RESEARCH ARTICLE

Clinical Prognosis in Neonatal Bacterial

Meningitis: The Role of Cerebrospinal Fluid
Protein
Jintong Tan1☯, Juan Kan2☯, Gang Qiu3☯, Dongying Zhao1, Fang Ren1, Zhongcheng Luo4,
Yongjun Zhang1,4*
1 Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China, 2 Ninth People’s
Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China, 3 Children's Hospital of
Shanghai, Shanghai Jiaotong University School of Medicine, Shanghai, China, 4 MOE and Shanghai Key
Laboratory of Children’s Environmental Health, Shanghai, China

☯ These authors contributed equally to this work.

* [email protected]

Abstract
Neonates are at high risk of meningitis and of resulting neurologic complications. Early rec-
ognition of neonates at risk of poor prognosis would be helpful in providing timely manage-
ment. From January 2008 to June 2014, we enrolled 232 term neonates with bacterial
meningitis admitted to 3 neonatology departments in Shanghai, China. The clinical status
OPEN ACCESS on the day of discharge from these hospitals or at a postnatal age of 2.5 to 3 months was
evaluated using the Glasgow Outcome Scale (GOS). Patients were classified into two out-
Citation: Tan J, Kan J, Qiu G, Zhao D, Ren F, Luo Z,
et al. (2015) Clinical Prognosis in Neonatal Bacterial come groups: good (167 cases, 72.0%, GOS = 5) or poor (65 cases, 28.0%, GOS = 1–4).
Meningitis: The Role of Cerebrospinal Fluid Protein. Neonates with good outcome had less frequent apnea, drowsiness, poor feeding, bulging
PLoS ONE 10(10): e0141620. doi:10.1371/journal. fontanelle, irritability and more severe jaundice compared to neonates with poor outcome.
pone.0141620
The good outcome group also had less pneumonia than the poor outcome group. Besides,
Editor: Ashlesh K Murthy, Midwestern University, there were statistically significant differences in hemoglobin, mean platelet volume, platelet
UNITED STATES
distribution width, C-reaction protein, procalcitonin, cerebrospinal fluid (CSF) glucose and
Received: July 23, 2015 CSF protein. Multivariate logistic regression analyses suggested that poor feeding, pneu-
Accepted: October 9, 2015 monia and CSF protein were the predictors of poor outcome. CSF protein content was
Published: October 28, 2015 significantly higher in patients with poor outcome. The best cut-offs for predicting poor out-
come were 1,880 mg/L in CSF protein concentration (sensitivity 70.8%, specificity 86.2%).
Copyright: © 2015 Tan et al. This is an open access
article distributed under the terms of the Creative After 2 weeks of treatment, CSF protein remained higher in the poor outcome group. High
Commons Attribution License, which permits CSF protein concentration may prognosticate poor outcome in neonates with bacterial
unrestricted use, distribution, and reproduction in any meningitis.
medium, provided the original author and source are
credited.

Data Availability Statement: All relevant data are

within the paper.

Funding: The authors have no support or funding to

report. Introduction
Competing Interests: The authors have declared Neonates are at high risk of meningitis and of resulting neurologic complications [1]. Despite
that no competing interests exist. the availability of newer and more potent antibiotics, the outcome of neonatal bacterial

PLOS ONE | DOI:10.1371/journal.pone.0141620 October 28, 2015 1/9

 Neonatal Bacterial Meningitis and CSF Protein

meningitis remains unsatisfactory. Neonatal bacterial meningitis is associated with significant

mortality and devastating neurological sequelae, including sensorineural hearing loss, seizures,
motor disorders, mental retardation and behavioral problems [2]. Signs of bacterial meningitis
are often subtle in the neonates; thus, the diagnosis of meningitis must be made by cerebrospi-
nal fluid (CSF) examination. Currently, a positive CSF culture remains the golden standard for
the diagnosis of neonatal bacterial meningitis in clinical practice. However, it may become neg-
ative within hours of antibiotic administration. Additionally, CSF culture has been shown to be
of poor sensitivity for the diagnosis of bacterial meningitis. Therefore, clinicians must also rely
on CSF glucose, white blood cell (WBC) count and protein to determine the presence of men-
ingitis [3,4].
Early recognition of neonates at risk of poor prognosis would be helpful in providing timely
management and treatment to improve outcome [5], and to identify individuals who warrant
early follow-up and intervention. Several risk factors associated with a poor clinical outcome of
bacterial meningitis in children and adults have been identified in previous studies, including
the presence of seizures, coma, hypotension, respiratory distress, hypoglycorrhachia, leukope-
nia or, thrombocytopenia, and delay in the initiation of antibiotic therapy [6–10]. However,
there is a lack of data on prognostic factors in bacterial meningitis in neonates.
The aim of the present study was to identify possible risk factors that may predict prognosis
in neonates with bacterial meningitis. Moreover, we wanted to clarify whether the CSF parame-
ters are independently associated with poor prognosis.

Methods
Patients and data
From January 2008 to June 2014, we enrolled 232 term neonates with bacterial meningitis
admitted to 3 neonatology departments in Shanghai, China, including Xinhua Hospital, Ninth
People’s Hospital and Children's Hospital of Shanghai. Neonatal bacterial meningitis was
defined as clinical symptoms and signs of meningitis plus either a positive culture in the cere-
brospinal fluid (CSF), or CSF WBC of >20×106/L in conjunction with a positive blood culture
[11,12]. Inclusion criteria were: 1) diagnosis of bacterial meningitis; 2) gestational age (GA) 
37 weeks; 3) age at diagnosis  28 days. The exclusion criteria were coexisting intrapartum
asphyxia, major congenital anomalies, genetic condition or chromosomal abnormality. The
study was approved by the Research Ethical Committees of Xinhua Hospital, Ninth People’s
Hospital and Children's Hospital of Shanghai. All parents or legal guardians of recruited
infants signed an agreement after being disclosed to necessary information on this study, and
had given written informed consent.
Outcome data were determined on the day of discharge from hospital or at a postnatal age
of 2.5 to 3 months. The clinical status was evaluated with the Glasgow Outcome Scale (GOS)
which ranges from 1 to 5: 1 = death; 2 = persistent vegetative state; 3 = severe disability;
4 = moderate disability; 5 = good recovery [13]. Moderate or severe disability was defined as
any of the following conditions: spasticity, muscle weakness and immobility in one or more
limbs; microcephaly; hydrocephalus; seizure disorder; hearing loss. For the purpose of this
analysis, patients with score 5 were defined as having good outcome while patients with score 1
to 4 were defined as having poor outcome.

Statistical analysis
All statistical analyses were performed using SPSS 16.0 (SPSS Inc., Chicago, IL, USA). Chi
square test or Fisher’s exact test was used for categorical variable comparisons. Student's t test
or Mann-Whitney test was used to compare continuous variables. Multivariate logistic

PLOS ONE | DOI:10.1371/journal.pone.0141620 October 28, 2015 2/9

 Neonatal Bacterial Meningitis and CSF Protein

regression was used to assess the predictors of poor outcome (prognosis) in neonatal meningi-
tis. The cut-off point for CSF protein to predict prognosis in neonatal bacterial meningitis was
calculated according to receiver operating characteristic (ROC). Area under the curve (AUC)
and sensitive-specific values with 95% confidence intervals were calculated. Results are pre-
sented as mean ± standard deviation or n and percentage. P values <0.05 were considered sta-
tistically significant.

Results
Clinical characteristics
Among the 232 patients with meningitis, 88 patients were male and 144 were female, all were
born at term. The mean age at onset of meningitis was 13.0 ± 7.7 days. 92 (39.7%) neonates
were born by cesarean section (CS), and 140 (60.3%) neonates were vaginal deliveries. The
mean birth weight was 3072 ± 422 g. There were 10 neonates with low birth weight (< 2500 g)
and 2 neonates with high birth weight (> 4000 g). The infection was observed in 29 (12.5%)
infants within the 3 days of life (early onset infection), including 9 (3.9%) on the first day. The
average duration of hospital stay was 28.6 ± 14.3 days (range: 1 to 93 days). The overall mortal-
ity was 3.0% (7 of 232 patients).
The predisposing factors for neonatal bacterial meningitis included maternal fever greater
than 38°C in 38 (16.4%) cases and prolonged rupture of membranes over 12 h in 45 (19.4%)
cases. In one case, the cord was cut using a pair of contaminated scissors. 30 (12.9%) cases of
vaginal colonization with group B streptococcus were noted. Furthermore, 17 cases had other
purulent infections (4 with septic arthritis, 2 with suppurative parotitis, and 11 with
omphalitis).
Bacteriological confirmation of meningitis was obtained in 232 cases. Positive cultures of
blood and cerebrospinal fluid were obtained in 95 (40.9%) cases and 169 (72.8%) cases, respec-
tively, including 32 (13.7%) cases with a positive culture in both blood and cerebrospinal fluid.
Bacteria identified as the causal agent for meningitis were: E. coli, 73 cases; Group B streptococ-
cus, 65 cases; Coagulase negative Staphylococci, 24 cases; Streptococcus pneumoniae, 18 cases;
Pseudomonas Aeruginosa, 16 cases; Corynebacterium, 12 cases; Listeria Monocytogenes, 10
cases; Haemophilus influenzae, 8 cases; Meningococcus, 2 cases; Proteusbacillus vulgaris, 2
cases; and Enterococcus feces, 2 case.

Glasgow Outcome Scale and Neurological Complications

According to the definition of GOS, patients were classified into two outcome groups: good
(167 cases, 72.0%, GOS = 5) or poor (65 cases, 28.0%, GOS = 1–4). The poor outcome group
included mortality in 7 patients, severe disability in 23 patients and moderate disability in 35
patients.
Neonatal meningitis has been associated with a variety of neurologic complications [14]. In
our study, the neurologic complications in poor outcome patients included subdural effusion
(15, 23.1%), ependymitis (17, 26.2%) and brain abscess (4, 6.2%). However there were only 8
(4.8%) cases of subdural effusion and none of ependymitis or brain abscess in good outcome
patients. It seems that patients with poor outcome had more complications than those with
good outcome. (p<0.05)

Clinical features, Blood and CSF findings

The clinical features of neonates with bacterial meningitis are summarized in Table 1. Overall,
fever excluding environmental causes (195, 84.1%) and jaundice with a bilirubin level of more

PLOS ONE | DOI:10.1371/journal.pone.0141620 October 28, 2015 3/9

 Neonatal Bacterial Meningitis and CSF Protein

Table 1. Baseline characteristics in 232 term neonates with bacterial meningitis by prognosis (poor or good outcome*) and predictor for the poor
outcome.

Good outcome* Poor outcome* P value Multivariate logistic

(n = 167) (n = 65) regression analysis

OR (95% CI) P value

Sex, male(n) 59(35.3%) 29(44.6%) 0.19
Birth weight <2500g(n) 7(4.2%) 3(4.6%) 1.00
Delivery mode, C-Section 59(35.3%) 33(50.8%) 0.03 1.84 (0.67–5.08) 0.24
(n)
Age at onset(days) 13.5(7.8) 11.7(7.3) 0.10
Hospital stay(days) 28.0(12.4) 30.3(18.2) 0.07
Clinical symptoms and Fever(n) 139(83.2%) 56(86.2%) 0.59
signs Apnea (n) 4(2.4%) 12(18.5%) <0.001 3.12(0.33– 0.32
29.72)
Drowsiness(n) 40(24.0%) 39(60.0%) <0.001 1.35(0.46–4.00) 0.58
Poor feeding(n) 40(24.0%) 47(72.3%) <0.001 3.83(1.22– 0.02
12.05)
Vomiting(n) 7(4.2%) 7(10.8%) 0.07
Jaundice(n) 73(43.7%) 18(27.7%) 0.03 0.40(0.13–1.23) 0.11
Seizures (n) 24(14.4%) 13(20.0%) 0.29
Bulging fontanelle(n) 5(3%) 8(12.3%) 0.01 1.81(0.26– 0.55
12.65)
Irritability(n) 10(6%) 18(27.7%) <0.001 1.22(0.31–4.77) 0.78
Hepatosplenomegaly(n) 8(4.8%) 4(6.2%) 0.74
Antecedent illness Sepsis(n) 74(44.3%) 21(32.3%) 0.10
Pneumonia(n) 61(36.5%) 41(63.1%) <0.001 3.37(1.15–9.84) 0.03
Impetigo neonatorum(n) 2(1.2%) 3(4.6%) 0.14
Diarrhea(n) 28(16.8%) 2(3.1%) 0.005 0.31(0.04–2.45) 0.27
Blood parameters White blood cell(×109/L) 16.7(6.5) 15.3(6.5) 0.15
Hemoglobin(g/L) 142.0(29.5) 125.3(29.2) <0.001 0.62(0.37–1.04) 0.07
Platelet(×109/L) 298.3(113.2) 274.9(159.0) 0.28
Thrombocytocrit (%) 0.47(0.19) 0.55(0.49) 0.11
Mean platelet volume(fl) 10.5(1.3) 11.5(1.5) <0.001 1.62(0.92–2.84) 0.10
Platelet distribution width(fl) 12.5(2.1) 13.4(2.2) 0.004 1.08(0.63–1.86) 0.77
C-reaction protein >8mg/L 111(66.5) 56(83.6) <0.001 1.45(0.53–3.95) 0.47
(n)
Procalcitonin0.05ug/L(n) 117(70.1%) 62(95.4%) <0.001 2.37(0.64–8.78) 0.20
CSF parameters WBCs (×106/L)
Mean ± SD 212.8(351.2) 886.0(2700.4) 0.15
<100 96(57.5%) 31(47.7%) 0.39
100*1000 60(35.9%) 28(43.1%)
>1000 11(6.6%) 6(9.2%)
CSF polykaryocyte (%) 55.6(20.5) 52.2(20.0) 0.09
CSF glucose(mmol/L) 2.3(1.1) 1.9(1.5) <0.001 0.90(0.61–1.33) 0.58
CSF protein(mg/L) 1387.0(781.6) 2549.2(1019.7) <0.001 4.07(2.33–7.11) <0.001

Data are n (%) or mean (SD)

CSF = cerebrospinal fluid; WBC = white blood cell.
*The prognosis outcome was defined by clinical status on hospital discharge or at a postnatal age about 2.5 to 3 months. Using Glasgow Outcome Scale
(GOS): 1 death, 2 persistent vegetative state, 3 severe disability, 4 moderate disability, 5 good recovery; GOS = 1–4: poor outcome, GOS = 5: good
outcome.

doi:10.1371/journal.pone.0141620.t001

PLOS ONE | DOI:10.1371/journal.pone.0141620 October 28, 2015 4/9

 Neonatal Bacterial Meningitis and CSF Protein

than 85 μmol/L (91, 39.2%) were the two leading presentations, followed by poor feeding (87,
37.5%) and drowsiness (79, 34.1%). The common antecedent illnesses were pneumonia (102,
44.0%), sepsis (95, 40.9%) and diarrhea (30, 12.9%).
Peripheral blood and CSF cyto-biochemical findings are also summarized in Table 1. WBC
varied between 2.45 and 35.98 ×109/L with a mean of 16.28×109/L, including 67 cases with a
leukocytosis more than 20.0×109/L and 2 cases with a leucopenia less than 4.0×109/L. Anemia
with a hemoglobin less than 145 g/L in 151 cases. 72.0% of cases had a C-reaction protein
(CRP) level over 8 mg/dl. Procalcitonin (PCT) was 0.05 μg / L or over in 77.2% of cases.
CSF cell count varied between 11 and 17870×106/L with a median of 80×106/L, including
105 cases with the number of cells more than 100×106/L. CSF polykaryocyte (%) > 50% was
observed in 65.9% of cases. Protein concentration varied between 438 and 4750 mg/L, with a
median of 1400 mg/L. CSF glucose <1.5 mmol/L in 25.0% of cases, and CSF glucose / blood
glucose ratio <0.5 in 62.1% of cases.
Comparison between the two groups showed there was no statistically significant difference
in the sex, age at onset, birth weight, and hospital stay between the two groups. However, neo-
nates with good outcome had less frequent apnea, drowsiness, poor feeding, bulging fontanelle,
irritability and more severe jaundice compared to neonates with poor outcome (p<0.05). The
good outcome group also had less pneumonia and more diarrhea than the poor outcome.
Besides, there were statistically significant differences in hemoglobin, mean platelet volume,
platelet distribution width, C-reaction protein, procalcitonin, CSF glucose and CSF protein.
(Table 1)

Predictor factors of poor outcome in neonatal bacterial meningitis

Multivariate logistic regression analyses were performed including variables found by univari-
ate analyses to be associated with poor outcome with p <0.05. Poor feeding (OR of 3.83, 95%
CI = 1.22–12.05, p = 0.02), pneumonia (OR of 3.37, 95% CI = 1.15–9.84, p = 0.03) and CSF pro-
tein (OR of 4.07, 95% CI = 2.33–7.11, p<0.001) were the predictors of poor outcome. (Table 1)
We next conducted ROC curve analysis to predict severity of bacterial meningitis by CSF
protein. The AUC predicting poor outcome was 0.842. The best cut-off for predicting poor out-
come was 1880 mg/L for CSF protein (sensitivity 70.8%, specificity 86.2%). (Fig 1)

Changes in CSF parameters after treatment

Despite the availability of routine effective treatment, unfortunately, 7 patients died due to the
infection within seven days of admission. The remaining patients had at least 2 weeks of antibi-
otic treatment. We compared the CSF parameters before and after 2 weeks of treatments. CSF
protein content remained higher and CSF glucose remained lower in the poor vs. the good out-
come groups (p<0.001). (Table 2)

Discussion
Newborns are especially vulnerable to infection. The cellular and humoral immune systems are
immature, including the phagocytic function. The incidence of meningitis ranges from 0.2 to
6.1 cases per 1,000 live newborns [15,16]. The clinically signs and symptoms of neonatal men-
ingitis are largely subtle. In our study, fever (84.1%), jaundice (39.2%), poor feeding (37.5%)
and drowsiness (34.1%) were the common symptoms as in previous studies of neonatal
meningitis [17,18]. However, these features could not help to establish an early diagnosis of
meningitis.
The incidence of meningitis confirmed by culture in the CSF was not high. But there is a
strong association of meningitis and sepsis with positive blood cultures [19]. Therefore, many

PLOS ONE | DOI:10.1371/journal.pone.0141620 October 28, 2015 5/9

 Neonatal Bacterial Meningitis and CSF Protein

Fig 1. Receiver operating characteristic curves for CSF protein in predicting outcomes (poor, good) in
neonates with bacterial meningitis. Sensitivity (true positive rate) is plotted against 1-specificity (false
positive rate). The area under the curve was 0.842 for the best cutoff value at 1880 (specificity = 70.8%,
sensitivity = 86.2%).
doi:10.1371/journal.pone.0141620.g001

studies defined meningitis by a positive culture from the blood and abnormal cerebrospinal
fluid parameters [2,6,20]. We used these definitions for patients' inclusion criteria in our study
as well. Moreover, coliforms and Group B streptococci are the common causal bacteria in men-
ingitis in neonates which is confirmed in our study [21,22].
Early recognition of meningitis infants at risk of poor prognosis would be helpful in provid-
ing prompt management and identifying those who warrant long-term follow-up and early
intervention [23–25]. Previous studies showed a number of possible early markers of poor

Table 2. CSF parameters in 225 term neonates with bacterial meningitis after two weeks of antibiotic
treatment*.

Variable Good outcome (n = 167) Poor outcome*(n = 58) P value

WBCs (×106/L) 14.2(19.8) 20.1(27.0) 0.90
CSF glucose(mmol/L) 3.1(0.6) 2.7(0.6) <0.001
CSF protein(mg/L) 922.7(428.3) 1582.5(686.8) <0.001

CSF = cerebrospinal fluid; WBC = white blood cell.

*The poor outcome had excluded 7 patients with Glasgow Outcome Scale (GOS) = 1

doi:10.1371/journal.pone.0141620.t002

PLOS ONE | DOI:10.1371/journal.pone.0141620 October 28, 2015 6/9

 Neonatal Bacterial Meningitis and CSF Protein

prognosis in neonatal meningitis. For example, Grimwood found that symptoms>24 h, sei-
zures after 72 h in hospital and focal neurological signs are independent risk factors of bacterial
meningitis [20]. Two retrospective studies showed that seizures, thrombocytopenia, high CSF
protein, and low CSF glucose concentration were important prognostic factors of complica-
tions in neonatal meningitis [5,26]. We found the poor outcome group had more neurological
symptoms and sequelae than the good outcome group including bulging fontanelle, irritability,
subdural effusion, ependymitis and brain abscess.
Besides, we found that the poor feeding, pneumonia and CSF protein were predictive of
poor outcome in our study. Weber et al found that reduced feeding ability may be an indepen-
dent predictor of severe disease [27]. However, it had limited specificity in distinguishing from
other severe diseases such as sepsis, meningitis, hypoxemia, or radiologically proven pneumo-
nia. Ben et al found that respiratory distress was one of the main factors of a poor prognosis in
neonatal bacterial meningitis [28]. We found that pneumonia was related to poor outcome in
neonatal meningitis.
It should be emphasized that CSF protein in the poor outcome group was extremely high in
our study. The level of cerebrospinal fluid protein content significantly influenced patient prog-
nosis. Though previous study showed that high CSF protein was associated with poor progno-
sis in childhood bacterial meningitis [29], no studies have shown the exactly level of CSF
protein is predictive of poor outcome in neonatal meningitis. However, we found that CSF pro-
tein ranged 438–4750 mg/L (median of 1400 mg/L), similar to Garges HP`s study reporting
that CSF protein in neonates with bacterial meningitis ranged 410–19640 mg/L (median: 2730
mg/L) [4]. Furthermore, we found that the best cutoff value was 1880 mg/L (specificity = 70.8%,
and specificity = 86.2%) for predicting poor prognosis in neonatal meningitis.
It has been recognized that WBCs, immunoglobulins, and complements are normally sparse
or absent in CSF. At the initial stage of neonatal meningitis, micro-organisms can cross the
blood—brain barrier via microbial interactions with host receptors, and replicate within the
subarachnoid space concomitantly. Later bacteria release endotoxins, teichoic acid, and other
substances that trigger an inflammatory response with mediators such as WBCs and TNF
resulting in increasing protein levels in CSF. Besides, the production of cytokines leads to the
attraction and activation of polymorphonuclear leukocytes and the production of high
amounts of reactive oxygen species. These free radicals are highly reactive and may cause
impairment of lipids, proteins, carbohydrates or nucleic acids, thus increasing the risk of poor
sequelae. Because of the high lipid content in the brain and low cerebral antioxidant defense,
the central nervous system is particularly susceptible to the deleterious properties of oxidative
stress [30,31]. So we speculated that the high protein in CSF was related to the intensity of the
inflammatory response. The inflammatory cascade in meningitis may result in deleterious neu-
rological morbidity. Furthermore, our study demonstrated that after 2 weeks of therapy, the
poor outcome group still had higher CSF protein levels, indicating that high CSF protein con-
tent may be of value in selecting patients for more intensive therapy and in identifying candi-
dates for new treatment strategies.
In summary, CSF protein may be a biomarker of severe CNS infection with poor prognosis
for identifying patients for timely and intensive treatment.

Author Contributions
Conceived and designed the experiments: YZ. Performed the experiments: JT JK GQ DZ. Ana-
lyzed the data: JT DZ FR. Contributed reagents/materials/analysis tools: JT JK GQ DZ. Wrote
the paper: YZ DZ ZL JT.

PLOS ONE | DOI:10.1371/journal.pone.0141620 October 28, 2015 7/9

 Neonatal Bacterial Meningitis and CSF Protein

References
1. Furyk JS, Swann O, Molyneux E. Systematic review: neonatal meningitis in the developing world. Trop
Med Int Health. 2011; 16: 672–679. doi: 10.1111/j.1365-3156.2011.02750.x PMID: 21395927
2. Gaschignard J, Levy C, Romain O, Cohen R, Bingen E, Aujard Y, et al. Neonatal Bacterial Meningitis:
444 Cases in 7 Years. Pediatr Infect Dis J. 2011; 30: 212–217. PMID: 21416693
3. Rajesh NT, Dutta S, Prasad R, Narang A. Effect of delay in analysis on neonatal cerebrospinal fluid
parameters. Arch Dis Child Fetal Neonatal Ed. 2009; 95: F25–29. doi: 10.1136/adc.2008.150292
PMID: 19671531
4. Garges HP, Moody MA, Cotten CM, Smith PB, Tiffany KF, Lenfestey R, et al. Neonatal meningitis: what
is the correlation among cerebrospinal fluid cultures, blood cultures, and cerebrospinal fluid parame-
ters? Pediatrics. 2006; 117: 1094–1100. PMID: 16585303
5. Klinger G, Chin CN, Beyene J, Perlman M. Predicting the outcome of neonatal bacterial meningitis.
Pediatrics. 2000; 106: 477–482. PMID: 10969090
6. Bargui F, D'Agostino I, Mariani-Kurkdjian P, Alberti C, Doit C, Bellier N, et al. Factors influencing neuro-
logical outcome of children with bacterial meningitis at the emergency department. Eur J Pediatr. 2012;
171: 1365–1371. doi: 10.1007/s00431-012-1733-5 PMID: 22527566
7. Auburtin M, Porcher R, Bruneel F, Scanvic A, Trouillet JL, Bédos JP, et al. Pneumococcal meningitis in
the intensive care unit: prognostic factors of clinical outcome in a series of 80 cases. Am J Respir Crit
Care Med. 2002; 165: 713–717. PMID: 11874820
8. Ostergaard C, Konradsen HB, Samuelsson S. Clinical presentation and prognostic factors of Strepto-
coccus pneumoniae meningitis according to the focus of infection. BMC Infect Dis. 2005; 5: 93. PMID:
16253143
9. de Jonge RC, van Furth AM, Wassenaar M, Gemke RJ, Terwee CB. Predicting sequelae and death
after bacterial meningitis in childhood: a systematic review of prognostic studies. BMC Infect Dis. 2010;
10: 232. doi: 10.1186/1471-2334-10-232 PMID: 20684796
10. Kastenbauer S, Pfister HW. Pneumococcal meningitis in adults: spectrum of complications and prog-
nostic factors in a series of 87 cases. Brain. 2003; 126: 1015–1025. PMID: 12690042
11. Heath PT, Nik Yusoff NK, Baker CJ. Neonatal meningitis. Arch Dis Child Fetal Neonatal Ed. 2003; 88:
F173–178. PMID: 12719388
12. Grimwood K, Nolan TM, Bond L, Anderson VA, Catroppa C, Keir EH. Risk factors for adverse outcomes
of bacterial meningitis. J Paediatr Child Health. 1996; 32: 457–462. PMID: 8933410
13. Koster-Rasmussen R, Korshin A, Meyer CN. Antibiotic treatment delay and outcome in acute bacterial
meningitis. J Infect. 2008; 57: 449–454. doi: 10.1016/j.jinf.2008.09.033 PMID: 19000639
14. Chu SM, Hsu JF, Lee CW, Lien R, Huang HR, Chiang MC, et al. Neurological complications after neo-
natal bacteremia: the clinical characteristics, risk factors, and outcomes. PLoS One. 2014; 9: e105294.
doi: 10.1371/journal.pone.0105294 PMID: 25364821
15. Thaver D, Zaidi AK. Burden of neonatal infections in developing countries: a review of evidence from
community-based studies. Pediatr Infect Dis J. 2009; 28: S3–9. doi: 10.1097/INF.0b013e3181958755
PMID: 19106760
16. Okike IO, Johnson AP, Henderson KL, Blackburn RM, Muller-Pebody B, Ladhani SN, et al. Incidence,
etiology, and outcome of bacterial meningitis in infants aged <90 days in the United kingdom and
Republic of Ireland: prospective, enhanced, national population-based surveillance. Clin Infect Dis.
2014; 59: e150–157. doi: 10.1093/cid/ciu514 PMID: 24997051
17. Palazzi DL, Klein JO, Baker CJ. Chapter 6—Bacterial Sepsis and Meningitis. In: Baker JSROKBWJ,
editor. Infectious Diseases of the Fetus and Newborn Infant ( Sixth Edition). Philadelphia: W.B. Saun-
ders. 2006; p.247–295.
18. Krebs VL, Costa GA. Clinical outcome of neonatal bacterial meningitis according to birth weight. Arq
Neuropsiquiatr. 2007; 65: 1149–1153. PMID: 18345420
19. Bentlin MR, Ferreira GL, Rugolo LM, Silva GH, Mondelli AL, Rugolo Júnior A. Neonatal meningitis
according to the microbiological diagnosis: a decade of experience in a tertiary center. Arq Neuropsi-
quiatr. 2010; 68: 882–887. PMID: 21243246
20. Molyneux E, Nizami SQ, Saha S, Huu KT, Azam M, Bhutta ZA, et al. 5 versus 10 days of treatment with
ceftriaxone for bacterial meningitis in children: a double-blind randomised equivalence study. Lancet.
2011; 377: 1837–1845. doi: 10.1016/S0140-6736(11)60580-1 PMID: 21620467
21. Chang CJ, Chang WN, Huang LT, Huang SC, Chang YC, Hung PL, et al. Neonatal bacterial meningitis
in southern Taiwan. Pediatr Neurol. 2003; 29: 288–294. PMID: 14643389
22. Paap CM, Bosso JA. Treatment options for the pharmacological therapy of neonatal meningitis. Drugs.
1992; 43: 700–712. PMID: 1379148

PLOS ONE | DOI:10.1371/journal.pone.0141620 October 28, 2015 8/9

 Neonatal Bacterial Meningitis and CSF Protein

23. Stevens JP, Eames M, Kent A, Halket S, Holt D, Harvey D. Long term outcome of neonatal meningitis.
Arch Dis Child Fetal Neonatal Ed. 2003; 88: F179–184. PMID: 12719389
24. de Louvois J, Halket S, Harvey D. Neonatal meningitis in England and Wales: sequelae at 5 years of
age. Eur J Pediatr. 2005; 164: 730–734. PMID: 16136294
25. Tarvij Eslami S, Nassirian H, Mojgan BM, Bahieh ZZ, Elham H, Alimohamad N, et al. Comparison of
cerebrospinal fluid in newborns and in infants </ = 2 months old with or without meningitis. Pediatr Int.
2012; 54: 336–340. doi: 10.1111/j.1442-200X.2011.03551.x PMID: 22192569
26. Anderson SG, Gilbert GL. Neonatal gram negative meningitis: a 10-year review, with reference to out-
come and relapse of infection. J Paediatr Child Health. 1990; 26: 212–216. PMID: 2257183
27. Weber MW, Carlin JB, Gatchalian S, Lehmann D, Muhe L, Mulholland EK, et al. Predictors of neonatal
sepsis in developing countries. Pediatr Infect Dis J. 2003; 22: 711–717. PMID: 12913772
28. Ben Hamouda H, Ben Haj khalifa A, Hamza MA, Ayadi A, Soua H, Khedher M, et al. Clinical outcome
and prognosis of neonatal bacterial meningitis. Arch Pediatr. 2013; 20: 938–944. PMID: 23829970
29. Lin MC, Chi H, Chiu NC, Huang FY, Ho CS. Factors for poor prognosis of neonatal bacterial meningitis
in a medical center in Northern Taiwan. J Microbiol Immunol Infect. 2012; 45: 442–447. doi: 10.1016/j.
jmii.2011.12.034 PMID: 22571998
30. Barichello T, Fagundes GD, Generoso JS, Elias SG, Simoes LR, Teixeira AL. Pathophysiology of neo-
natal acute bacterial meningitis. J Med Microbiol. 2013; 62: 1781–1789. doi: 10.1099/jmm.0.059840-0
PMID: 23946474
31. Kim KS. Acute bacterial meningitis in infants and children. Lancet Infect Dis. 2010; 10: 32–42. doi: 10.
1016/S1473-3099(09)70306-8 PMID: 20129147

PLOS ONE | DOI:10.1371/journal.pone.0141620 October 28, 2015 9/9