Journal of Clinical Neuroscience xxx (2016) xxx–xxx

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Journal of Clinical Neuroscience

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

Opinion paper

Procalcitonin as a potential predicting factor for prognosis in bacterial

meningitis
Bong Soo Park a,1, Si Eun Kim b,1, Si Hyung Park a, Jinseung Kim c, Kyong Jin Shin b, Sam Yeol Ha b,
JinSe Park b, Sung Eun Kim b, Byung In Lee b, Kang Min Park b,⇑
a
Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea
b
Department of Neurology, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea
c
Department of Family Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea

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

Article history: We investigated the potential role of serum procalcitonin in differentiating bacterial meningitis from
Received 27 July 2016 viral meningitis, and in predicting the prognosis in patients with bacterial meningitis. This was a retro-
Accepted 3 October 2016 spective study of 80 patients with bacterial meningitis (13 patients died). In addition, 58 patients with
Available online xxxx
viral meningitis were included as the disease control groups for comparison. The serum procalcitonin
level was measured in all patients at admission. Differences in demographic and laboratory data, includ-
Keywords: ing the procalcitonin level, were analyzed between the groups. We used the mortality rate during hospi-
Bacteria
talization as a marker of prognosis in patients with bacterial meningitis. Multiple logistic regression
Virus
Procalcitonin
analysis showed that high serum levels of procalcitonin (>0.12 ng/mL) were an independently significant
Death variable for differentiating bacterial meningitis from viral meningitis. The risk of having bacterial menin-
gitis with high serum levels of procalcitonin was at least 6 times higher than the risk of having viral
meningitis (OR = 6.76, 95% CI: 1.84–24.90, p = 0.004). In addition, we found that high levels of procalci-
tonin (>7.26 ng/mL) in the blood were an independently significant predictor for death in patients with
bacterial meningitis. The risk of death in patients with bacterial meningitis with high serum levels of pro-
calcitonin may be at least 9 times higher than those without death (OR = 9.09, 95% CI: 1.74–47.12,
p = 0.016). We found that serum procalcitonin is a useful marker for differentiating bacterial meningitis
from viral meningitis, and it is also a potential predicting factor for prognosis in patients with bacterial
meningitis.
Ó 2016 Elsevier Ltd. All rights reserved.

1. Introduction Procalcitonin (PCT) is a precursor of calcitonin consisting of 116

Bacterial meningitis has high morbidity and mortality world-
wide, with 1.2 million cases per year, resulting in 135,000 deaths
[1]. The mortality rate of acute bacterial meningitis and the fre-
quency of neurologic sequelae are especially high when the diag-
nosis and antibiotic administration are delayed [2,3]. The
previous studies have demonstrated that patients with a low Glas-
gow Coma Scale (GCS) at the initiation of antibiotic therapy, low
thrombocyte counts, old age, pneumonia, heart failure and seizures
after therapy have a high mortality rate in acute bacterial menin-
gitis [4,5].
⇑ Corresponding author at: Department of Neurology, Haeundae Paik Hospital,
Inje University College of Medicine, Haeundae-ro 875, Haeundae-gu, Busan 612-
896, Republic of Korea. Fax: +82 51 797 1196.
E-mail address: smilepkm@hanmail.net (K.M. Park).
1
These two authors have contributed equally to this work.
amino acids [6]. PCT is usually secreted by the thyroid gland, and
trace amounts of PCT can be measured in the blood in healthy sub-
jects [6]. However, expression of the CALC1 gene, which makes
PCT, is rapidly increased by the stimulation of inflammatory
cytokines in an infectious condition [6]. In the infectious condition,
the PCT is largely secreted from the thyroid gland as well as the
spleen, liver and kidney, and it is rapidly secreted into the blood
[7,8]. There is much evidence that the serum PCT is a useful bio-
marker distinguishing a bacterial infection from a viral infection
[9–13]. A previous study has demonstrated that the serum PCT
assay is a highly accurate and powerful test for rapidly differenti-
ating between bacterial and viral meningitis in children [12,13].
The serum PCT also differentiates between bacterial infections
and viral infections more effectively than the C-reactive protein
(CRP) in children with lower respiratory tract infections [10]. In
addition, the serum PCT could predict the severity of the disease
and the prognosis in patients with pneumonia [9]. Moreover, the

http://dx.doi.org/10.1016/j.jocn.2016.10.005
0967-5868/Ó 2016 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Park BS et al. Procalcitonin as a potential predicting factor for prognosis in bacterial meningitis. J Clin Neurosci (2016),
http://dx.doi.org/10.1016/j.jocn.2016.10.005
2 B.S. Park et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
serum PCT levels are increased significantly in children with febrile
urinary tract infections when renal parenchymal involvement is
present, and allowed for the prediction of patients at risk of severe
renal lesions [14]. These findings suggest that the serum PCT is
very useful for clinical practice in various infectious diseases. How-
ever, to our knowledge, no comprehensive study to assess the
potential role of serum PCT predicting the prognosis in adult
patients with bacterial meningitis has been available until now.
Therefore, we investigated the potential role of serum PCT in
differentiating bacterial meningitis from viral meningitis, and in
predicting the prognosis in patients with bacterial meningitis.
2. Methods
2.1. Participants
This study was approved by the Institutional Review Board at
our institution. This was a retrospective study of patients with a
clinical suspicion of bacterial meningitis admitted to the Neurology
Departments of two tertiary hospitals in Busan, Korea from January
2009 to May 2016. All patients had typical clinical histories and
laboratory findings of bacterial meningitis. In addition, all patients
admitted to centers with a clinical suspicion of viral meningitis
during the same period were included as the disease control group
for comparisons.
The inclusion criteria of the patients with bacterial meningitis
were having (1) clinical features, such as a headache, fever, and
signs of meningeal irritation; (2) positive cerebrospinal fluid (CSF)
findings, including pleocytosis (P5 mm3, mainly neutrophilic), ele-
vated protein concentrations (P45 mg/dL), and a reduced ratio of
CSF glucose to serum glucose (60.60); (3) a negative CSF stain, cul-
ture, or polymerase chain reaction (PCR) for viruses, mycobacteria,
and fungi; and (4) a positive CSF culture, smear, or PCR for bacterial
pathogens or a good specific response to anti-bacterial therapy [15].
We defined viral meningitis based on a combination of the clinical
history and laboratory findings. These included (1) clinical features,
such as the acute onset of headache, fever, and signs of meningeal
irritation; (2) positive CSF findings, including pleocytosis
(P5 mm3, mainly lymphocytic), normal or slightly elevated protein
concentrations (P45 mg/dL), normal ratio of CSF glucose to serum
glucose (60.60); and (3) a negative CSF stain, culture, or PCR for
bacteria, mycobacteria, and fungi [15]. We excluded patients who
did not have an assessment of their blood procalcitonin levels.
A total of 80 patients with bacterial meningitis met the inclu-
sion criteria for this study. In addition, we included 58 patients
with viral meningitis as disease control groups. Of the 80 patients
with bacterial meningitis, 13 patients expired during hospitaliza-
tion. Of the 80 patients with bacterial meningitis, 47 had a positive
CSF culture, smear, or PCR for bacterial pathogens, comprising 24
with Streptococcus species, 8 with Staphylococcus species, 6 with
Klebsiella species, 5 with Listeria species, and 4 with other species.
Of the 58 patients with viral meningitis, 25 with viral pathogens
were identified using PCR of the CSF, comprising 16 with entero-
virus, 5 with herpes simplex virus, 3 with herpes zoster virus,
and 1 with Epstein-Barr virus.
2.2. Measurements
Initially, we analyzed the diagnostic value of serum PCT in dis-
tinguishing bacterial meningitis from viral meningitis. In addition,
we investigated the potential value of serum PCT in predicting the
prognosis in patients with bacterial meningitis. We used the mor-
tality rate during hospitalization as a Smarker of prognosis in
patients with bacterial meningitis. Thus, we divided the patients
with bacterial meningitis into two groups: with and without death.
Please cite this article in press as: Park BS et al. Procalcitonin as a potential predicting factor for prognosis in bacterial meningitis. J Clin Neurosci (2016),
http://dx.doi.org/10.1016/j.jocn.2016.10.005
The differences between the groups were analyzed using demo-
graphic profiles including sex, age, and diabetes mellitus (DM),
blood profiles including white blood cells (WBCs), platelet, CRP,
and PCT, CSF profiles including WBCs, protein, and glucose ratio
(CSF/blood), and clinical profiles including systolic and diastolic
blood pressure, heart rate, the GCS at the time of admission, and
death as independent variables. We analyzed the blood, CSF, and
clinical profiles that were obtained on the day of admission. The
serum PCT concentrations were measured using an electrical
chemiluminescence assay (cobas e 411, Roche Diagnostics, Indi-
anapolis, IN, USA), and the measuring range was 0.05–200 ng/mL.
2.3. Statistical analysis
Comparisons were analyzed using Chi-square test or Fisher’s
exact test for categorical variables and Student’s t-test or Mann–
Whitney U-test for numerical variables. Categorical variables were
presented as the frequency and percentage. Numerical variables
with normal distribution were presented as the mean ± standard
deviation (SD), and those without normal distribution were
described as the median with range. In addition, separate bivariate
logistic regression models for each tool were used to determine the
odds ratio in predicting bacterial meningitis and death. To perform
multivariate analyses and evaluate the sensitivity and specificity
for predicting bacterial meningitis and death, we analyzed the
clear cutoff values with the Receiver Operating Characteristic curve
(ROC). Continuous variables were converted into categorical vari-
ables by dichotomizing them in accordance with the clear cutoff
values in the logistic regression analysis. The statistically signifi-
cant p-value was set to <0.05. All statistical tests were performed
using MedCalcÒ (MedCalc Software version 13, Ostend, Belgium).
3. Results
3.1. Differences in measurements between patients with bacterial and
viral meningitis
Table 1 shows a comparison of the demographic and laboratory
profiles between the patients with bacterial and viral meningitis.
The demographic profiles including age and DM; the blood profiles
including WBCs, platelet, CRP, and PCT; the CSF profiles including
WBCs, protein, and glucose ratio; and the clinical profiles including
GCS and death were significantly different between the patients
with bacterial and viral meningitis. The best cut-offs for predicting
bacterial meningitis were 39 years in age, 12,310  106/L in WBCs
of blood, 0.12 ng/mL in PCT, 800/mm3 in WBCs of CSF, and 15 in
GCS, respectively. Multiple logistic regression analysis showed that
old age, high levels of WBCs and PCT in the blood, high levels of
WBCs in the CSF, and low levels of GCS were independently signif-
icant variables for predicting bacterial meningitis (Table 2). The
risk of having bacterial meningitis with high serum levels of PCT
(>0.12 ng/mL) was at least 6 times higher than the risk of having
viral meningitis (OR = 6.76, 95% CI: 1.84–24.90, p = 0.004). The sen-
sitivity, specificity, positive likelihood ratio, negative likelihood
ratio, positive predictive values, and negative predictive values of
PCT for predicting bacterial meningitis were 88.75%, 74.14%, 3.43,
0.15, 82.56%, and 82.69%, respectively.
3.2. Differences in measurements between bacterial meningitis
patients with and without death
Of the 80 patients with bacterial meningitis, 13 patients died
during hospitalization. The demographic profiles, including age
and DM, the blood profile including PCT, and the clinical profiles
including GCS, were significantly different between the patients
 B.S. Park et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx 3

Table 1
Comparison of demographic and laboratory profiles between patients with bacterial and viral meningitis.

Parameter Bacterial meningitis (n = 80) Viral meningitis (n = 58) p

Demographic profile
Men, n (%) 49 (61.3) 30 (51.7) 0.266
a
Age, years 66 (16–91) 37 (15–81) <0.001*
Diabetes mellitus, n (%) 18 (22.5) 3 (5.2) 0.005*
Blood profile
a
WBCs, 106/L 14,015 (1,930–37,030) 7,370 (1,760–11,560) <0.001*
a
Platelets, 109/L 172 (13–315,000) 213 (77–359,000) 0.013*
a
CRP, mg/dL 10.87 (0.16–40.00) 1.04 (0.03–93.00) <0.001*
a
Procalcitonin, ng/mL 2.98 (0.05–100.00) 0.05 (0.05–5.99) <0.001*
CSF profile
a
WBCs, /mm3 935 (5–14,400) 80 (5–2,280) <0.001*
a
Protein, mg/dL 191.1 (25.0–1073.4) 69.9 (16.7–294.2) <0.001*
a
Glucose ratio (CSF/blood) 0.33 (0.00–0.77) 0.56 (0.19–0.92) <0.001*
Clinical profile
a
Systolic blood pressure, mmHg 120 (80–192) 120 (70–170) 0.524
b
Diastolic blood pressure, mmHg 75 ± 14 74 ± 10 0.884
a
Heart rate, /minute 86 (57–148) 85 (57–127) 0.275
a
GCS at admission 12 (3–15) 15 (7–15) <0.001*
Death, n (%) 13 (16.3) 0 (0) <0.001*
a
Median (interquartile range).
b
mean ± standard deviation.
*
p < 0.05.
WBCs = white blood cells, CRP = C-reactive protein, CSF = cerebrospinal fluid, GCS = the Glasgow Coma Scale.

Table 2
Results of the multivariate analysis of variables for distinguishing bacterial meningitis
from viral meningitis.
Table 4
Independent variable Adjusted 95% Confidence p Results of the multivariate analysis of variables that are predictive of death in patients
odds ratio interval with bacterial meningitis.

Age (>39 years) 5.64 1.27–25.13 0.023* Independent variable Adjusted 95% Confidence p
a
WBCs (>12,310  106/L) 2.69 0.62–11.56 0.185 odds ratio interval
Procalcitonin (>0.12 ng/mL) 6.76 1.84–24.90 0.004*
b
WBCs (>800/mm3) 10.90 1.96–60.64 0.006* Age (>71 years) 6.49 1.28–33.01 0.024*
GCS at admission (<15) 5.75 1.48–22.38 0.012* Diabetes mellitus 5.77 1.23–26.97 0.026*
Procalcitonin (>7.26 ng/mL) 9.09 1.74–47.12 0.016*
a
Blood. GCS at admission (<9) 3.56 0.82–15.53 0.091
b
CSF. *
*
p < 0.05. p < 0.05.
WBCs = white blood cells, GCS = the Glasgow Coma Scale. GCS = the Glasgow Coma Scale.

Table 3
Comparison of demographic and laboratory profiles between bacterial meningitis patients with and without death.

Parameter With death (n = 13) Without death (n = 67) p

Demographic profile
Men, n (%) 8 (61.5) 41 (61.2) 0.982
a
Age, years 73 (43–85) 64 (16–91) 0.041*
Diabetes mellitus, n (%) 6 (46.2) 12 (17.9) 0.027*
Blood profile
b
WBCs,106/L 12,879 ± 7,867 15,872 ± 8,561 0.247
a
Platelets,109/L 118 (71–315,000) 182 (13–149,000) 0.243
a
CRP, mg/dL 15.35 (1.26–33.09) 10.09 (0.16–40.00) 0.179
b
Procalcitonin, ng/mL 9.66 (0.25–84.13) 2.33 (0.05–100.00) 0.026*
CSF profile
a
WBCs, /mm3 1070 (8–12800) 910 (5–14400) 0.974
a
Protein, mg/dL 250.7 (25.0–596.1) 184.3 (44.8–1073.4) 0.700
a
Glucose ratio (CSF/blood) 0.32 (0.00–0.65) 0.33 (0.00–0.77) 0.953
Clinical profile
a
Systolic blood pressure, mmHg 120 (90–150) 120 (80–192) 0.419
b
Diastolic blood pressure, mmHg 72 ± 14 75 ± 14 0.359
a
Heart rate, /minute 97 (73–132) 85 (57–148) 0.331
b
GCS at admission 8.5 ± 4.2 11.3 ± 3.2 0.006*
Steroid treatment, n (%) 5 (38.5) 24 (35.8) 0.917
a
Median (interquartile range).
b
Mean ± standard deviation.
*
p < 0.05.
WBCs = white blood cells, CRP = C-reactive protein, CSF = cerebrospinal fluid, GCS = the Glasgow Coma Scale.

Please cite this article in press as: Park BS et al. Procalcitonin as a potential predicting factor for prognosis in bacterial meningitis. J Clin Neurosci (2016),
http://dx.doi.org/10.1016/j.jocn.2016.10.005
4 B.S. Park et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
with and without death (Table 3). The best cut-offs for predicting
bacterial meningitis with death were 71 years in age, 7.26 ng/mL
in PCT, and 9 in GCS, respectively. Multiple logistic regression anal-
ysis showed that old age, DM, and high levels of PCT in the blood
were independent and significant predictors for a death in patients
with bacterial meningitis (Table 4). The risk of having a death in
patients with bacterial meningitis with high serum levels of PCT
(>7.26 ng/mL) may be at least 9 times higher than those without
death (OR = 9.09, 95% CI: 1.74–47.12, p = 0.016). The sensitivity,
specificity, positive likelihood ratio, negative likelihood ratio, pos-
itive predictive values, and negative predictive values of PCT for
predicting bacterial meningitis with death were 69.23%, 71.64%,
2.44, 0.43, 32.14%, and 92.13%, respectively.
4. Discussion
In the present study, we confirmed the findings of previous
reports that the serum PCT is a useful biomarker in differentiating
bacterial meningitis from viral meningitis [12,13]. We demon-
strated that high serum levels of procalcitonin (>0.12 ng/mL) were
an independently significant variable for differentiating bacterial
meningitis from viral meningitis. In addition, we newly found that
the serum PCT plays a potential role in predicting the prognosis of
bacterial meningitis. We demonstrated that high serum levels of
PCT (>7.26 ng/mL) were a significant predictor for death in patients
with bacterial meningitis. To our knowledge, only one previous
study demonstrated the potential role of the serum PCT in predict-
ing the prognosis of bacterial meningitis. Hu et al. investigated the
relationship between the serum PCT and the prognosis in child
patients with bacterial meningitis, and revealed that the serum
PCT was related to the severity of disease in these patients [16].
The results were consistent with our findings. However, the present
study was the first study to assess the potential role of serum PCT in
predicting the prognosis in adult patients with bacterial meningitis.
Although the serum PCT can rarely increase with non-infectious
conditions, such as severe trauma, surgery, burns, and cardiogenic
shock [21,22], many previous studies have reported that the serum
PCT has a high specificity (ranging from 90% to 98%) for bacterial
infections and is suitable for the discrimination of bacterial infec-
tion with viral disease, as well as non-infectious febrile disease
[17,18]. Several laboratory studies discovered the basis to explain
the reason why the serum PCT was high in patients with bacterial
meningitis and especially in poor prognoses. One microbiological
study showed that the higher the serum PCT, the shorter the time
to positivity of blood culture, which is defined as the time from the
start of incubation of bacteria to the start of the alert signal [19].
The time to blood culture positivity highly depends on the amount
of systemic bacterial loads. Therefore, this study suggested that the
level of serum PCT could reflect the amount of systemic bacterial
loads, and the co-relations between the serum PCT and the time
to blood culture positivity supported that PCT may serve as a pre-
dictive biomarker for the degree and severity of the bacterial infec-
tion. In addition, another study revealed that the plasma level of
endotoxin, reflects the amount of bacterial loads, was well corre-
lated with the serum PCT [20]. The endotoxemia is a well-known
predictor for a high risk of mortality, and septic shock occurs more
frequently among patients with both endotoxemia and bacteremia,
compared with those with bacteremia only [21]. These findings
were consistent with the clinical studies that the serum PCT was
correlated with the severity and course of the disease in patients
with sepsis, pneumonia, and urinary tract infection [22,23].
Besides, the serum PCT levels during treatment are also helpful
to assess treatment response and failure. There are many studies
stating that the proper clinical application of the serum PCT levels
might decrease the unnecessary use of antibiotics and side effects,
Please cite this article in press as: Park BS et al. Procalcitonin as a potential predicting factor for prognosis in bacterial meningitis. J Clin Neurosci (2016),
http://dx.doi.org/10.1016/j.jocn.2016.10.005
such antibiotic resistance [12,13,24]. These results also applied to
the patients with bacterial meningitis. These properties distinguish
bacterial meningitis from viral meningitis, and explain what seems
to be a poor prognosis in patients with high levels of serum PCT.
The PCT has several advantages compared with the CRP [6]. The
range of serum PCT level is broader than that of CRP. Therefore, PCT
can more accurately reflect the severity of infection and systemic
inflammation, especially during severe bacterial infections.
Another advantage of PCT is related to its rapid kinetics. In a previ-
ous experimental study, after the injection of extracted endotoxin
from Escherichia coli, the serum PCT level rapidly started increasing
in 2–4 h, reached a peak in 6–12 h, and maintained a blood concen-
tration in 12–24 h. On the other hand, the CRP level started
increasing after 12 h and reached its peak after 30 h. Because the
concentration of serum PCT increases faster than that of CRP in
the systemic inflammatory response to bacterial infection, PCT
has the merit of facilitating the early diagnosis of infection [24].
In addition, CRP is neither highly specific nor sensitive for bacterial
infections, because it can remain present at low concentrations in
bacterial infections, and can be significantly increased in viral
infections [6]. Moreover, our study demonstrated that the serum
PCT was more useful for predicting the prognosis of bacterial
meningitis than the serum CRP.
There were several limitations in this study. First of all, this is a
retrospective study with a relatively small sample size. Because we
enrolled only the patients who had their blood levels of PCT
assessed at admission, we have a small sample size, especially in
patients with viral meningitis. Second, initial elevated PCT level
might be related to the lead-time bias because of the differences
of symptoms to visit time. Third, we did not confirm the long-
term prognosis, but analyzed the prognosis at the time of dis-
charge. We only used the primary outcome as death during hospi-
talization as a marker of prognosis in patients with bacterial
meningitis. Despite these limitations, this is the first study to
investigate the potential role of the serum PCT in predicting the
prognosis of adult bacterial meningitis. Further prospective studies
with a large sample size may be needed to confirm our findings.
5. Conclusions
We found that serum procalcitonin is a useful marker for differ-
entiating bacterial meningitis from viral meningitis, and it is also a
potential predicting factor for prognosis in patients with bacterial
meningitis.
Conflicts of interest/disclosures
The authors declare that they have no financial or other con-
flicts of interest in relation to this research and its publication.
Acknowledgements
None.
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