with a cut-off value of 0.075 ng/mL for procalcitonin and 3.45 mmol/L for lactate. Moreover, these values are especially useful in detecting PNBM in clinical practice. When a single parameter is applied to determine intracranial bacterial infection alone, the detection power may not be adequate for clinical application. By combining laboratory test results (procalcitonin, lactate, CSF regular and biochemistry test, CSF culture, etc.), clinical symptom and the usage of antibiotics, we demonstrated their efficient diagnostic value for intracranial bacterial infection. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgments We would like to acknowledge the support from the Center of Brain Tumor, Beijing Institute for Brain Disorders (BIBD-PXM2013_ 014226_07_000084). References [1] Blomstedt GC. Infections in neurosurgery: a retrospective study of 1143 patients and 1517 operations. Acta Neurochir 1985;78(3–4):81–90.
Please cite this article as: Li Y, et al, The diagnostic value of cerebrospinal fluids procalcitonin and lactate for the differential diagnosis of postneurosurgical bacter..., Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.10.007
Y. Li et al. / Clinical Biochemistry xxx (2014) xxx–xxx [2] Leib SL, Boscacci R, Gratzl O, Zimmerli W. Predictive value of cerebrospinal fluid (CSF) lactate level versus CSF/blood glucose ratio for the diagnosis of bacterial meningitis following neurosurgery. Clin Infect Dis 1999;29(1):69–74. [3] Korinek AM, Golmard JL, Elcheick A, et al. Risk factors for neurosurgical site infections after craniotomy: a critical reappraisal of antibiotic prophylaxis on 4,578 patients. Br J Neurosurg 2005;19(2):155–62. [4] Durand ML, Calderwood SB, Weber DJ, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med 1993;328(1):21–8. [5] Mekitarian FE, Horita SM, Gilio AE, Nigrovic LE. Cerebrospinal fluid lactate level as a diagnostic biomarker for bacterial meningitis in children. Int J Emerg Med 2014; 7(1):14. [6] Tamune H, Takeya H, Suzuki W, et al. Cerebrospinal fluid/blood glucose ratio as an indicator for bacterial meningitis. Am J Emerg Med 2014;32(3):263–6. [7] Simon TD, Pope CE, Browd SR, et al. Evaluation of microbial bacterial and fungal diversity in cerebrospinal fluid shunt infection. PLoS One 2014;9(1):e83229. [8] Hagiya H, Otsuka F. Actinomyces meyeri meningitis: the need for anaerobic cerebrospinal fluid cultures. Intern Med 2014;53(1):67–71. [9] Lai WA, Lu CH, Chang WN. Mixed infection in adult post-neurosurgical bacterial meningitis: a hospital-based study. Biomed J 2013;36(6):295–303. [10] Eross J, Silink M, Dorman D. Cerebrospinal fluid lactic acidosis in bacterial meningitis. Arch Dis Child 1981;56(9):692–8. [11] Sanchez GB, Kaylie DM, O'Malley MR, Labadie RF, Jackson CG, Haynes DS. Chemical meningitis following cerebellopontine angle tumor surgery. Otolaryngol Head Neck Surg 2008;138(3):368–73. [12] Foushee JA, Hope NH, Grace EE. Applying biomarkers to clinical practice: a guide for utilizing procalcitonin assays. J Antimicrob Chemother 2012;67(11):2560–9. [13] Alkholi UM, Abd AN, Abd EAA, Sultan MH. Serum procalcitonin in viral and bacterial meningitis. J Glob Infect Dis 2011;3(1):14–8. [14] Choi SH, Choi SH. Predictive performance of serum procalcitonin for the diagnosis of bacterial meningitis after neurosurgery. Infect Chemother 2013;45(3):308–14. [15] Gray LD, Fedorko DP. Laboratory diagnosis of bacterial meningitis. Clin Microbiol Rev 1992;5(2):130–45. [16] White K, Ostrowski K, Maloney S, Norton R. The utility of cerebrospinal fluid parameters in the early microbiological assessment of meningitis. Diagn Microbiol Infect Dis 2012;73(1):27–30. [17] Lleo MM, Ghidini V, Tafi MC, Castellani F, Trento I, Boaretti M. Detecting the presence of bacterial DNA by PCR can be useful in diagnosing culture-negative cases of infection, especially in patients with suspected infection and antibiotic therapy. FEMS Microbiol Lett 2014;354(2):153–60.
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[18] Lee MS, Chang WH, Chen SC, et al. Molecular diagnosis of periprosthetic joint infection by quantitative RT-PCR of bacterial 16S ribosomal RNA. ScientificWorldJournal 2013;2013:950548. [19] Simon TD, Van Yserloo B, Nelson K, et al. Use of quantitative 16S rRNA PCR to determine bacterial load does not augment conventional cerebrospinal fluid (CSF) cultures among children undergoing treatment for CSF shunt infection. Diagn Microbiol Infect Dis 2014;78(2):188–95. [20] Tien lHT, Sugiyama N, Duangsonk K, Tharavichitkul P, Osawa R. Phenotypic and PCRbased identification of bacterial strains isolated from patients with suspected Streptococcus suis infection in northern Thailand. Jpn J Infect Dis 2012;65(2):171–4. [21] Miller JC. Example of real-time quantitative reverse transcription-PCR (Q-RT-PCR) analysis of bacterial gene expression during mammalian infection: Borrelia burgdorferi in mouse tissues. Curr Protoc Microbiol 2005 Chapter 1D: Unit 1D.3.1-1D.3.28. [22] Fuursted K, Arpi M, Lindblad BE, Pedersen LN. Broad-range PCR as a supplement to culture for detection of bacterial pathogens in patients with a clinically diagnosed spinal infection. Scand J Infect Dis 2008;40(10):772–7. [23] Liu CH, Lehan C, Speer ME, Fernbach DJ, Rudolph AJ. Degenerative changes in neutrophils: an indicator of bacterial infection. Pediatrics 1984;74(5):823–7. [24] Hatzistilianou M, Rekliti A, Athanassiadou F, Catriu D. Procalcitonin as an early marker of bacterial infection in neutropenic febrile children with acute lymphoblastic leukemia. Inflamm Res 2010;59(5):339–47. [25] Sakushima K, Hayashino Y, Kawaguchi T, Jackson JL, Fukuhara S. Diagnostic accuracy of cerebrospinal fluid lactate for differentiating bacterial meningitis from aseptic meningitis: a meta-analysis. J Infect 2011;62(4):255–62. [26] Levinson A. The hydrogen-ion concentration of cerebrospinal fluid: studies in meningitis. J Infect Dis 1917;21:556–70. [27] Killian JA. Lactic acid of normal and pathological spinal fluids. Proc Soc Exp Biol Med 1925;23:255–7. [28] De Sanctis AG KJA, Garcia T. Lactic acid of spinal fluid in meningitis. Am J Dis Child 1933;46:239–49. [29] Viallon A, Desseigne N, Marjollet O, et al. Meningitis in adult patients with a negative direct cerebrospinal fluid examination: value of cytochemical markers for differential diagnosis. Crit Care 2011;15(3):R136. [30] Huy NT, Thao NT, Diep DT, Kikuchi M, Zamora J, Hirayama K. Cerebrospinal fluid lactate concentration to distinguish bacterial from aseptic meningitis: a systemic review and meta-analysis. Crit Care 2010;14(6):R240.
Please cite this article as: Li Y, et al, The diagnostic value of cerebrospinal fluids procalcitonin and lactate for the differential diagnosis of postneurosurgical bacter..., Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.10.007
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Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
The diagnostic value of cerebrospinal fluids procalcitonin and lactate for the differential diagnosis of post-neurosurgical bacterial meningitis and aseptic meningitis☆ Youran Li a, Guojun Zhang a,b,⁎, Ruimin Ma a, Yamei Du a, Limin Zhang a, Fangqiang Li a, Fang Fang a, Hong Lv a, Qian Wang a, Yan Zhang a, Xixiong Kang a,b a b
Department of Clinical Laboratory, Beijing Tiantan Hospital, Capital Medical University, Beijing, China China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
a r t i c l e
i n f o
Article history: Received 21 August 2014 Accepted 22 October 2014 Available online xxxx Keywords: Procalcitonin Lactate CSF Bacterial meningitis
a b s t r a c t Objectives: Distinguishing between post-neurosurgical bacterial meningitis (PNBM) and aseptic meningitis is difficult. This study aims to evaluate the combined diagnostic value of CSF procalcitonin and lactate as novel PNBM markers in hospitalized post-neurosurgery patients. Design and methods: This study was performed using CSF samples, collected by lumbar puncture, from 178 PNBM-suspected patients enrolled in a retrospective clinical study. The levels of CSF procalcitonin and lactate were appropriately assayed and the combined diagnostic value of these markers was assessed using receiver operating characteristic (ROC) curves, a two by two table, and non-parametric tests. Results: Fifty of the 178 patients were diagnosed with PNBM, based on the clinical symptoms and laboratory results. These PNBM patients showed significantly elevated levels of CSF procalcitonin and CSF lactate compared with the non-PNBM group (p b 0.001 for both). It was revealed that the cut-off values for the diagnosis of PNBM were: 0.075 ng/mL (sensitivity, 68%; specificity, 73%) for procalcitonin and 3.45 mmol/L (sensitivity, 90%; specificity, 85%) for lactate. A serial test combining the levels of these two markers showed decreased sensitivity (64%) and increased specificity (91%), compared with either marker alone. In contrast, a parallel test combining the levels of these both markers showed increased sensitivity (96%) and decreased specificity (65%), compared with either marker alone. Conclusion: Our study shows that the combined use of CSF procalcitonin and lactate can reliably distinguish between PNBM and non-PNBM and can be included in the design of diagnostic approaches to circumvent the shortcomings of conventional methods. © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Introduction Bacterial meningitis after neurosurgical procedures is relatively uncommon with a low incidence of about 0.3%–1.5% [1], but it is a severe and life threatening infection with a high mortality that ranges from 20 to 50% [2]. At present, post-neurosurgery bacterial meningitis Abbreviations: PNBM, post-neurosurgery bacterial meningitis; CSF, cerebrospinal fluid; WBC, white blood cell; ROC, receiver operator curve; AUC, area under curve; PPV, positive predictive value; NPV, the negative predictive value; PLR, the positive likelihood ratio; NLR, the negative likelihood ratio. ☆ This work was supported by the Natural Science Foundation of Beijing (7142051), the High Level Technical Talent Development of Beijing Health System (2013-3-052), the State Science and Technology Support Program—Application Evaluation of Basic Biological and Chemical Equipment (3013BAI17B04) and the National Key Technology Research and Development Program of the Ministry of Science and Technology of the People's Republic of China (2013BAI09B03). ⁎ Corresponding author at: Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing 100050, China. E-mail address: [email protected] (G. Zhang).
(PNBM) is diagnosed based on the criteria proposed by the Center for Disease Control and Prevention (CDC) [3], the Massachusetts General Hospital (MGH) [4], the Infectious Diseases Society of America (IDSA) and our local criteria. Our criteria included clinical symptoms, various biochemical parameters of the cerebrospinal fluid (CSF) and the blood, and the CSF bacterial culture, which constitutes the golden standard for the diagnosis of bacterial meningitis. However, the low level of the various blood and CSF biochemical parameters does not always rule out bacterial meningitis and should be used with caution. Actually, PNBM and aseptic meningitis share some clinical symptoms and physical signs, including headache, fever, neck stiffness, and vomiting [5]. In addition, hemorrhage, surgical procedure, trauma, and bone dust all appear to trigger an inflammatory response that mimics the bacterial meningitis CSF changes and fail to demonstrate a high diagnostic accuracy [5,6]. Moreover, the time-consuming nature and propensity to contamination of the CSF bacterial culture contribute to the low detection rate of positive culture, reported to be about 6–9% [7–9]. Given all these influencing factors, it is necessary to introduce novel diagnostic
http://dx.doi.org/10.1016/j.clinbiochem.2014.10.007 0009-9120/© 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Please cite this article as: Li Y, et al, The diagnostic value of cerebrospinal fluids procalcitonin and lactate for the differential diagnosis of postneurosurgical bacter..., Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.10.007
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Y. Li et al. / Clinical Biochemistry xxx (2014) xxx–xxx
markers to assist in the diagnosis of PNBM in order to offer more diagnostic options and to evaluate the utility of antibiotic drugs. It has been established that the production of the CSF lactate by the astrocytes is triggered by bacterial infection. Recently, the CSF lactate has been shown to be correlated with bacterial infection and was suggested as a potential marker for distinguishing between infection and inflammation, as well as a biomarker for PNBM for its excellent discriminatory power [10,11]. Serum procalcitonin has also been proposed as a novel biomarker with high sensitivity and specificity for both diagnostic and prognostic values in various severe infections [12–14]. Although this biomarker has been studied as an aid to classify infections according to severity and to guide therapy durations the clinical value of CSF procalcitonin in the differential diagnosis of PNBM is rarely investigated. Thus, whether the combined use of CSF procalcitonin and lactate as biomarkers could improve the diagnostic efficacy is still unclear. Method Patients The current study retrospectively analyzed 178 patients who underwent neurosurgery at our institute between October 2013 and March 2014. This study was approved by our Institutional Review Board and written informed consent was obtained from all the patients enrolled. Patients who showed clinical symptoms of bacterial meningitis such as fever, headache, neck stiffness, and disturbance of consciousness, within 48 to 72 h after surgery were subjected to lumbar puncture in order to collect CSF samples for diagnostic analysis, which included protein content, glucose, chloride, WBC count, etc. The residual CSF samples were used to assay levels of procalcitonin and lactate. The diagnosis of bacterial meningitis was based on the following criteria [15]: 1) clinical symptoms including headache, fever (N38.5 °C), meningeal irritation sign, and disturbance of consciousness; 2) positive bacterial CSF culture or Gram stain; 3) CSF WBC count ≥ 1000/μL and polykaryocyte percentage ≥ 75%; and 4) CSF glucose b2.5 mmol/L or when the ratio of CSF glucose to blood glucose was lower than 0.4. Patients who did not meet the above criteria and with a WBC count b 500/μL were classified into the non-PNBM group. Measurements After CSF samples were collected the levels of glucose, protein, chloride, procalcitonin, lactate, as well as the WBC count, and polykaryocyte percentage were determined immediately. The procalcitonin concentration was measured using a commercially available enzyme-linked fluorescent assay (VIDAS® B.R.A.H.M.S procalcitonin, Berlin, Germany), which has a lower detection limit of 0.05 ng/mL; when the CSF procalcitonin level of the patients was below this detection limit we regarded it as 0 ng/mL. The lactate concentration in the CSF was measured using a VITROS chemistry products lactate slides (Ortho-Clinical Diagnostics, Inc., New York, USA), which has a lower detection limit of 0.50 mmol/L. The CSF lactate and other biomarkers, including polykaryocyte percentage, WBC count, CSF protein, CSF chloride, and CSF glucose were assessed quantitatively on the VITROS 5,1 FS Automatic Chemistry Analyzer device using the velocity method. The positive result of the serial test was confirmed when all the included sub-tests were positive. While the positive result of the parallel test was defined as that in which at least one sub-test was positive. Statistical analysis Since neither the procalcitonin nor the lactate data followed a normal distribution (Kolmogorov–Smirnov, p b 0.05), the non-parametric test (Mann–Whitney test) was used to compare the medians of the CSF procalcitonin and lactate levels to ascertain whether there was a
relevant relationship between the PNBM and non-PNBM groups. The optimal cut-off value was calculated using the receiver operator curve (ROC) analysis for procalcitonin and lactate in CSF. Two-by-two tables were created based on the cut-off values and were used to calculate the positive and negative predictive values, the positive and negative likelihood ratio, the accuracy, and the diagnostic index. Subsequently, the serial and parallel tests were applied to determine the diagnostic accuracy of the combined procalcitonin and lactate levels in CSF. All the analyses were done using IBM SPSS Statistics, version 19.0 (IBM, Armonk, NY, USA). Results The 178 patients enrolled in this study were divided into 50 patients to the PNBM group and 128 to the non-PNBM group. The values for each of the various parameters were not normally distributed when examined by category. The medians of the parameters for diagnosis (age, sex, CSF procalcitonin, CSF lactate, CSF WBC count and polykaryocyte percentage, CSF protein, CSF chloride, and CSF glucose) were compared and the comparison results are given in Table 1. In the PNBM group, the median of the CSF procalcitonin levels was 0.2 ng/mL, ranging from 0 ng/mL to 3.1 ng/mL, and the median of the CSF lactate levels was 5.3 mmol/L, ranging from 2.2 mmol/L to 10.6 mmol/L. The performance of the procalcitonin and the lactate tests in the diagnosis of PNBM is summarized in Table 2. The difference in the CSF procalcitonin levels between the PNBM and the non-PNBM groups was statistically significant (p b 0.001) (Fig. 1). Similarly the CSF lactate levels for the PNBM and the non-PNBM groups also showed significant difference (p b 0.001) (Fig. 2). The ROC curve analysis of the CSF procalcitonin and lactate data revealed that the cut-off values were: 0.075 ng/mL (AUC = 0.746, p b 0.001, sensitivity, 68.0%; specificity, 72.7%) for the CSF procalcitonin; and 3.45 mmol/L (AUC = 0.943, p b 0.001, sensitivity, 90.0%; specificity, 84.4%) for the CSF lactate (Fig. 3). Together these ROC curve analysis results suggest that CSF lactate and procalcitonin hold significant diagnostic value for PNBM. In addition, the accuracy, the diagnostic index, the positive predictive value (PPV), the negative predictive value (NPV), the positive likelihood ratio (PLR), and the negative likelihood ratio (NLR) of CSF procalcitonin, CSF lactate, serial test and parallel test of CSF procalcitonin and lactate were determined. The diagnostic power of the CSF procalcitonin plus lactate was also determined by using the serial and the parallel tests. When combined for the diagnosis of PNBM, the diagnostic criteria of the CSF procalcitonin and lactate, together, showed lower sensitivity (64.0%) and higher specificity (91.4%) compared with the result of either marker alone. When the parallel test of the CSF procalcitonin and lactate was applied, there was a higher sensitivity (96.0%) and a lower specificity (64.8%) in comparison with the result of either marker alone. The relationship between procalcitonin, lactate and conventional laboratory indicators including polykaryocyte percent, WBC count, protein level and glucose level is shown in Table 3. When the values of conventional indicators were classified by the diagnostic threshold value (0.075 ng/mL) of procalcitonin estimated above, the variation trend of procalcitonin was consistent with that of the conventional markers; a Table 1 CSF data of all patients. Parameters
PNBM
Non-PNBM
Age (yrs, range) Sex (M/F) WBC/μL Polykaryocyte percent CSF protein (mg/dL) CSF chloride (mmol/L) CSF glucose (mmol/L) Procalcitonin (ng/mL) Lactate (mmol/L)
42 (21–67) 23/27 2237 (1000–18,757) 90.4% (75.1–99.4%) 148.7 (64.3–587.5) 113.0 (102.7–129.0) 2.1 (0.3–4.3) 0.2 (0–3.1) 5.3 (2.2–10.6)
42 (17–69) 49/79 98 (1–2567) 41.9% (0–97.7%) 72.4 (19.6–305.8) 114.0 (48.7–132.6) 3.3 (1.0–9.0) 0 (0–0.5) 2.3 (1.2–5.4)
Please cite this article as: Li Y, et al, The diagnostic value of cerebrospinal fluids procalcitonin and lactate for the differential diagnosis of postneurosurgical bacter..., Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.10.007
Y. Li et al. / Clinical Biochemistry xxx (2014) xxx–xxx
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Table 2 The diagnostic efficacy evaluation of CSF procalcitonin and lactate for PNBM. Procalcitonin Lactate Procalcitonin + lactate Procalcitonin/ lactate AUC 0.746 Cut-off point 0.075 p value b0.001 Sensitivity (%) 68.0 Specificity (%) 72.7 Accuracy (%) 71.3 Diagnostic index 1.4 PPV (%) 49.3 NPV (%) 85.3 PLR (%) 2.49 NLR (%) 0.44
0.943 3.450 b0.001 90.0 84.4 86 1.7 69.2 95.6 5.77 0.12
– – – 64.0 91.4 83.7 1.6 74.4 86.7 7.44 0.39
– – – 96.0 64.8 73.6 1.6 51.6 97.6 2.73 0.06
AUC: area under the curve; PPV: positive predictive value; NPV: negative predictive value; PLR: positive likelihood ratio; NLR: negative likelihood ratio.
Fig. 2. Lactate level in CSF for the PNBM and the non-PNBM groups showing significant difference (Mann–Whitney, p b 0.001).
similar tendency was also observed for the lactate threshold value (3.45 mmol/L). When the data of the CSF procalcitonin and lactate were combined, an increased trend for the conventional markers was revealed in both the serial and the parallel tests. Furthermore, it was established that the serial test was more suitable for the diagnosis of PNBM since all the conventional indicators for the definite diagnosis of PNBM were higher than the thresholds under the circumstance.
and to establish a novel diagnostic method which offers more sensitivity and specificity in the diagnosis of PNBM, we combined the CSF procalcitonin and lactate data to test the diagnostic efficacy of this new approach. Our results demonstrated that the combined CSF procalcitonin and lactate levels in the patients with bacterial meningitis are significantly higher than those in the aseptic meningitis patients. The ROC analysis results revealed that the CSF lactate assay exhibited a high sensitivity and specificity in distinguishing between PNBM and aseptic meningitis, even in patients under antibiotic treatment [25,26]. Combining the CSF procalcitonin and lactate data results in a higher sensitivity and specificity compared with the CSF lactate alone, indicating that the combined biomarker method is more powerful for the diagnosis of PNBM. The use of the CSF lactate level as another useful biomarker in diagnosing bacterial meningitis has been suggested in many previous reports. Indeed, it is well known that the production of lactate by the astrocytes in the CSF is triggered by bacterial infection, and that the lactate in CSF is rarely affected by serum lactate; and thus can reflect the intracranial infection accurately [27–29]. Several meta-analyses demonstrated that the CSF lactate level served as a better marker for bacterial meningitis than conventional markers such as CSF glucose, CSF protein, and CSF cell count [25-30]. In addition, Leib et al. [2] considered that the determination of the CSF lactate value is a quick, sensitive, and specific test to identify patients with bacterial meningitis after neurosurgery. In their study, the CSF lactate values (cut-off, 4 mmol/L), in comparison with the CSF/blood glucose ratios (cut-off, 0.4), were associated with higher sensitivity (0.88 vs. 0.77), specificity (0.98 vs. 0.87), and positive (0.96 vs. 0.77) and negative (0.94 vs. 0.87) predictive values. Our study shows that the CSF lactate is a reliable marker to distinguish between PNBM and aseptic meningitis. High sensitivity and negative predictive values were achieved with a cut-off value of 3.45 mmol/L (sensitivity,
Discussion Conventional laboratory biomarkers are always applied to the diagnosis of PNBM, including the CSF bacterial culture, polymerase chain reaction (PCR) testing of CSF bacteria, WBC count, protein, glucose, and chloride in the CSF [16]. Although the CSF bacterial culture remains the golden standard, the percent positive results are only about 10% due to a variety of reasons, including the low amount and contamination of CSF sample, time constraints, and antibiotic drug administration [7,9]. Incidentally, in our cohort study the percent of CSF culture positive results was about 6–8%. Another consideration is the limitations of PCR testing, including a high false positive rate due to sample contamination during the lumbar puncture and the interaction between the gene probes and other unrelated germ, resulting in a low specificity of the technique [17–20]. Moreover, the high cost and the complexity of the procedure also limit the wide clinical application of PCR testing [21,22]. Although the sensitivity and specificity of the CSF WBC count appear very high, many factors can affect its diagnostic accuracy for PNBM, such as the considerable inter-observer variation, poor repeatability and specificity, and problematic standardization [23]. The diagnostic efficacy of other biomarkers including the CSF protein content, glucose and chloride levels also has limitations [24]. In order to circumvent the potential shortcomings of the current diagnostic parameters
Fig. 1. The difference in procalcitonin level in CSF between the PNBM and the non-PNBM groups showed statistical significance (Mann-Whitney, p b0.001).
Fig. 3. ROC analysis illustrating that the CSF procalcitonin and the CSF lactate are significant predictors of the PNBM (AUC = 0.746, p b 0.001, and AUC = 0.943, p b 0.001, respectively).
Please cite this article as: Li Y, et al, The diagnostic value of cerebrospinal fluids procalcitonin and lactate for the differential diagnosis of postneurosurgical bacter..., Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.10.007
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Table 3 The relationship between the procalcitonin, the lactate and the conventional laboratory indicators. Procalcitonin (ng/mL)
LA (mmol/L)
b0.075 ≥0.075 – – b0.075 b0.075 ≥0.075 ≥0.075
– b3.45 ≥3.45 b3.45 ≥3.45 b3.45 ≥3.45
Polykaryocyte percent (%) (mean ± SD)
WBC (/μL) (mean ± SD)
Protein (mg/dL) (mean ± SD)
Glucose (mmol/L) (mean ± SD)
44.7 71.9 40.1 81.5 43.9 64.0 72.0 76.5
590.4 1829.5 119.5 2593.1 566.2 1368.7 1829.5 2021.0
88.2 152.7 81.3 167.7 88.1 117.5 152.7 162.3
3.3 2.9 3.6 2.4 3.3 2.9 2.9 2.9
± ± ± ± ± ± ± ±
36.8 30.4 35.6 21.0 36.7 33.2 30.4 26.4
90.0%; specificity, 84.6%). However, some of the indicators of the CSF lactate were not powerful enough for the accurate diagnosis of PNBM, including the specificity, PPV, PLR and even the NLR, which would increase the possibility of misdiagnosis or false negative results. Serum procalcitonin has been studied extensively as a novel biomarker for the diagnosis of bacterial meningitis with a satisfactory sensitivity and specificity in various severe infections [12]. Calcitonin is primarily produced by the C cells of the thyroid gland and is the product of the calcitonin-related polypeptide alpha (CALCA) gene. It is thought that bacterial endotoxins and cytokines produced during the immune response blunt the final step in the synthesis of calcitonin, creating an abundance of the precursor hormone, procalcitonin [12]. However, the usefulness of CSF procalcitonin in the diagnosis of intracranial infection has not been well investigated. We investigated the efficacy of the CSF procalcitonin level in diagnosing PNBM by ROC curve analysis and demonstrated that the CSF procalcitonin level was higher in the PNBM group than that in the non-PNBM group (p b 0.001). Indeed, the results show the usefulness of the CSF procalcitonin as a diagnostic biomarker for bacterial meningitis with a cut-off value of 0.075 ng/mL (AUC = 0.746; sensitivity, 68.0%; specificity 72.7%, p b 0.001). Nevertheless, the reference values of the CSF procalcitonin, such as the sensitivity, specificity, PPV, and PLR were even more unsatisfactory and seemed to be inadequate for the clinical demands of the PNBM diagnosis. As discussed previously, although the CSF lactate appeared to be a good detective factor for the PNBM diagnosis with a relatively high sensitivity and specificity, some of the indicators of CSF lactate were not powerful enough to guarantee the accurate diagnosis of PNBM in the current study. Accordingly, we combined the CSF procalcitonin and the CSF lactate to determine the diagnosis usefulness (diagnostic accuracy, diagnostic index, PPV, NPV, PLR and NLR) of the serial and the parallel tests, aiming at identifying a novel combined diagnosis indicator whose use in the diagnosis of PNBM was clinically feasible. The serial and the parallel tests with the combined procalcitonin and the lactate data demonstrated an increased specificity and sensitivity compared with the level of either marker alone. For all the potential PNBM patients with a CSF lactate level higher than the diagnostic threshold, the percent of actual PNBM patients was reflected by the PPV. Although the CSF lactate has a PPV of 69.2%, a higher PPV of 74.4% was observed in the serial test when combined with the CSF procalcitonin, indicating that this method is better suited to accurately diagnose PNBM. Similarly, for all the potential non-PNBM patients with a CSF lactate level lower than the diagnostic threshold, the percent of actual non-PNBM patients was reflected by the NPV. Although the CSF lactate has a PPV of 95.6%, a higher NPV of 97.6% was also shown in the parallel test when combined with the CSF procalcitonin, indicating that this test method is more suitable to discriminate the non-PNBM patients. Unlike PPV and NPV, the accuracy of PLR and NLR was not affected by the morbidity and can be used to evaluate the diagnostic test more effectively. A higher PLR and a lower NPV indicate an enhanced diagnostic efficacy of a certain test. Although CSF lactate showed a relatively high PLR and a low NLR, the serial and the parallel tests of the combined CSF lactate and procalcitonin demonstrated a more favorable PLR and NLR compared to lactate alone. However, when we combined lactate with procalcitonin, the diagnostic
± ± ± ± ± ± ± ±
1978.2 2389.0 298.2 3123.4 1974.2 3198.8 2389.0 2470.8
± ± ± ± ± ± ± ±
54.8 102.9 49.0 100.6 55.2 63.4 103.0 105.0
± ± ± ± ± ± ± ±
1.1 1.4 1.1 1.2 1.1 1.3 1.4 1.5
index of both the serial and the parallel tests did not show a satisfactory result. So, the selection and application of the various testing methods rely on the purpose of clinical diagnosis. For instance, when we need to screen patients with suspected PNBM, we can choose the parallel test of the combined CSF lactate and procalcitonin with higher sensitivity, NPV and lower NLR. Whereas, if we want to confirm the patients with PNBM, we can choose the serial test with a higher specificity, PPV and PLR. In order to confirm the diagnostic efficacy of CSF procalcitonin, CSF lactate, and the combined indicator, we categorized the conventional markers based on the CSF procalcitonin and lactate thresholds in our study. The CSF procalcitonin and lactate both demonstrated their elevated trend, as conventional markers showed in PNBM patients, which suggests that the CSF procalcitonin and lactate could be potential markers for the diagnosis of PNBM. Under the circumstance of the combined indicators, a potential interaction between CSF procalcitonin and lactate may exist. The procalcitonin was more sensitive than the lactate in monitoring the alternation of conventional indicators in patients with PNBM. Nevertheless, this study has several limitations. First, patients' information was retrospectively collected from a single institution, which may not reflect an appropriate definition for PNBM. Second, the diagnostic criteria we used to discriminate PNBM from non-PNBM were based on the study by Gray and Fedorko [15] two decades ago, which may not reflect recent progress in the study of PNBM. Third, the study was not designated to have the CSF lactate differentiate between those with proven and presumed PNBM. In conclusion, our study shows that CSF procalcitonin and lactate are reliable markers to distinguish between PNBM and non-PNBM, and current sensitivity and negative predictive values are achieved with a cut-off value of 0.075 ng/mL for procalcitonin and 3.45 mmol/L for lactate. Moreover, these values are especially useful in detecting PNBM in clinical practice. When a single parameter is applied to determine intracranial bacterial infection alone, the detection power may not be adequate for clinical application. By combining laboratory test results (procalcitonin, lactate, CSF regular and biochemistry test, CSF culture, etc.), clinical symptom and the usage of antibiotics, we demonstrated their efficient diagnostic value for intracranial bacterial infection. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgments We would like to acknowledge the support from the Center of Brain Tumor, Beijing Institute for Brain Disorders (BIBD-PXM2013_ 014226_07_000084). References [1] Blomstedt GC. Infections in neurosurgery: a retrospective study of 1143 patients and 1517 operations. Acta Neurochir 1985;78(3–4):81–90.
Please cite this article as: Li Y, et al, The diagnostic value of cerebrospinal fluids procalcitonin and lactate for the differential diagnosis of postneurosurgical bacter..., Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.10.007
Y. Li et al. / Clinical Biochemistry xxx (2014) xxx–xxx [2] Leib SL, Boscacci R, Gratzl O, Zimmerli W. Predictive value of cerebrospinal fluid (CSF) lactate level versus CSF/blood glucose ratio for the diagnosis of bacterial meningitis following neurosurgery. Clin Infect Dis 1999;29(1):69–74. [3] Korinek AM, Golmard JL, Elcheick A, et al. Risk factors for neurosurgical site infections after craniotomy: a critical reappraisal of antibiotic prophylaxis on 4,578 patients. Br J Neurosurg 2005;19(2):155–62. [4] Durand ML, Calderwood SB, Weber DJ, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med 1993;328(1):21–8. [5] Mekitarian FE, Horita SM, Gilio AE, Nigrovic LE. Cerebrospinal fluid lactate level as a diagnostic biomarker for bacterial meningitis in children. Int J Emerg Med 2014; 7(1):14. [6] Tamune H, Takeya H, Suzuki W, et al. Cerebrospinal fluid/blood glucose ratio as an indicator for bacterial meningitis. Am J Emerg Med 2014;32(3):263–6. [7] Simon TD, Pope CE, Browd SR, et al. Evaluation of microbial bacterial and fungal diversity in cerebrospinal fluid shunt infection. PLoS One 2014;9(1):e83229. [8] Hagiya H, Otsuka F. Actinomyces meyeri meningitis: the need for anaerobic cerebrospinal fluid cultures. Intern Med 2014;53(1):67–71. [9] Lai WA, Lu CH, Chang WN. Mixed infection in adult post-neurosurgical bacterial meningitis: a hospital-based study. Biomed J 2013;36(6):295–303. [10] Eross J, Silink M, Dorman D. Cerebrospinal fluid lactic acidosis in bacterial meningitis. Arch Dis Child 1981;56(9):692–8. [11] Sanchez GB, Kaylie DM, O'Malley MR, Labadie RF, Jackson CG, Haynes DS. Chemical meningitis following cerebellopontine angle tumor surgery. Otolaryngol Head Neck Surg 2008;138(3):368–73. [12] Foushee JA, Hope NH, Grace EE. Applying biomarkers to clinical practice: a guide for utilizing procalcitonin assays. J Antimicrob Chemother 2012;67(11):2560–9. [13] Alkholi UM, Abd AN, Abd EAA, Sultan MH. Serum procalcitonin in viral and bacterial meningitis. J Glob Infect Dis 2011;3(1):14–8. [14] Choi SH, Choi SH. Predictive performance of serum procalcitonin for the diagnosis of bacterial meningitis after neurosurgery. Infect Chemother 2013;45(3):308–14. [15] Gray LD, Fedorko DP. Laboratory diagnosis of bacterial meningitis. Clin Microbiol Rev 1992;5(2):130–45. [16] White K, Ostrowski K, Maloney S, Norton R. The utility of cerebrospinal fluid parameters in the early microbiological assessment of meningitis. Diagn Microbiol Infect Dis 2012;73(1):27–30. [17] Lleo MM, Ghidini V, Tafi MC, Castellani F, Trento I, Boaretti M. Detecting the presence of bacterial DNA by PCR can be useful in diagnosing culture-negative cases of infection, especially in patients with suspected infection and antibiotic therapy. FEMS Microbiol Lett 2014;354(2):153–60.
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[18] Lee MS, Chang WH, Chen SC, et al. Molecular diagnosis of periprosthetic joint infection by quantitative RT-PCR of bacterial 16S ribosomal RNA. ScientificWorldJournal 2013;2013:950548. [19] Simon TD, Van Yserloo B, Nelson K, et al. Use of quantitative 16S rRNA PCR to determine bacterial load does not augment conventional cerebrospinal fluid (CSF) cultures among children undergoing treatment for CSF shunt infection. Diagn Microbiol Infect Dis 2014;78(2):188–95. [20] Tien lHT, Sugiyama N, Duangsonk K, Tharavichitkul P, Osawa R. Phenotypic and PCRbased identification of bacterial strains isolated from patients with suspected Streptococcus suis infection in northern Thailand. Jpn J Infect Dis 2012;65(2):171–4. [21] Miller JC. Example of real-time quantitative reverse transcription-PCR (Q-RT-PCR) analysis of bacterial gene expression during mammalian infection: Borrelia burgdorferi in mouse tissues. Curr Protoc Microbiol 2005 Chapter 1D: Unit 1D.3.1-1D.3.28. [22] Fuursted K, Arpi M, Lindblad BE, Pedersen LN. Broad-range PCR as a supplement to culture for detection of bacterial pathogens in patients with a clinically diagnosed spinal infection. Scand J Infect Dis 2008;40(10):772–7. [23] Liu CH, Lehan C, Speer ME, Fernbach DJ, Rudolph AJ. Degenerative changes in neutrophils: an indicator of bacterial infection. Pediatrics 1984;74(5):823–7. [24] Hatzistilianou M, Rekliti A, Athanassiadou F, Catriu D. Procalcitonin as an early marker of bacterial infection in neutropenic febrile children with acute lymphoblastic leukemia. Inflamm Res 2010;59(5):339–47. [25] Sakushima K, Hayashino Y, Kawaguchi T, Jackson JL, Fukuhara S. Diagnostic accuracy of cerebrospinal fluid lactate for differentiating bacterial meningitis from aseptic meningitis: a meta-analysis. J Infect 2011;62(4):255–62. [26] Levinson A. The hydrogen-ion concentration of cerebrospinal fluid: studies in meningitis. J Infect Dis 1917;21:556–70. [27] Killian JA. Lactic acid of normal and pathological spinal fluids. Proc Soc Exp Biol Med 1925;23:255–7. [28] De Sanctis AG KJA, Garcia T. Lactic acid of spinal fluid in meningitis. Am J Dis Child 1933;46:239–49. [29] Viallon A, Desseigne N, Marjollet O, et al. Meningitis in adult patients with a negative direct cerebrospinal fluid examination: value of cytochemical markers for differential diagnosis. Crit Care 2011;15(3):R136. [30] Huy NT, Thao NT, Diep DT, Kikuchi M, Zamora J, Hirayama K. Cerebrospinal fluid lactate concentration to distinguish bacterial from aseptic meningitis: a systemic review and meta-analysis. Crit Care 2010;14(6):R240.
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