This article appeared in a journal published by Elsevier. The attached [601519]

This article appeared in a journal published by Elsevier. The attached
copy is furnished to the author for internal non-commercial research
and education use, including for instruction at the authors institution
and sharing with colleagues.
Other uses, including reproduction and distribution, or selling or
licensing copies, or posting to personal, institutional or third party
websites are prohibited.
In most cases authors are permitted to post their version of the
article (e.g. in Word or Tex form) to their personal website or
institutional repository. Authors requiring further information
regarding Elsevier’s archiving and manuscript policies are
encouraged to visit:
http://www.elsevier.com/authorsrights

Author's personal copy
IL6-174 G/C gene polymorphism and its relation to serum IL6 in Egyptian
children with community-acquired pneumonia
Haidy E. Zidana,⇑, Rabab M. Elbehedyb, Seham F. Azabb
aMedical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
bPediatrics Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
article info
Article history:
Received 24 December 2013
Received in revised form 12 February 2014Accepted 28 February 2014Available online 24 March 2014
Keywords:Interleukin-6Genetic polymorphismsPediatricsCommunity acquired pneumoniaabstract
Cytokines are involved in the pathogenesis of community acquired pneumonia (CAP). The aim of this
study is to investigate the association of IL6-174 G /Cgene polymorphism with CAP in Egyptian children,
to assess its effect on CAP outcome and to determine its effect on the serum IL6levels in these children.
IL6-174 G /Cgene polymorphism was genotyped in 210 Egyptian children (100 patients with CAP and
110 healthy controls) using PCR-RFLP, while the serum IL6levels were measured by ELISA method.
We found a significant association between the GG genotype, G allele of IL6-174 G /CSNP and suscep-
tibility to CAP ( P= 0.02, 0.01 respectively). However, GG genotype and G allele were protective against
severe sepsis ( p= 0.004), acute respiratory failure ( p< 0.001) and hospital mortality ( p< 0.001). Serum
IL6levels were significantly increased in these children while there was no relation between GG genotype
and serum IL6.
In conclusion, IL6-174 G /Cgene polymorphism may contribute to susceptibility to CAP in Egyptian
children.
/C2112014 Elsevier Ltd. All rights reserved.
1. Introduction
Community-acquired pneumonia (CAP) is considered one of the
most common pediatric infections with a prevalence of 34–40 cases
per 1000 in Europe and North America. In third world countries, CAP
is more common, more severe, and the most prevalent cause of
death in children [1]. CAP is the leading cause of community-ac-
quired infection requiring hospitalization and has an overall mortal-
ity of 8.7% [2]. Lung injury resulting in respiratory failure is the
primary complication of CAP. The mechanisms underlying and
affecting lung injury are complex and involve a variety of molecular
and cellular processes that may be influenced by genetic factors [3].
Severe sepsis (SS) is common in hospitalized CAP patients, and is the
leading cause of death in these patients. Since deregulation of innate
immunity is believed to be central to the manifestation of sepsis,
studies of genetic susceptibility and outcome of CAP have focused
on genes involved in inflammatory pathways [4]. In sepsis, systemic
cytokine levels are associated with the severity of disease. In bacte-
rial pneumonia the cytokine response is mostly confined to the
affected lung, but systemic levels of cytokines are also raised. [5].
Interleukin6 ( IL6) is a pleiotropic cytokine involved in many
physiological and pathological processes, particularly in theinflammatory response to pulmonary infection [6].IL6is secreted
by a variety of cells such as T-lymphocytes, macrophages, endothe-
lial cells and epithelial cells. The systemic concentrations of IL6are
mainly regulated at the level of expression, because IL6is rapidly
cleared from the plasma as it has a plasma half-life of 20–60 min.
[7,8] .
A biallelic polymorphism within the human IL6-174 G /Cgene
promoter region has been shown to affect IL6 transcription
in vitro and IL6plasma levels in healthy adults [9].
Interleukin 6 plays an important role in the development, path-
ogenesis and outcome of sepsis. Plasma levels of IL6are elevated in
patients with sepsis and high IL6concentrations are associated
with increased mortality [10].
On the basis of these considerations, we designed this study to
investigate whether polymorphism in IL6-174 G /Cmay be associ-
ated with susceptibility, severity of illness or outcome in Egyptian
children with CAP and also we measured the serum level of IL6to
assess its relation to such polymorphism aiming to improve diag-
nosis, assess severity, and thus seek for new treatment modalities
of such disease.
2. Subjects and methods
This study was conducted by the Medical Biochemistry and
Pediatric Departments at the faculty of medicine of Zagazig Univer-
sity – Egypt.
http://dx.doi.org/10.1016/j.cyto.2014.02.013
1043-4666/ /C2112014 Elsevier Ltd. All rights reserved.⇑Corresponding author. Address: Lecturer of Medical Biochemistry, Zagazig
university, Zagazig, Egypt. Tel.: +20 1005052080.
E-mail address: haidy_menna@hotmail.com (H.E. Zidan).Cytokine 67 (2014) 60–64
Contents lists available at ScienceDirect
Cytokine
journal homepage: www.journa ls.elsevier. com/cytokine

Author's personal copy
2.1. Patients
2.1.1. Study design
This study was a prospective cohort study of patients admitted
to the Zagazig University Pediatric Hospital with CAP between May
2011 and June 2013. Patients were enrolled once they met the
inclusion criteria as outlined subsequently.
2.1.2. Inclusion criteria
For the purpose of this study CAP was defined by previously
published guidelines [11]; an acute illness (<14 days of symptoms),
the presence of a new chest radiographic infiltrate or consolidation
confirmed by a radiologist (blinded to the patient genotype), and
clinical features compatible with pneumonia. The clinical features
required were one of the following three: fever >37.8 /C176C,
hypothermia <36 /C176C, peripheral blood count >10,000/ lLo r
<4500/ lL or >15% immature neutrophils; and two of the following
three: tachypnea (respiratory rate > 2 standard deviations from the
mean for age), dyspnea, or hypoxemia (pulse oximetry 694% on
room air on initial evaluation without a known mixing heart
lesion).
2.1.3. Exclusion criteria
Children were excluded if there was (1) clinical diagnosis of
Bronchiolitis (2) patients with severe immunodeficiency including
acquired immune deficiency syndrome as defined by the Centers
for Disease Control criteria [12]. (3) Patients receiving chemother-
apy in the past 60 days; (4) patients receiving treatment with
corticosteroids equivalent to prednisolone20 mg/d for more than
14 days; (5) patients on cyclosporine, cyclophosphamide or azathi-
oprine; (6) patients from chronic care facilities; (7) patients hospi-
talized within the past 30 days.
2.1.4. Severity criteria
The following data were collected at admission: social demo-
graphic data, comorbidities, and prehospital treatment. Severity
of pneumonia was assessed for each child on hospital admission.
Severity criteria were derived from severity definitions within
the management guidelines from the British Thoracic Society
[13]. Any of the following led to a classification of ‘Severe disease’:
tachypnoea (RR > 70 for infants <1 year old, RR > 50 for children
>1 year old); dyspnoea; oxygen saturation <93%; oxygen given;
nasogastric feeds; intravenous fluid infusion; septicaemia; empy-
ema; high dependency or intensive care. ‘Mild ‘ included immedi-
ate home discharge or hospital stay of <3 days and no oxygen, no
intravenous or nasogastric feeds, or ‘Moderate disease’with neither
category.
During hospitalization, patients were closely monitored and the
occurrence of severe sepsis and respiratory failure were identified
to quantify illness severity.
The endpoints of the clinical outcome were defined as intensive
care unit (ICU) admission, and mortality.
In the presence of a documented infection, severe sepsis was
defined as systemic inflammatory response syndrome in combina-
tion with organ failure [14]. Acute respiratory failure (ARF) was
defined as an oxygen saturation of less than 90% on room air, or
a PaO 2less than 60 mm Hg.
2.1.5. Controls
The control group consisted of 110 children.
Patients and controls belonged to the same ethnic group:
African Caucasian. The study was approved by the ethical commit-
tee of Faculty of Medicine, Zagazig University and written
informed consent was obtained from all parents’ participants.
Characteristics of the participants are presented in Table 1 .2.2. Methods
2.2.1. Blood sampling
Blood samples were drawn from all subjects at admission and
divided into 2 portions: 2 ml of whole blood was collected into
tubes containing EDTA, for genomic DNA extraction. Serum were
separated immediately from remaining part of the sample and
stored at /C020/C176C until analysis.
2.2.2. Genomic DNA extraction
Genomic DNA was extracted from EDTA whole blood sample
using a spin column method according to the protocol (QIAamp
Blood Kit; Qiagen GmbH, Hilden, Germany). DNA was stored at
/C020/C176C till the time of use.
2.2.3. Amplification of IL6-174 G/C polymorphism
The subjects were genotyped for IL6-174 G /C(rs1800795) poly-
morphism by polymerase chain reaction–restriction fragment
length polymorphism (PCR-RFLP) as described by Duch et al.
[15]. The primers 50-TGTCAAGACATGCCAAAGTG-30(IL6-sense)
and 50-TCAGACATCTCCAGTCCTATA-30(IL6-antisense) were used.
The initial denaturation at 95 /C176C for5 min was followed by 40
cycles of 94 /C176C for 30 s, 56 /C176C annealing for 40 s, and extension at
72/C176C for 30 s.
The amplified products were digested overnight with 5 units of
NlaIII at 37 /C176C and analyzed by electrophoresis in a 2.5% agarose
gel stained with ethidium bromide. The generated fragments of
135 + 111 + 45 bp correspond to allele C while the fragments of
245 + 45 bp to allele G.
2.2.4. Measurement of serum interleukin 6 (IL6) levels
The concentrations of IL6in serum were determined using a
double antibody sandwich ELISA (kit provided by Biosource Europe
Table 1
Demographic and clinical characteristics of patients with CAP.
Characteristics N= 100
Age
Median 2.1Range 60 days-13 years
N %
Sex
Male 52 (52)Female 48 (48)
Co-morbidity
No 83 (83)Asthma 12 (12)
Chronic lung disease 5 (5)
Pneumonia severity
Mild 26 (26)Moderate 39 (39)Severe 35 (35)
ICU admission
No 73 (73)
Yes 27 (27)
ARF
No 87 (87)Yes 13 (13)
Severe sepsis
No 79 (79)Yes 21 (21)
Hospital mortality
No 93 (93)Yes 7 (7)H.E. Zidan et al. / Cytokine 67 (2014) 60–64 61

Author's personal copy
S.A., Belgium) according to the manufacturer’s instructions by
using standard curve.
3. Statistical analysis
Descriptive statistics were performed for all variables. After cal-
culation of the Hardy–Weinberg equilibrium, Pearson chi2test was
used to determine differences in the frequencies of the different
IL6-174 G /Cgenotypes between patients and controls and between
clinical outcomes within patients. In the case of statistically signif-
icant results, logistic regression analysis was performed with the
significant variable in combination with clinical characteristics of
the disease. The odds ratios (ORs) and 95% confidence intervals
(95% CIs) were calculated as a measure of the association of IL6-
174 G /Cwith CAP outcome. Continuous parameters were investi-
gated with independent-sample ttests or ANOVA tests, depending
on the distribution of the data. The appropriate sample size and
power of the study were determined using PAWE-3D. PAWE-3D
calculations showed that the sample size, together with the speci-
fied study design, allele frequencies, and allowable error rates, can
give as high as 90% power and can detect variant allele frequency
of at least 0.05 and genotype relative risk of P1.8 at 80% power.
The significance level was set at P< 0.05 unless reported otherwise.
Data were analyzed using SPSS software version 11 (SPSS Inc., Chi-
cago, Illinois, USA) [16].
4. Results
4.1. Characteristics of CAP patients and controls
100 patients were included in this study. Of these patients, 52
were males (52%) and 48 were females (48%). Their age ranged be-
tween 60 days – 13 years. The median age was 2.1. 12% of children
had asthma and 5% had other chronic lung diseases.
According to CAP severity, 26 (26%) of children had mild CAP 39
(39%) of children had moderate CAP and 35 (35%) had severe. Dur-
ing their hospital stay, 27 (27%) patients were admitted to the ICU
and 7 (7%) patients died. 21 (21%) patients suffered from severe
sepsis. 13 (13%) patients suffered from ARF.
The control group included110 healthy unrelated children with
matched age and sex and from the same geographical area as the
patients ( Table 1 ).
4.2. IL6-174 G/C genotype and susceptibility to CAP
Distribution of IL6-174 G /Cgenotypes, alleles and serum IL6lev-
els in patients with community-acquired pneumonia (CAP) and
controls are summarized in Table 2 .
The genotype frequencies of IL6-174 G /Cwere conformed to the
Hardy–Weinberg equilibrium in which P for patients 0.16 and for
controls 0.32.
In CAP patients, the frequencies were 32% for GG homozygous
individuals, 55% for GC heterozygous individuals, and 13% for CC
homozygous individuals, while in the control group they were 20%,
54.6%, and 25.4% respectively. The frequency of G allele in CAP pa-
tients and controls were 59.5% and 47.3% respectively and the fre-
quency of C allele in both groups respectively were 40.5% and 52.7%.
There was a significant association between the GG genotype
and susceptibility to CAP in general ( P< 0.02), as did the G allele
(p< 0.012) [OR and 95% CI for the G allele: 1.6 (1.1–2.4)] ( Table 2 ).
4.3. IL6-174 G/C genotype and outcome of CAP
In patients with the CC genotype, the frequency of severe sepsis
(53.8%) was significantly higher than in patients with the GC (20%)and GG genotypes (9.4%). GG genotype was protective against se-
vere sepsis ( p= 0.004). The frequency of ARF was in significant
association in patients with CC genotypes (46.2%) than in patientswith GC genotype (9.1%), GG genotypes (6.3%) and GG genotype
was associated with low risk of ARF ( p< 0.001). The genotype
and allele distribution in patients who had been admitted to
the ICU during their hospital stay were as follow GG genotype
(15.6%), GC genotype (23.6%), CC genotype (69.2%). CC genotype
carried the risk of ICU admission and GG genotype was protective
(p< 0.001).
The hospital mortality were in significant association in pa-
tients with CC genotype (30.8%) than in patient with GC genotype
(5.4%), GG genotype (0%). GG genotype was protective against hos-
pital mortality ( p< 0.001) ( Table 3 ).
By logistic regression analysis, GG genotype and G allele, had
less severe clinical course as reflected by lower risk of severe sepsis
(OR, 0.44; 95% CI,0.19–0.98), p= 0.027 and lower risk of hospital
mortality (OR, 0.27; CI, 0.06–0.99), p= 0.04.
4.4. Serum IL6 levels and IL6-174 G/C genotypes
Serum IL 6levels were significantly higher in patients with CAP
than controls p< 0.001 ( Table 2 ).
No association between IL6-174 G /Cgenotypes and alleles in
which serum IL6levels in GG genotypes were (31.3 ± 7.4), in GC
genotypes were (30 ± 5.5), in CC genotypes were (32.2 ± 4.5) and
in G alleles were (30 ± 5.5) and in C alleles were (31 ± 4.2) and
P= 0.44 ( Table 3 ).
5. Discussion
Community-acquired pneumonia (CAP) is a major cause of mor-
bidity and mortality worldwide [17]. Mechanisms underlying and
influencing lung injury associated with CAP are complex and in-
volve a variety of molecular and cellular processes that may be
influenced by genetic factors [18].
Interleukin 6 ( IL6) plays an important role in the development,
pathogenesis and the outcome of SIRS, sepsis and septic shock [19].
Studies concerning CAP-associated lung injury in children are lim-
ited, conflicting results are often inferred from adult studies.
Thus we studied the influence of IL6-174 G /CSNP polymor-
phism on the clinical course of CAP in Egyptian children as contra-
dictory findings about the role of several genetic variants in sepsis
had been reported aiming to find a solution to such problem. To the
best of our knowledge, this is the first evaluation of the association
ofIL6-174G /Cpolymorphism with the incidence and severity of
CAP in Egyptian children.
As regards IL6polymorphism, we found significant difference in
the genotype frequency of IL6-174 G /Cpolymorphism between
children with CAP and control group with increased frequency ofTable 2
Distribution of IL-6-174 G/C genotypes, alleles and serum IL-6 levels in patients withcommunity-acquired pneumonia (CAP) and controls.
Genotype Patient group Control group P
(n= 100) % ( n= 110) %
GG 32 (32) 22 (20) 0.02*
GC 55 (55) 60 (54.6)
CC 13 (13) 28 (25.4)
Alleles
G 119 (59.5) 104 (47.3) 0.012*
C 81 (40.5) 116 (52.7)
IL6 pg/ml 29.3 ± 8.5 10.57 ± 0.98 <0.0001*
*p< 0.05 when compared to control group.62 H.E. Zidan et al. / Cytokine 67 (2014) 60–64

Author's personal copy
GG genotypes and G allele in patients group in comparison to
control group.
Similar to our results, a study done by Salnikova et al. [20] re-
vealed that individuals bearing IL6-174 homozygous genotypes
G/G had a higher susceptibility to CAP. In contrary Gallagher
et al. [21] found that the IL6-174 G /Cpromoter SNP was of no risk
for CAP in general. Schaaf et al. [22] also found no significant differ-
ences in the allele distribution between patients and controls.
Discrepancies between previously published studies and our
study could probably be explained by the differences in age;
study design or geographic/ethnicity, or by gene–gene or gene–
environmental interactions. The genetic predisposition to CAP
could be polygenous, with many variants in multiple gene locuses,
playing an important role.
Collectively, our data supported the possibility of the presence of
theIL6-174 G /CSNP that may account for individual differences in
the severity and outcome of CAP. We observed an association be-
tween homozygosity for IL6-174 G /Gand a protection against severe
sepsis, respiratory failure, ICU admission and hospital mortality.
In accordance with our results, Tischendorf et al. [23] demon-
strated that a significantly lower frequency of the IL6-174 G /Ggeno-
type was associated with higher mortality in septic patients
compared to surviving septic patients, suggesting that the GG geno-
type was in some fashion protective, or conversely carriage the C al-
lele placed individuals at risk. Also Michalek et al. [24] were able to
demonstrate that the less common CC homozygous variant at posi-
tion /C0174 of the IL6gene seemed to be associated with septic shock
and that the variant in the IL6gene played an important role in chil-
dren with sepsis. They concluded this, despite the fact that they had
used healthy adults as controls. Michalek et al. [24] did not know
the exact mechanism by which the G variant was protective, but
they stated that it would be interesting to study its association with
other gene polymorphisms. Furthermore, Schluter et al. [9]de-
scribed that the IL6-174 G /Ggenotype was associated with im-
proved sepsis outcome, what was in accordance with our results,
and with Michalek et al. [24] results which suggested that C/C geno-
type in a general Caucasian population is probably less protective
against serious conditions leading to sepsis.
In the contrary, the influence of genetic polymorphisms of IL6
gene promoter – 174 G /Con the severity of systemic inflammatory
response syndrome (SIRS) associated with CAP was studied by
Martín-Loeches et al. [25]. This research showed that the distribu-
tion of the IL6-174G /Cgenotype was similar in CAP patients and
controls. In patients who were admitted with CAP, no significant
differences were observed compared with progression between
groups. These findings demonstrated that the IL6-174G /Cpolymor-
phism was not associated with risk and outcome of CAP in the
Spanish white Caucasian population.
Also Gallagher et al. [21] did not find any association of the
IL6-174G /CSNP with susceptibility and severity of CAP. They tried
to explain their results stating that possible explanations for the
discrepancies included limited statistical power, heterogeneous
patient populations with unrecognized confounding factors, andstratification of population substructure and/or imprecise defini-
tions of phenotype.
In an attempt to explain our results concerning the protective ef-
fect of G/G genotype of IL6-174G /C, we studied the serum level of IL6
in our patients, which was significantly elevated in comparison to
controls, however, there was a lack of association of the IL6-174G /
Cpromoter polymorphism with serum IL6levels. In accordance
with our results, Endeman et al. [26] showed that IL6significantly
elevated as acute phase proteins in CAP. These findings confirmed
in human and experimental pneumococcal pneumonia, in which
the inflammatory response was characterized by an extended
pro-inflammatory response resulting in high levels of IL6[27–30] .
Michaleka et al. [24] recorded that elevated IL6level was de-
tected in sepsis patients and the G allele could be associated with
increased levels of plasma IL6in sepsis patients. They explained
their results stating that elevated levels of proinflammatory cyto-
kine IL6activate neutrophils, causing higher expression of CD11
and CD18 molecules. In addition vascular adhesion molecules are
activated causing neutrophil adhesion to the endothelium and acti-
vation of endothelial cells. Moreover neutrophils produce reactive
oxygen and endothelial cells produce nitric oxide. These molecules
contribute to the production of peroxynitrite which leads to cell
damage and organ failure [24]. Also, Schluter et al. [9]found that
median systemic IL6levels in septic patients markedly elevated
but were not associated with the IL6promoter genotype. Müller-
Steinhardt et al. [31] found that the allele IL6-174C was associated
with increased IL6 secretion. Against our results, Terry et al. [32]
found that the IL6-174G /Cpolymorphism affects transcription by
altering the serum levels of IL6, with the C allele associated with
significantly lower levels of plasma IL6. It was described by Fish-
man et al. [33] that individuals with IL6 C -174allele have signifi-
cantly lower plasma concentrations of IL6, in line with these
results Kilpinen et al. [34] found this allele was associated with re-
duced IL6plasma levels in newborns.
However, Müller-Steinhardt et al. [31] found that the allele IL6-
174G was associated with low levels of IL6. Endler et al. [35] tried to
explain these conflicting findings stating that the localized tissue-
specific effects were IL6production modulated by the IL6-174G /C
polymorphism, whereas systemic IL6concentrations remained
unaffected and many of the best prognostic markers in CAP were re-
lated to the systemic effects of sepsis rather than pulmonary effects.
Endler et al. [35] added that other polymorphisms within the
IL6promoter, such as the IL6-572G /Cpromoter polymorphism
[36] or complex haplotypes of other promoter polymorphisms
[32] had been discussed as influencing IL6concentrations. How-
ever, these genetic variants are considerably less frequent than
the IL6-174G /Cpolymorphism and thus would have required a
large sample size which was not feasible in their study. The reason-
able conclusion from all this is to do with the fact that this SNP can
be a marker for local or systemic Il6secretion, as well as a marker
for a different function of IL6.
In our study, the protective effect of GG genotype was not
related to serum IL6, but other factors may be involved. The func-Table 3
Association of IL6-174G/C genotypes and serum IL-6 levels with severity and outcome in patients with CAP.
GG ( n= 32) GC ( n= 55) CC ( n= 13) P
N% N % N%
Severe sepsis 3 (9.4) 11 (20) 7 (53.8) 0.004*
Acute respiratory faliure 2 (6.3) 5 (9.1) 6 (46.2) <0.001*
ICU 5 (15.6) 13 (23.6) 9 (69.2) <0.001*
Hospital mortality 0 3 (5.4) 4 (30.8) <0.001*
IL-6 pg/ml 31.3 ± 7.4 30 ± 5.5 32.2 ± 4.5 0.44**
*Calculated by chi2test.
**Calculated by ANOVA test.H.E. Zidan et al. / Cytokine 67 (2014) 60–64 63

Author's personal copy
tional importance of this polymorphism remains to be elucidated,
and many SNPs may simply represent genomic markers for other
more functionally relevant genetic variants in linkage disequilib-
rium. These observations should be obviously confirmed in other
populations.
In conclusion, our data brought a novel observation of genetic
predisposition to CAP and its complications, associated with a
polymorphism in the IL6gene in children. Further studies are
needed to clarify its role in association with other similar proteins
and molecules involved in the local and systemic inflammatory
response to infection.
It is supposed that genetic information will be used in the
future by clinicians to define different subtypes of the disease
and to stratify patients according to their risk for poor outcomes.
Genotyping will be used also to determine optimal drugs anddosage for treating individuals while minimizing adverse effects.
References
[1]McIntosh K. Community-acquired pneumonia in children. N Engl J Med
2002;346:429–37 .
[2]Garau J, Baquero F, Perez-Trallero E, Pérez JL, Martín-Sánchez AM, García-Rey
C, et al. Factors impacting on length of stay and mortality of community-
acquired pneumonia. Clin Microbiol Infect 2008;14:322–9 .
[3]Wunderink RG, Waterer GW. Genetics of community-acquired pneumonia.
Semin Respir Crit Care Med 2005;26:553–62 .
[4]Solé-Violán J, de Castro Fv, García-Laorden MI, Blanquer J, Aspa J, Borderías L,
et al. Genetic variability in the severity and outcome of community-acquired
pneumonia. Respir Med 2010;104:440–7 .
[5]von Dossow V, Rotard K, Redlich U, Hein OV, Spies CD. Circulating immune
parameters predicting the progression from hospital-acquired pneumonia to
septic shock in surgical patients. Crit Care 2005;9:R662–9 .
[6]Zobel K, Martus P, Pletz MW, Ewig S, Prediger M, Welte T, et al. Interleukin 6,
lipopolysaccharide-binding protein and interleukin 10 in the prediction of risk
and etiologic patterns in patients with community acquired pneumonia:
results from the German competence network CAPNETZ. BMC Pulm Med
2012;12:6 .
[7]Jones SA. Directing transition from innate to acquired immunity: defining a
role for IL-6. J Immunol 2005;175:3463–8 .
[8]Fischer CP. Interleukin-6 in acute exercise and training: what is the biological
relevance? Exerc Immunol Rev 2006;12:6–33 .
[9]Schluter B, Raufhake C, Erren M, Schotte H, Kipp F, Rust S. Effect of the
interleukin-6 promoter polymorphism (-174 G/C) on the incidence and
outcome of sepsis. Crit Care Med 2002;30:32–7 .
[10] Waage A, Brandtzaeg P, Halstensen A, Kierulf P, Espevik T. The complex pattern
of cytokines in serum from patients with meningococcal septic shock:
association between interleukin 6, interleukin 1 and fatal outcome. J Exp
Med 1989;169(1):333–8 .
[11] Chow AW, Hall CB, Klein JO, Kammer RB, Meyer RD, Remington JS. Evaluation
of new anti-infective drugs for the treatment of respiratory tract infections.
Infectious Diseases Society of America and the Food and Drug Administration.
Clin Infect Dis 1992;15(Suppl 1):S62–88 .
[12] Castro K, Ward J, Slutsker L, et al. Revised classification system for HIV
infection and expanded surveillance case definition for AIDS amongadolescents and adults. MMWR Recomm Rep 1992;41(RR-17):1–19
.
[13] British Thoracic Society of Standards of Care Committee. BTS Guidelines for the
management of community acquired pneumonia in childhood. Thorax
2011;57. 1i-24 .
[14] Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions
for sepsis and organ failure and guidelines for the use of innovative therapies
in sepsis. Chest 1992;101:1644–55 .
[15] Duch CR, Figueiredo MS, Ribas C, Almeida MS, Colleoni GW, Bordin JO. Analysis
of polymorphism at site -174 G/C of interleukin-6 promoter region in multiple
myeloma. Braz J Med Biol Res 2007;40:265–7 .[16] SPSS for Windows. Statistical Package for the Social Sciences, version 11.0.1.
SPSS Inc., Chicago; 2001.
[17] Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC,
et al. Infectious Diseases Society of America/American Thoracic Society
consensus guidelines on the management of community-acquired
pneumonia in adults. Clin Infect Dis 2007;44(Suppl 2):S27–72 .
[18] Patwari PP, O’Cain P, Goodman DM, Smith M, Krushkal J, Liu C, et al.
Interleukin-1 receptor antagonist intron 2 variable number of tandem repeats
polymorphism and respiratory failure in children with community-acquired
pneumonia. Pediatr Crit Care Med 2008;9(6):553–9 .
[19] Hack CE, Huijens JH, Felt-Bersma RJ, Schreuder WO, Eerenberg- Belmer AJ,
Paardekooper J, et al. Increased plasma levels of interleukin-6 in sepsis. Blood
1989;74(5):1704–10 .
[20] Salnikova LE, Smelaya TV, Moroz VV, Golubev AM, Rubanovich AV. Functional
polymorphisms in the CYP1A1, ACE, and IL-6 genes contribute to susceptibility
to community-acquired and nosocomial pneumonia. Int J Infect Diseases
2013;17(6):433–42 .
[21] Gallagher PM, Lowe G, Fitzgerald T, Bella A, Greene CM, McElvaney NG, et al.
Association of IL-10 polymorphism with severity of illness in community
acquired pneumonia. Thorax 2003;58(2):154–6 .
[22] Schaaf B, Rupp J, Müller-Steinhardt M, Kruse J, Boehmke F, Maass M, et al. The
interleukin-6_174 promoter polymorphism is associated with extrapulmonary
bacterial dissemination in Streptococcus pneumoniae infection. Cytokine2005;31:324–8
.
[23] Tischendorf JJ, Yagmur E, Scholten D, Vidacek D, Koch A, Winograd R, et al. The
interleukin-6 (IL6)-174 G/C promoter genotype is associated with the presence
of septic shock and the ex vivo secretion of IL6. Int J Immunogenet
2007;34(6):413–8 .
[24] Michalek J, Svetlikova P, Fedora M, Klimovic M, Klapacova L, Bartosova D, et al.
Interleukin-6 gene variants and the risk of sepsis development in children.
Hum Immunol 2007;68:756–60 .
[25] Martín-Loeches I, Solé-Violán J, de Castro F Rodríguez, García-Laorden MI,
Borderías L, Blanquer J, et al. Variants at the promoter of the interleukin-6 gene
are associated with severity and outcome of pneumococcal community-
acquired pneumonia. Intensive Care Med 2012;38:256–62 .
[26] Endeman H, Meijvis SC, Rijkers GT, van Velzen-Blad H, van Moorsel CH,
Grutters JC, et al. Systemic cytokine response in patients with community-
acquired pneumonia. Eur Respir J 2011;37:1431–8 .
[27] Kolling UK, Hansen F, Braun J, Rink L, Katus HA, Dalhoff K. Leucocyte response
and anti-inflammatory cytokines in community acquired pneumonia. Thorax2001;56:121–5
.
[28] Khan AQ, Shen Y, Wu ZQ, Wynn TA, Snapper CM. Endogenous pro- and anti-
inflammatory cytokines differentially regulate an in vivo humoral response to
Streptococcus pneumonia. Infect Immun 2002;70:749–61 .
[29] Antunes G, Evans SA, Lordan JL, Frew AJ. Systemic cytokine levels in
community-acquired pneumonia and their association with disease severity.
Eur Respir J 2002;20:990–5 .
[30] Menéndez R, Martínez R, Reyes S, Mensa J, Filella X, Marcos MA, et al.
Biomarkers improve mortality prediction by prognostic scales in community-
acquired pneumonia. Thorax 2009;64(7):587–91 .
[31] Müller-Steinhardt M, Ebel B, Härtel C. The impact of interleukin-6
promoter-597/-572/-174 genotype on interleukin-6 production after
lipopolysaccharide stimulation. Clin Exp Immunol 2007;147:339–45 .
[32] Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms
on interleukin 6 transcriptional regulation. J Biol Chem 2000;275:18138–44 .
[33] Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, et al.
The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6
transcription and plasma IL-6 levels, and an association with systemic-onset
juvenile chronic arthritis. J Clin Invest 1998;102:1369 .
[34] Kilpinen S, Hulkkonen J, Wang XY, Hurme M. The promoter polymorphism of
the interleukin-6 gene regulates interleukin-6 production in neonates but not
in adults. Eur Cytokine Netw 2001;12:62–8 .
[35] Endler G, Marsik C, Joukhadar C, Marculescu R, Mayr F, Mannhalter C, et al. The
Interleukin-6 G(_174)C Promoter Polymorphism does not determine Plasmainterleukin-6 concentrations in experimental endotoxemia in humans. Clin
Chem 2004;50(1):195–200
.
[36] Brull DJ, Leeson CP, Montgomery HE, Mullen M, deDivitiis M, Humphries SE,
et al. The effect of the interleukin-6_174G_C promoter gene polymorphism on
endothelial function in healthy volunteers. Eur J Clin Invest 2002;32:153–7 .64 H.E. Zidan et al. / Cytokine 67 (2014) 60–64