RESEARCH PAPER

Human Vaccines & Immunotherapeutics 10:9, 2706--2712; September 2014; 2014 Taylor & Francis Group, LLC

Meningitis caused by Neisseria Meningitidis,

Hemophilus Inuenzae Type B and Streptococcus
Pneumoniae during 20052012 in Turkey
A multicenter prospective surveillance study
Mehmet Ceyhan1,y, Nezahat G urler2,y, Yasemin Ozsurekci1,y,*, Melike Keser3,y, Ahmet Emre Aycan1,y, Venhar Gurbuz1,y,
Nuran Salman , Yildiz Camcioglu5,y, Ener Cagri Dinleyici6,y, Sengul Ozkan7,y, Gulnar Sensoy8, Nursen Belet8,y, Emre Alhan9,
4,y

Mustafa Hacimustafaoglu10,y, Solmaz Celebi10,y, Hakan Uzun11,y, Ahmet Faik Oner12,y, Zafer Kurugol13,y, Mehmet Ali Tas14,y,
Denizmen Aygun15,y, Eda Karadag Oncel1,y, Melda Celik1,y, Olcay Yasa16,y, Fatih Akin17,y, and Yavuz Coskun18,y
1
Department of Pediatric Infectious Diseases; Hacettepe University Faculty of Medicine; Ankara, Turkey; 2Department of Microbiology and Clinical Microbiology; Istanbul Univer-
sity Faculty of Medicine; Istanbul, Turkey; 3Department of Pediatrics; Selcuk University Meram Faculty of Medicine; Konya, Turkey; 4Department of Pediatrics; Istanbul University
Faculty of Medicine; Istanbul, Turkey; 5Department of Pediatrics; Istanbul University; Cerrahpasa Faculty of Medicine; Istanbul, Turkey; 6Department of Pediatrics; Osmangazi Uni-
versity Faculty of Medicine; Eskisehir, Turkey; 7Microbiology Laboratory; Dr. Sami Ulus Childrens Health and Diseases Training and Research Hospital; Ankara, Turkey; 8Department
of Pediatric Infectious Diseases; Ondokuz Mayis University Faculty of Medicine; Samsun, Turkey; 9Department of Pediatrics, Cukurova University Faculty of Medicine; Adana,
Turkey; 10Department of Pediatric Infectious Diseases; Uludag University Faculty of Medicine; Bursa, Turkey; 11Department of Pediatrics; Duzce University Faculty of Medicine;
Duzce, Turkey; 12Department of Pediatrics; Yuzuncu Yil University Faculty of Medicine; Van, Turkeya; 13Department of Pediatric Infectious Diseases; Ege University Faculty of
Medicine; Izmir, Turkey; 14Department of Pediatrics; Dicle University Faculty of Medicine; Diyarbakir, Turkey; 15Department of Pediatrics; Firat University Faculty of Medicine; Elazig,
Turkey; 16Goztepe Research and Training Hospital; Department of Pediatrics; Istanbul, Turkey; 17Department of Pediatrics; Konya Training and Research Hospital; Konya, Turkey;
18
Gaziantep University; Faculty of Medicine; Department of Pediatrics; Gaziantep, Turkey

y
Turkish Meningitis Surveillance Team

Keywords: Meningitis, Turkey, etiologic agents, N. meningitidis, S. pneumoniae, Hib, epidemiology, surveillance

Successful vaccination policies for protection from bacterial meningitis are dependent on determination of the
etiology of bacterial meningitis. Cerebrospinal uid (CSF) samples were obtained prospectively from children from 1
month to
18 years of age hospitalized with suspected meningitis, in order to determine the etiology of meningitis in
Turkey. DNA evidence of Neisseria meningitidis (N. meningitidis), Streptococcus pneumoniae (S. pneumoniae), and
Hemophilus inuenzae type b (Hib) was detected using multiplex polymerase chain reaction (PCR). In total, 1452 CSF
samples were evaluated and bacterial etiology was determined in 645 (44.4%) cases between 2005 and 2012; N.
meningitidis was detected in 333 (51.6%), S. pneumoniae in 195 (30.2%), and Hib in 117 (18.1%) of the PCR positive
samples. Of the 333 N. meningitidis positive samples 127 (38.1%) were identied as serogroup W-135, 87 (26.1%)
serogroup B, 28 (8.4%) serogroup A and 3 (0.9%) serogroup Y; 88 (26.4%) were non-groupable. As vaccines against the
most frequent bacterial isolates in this study are available and licensed, these results highlight the need for broad
based protection against meningococcal disease in Turkey.

Introduction fer permanent sequel, including epilepsy, mental retardation, or

Acute bacterial meningitis is one of the most severe infectious
diseases, not only causing physical and neurologic sequelae, but
also continues to be an important cause of mortality.1,2 Although
most disease occurs in infants and young children, high incidence
may be observed in healthy older children and adolescents.
Despite the continuing development of new antibacterial agents,
bacterial meningitis fatality rates remain high, with reported rates
between 2% and 30%.3,4 Furthermore, 1020% of survivors suf-
sensorineural deafness.5-7
In infants and children, before the introduction of modern
vaccines, 90% of reported cases of acute bacterial meningitis
were caused by Hemophilus influenzae type b (Hib), Streptococcus
pneumoniae (S. pneumoniae), or Neisseria meningitidis (N. menin-
gitidis).8,9 Hib meningitis primarily affects very young children,
most cases occurring in children from 1 mo to 3 y of age.3,9 The
introduction of highly effective Hib polysaccharide-protein con-
jugate vaccines has virtually eliminated invasive Hib disease in

*Correspondence to: Yasemin Ozsurekci; Email: yas.oguz99@yahoo.com

Submitted: 02/20/2014; Revised: 06/10/2014; Accepted: 06/21/2014
http://dx.doi.org/10.4161/hv.29678

2706 Human Vaccines & Immunotherapeutics Volume 10 Issue 9

most industrialized countries where routine Hib vaccination has
been implemented.8,9
In most countries, S. pneumoniae was the next major cause of
childhood bacterial meningitis, particularly in those where Hib
disease has been eliminated by vaccination.10 In some European
and sub-Saharan African countries, it is the second most fre-
quently reported cause of septic meningitis after meningococcal
cases.4,10 The ongoing development and introduction into rou-
tine immunization schedules of glycoconjugate pneumococcal
vaccines has markedly reduced the incidence of disease caused
by vaccine serotypes, initially against the seven serotypes in the
first vaccine, and now with coverage increasing from 10 or 13
serotypes in recent years.
The success of these vaccines means N. meningitidis is now
considered to be the leading cause of bacterial meningitis in
many regions of the world, causing an estimated 1.2 million cases
of bacterial meningitis and sepsis worldwide each year.11,12 There
are 12 recognized serogroups of N.meningitidis, but the vast
majority of invasive disease is related to six meningococcal
serogroups: (Men) A, B, C, W-135, X and Y.13-15 The epidemi-
ology and distribution of these disease-causing serogroups varies
widely by geographic region: so while Men A is the most pre-
dominant disease-causing serogroup in sub-Saharan Africa and
remains an important factor in parts of Asia, it now seldom if
ever occurs in Western Europe or North America, where cases of
Men A used to occur. In contrast, Men B and Men C dominate
in the industrialized countries of North and South America,15,16
while the introduction of routine childhood vaccination with
monovalent meningococcal serogroup C conjugate vaccines into
Europe and Australia has markedly decreased incidence there.
Serogroup W-135 has recently emerged in some parts of the
world, primarily in the Middle East and Africa, in some instances
causing large epidemics, and has been associated with small out-
breaks in Europe due to pilgrims returning from Hajj.17 Men Y
has been increasing in relative incidence over recent years in
North America, South America and South Africa, and most
recently, cases of Men X disease have emerged in sub-Saharan
Africa. Men ACWY conjugate vaccines have been available for
years but are not widely used. On the other hand, MenC conju-
gate vaccine has been widely used in Europe and MenA conjugate
vaccine in sub-Saharan Africa through mass vaccination cam-
paign and that their impact (MenA and MenC) has been dra-
matic in reducing meningitis due to the respective
serotypes.15,17-19 Since 2002, in accordance with the Saudi Ara-
bian requirements, all Turkish pilgrims to the Hajj in Mecca
have received a quadrivalent meningococcal polysaccharide vac-
cine before travel. However, MenB and MenACWY conjugate
vaccines are not yet routinely recommended for infants in
Turkey. Hib vaccine was included in the Turkish immunization
schedule and was administered as a separate injection in 2006 as
DPTCOPVCHib. DTaP-IPV/Hib combined vaccine replaced
them in 2008. The seven-valent pneumococcal conjugate vaccine
(PCV-7) has been implemented into the Turkish national immu-
nization schedule at ages 2, 4, 6, and 12 mo of age in 2008. This
was replaced with the 13-valent vaccine (PCV-13) in
2011.
www.landesbioscience.com Human Vaccines & Immunotherapeutics
As knowledge of the local epidemiology is necessary to sup-
port policymakers decision on the most appropriate vaccine to be
used against bacterial meningitis, since 2005 we have been per-
forming a nationwide hospital-based meningitis surveillance
study across several regions of Turkey. We present here the
results from 2005 to 2012.
Materials and Methods
Study design
This multicenter, hospital-based, prospective, epidemiological
study was conducted in Turkey between February 2005 and
December 2012 among children and adolescents younger than
18 y of age. The study was reviewed and approved by the Hacet-
tepe University Institutional Ethics Committee. This ethical
approval was sufficient for the other study sites as well. Patients
with suspected meningitis were screened and hospitalized in 12
hospitals located in 7 regions of Turkey [Central Anatolia, Mar-
mara, South East Anatolia, Aegean, East Anatolia, Mediterra-
nean, and Black Sea] which provide healthcare services to
approximately 32% of the Turkish population. After patients
parents/legal guardians had given informed consent, specimens
were collected for the diagnosis.
Hospital pediatricians identified suspected cases of acute bac-
terial meningitis based on the following standard criteria: any
sign of meningitis (fever [38 C], vomiting [3 episodes in
24 h], headache, signs of meningeal irritation [bulging fontanel,
Kernig or Brudzinski signs, or neck stiffness]) in children >1 y of
age; fever without any documented source; impaired conscious-
ness (Blantyre Coma Scale <4 if <9 mo of age and <5 if 9
mo of age)20; prostration (inability to sit unassisted if  9 mo of
age or breastfeed if <9 mo of age) in those <1 y of age; and seiz-
ures (other than those regarded as simple febrile seizures with full
recovery within 1 h). For each suspected case, demographic data,
main clinical signs and symptoms, prior clinical history including
use of antimicrobial agents, treatment, and laboratory results and
outcome data were recorded on a standardized case report form.
In addition, cerebrospinal fluid (CSF) samples were obtained
from all patients <18 y of age with clinically suspected meningi-
tis. Since the pathogens responsible for neonatal meningitis are
different from older patients, neonates (patients <1 mo of age)
were not included in the study.3
Laboratory analyses
Samples were analyzed if CSF had the following criteria: 1) >
10 leukocytes/mm3 in the CSF, and/or 2) higher CSF protein lev-
els than normal for the patients age, and/or 3) lower CSF glucose
levels than normal for the patients age. In addition, all patients
who had positive test results to CSF culture, polymerase chain
reaction (PCR), Gram stain, or antigen detection test were also
included in the study. CSF cultures and Gram stain were per-
formed in the local hospitals, but CSF samples (minimum of
0.5 mL) from each patient was stored at 20 C until transporta-
tion to the Central Laboratory at Hacettepe University Pediatric
Infectious Diseases Unit, Ankara, Turkey for PCR analysis. If
2707
available, bacterial isolates were also sent to the Central Labora-
tory, where they were re-cultured on chocolate and blood agars
and grown at 37 C in 5% CO2. Suspected meningococcal colo-
nies were characterized by Gram stain, oxidase test, and rapid car-
bohydrate utilization test Api (API NH ref. 10400, BioMerieux,
Germany). The microbiology laboratory records were crosschecked
in each hospital for missing data. Hospitals databases were
searched for diagnosis of meningitis. Laboratory records were
crosschecked on weekly basis with the hospital database. The phe-
notypic determination, based on the antigenic formula (serogroup:
serotype: serosubtype) of meningococcal isolates, was performed
by standard methods in the Meningococcal Reference Unit,
Health Protection Agency, Manchester, United Kingdom.17,21-23
All samples transferred to the Central Laboratory were stored
at 80 C and thawed immediately before each test. DNA was
isolated as previously reported.24 Single tube, multiplex PCR
assay was performed for the simultaneous identification of bacte-
rial agents. The specific gene targets were ctrA, bex, and ply for N.
meningitidis, Hib, and S. pneumoniae, respectively.24,25 PCR was
performed by using a DNA thermal cycler (GeneAmp PCR Sys-
tem model 9700, Applied Biosystems, Foster City, CA, USA).
PCR positive samples were recorded as laboratory-confirmed
acute bacterial meningitis.
In samples positive for N. meningitidis, serogroup prediction
(A, B, C, W-135, and Y) was based on the oligonucleotides in
the siaD gene for serogroups B, C, W-135, and Y, and in orf-2
of a gene cassette required for serogroup A.25,26
All amplicons were analyzed by electrophoresis on standard
3% agarose gels and visualized using UV fluorescence. A negative
control consisting of distilled water and positive control consist-
ing of an appropriate reference strain (S. pneumoniae ATCC
49613, Hib ATCC 10211, N. meningitidis serogroup C L94
Figure 1. Distribution of causative agents of bacterial meningitis and meningococcal serogroups (Table 1).
in Turkey, 20052012. Of 645 PCR-conrmed cases, 333 (51.6%) were attributable to Neisseria
meningitidis, 195 (30.2%) to Streptococcus pneumoniae, and 117 (18.1%) to Hemophilus inuenzae
type b (Hib). Among meningococcal meningitis, serogroup A, B and W-135 were 8.4%, 26.1%,
and 38.1%, respectively. Serogroup Y was only detected 2.2%. Non-groupable cases were 26.4%.
5016 also known as C11 [C:16:P1.71.1], serogroup A M99
243594 [A:4,21:P1.20,9], serogroup Y M05 240122 [Y:NT:
P1.5], serogroup W-135 M05 240125 [W135:2a: NST],
serogroup B M05 240120 [B:NT:NST] were analyzed
simultaneously.
Results
During 20052012 a total of 1452 children were hospitalized
with a clinical diagnosis of meningitis. CSF sample were obtained
from each patient. The mean age was 4.8 4.2 y (range, 1 mo
and 18 y) and the boy-to-girl ratio was 1.56:1. There were 37
deaths, 21 of whom in patients with laboratory-confirmed cases.
The case-fatality rate for the laboratory confirmed cases was
3.3%. The median age of fatal cases was 11 mo (interquartile
range [IQR], 421). The etiology of the mortality were deter-
mined N.meningitis, S. pneumoniae, and Hib as 52.4% (n D 11),
33.3% (n D 7), and 14.3% (n D 3), respectively. Bacterial men-
ingitis was confirmed by PCR in 645 (44.4%) patients, the diag-
nosis of bacterial meningitis was confirmed by CSF culture only
in 105 (16.2%) of these. Overall, 476 patients received various
antibiotic treatments before the lumbar puncture.
Laboratory-confirmed cases and etiology
Of the 645 diagnosed cases of bacterial meningitis by PCR
over the whole period of 20052012, 333 (51.6%) were menin-
gococcal; 195 (30.2%) (n D 195) were pneumococcal and 117
(18.1%) were due to Hib (Fig. 1).
Among meningococcal meningitis, cases of serogroup A, B
and W-135 were 0.8% (n D 1), 31.1% (n D 43), and 42.7%
(n D 59) in 20052006; 8.3% (n D 9), 35.1% (n D 38), and
17.6% (n D 19) in 20072008; 36.6% (n D 15), 7.3% (n D 3),
and 56.1% (n D 23) in 20092010; and
6.5% (n D 3), 6.5% (n D 3), and 56.5%
(n D 26) in 20112012, respectively
(Table 1). Of meningococcal meningitis
cases during 20052012, serogroup A, B
and W-135 were identified in 8.4% (n D
28), 26.1% (n D 87), and 38.1% (n D
127), respectively (Fig. 1). No serogroup C
was detected among meningococcal cases
between 2005 and 2012. Serogroup Y was
only detected in 20052006, representing
2.2% (n D 3) of meningococcal cases.
Pneumococcal and Hib meningitis
accounted for 22.6% (n D 55) and 20.6%
(n D 50) of cases in 20052006; 36.7% (n
D 98) and 22.8% (n D 61) in 20072008;
31.8% (n D 21) and 6.1% (n D 4) in
20092010; and 30.4% (n D 21) and 2.9%
(n D 2) in 20112012, respectively
Age distribution
Among meningococcal meningitis, cases
in subjects
1 y, 14 y, 59 y, 1014 y,

2708 Human Vaccines & Immunotherapeutics Volume 10 Issue 9

Table 1. Distribution of causative agents of bacterial meningitis and meningococcal serogroups per year in Turkey
Study Period (Year) 20052006 20072008 20092010 20112012 20052012

Causative Bacteria n % n % n % n % n %

Serogroup W-135 59 42.7 19 17.6 23 56.1 26 56.5 127 38.1

Serogroup B 43 31.1 38 35.1 3 7.3 3 6.5 87 26.1
Serogroup A 1 0.8 9 8.3 15 36.6 3 6.5 28 8.4
Serogroup C 0 0 0 0 0 0 0 0 0 0
Serogroup Y 3 2.2 0 0 0 0 0 0 3 0.9
Nongroupable 32 23.2 42 39 0 0 14 30.5 88 26.4
N. meningitidis (Total) 138 56.8 108 40.4 41 62.1 46 66.6 333 51.6
S. pneumonia 55 22.6 98 36.7 21 31.8 21 30.4 195 30.2
H. inuenzae type b 50 20.6 61 22.8 4 6.1 2 2.9 117 18.1
Total number of Positive Samples 243 100 267 100 66 100 69 100 645 100
Total number of Evaluated Clinical Samples 408 NA 372 NA 355 NA 317 NA 1452 NA

and 1518 y old were 18.3%, 32.4%, 26.2%, 18.3%, and 4.8%
in 20052012, respectively. Pneumococcal meningitis cases were
reported in subjects
1 y, 14 y, 59 y, 1014 y, and 1518 y
old as 12.3%, 44.1%, 23.1%, 11.3%, and 9.2% in 20052012,
respectively. N.meningitidis was the predominant agent responsi-
ble for acute bacterial meningitis in children <5 y of age, in
20052006. Whereas, in 20072008 pneumococcal meningitis
was the leading cause of acute bacterial meningitis, in the same
age group. Among Hib meningitis, cases in subjects
1 y, 14 y,
59 y, 1014 y, and 1518 y were 14.5%, 29.9%, 27.4%,
18.8%, and 9.4% in 20052012, respectively. Hib meningitis
was seen only one case in each 14 y and 1518 y in 20112012.
When we consider the entire study period (20052012), more
bacterial meningitis cases were occurred in children under 5 y of
age (51.3% of all cases) with a highest rate of 14 y (35.5%).
Acute bacterial meningitis in children under 1 y of age
(Fig. 2) occurred mostly <6 mo of age. N.meningitidis was the
leading cause of the meningitis in 6 mo, followed by S.pneumo-
niae. Hib represents 1/3 of the children in 13 mo.
Incidence and regional distribution
The annual incidence of acute laboratory-confirmed bacterial
meningitis gradually decreased from 3.5 cases / 100,000 popu-
lation in 20052006 to 0.9 cases/ 100,000 in 20112012
(Fig. 3).
The regional distribution of etiologic pathogens during
20052012 showed that bacterial meningitis was most prevalent
in the Central Anatolia, followed by Marmara and South East
Anatolia (Fig. 4). The population of children 1 mo through 18 y
of age was calculated per region according to the data of Turkish
Statistical Institute. Therefore, the incidence of acute bacterial
meningitis was 4.5/100.000 in Central Anatolia, 1.3/100.000 in
Marmara, 8/100.000 in Southeast Anatolia, 3/100.000 in
Aegean, 6/100.000 in Eastern Anatolia, 2.5/100.000 in Mediter-
ranean, and 1/100.000 in Black Sea region in the study period of
20112012.
Discussion

To efficiently implement regional and

national immunization programs the avail-
ability of recent epidemiologic data on the
vaccine-preventable diseases prevalent in
those areas represents critical piece of infor-
mation. We have monitored the incidence
and nature of bacterial meningitis cases in
Turkey from 2005 to 2012. At the begin-
ning of this study period the annual inci-
dence of acute bacterial meningitis in
Turkey was 3.5 cases/ 100,000 popula-
tion.24 This annual incidence decreased to
0.9 cases/ 100,000 in 20112012. Hib
vaccination for children <1 y of age was
implemented in the Turkish National
Immunization Program (NIP) in 2006,
leading to a marked decrease in incidence of
Hib meningitis. Routine vaccination with
PCV-7 for children <1 y of age was agreed
on paper at the end of 2008 and included in
Figure 2. Age distribution of bacterial meningitis in infants in Turkey (20062012) the NIP in 2009, and PCV-7 was replaced

www.landesbioscience.com Human Vaccines & Immunotherapeutics 2709

 standard method, PCR allowed to identify
the etiological agent in most cases27 of acute
bacterial meningitis in culture-negative
patients.
We identified N. meningitidis as the most
common cause of bacterial meningitis
(51.6%) in Turkey, especially in children
<5 y of age. Additionally, N. meningitidis
was the highest reason of the fatality. The
case-fatality rate (3.3%) in the present study
was lower than the literature that reported
between 5.3% and 26.2%.30 This result
may be attributed that receiving effective
hospital antibiotic treatment and reaching a
more qualified health care facility for the
acute meningitis episode may be easier in
Turkey than the low-income countries.
There were no significant variations in the
incidence of the bacterial meningitis in per
Figure 3. Annual incidence of causative agents of bacterial meningitis per 100,000 and effect of region according to years. However, there
Hib and PCV vaccinations in Turkey. Because our study centers provide service to 32% of the pop- was large variation in the incidence of dis-
ulation of Turkey, extrapolation from the number of cases recorded was calculated for the possi- ease caused by specific serogroups,
ble number of acute bacterial meningitis cases (excluding neonatal cases) per year occur in the
whole country. The population of children 1 mo through 18 y of age was calculated as
serogroup B dominating in some years and
23.9 million. W-135 in others, while disease caused by
serogroup A has increased recently; there
were no serogroup C cases observed in this
by PCV-13 in November 2011. Between 20102013, approxi- study, and only a small number of serogroup Y cases. These data
mately 97% of the target population was vaccinated with PCV.27 are in contrast to those from many parts of Europe, where
However, in spite of the availability of these pneumococcal vac- serogroups B and C dominate.12,31,32 The reason for the sudden
cines; there has been no major decrease in pneumococcal menin- decrease in serogroup B disease in Turkey is not clear as there is
gitis incidence. This may be because the introduction of no serogroup B vaccine currently available, but the epidemiology
vaccination against pneumococcal disease is too recent and the of serogroup B has been observed to vary with time in many
effects of vaccination are not yet evident. Therefore, the main countries without any apparent reason. In the United States, the
contribution to the overall decrease in annual incidence in Tur- proportion of disease caused by serogroup Y has increased over
key can be attributed to the dramatic vaccination-induced
decrease in Hib meningitis introduced in 2006 and with cover-
age of 97%.
In this study, 645 cases of laboratory-confirmed acute bacte-
rial meningitis were recorded, but bacterial isolation was only
possible in 105 (16.2%) of those confirmed cases. This may
have been related to the use of antibiotics before admission to
the study centers, as the majority of patients received various
treatments before the lumbar puncture. Therefore, non-culture
techniques might be necessary to detect the causative organ-
isms.27 Laboratory confirmation of the etiology of acute bacte-
rial meningitis is critical for providing optimal patient therapy
and to ensure appropriate case contact management. In addi-
tion, case confirmation provides epidemiological information
necessary for making decisions concerning immunization pro-
grams, and implementation of new available vaccines against
the most common bacterial meningitis pathogens.24,25,28 Of
the non-culture diagnostic tests, PCR is the most common
method that is sufficiently accurate and reliable, especially
when there is a history of antimicrobial drug use before lumbar
puncture.24,29 In our study only 16,2% of cases were confirmed Figure 4. Regional distribution of bacterial meningitis cases in Turkey
(20052012)
by CSF culture, and although bacterial culture is considered the

2710 Human Vaccines & Immunotherapeutics Volume 10 Issue 9

the past decade to over one third of cases,33 while serogroups C
has declined in many European countries since the introduction
of serogroup C vaccines into routine immunization programs.21
The reason why serogroups C and Y are rare in Turkey is unclear,
as no vaccine has been used against these serotypes. Several points
should be taken into account: the coverage of our study centers,
population dynamics, diagnostic procedures, and possible impor-
tation of serogroups such as W-135 from other countries that
may have decreased the proportion of some serogroups.
The first Turkish patient with meningitis caused by serogroup
W-135 was reported in 2003.22 Most of the Turkish population
is Muslim, and 150,000 pilgrims travel annually to the Hajj in
Saudi Arabia. Since 2002, all Turkish pilgrims have received a
quadrivalent (A, C, W, Y) meningococcal polysaccharide vaccine
before travel. Although this vaccine generates a robust immune
responses against all constituent serogroups, unlike conjugate
vaccines, meningococcal polysaccharide vaccines do not prevent
asymptomatic carriage.24,34 The rapid rise in the proportion of
cases caused by serogroup W-135 may be attributable to trans-
mission from pilgrims returning from the Hajj carrying W-
135,24 despite their vaccination with polysaccharide vaccine. Of
11 family members of pilgrims who acquired W-135 carriage at
the Hajj, 10 (91%) had acquired carriage of serogroup W-135.35
This study illustrated the acquisition of meningococcal carriage,
predominantly of serogroup W-135 by pilgrims attending the
Hajj, the transmission to their family members on their return,
as the possible explanation for the presence of W-135 meningo-
coccal disease in Turkey. Similar observations have been made in
the UK and France.17 For this reason, the Turkish National
Immunization Board has decided to change recommendation
from a polysaccharide to a conjugated quadrivalent meningococ-
cal vaccine for pilgrims and Umrah visitors, which may help to
reduce carriage rates and decrease the burden of W-135 in
Turkey.36
This study has several limitations. First, because previous anti-
biotic treatment had high rates, we did not find enough labora-
tory-confirmed cases to drive accurate incidence rates for each
pathogen, thus limiting the generalizability of those data. Second,
our study likely missed many bacterial meningitis cases, particu-
larly among case-patients whose illnesses did not meet the case
definition. Despite the limitations, this project has provided use-
ful insights into the incidence and epidemiology of bacterial
References
1. Li Y, Yin Z, Shao Z, Li M, Liang X, Sandhu HS,
Hadler SC, Li J, Sun Y, Li J, et al.; Acute Meningitis 5.
and Encephalitis Syndrome Study Group. Population-
based surveillance for bacterial meningitis in China,
September 2006-December 2009. Emerg Infect Dis
2014; 20:61-9; PMID:24377388; http://dx.doi.org/ 6.
10.3201/eid2001.120375
2. Kim KS. Acute bacterial meningitis in infants and chil-
dren. Lancet Infect Dis 2010; 10:32-42;
PMID:20129147; http://dx.doi.org/10.1016/S1473- 7.
3099(09)70306-8
3. Feigin RD, Curter WB. Bacterial Meningitis Beyond
The Neonatal Period. In: Feigin & Cherrys Textbook and meta-analysis. Lancet Infect Dis 2010; 10:317-28;
of Pediatric Infectious Diseases edn. Edited by Feigin
RD, Cherry JD, Harrison RE, Kaplan SL; 2009.
4. Saez-Llorens X, McCracken GH Jr. Bacterial meningi- 8.
tis in children. Lancet 2003; 361:2139-48; PMID:
www.landesbioscience.com
meningitis in Turkey. All the data presented in this study were
gathered through study centers. This method (sentinel surveil-
lance) is the appropriate way to collect data for common infec-
tious diseases like influenza, but for rare diseases like
meningococcal meningitis, we need nationwide study centers in
Turkey where we may catch more cases through an active surveil-
lance system.
It has been shown that introduction of conjugate vaccines can
dramatically reduce meningitis disease incidence, if vaccines are
administered to the target population with high vaccine cover-
age.1,14,37 Hib and PCV-13 vaccines are already available for
infants starting from two months of age in the Turkish NIP and
the meningococcal vaccine for Hajj pilgrims has already been
switched to conjugated quadrivalent vaccine in order to decrease
carriage of the microorganism by returning pilgrims. In this
study we observed a drastic decreased of Hib meningitis in Turk-
ish children since Hib vaccine has been introduced in NIP.
The epidemiology and etiology of bacterial meningitis may
change over time and by regions in a way that cannot be pre-
dicted. In our study we showed that 51.6% of meningitis in seven
Turkish regions in 118 y old children was caused by N. menin-
gitidis. Although the number of Men B cases decreased in the last
few years, serogroup B was still the second most common causa-
tive agent of meningococcal meningitis (26.1%) in Turkey over
the entire study period (20052012).
As conjugated quadrivalent meningococcal ACWY vaccines as
well as the recently licensed 1 meningococcal B vaccine38 are
available, their use in 118 y old could dramatically reduce the
burden of meningococcal disease in Turkey.
Disclosure of Potential Conflicts of Interest
The study was supported by Novartis Vaccines and Diagnos-
tics (for 5 years) and by GlaxoSmithKline (for 2 years). The
authors declare that they have no other conflicts of interest.
Acknowledgments
Serdar Altinel MD PhD and Kathleen Jenks PhD, both
employees of Novartis Vaccines and Diagnostics, provided edito-
rial support.
12826449; http://dx.doi.org/10.1016/S0140-6736(03) Mulholland K, Hajjeh R, et al. Mortality and neurode-
13693-8 velopmental outcomes of acute bacterial meningitis in
Baraff LJ, Lee SI, Schriger DL. Outcomes of bacterial children aged <5 years in Pakistan. J Pediatr. 2013
meningitis in children: a meta-analysis. Pediatr Infect Jul;163(1 Suppl):S86-S91.e1
Dis J 1993; 12:389-94; PMID:8327300; http://dx.doi. 9. Agrawal S, Nadel S. Acute bacterial meningitis in
org/10.1097/00006454-199305000-00008 infants and children: epidemiology and management.
Grandgirard D, Leib SL. Strategies to prevent neuronal Paediatr Drugs 2011; 13:385-400; PMID:21999651;
damage in paediatric bacterial meningitis. Curr Opin http://dx.doi.org/10.2165/11593340-000000000-000
Pediatr 2006; 18:112-8; PMID:16601488; http://dx. 00
doi.org/10.1097/01.mop.0000193292.09894.b7 10. Melegaro A, Edmunds WJ, Pebody R, Miller E,
Edmond K, Clark A, Korczak VS, Sanderson C, Grif- George R. The current burden of pneumococcal disease
fiths UK, Rudan I. Global and regional risk of disabling in England and Wales. J Infect 2006; 52:37-48;
sequelae from bacterial meningitis: a systematic review PMID:16368459; http://dx.doi.org/10.1016/j.jinf.20
05.02.008
PMID:20417414; http://dx.doi.org/10.1016/S1473- 11. Pathan N, Faust SN, Levin M. Pathophysiology of
3099(10)70048-7 meningococcal meningitis and septicaemia. Arch Dis
Khowaja AR, Mohiuddin S, Cohen AL, Khalid A, Child 2003; 88:601-7; PMID:12818907; http://dx.
Mehmood U, Naqvi F, Asad N, Pardhan K, doi.org/10.1136/adc.88.7.601
Human Vaccines & Immunotherapeutics 2711
12. Outbreak news. Meningococcal disease, African menin-
gitis belt, epidemic season 2006. Wkly Epidemiol Rec
2006; 81:119-20; PMID:16673512
13. Rosenstein NE, Perkins BA, Stephens DS, Popovic T,
Hughes JM. Meningococcal disease. N Engl J Med
2001; 344:1378-88; PMID:11333996; http://dx.doi.
org/10.1056/NEJM200105033441807
14. Harrison LH. Prospects for vaccine prevention of
meningococcal infection. Clin Microbiol Rev 2006;
19:142-64; PMID:16418528; http://dx.doi.org/
10.1128/CMR.19.1.142-164.2006
15. Stephens DS. Conquering the meningococcus. FEMS
Microbiol Rev 2007; 31:3-14; PMID:17233633;
http://dx.doi.org/10.1111/j.1574-6976.2006.00051.x
16. Harrison LH, Trotter CL, Ramsay ME. Global epide-
miology of meningococcal disease. Vaccine 2009; 27
(Suppl 2):B51-63; PMID:19477562; http://dx.doi.
org/10.1016/j.vaccine.2009.04.063
17. Taha MK, Achtman M, Alonso JM, Greenwood B,
Ramsay M, Fox A, Gray S, Kaczmarski E. Serogroup
W135 meningococcal disease in Hajj pilgrims. Lancet
2000; 356:2159; PMID:11191548; http://dx.doi.org/
10.1016/S0140-6736(00)03502-9
18. Tan LK, Carlone GM, Borrow R. Advances in the
development of vaccines against Neisseria meningitidis.
N Engl J Med 2010; 362:1511-20; PMID:20410516;
http://dx.doi.org/10.1056/NEJMra0906357
19. Bertherat E, Yada A, Djingarey MH, Koumare B. [First
major epidemic caused by Neisseria meningitidis
serogroup W135 in Africa?]. Med Trop (Mars).
2002;62(3):301-4.
20. Berkley JA, Versteeg AC, Mwangi I, Lowe BS, Newton
CR. Indicators of acute bacterial meningitis in children
at a rural Kenyan district hospital. Pediatrics 2004;
114:e713-9; PMID:15574603; http://dx.doi.org/
10.1542/peds.2004-0007
21. Gray SJ, Trotter CL, Ramsay ME, Guiver M, Fox AJ,
Borrow R, Mallard RH, Kaczmarski EB; Meningococ-
cal Reference Unit. Epidemiology of meningococcal
disease in England and Wales 1993/94 to 2003/04:
contribution and experiences of the Meningococcal
Reference Unit. J Med Microbiol 2006; 55:887-96;
PMID:16772416; http://dx.doi.org/10.1099/jmm.0.
46288-0
2712
22. Doganci L, Baysallar M, Saracli MA, Hascelik G, Pahsa
A. Neisseria meningitidis W135, Turkey. Emerg Infect
Dis 2004; 10:936-7; PMID:15200836; http://dx.doi.
org/10.3201/eid1005.030572
23. Kilic A, Urwin R, Li H, Saracli MA, Stratton CW,
Tang YW. Clonal spread of serogroup W135 meningo-
coccal disease in Turkey. J Clin Microbiol 2006;
44:222-4; PMID:16390974; http://dx.doi.org/10.
1128/JCM.44.1.222-224.2006
24. Ceyhan M, Yildirim I, Balmer P, Borrow R, Dikici B,
Turgut M, Kurt N, Aydogan A, Ecevit C, Anlar Y,
et al. A prospective study of etiology of childhood acute
bacterial meningitis, Turkey. Emerg Infect Dis 2008;
14:1089-96; PMID:18598630; http://dx.doi.org/
10.3201/eid1407.070938
25. Taha MK. Simultaneous approach for nonculture
PCR-based identification and serogroup prediction of
Neisseria meningitidis. J Clin Microbiol 2000; 38:855-
7; PMID:10655397
26. Tsolia MN, Theodoridou M, Tzanakaki G, Kalabalikis
P, Urani E, Mostrou G, Pangalis A, Zafiropoulou A,
Kassiou C, Kafetzis DA, et al. The evolving epidemiol-
ogy of invasive meningococcal disease: a two-year pro-
spective, population-based study in children in the area
of Athens. FEMS Immunol Med Microbiol 2003; 36:
87-94; PMID:12727371; http://dx.doi.org/10.1016/
S0928-8244(03)00083-X
27. Ceyhan M, Ozsurekci Y, Gurler N, Ozkan S, Sensoy G,
Belet N, Hacimustafaoglu M, Celebi S, Keser M, Din-
leyici EC, et al. Serotype Distribution of Streptococcus
pneumoniae Causing Parapneumonic Empyema in
Turkey. Clin Vaccine Immunol. 2013 Jul;20(7):972-6
28. Gray LD, Fedorko DP. Laboratory diagnosis of bacte-
rial meningitis. Clin Microbiol Rev 1992; 5:130-45;
PMID:1576585
29. Tzanakaki G, Tsopanomichalou M, Kesanopoulos K,
Matzourani R, Sioumala M, Tabaki A, Kremastinou J.
Simultaneous single-tube PCR assay for the detection
of Neisseria meningitidis, Haemophilus influenzae type
b and Streptococcus pneumoniae. Clin Microbiol
Infect. 2005 May;11(5):386-90
30. Luksic I, Mulic R, Falconer R, Orban M, Sidhu S,
Rudan I. Estimating global and regional morbidity
from acute bacterial meningitis in children: assessment
Human Vaccines & Immunotherapeutics
of the evidence. Croat Med J 2013; 54:510-8; PMID:
24382845; http://dx.doi.org/10.3325/cmj.2013.54.
510
31. Snape MD, Pollard AJ. Meningococcal polysaccharide-
protein conjugate vaccines. Lancet Infect Dis 2005;
5:21-30; PMID:15620558; http://dx.doi.org/10.1016/
S1473-3099(04)01251-4
32. Lind I, Berthelsen L. Epidemiology of meningococcal
disease in Denmark 1974-1999: contribution of the
laboratory surveillance system. Epidemiol Infect 2005;
133:205-15; PMID:15816145; http://dx.doi.org/
10.1017/S0950268804003413
33. Rosenstein NE, Perkins BA, Stephens DS, Lefkowitz L,
Cartter ML, Danila R, Cieslak P, Shutt KA, Popovic
T, Schuchat A, et al. The changing epidemiology of
meningococcal disease in the United States, 1992-
1996. J Infect Dis 1999; 180:1894-901;
PMID:10558946; http://dx.doi.org/10.1086/315158
34. Maiden MC, Stuart JM, UK Meningococcal Carraige
Group. Carriage of serogroup C meningococci 1 year
after meningococcal C conjugate polysaccharide vacci-
nation. Lancet 2002; 359:1829-31; PMID:12044380;
http://dx.doi.org/10.1016/S0140-6736(02)08679-8
35. Ceyhan M, Celik M, Demir ET, Gurbuz V, Aycan AE,
Unal S. Acquisition of meningococcal serogroup W-
135 carriage in Turkish Hajj pilgrims who had received
the quadrivalent meningococcal polysaccharide vaccine.
Clin Vaccine Immunol 2013; 20:66-8; PMID:231
36117; http://dx.doi.org/10.1128/CVI.00314-12
36. Dinleyici EC, Ceyhan M. The dynamic and changing
epidemiology of meningococcal disease at the country-
based level: the experience in Turkey. Expert Rev Vac-
cines 2012; 11:515-8; PMID:22827237; http://dx.doi.
org/10.1586/erv.12.29
37. Pellegrino P, Carnovale C, Perrone V, Salvati D, Gen-
tili M, Brusadelli T, Antoniazzi S, Pozzi M, Radice S,
Clementi E. Epidemiological analysis on two decades
of hospitalisations for meningitis in the United States.
Eur J Clin Microbiol Infect Dis. 2014.
38. Gasparini R, Amicizia D, Domnich A, Lai PL, Panatto
D. Neisseria meningitidis B vaccines: recent advances
and possible immunization policies. Expert Rev Vac-
cines 2014; 13:345-64; PMID:24476428; http://dx.
doi.org/10.1586/14760584.2014.880341
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