Pediatrics and Neonatology (2018) 59, 329e338

Available online at www.sciencedirect.com

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journal homepage: http://www.pediatr-neonatol.com

Review Article

Evaluate the diagnosis of neonatal sepsis by

measuring interleukins: A systematic review
Hassan Boskabadi a, Maryam Zakerihamidi b,*

a
Department of Pediatrics, Mashhad University of Medical Sciences, Mashhad, Iran
b
Department of Midwifery, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran

Received Nov 19, 2016; received in revised form Sep 22, 2017; accepted Oct 13, 2017
Available online 20 October 2017

Key Words Neonatal sepsis is a dangerous and common disease among infants which is associated with high
diagnosis; morbidity and mortality. Interleukins may be helpful for diagnosis of neonatal sepsis. Therefore,
interleukins; this study is conducted to investigate the role of interleukins in the diagnosis of neonatal sepsis.
neonatal; In this study, databases including PubMed, Cochrane Library, ISI and Google Scholar were
sepsis searched up to 2016. Keywords were: Sepsis, neonatal, interleukins, prediction and diagnosis.
Study inclusion criteria were: Articles about the relationship between the diagnosis of neonatal
sepsis and interleukins; studies on babies; English and Persian articles and enough information
from test results. Articles that had focused on adult sepsis or had used other markers except
ILs or just their abstracts were available were excluded from the study. Of 100 searched studies,
eventually, 16 articles were considered including 12 prospective studies, 3 cross-sectional
studies and 1 retrospective study. IL6 has been studied more than other interleukins (50% of ar-
ticles). ILs 6, 8 and 10 are among the initial markers of neonatal sepsis diagnosis. IL6 above
68 pg/ml had 85% sensitivity and 80% specificity, IL8 above 269.51 pg/ml had 80% sensitivity
and 50% specificity, IL10 above 27 pg/ml had 60% sensitivity and 87% specificity and combined
interleukins above 186.83 pg/ml had 75.63% sensitivity and 71.49% specificity in sepsis diagnosis.
Interleukins can be helpful in the diagnosis of neonatal sepsis based on the results of this study.
IL6 had the most sensitivity and IL10 had the most specificity for diagnosis of sepsis.
Copyright ª 2017, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).

1. Introduction preterm babies.1,2 Neonatal infections are a major cause of

infant mortality so that in our center, it was the third
Neonatal sepsis is along with high neonatal morbidity (1e10 leading cause of neonatal death and had allocated about
per 1000 live birth) and mortality (15e50%), especially in 25% of causes of neonatal death to itself.1 Neonatal sepsis is
a major challenge for newborns specialists generally due to

* Corresponding author. Department of Midwifery, School of Medicine, Islamic Azad University, Tonekabon Branch, Tonekabon, Iran.
E-mail address: maryamzakerihamidi@yahoo.co.nz (M. Zakerihamidi).

https://doi.org/10.1016/j.pedneo.2017.10.004
1875-9572/Copyright ª 2017, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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330
non-specific symptoms as well as the absence of an early
definitive diagnostic test2.
Since the amount of successful treatment depends on
early initiation of appropriate antibiotic, empirical anti-
microbial therapy usually starts very early in all infants with
clinical signs of sepsis. On the other hand, this clinical
practice exposes babies to adverse effects of antimicrobial
agents as well. In addition, it increases the duration of
hospitalization and costs and creates and expands the cases
resistance to different types of bacteria.3 Early detection
of neonatal sepsis is an essential prerequisite for improving
survival and treatment outcomes.4
It was found in a retrospective study on infants under
investigation and treatment of neonatal sepsis with clinical
symptoms suspected to primary infection during the first
week of life that most of these infants did not require
Figure 1 Search strategy and selected articles.
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H. Boskabadi, M. Zakerihamidi
antibiotic. This means that only 10% of these infants had
specified confirmed neonatal sepsis, while about 90% of
babies were taking unnecessary antibiotics.5 Conventional
hematological and microbiological methods which are
routinely used for diagnosis of neonatal sepsis cannot
reduce deaths and serious complications of neonatal sepsis.
One of the wishes of babies’ specialists is to find an ideal
biomarker or biomarkers to provide early, specific and valid
detection of babies at risk of infection. Increasing under-
standing of the ability of the immune system of infants in
response to infection will lead to a better identification of
biomarkers for improving diagnosis, treatment and prog-
nosis of neonatal sepsis in future.6
Isolation of microorganisms from body fluids including
blood, cerebrospinal fluid and urine are methods of gold
standard for diagnosis of neonatal infection. But, microbi-
ological culture is not available before at least 36e48 h.7 So
accurate laboratory tests are required to rule out infection
and reduce unnecessary antibiotic treatment.8 So hema-
tological parameters and interleukins may be helpful for
early diagnosis of neonatal sepsis.9 Many studies have tried
to find valid initial reaction of cytokines for early diagnosis
of neonatal sepsis.10 Inflammatory process in sepsis is very
complex in terms of biochemical. Based on the results of
laboratory and clinical studies, it has been clear that some
pro-inflammatory cytokines reach their peak very quick
within one to four hours after the onset sepsis.11 Analysis of
immunological mediators may contribute to definitive and
timely diagnosis of sepsis. Measuring cytokines as markers
of sepsis has been taken into consideration in recent years12
and biochemical markers such as CRP, TNF-a and ILs have
been evaluated as the main indicators for early detection of
neonatal sepsis.13 Cytokines are polypeptide messengers
with low molecular weight which are created by macro-
phages and lymphocytes in response to antigenic stimula-
tions or products of inflammation.12 One of identifying
factors of neonatal sepsis is measuring interleukins. So that
it is proposed to increase serum levels of interleukins 6, 8
and 10 as a valuable marker for early diagnosis and pre-
diction of sepsis consequences. Levels of IL10 can predict
the diagnosis of late neonatal sepsis before positive blood
culture.1 IL10 is an anti-inflammatory cytokine that is often
produced by T and B lymphocytes and macrophages and its’
level increases in the incidence of neonatal bacterial in-
fections.14 Despite recognition of various biomarkers, no
single biomarker could be used exclusively for the accurate
diagnosis of neonatal sepsis. However, the combination of
biomarkers may improve sensitivity of detection and
treatment.6 The results of Boskabadi et al., (2013) showed
that IL6 with boundary values of 10.85 pg/ml is distinctive
to differentiate sepsis patients and healthy controls and
values higher than 78.2 pg/ml from this factor can be used
to predict neonatal mortality. IL8 in boundary values of
60.05 pg/ml is used for differentiation of specified infection
from unspecified.15 Results of a study showed that the
values of IL10 and CRP in specified infection (sepsis clinical
trial) were higher than the control group. The values higher
than 14 pg/ml for IL10 in diagnosis of neonatal sepsis had
77.7% sensitivity, 78.8% specificity, 73.6% positive predic-
tive value and 90% negative predictive value.16
As interleukins are known as one of the early inflam-
matory responses to infections, they are potentially
Neonatal sepsis by measuring ILs
important in early diagnosis and hence proper management
of infectious before the establishment of fulminant stage.
Since neonatal sepsis is a major cause of mortality and
morbidity in infants, and also early detection of neonatal
sepsis leads to appropriate treatment and improve neonatal
outcomes, this study has systematically reviewed the
diagnosis of neonatal sepsis with interleukins.
2. Methods
2.1. Selecting ILs for diagnosis of neonatal sepsis
After initial review of searched articles, the list of in-
terleukins were prepared to carry out a systematic review
and only the articles were investigated that have worked on
the role ILs in diagnosis of neonatal sepsis. In this regard,
the articles containing interleukins such as IL6, IL8 and IL10
or their combination were enrolled for diagnosis of
neonatal sepsis.
2.2. Search strategy
We used PubMed, EMBASE and Google Scholar databases in
order to do a systematic review and find studies including
measures for diagnosis of neonatal sepsis by interleukins.
We used the keywords “neonatal sepsis”, “interleukin” and
“diagnosis” to search the articles. 100 studies had inclusion
criteria which were collected in a separate library file using
EndNote software. Among these, 30 duplicated articles
were removed. The searched articles were evaluated in
terms of title and abstract and 40 articles were also
excluded in this stage. From the 30 remaining studies, 15
articles were excluded due to incomplete data, lack of full
text, and uncertainty of the type of the study and target
group. Finally, 15 articles related to the subject of the
study were selected.
2.3. Inclusion criteria
Articles were selected based on the following criteria: 1)
Study population is the infants. 2) Neonatal sepsis is
confirmed. 3) Interleukins are evaluated for detecting or
predicting neonatal sepsis. 4) Articles are in Persian and
English language. 5) There is sufficient data from test
results.
2.4. Exclusion criteria
To prepare articles appropriate and relevant to the subject,
the following articles were excluded: 1) Articles which had
reviewed sepsis in adults or animals. 2) Articles which had
used other markers than interleukins. 3) The articles that
only their abstract was available.
2.5. Data extraction and quality assessment of
articles
Articles with full text were received from mentioned da-
tabases. Extracted data from them was drawn in Excel
software with following titles: name and family name of
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331
authors, year of study, study method, study area, subject
group, control group, type of IL, IL measurement time,
sensitivity, specificity, positive predictive value, negative
predictive value and the results of the investigations.
We determined the methodological quality of papers
using quality control tool for diagnostic accuracy of studies
(QUADAS). This tool consists of 14 questions and “yes”,
“no” and “uncertain” answers with scores of respectively 1,
1 and 0 and maximum score of 14.17
Of 100 found articles, finally, 16 articles were reviewed
with a sample of 1650 infants (see Fig. 1). The searched
articles were related to the years 1994e2016. 8 articles
(50%) had evaluated IL6 and 1 article (6.25%) had evaluated
IL8, 1 article (6.25%) had reviewed IL10 and 6 articles
(37.5%) had used combined markers.
3. Results
3.1. Prevalence studies conducted on IL
The review of studies that have been conducted from 1994
to 2016 show that IL6 is a biomarker that has been studied
more than any other interleukin (8 articles, 50% of articles).
6 articles were related to the combination of interleukins,
one article was about IL8 and one study was about IL10.
3.2. Heterogeneity of studies
The searched studies on the relationship of interleukins and
diagnosis of neonatal sepsis were different in terms of in-
clusion criteria of infants, defining the subject group,
research methodology, sample size, interleukins boundary
limit and interleukins diagnostic value. One retrospective
study, three cross-sectional studies and 12 prospective
studies were conducted. The cutoff for IL6 was between 10
and 181 pg/ml, IL8 was between 54 and 900 pg/ml, IL10 was
between 14 and 40 pg/ml. Sensitivity, specificity, positive
predictive value and negative predictive value of ILs in
searched studies were different (Table 1).
3.3. Global distribution of studies related to
interleukins
Most studies related to diagnosis of neonatal sepsis is con-
ducted using interleukins in Iran (6 studies, 37.5%) and then
in India (4 studies, 25%), china (1 study, 6.25%), Greece (1
study, 6.25%), Bangladesh (1 study, 6.25%), Denmark (1
study, 6.25%), Brazil (1 study, 6.25%) and Germany (1 study,
6.25%).
3.4. Articles related to the assessment of IL6 (8
article)
Sonawane et al., (2015) in a prospective study evaluated
the efficiency of IL6 as a primary diagnostic marker of
sepsis. 40 infants with risk factors, clinical signs and
symptoms of sepsis as the subject group and 40 healthy
infants without risk factors of sepsis were studied as the
control group. IL6 had 100 pg/ml, 95.83% sensitivity, 87.50%
specificity, 92% positive predictive value, 93.33% negative
 332
Table 1 Summary of conducted articles about diagnosis of neonatal sepsis by interleukins.
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Author/year Study Location Subject group Control group Markers Measurement time Turning point Sensitivity Specificity Positive Negative predictive Results QUADAS
method predictive value scores
value
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Zhao et al., Prospective China 140 infants susceptible of 61 infants without IL6, 8 Before and 3 days IL6: 32 pg/ml IL6:87.8% IL6:79.6%IL8: Diagnostic value of IL6 was more 13
20154 having infection (49 infection after treatment IL8: 54 pg/ml IL8:77.6% IL6,8: 63.8%IL6,8: than IL8.
infants with sepsis and 91 71.4% 86.2%
with Local infection)
Boskabadi Prospective Iran 36 infants 41 infants IL10 Within the first 6 h 14 pg/ml 77.7% 87.8% IL10 is an early predictive marker 13
et al., after occurring for neonatal infection and its’ high
20115 infection signs values are related to sever
infection.
Sonawane Prospective India 40 infants 40 infants IL6 During the first 100 pg/ml 95.83% 87.5% 92% 93.33% IL6 level in patients with sepsis is 12
et al., 24 h of life increased and its’ increase rate
2015 depends on sepsis severity.
Arani et al., Analytic Iran 142 infants IL6 12 h after Inflammatory 11
2013 description hospitalization markers are
effective in
diagnosis of
neonatal sepsis
Basu et al., prospective India 36 signed infants with 36 infants without IL6 Soon after birth 40.5 pg/ml 92.3% 90.48% IL6 Umbilical cord blood can be 13
2012 positive blood culture sign and risk factor used as an early diagnostic marker
with high sensitivity and specificity
and with 40.5 pg/ml boundary
limit.
El-Sonbaty prospective Greece 36 infants susceptible of 32 infants without CRP, TNF, IL6 6 h after CRP: 12 mg/l CRP: 91% CRP: 100% TNF and CRP markers are superior 10
et al., having clinical sepsis, 48 infection and IL1 hospitalization TNF: 113/ TNF:83% IL6: TNF:100% IL6: in sepsis diagnosis towards
2016 infants with confirmed 2 ng/ml IL6: 100% IL1: 100% 47% IL1: 47% determining IL6 and IL1 values
sepsis by culture 16/8 pg/ml
IL1: 15 pg/ml
Kumar Prospective India 41 infants with 42 healthy infants IL6 and CRP IL6: 181 pg/ml IL6: 80/1% CRP: IL6: 85/7% IL6: 84/6% IL6: 81/8% CRP: IL6 is a new biomarker with high 12
et al., susceptible sepsis without clinical and CRP: 3.78 mg/ 61% CRP:90.5% CRP:86.2% 70.3% sensitivity and good specificity for
2016 laboratory signs of dl sepsis. IL6 has higher diagnostic
infection value than CRP
Khaled Noor prospective Bangladesh 45 infants susceptible of 30 healthy infants IL6 The first day of IL6:10 pg/ml 55.6% 83.3% Determining the rate of IL6 at the 13
et al., having sepsis occurring beginning of signs and symptoms of
2008 symptoms or the infection can be helpful for
first day of diagnosis of neonatal sepsis.
hospitalization
Bender et Retrospective Denmark Sepsis group: A1 with IL6 IL8 IL10 8-hour intervals IL8: 900 pg/ml IL6: 71% IL6: 88% Combination of an early marker 11
al., 2008 positive blood culture in IL18 TNF-a (at 0, 8, 16, 24, 48 PCT: 25 ng/ml PCT:70% IL8: PCT:86% IL8: with a late marker may reduce the
terms of bacteremia and INF-g PCT CRP and 72 h after IL6: 250 pg/ml 50% I/T: 59% 88% I/T: 88% period without paraclinic
B1 high susceptible of suspecting to I/T: 0.35 IL10: IL10: 43% IL10: 87% diagnostic result.

H. Boskabadi, M. Zakerihamidi
having sepsis (25 infants) neonatal sepsis) 40 pg/ml
Campos Cross- Brazil 55 infants with sepsis CPR, and blood At the day of IL6:97% IL6: 93% In infants with 11
et al., sectional laboratory and clinical Glucose level, blood sepsis IL8: 44% IL8: 97% high levels of
2010 evident in first 72 h who culture, IL6, IL10, diagnosis cytokines while
have been alive at least IL8 and TNF-a birth, abnormality of
to first 7 days. these parameters
will be continued in
whole infectious
process.
 Neonatal sepsis by measuring ILs
Boskabadi Prospective Iran 41 with sepsis clinical 43 healthy infants IL6, IL8 At screening time IL6: 10/85 pg/ IL6: 92/5% IL8: IL6: 97/3% IL8: IL6:97.3% IL6: 93/1% IL8: 97% Simultaneous assessment of IL6, 13
et al., and laboratory findings or of neonatal sepsis ml IL8: 64/ 93/7% 44% IL8:44% IL8 and IL 10 can improve
2013 positive blood culture or 05 pg/ml diagnostic sensitivity and
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cerebrospinal fluid specificity of early neonatal sepsis.

Boskabadi Prospective Iran 38 infants with specified 42 healthy infants IL8, CRP During the primary IL8: 60 pg/ml IL8:95% IL8:10% IL8:97% IL8:10% CRP:69% IL8 is a valid and primary predictive 13
et al., infection or clinical assessment CRP: 6 mg/dl CRP:83% CRP:86% CRP:83% marker for neonatal infection and
2010 sepsis is related to the infection severity.
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Ganesan Prospective India 40 infants susceptible of 40 healthy infants IL6, CRP and IL6:51.29 pg/ CRP: 80% IL6: IL6:62.86% IL6 is a very sensitive marker and 11
et al., having sepsis hs-CRP ml CRP: 100% hp-CRP: CRP:65.70% hs- CRP is a very specific marker for
2016 13.49 mg/l 90% CRP: 32.86% diagnosis of neonatal sepsis.
Buck et al., prospective Germany 11 infants with positive blood culture, CRP, CBC and At the time of IL6: 73% IL6:78% IL6 is a sensitive marker and CRP is 11
1994 15 infants with clinical sepsis, IL6 admission and 24 h CRP:58% a specific marker.
41 infants with infection, 54 infants after admission
without clinical and laboratory
evident and 101 remaining infants
as a complex group
Adib et al., Cross- Iran First group 19 infants with positive IL6, CRP At the time of IL6: 30 pg/ml IL6: 78% IL6: 95% IL6:100% IL6:87% Measuring IL6 for diagnosis of 13
2007 sectional blood culture having sepsis symptoms, admission CRP: 10 mg/ CRP: 57% CRP: 100% neonatal sepsis especially before
second group 31 infants with negative ml the onset of full symptoms of sepsis
blood culture but having 2 or 3 sepsis within the first 24 h of infection is
symptoms, third group 10 healthy more useful than CRP.
infants without sepsis symptoms.
Gharehbaghi Prospective Iran 141 preterm infants including: 1) CRP, IL6 Immediately after IL6: 18 pg/ml IL6: 72% IL6: 55% 33% 92% IL6 has fairly good sensitivity and
et al., group A, 12 infants with early birth and after medium specificity for detecting
2015 sepsis signs and symptoms based cutting umbilical early sepsis and non-infectious ill
on positive blood culture in first 72 h cord infants.
of birth. 2) group B, 24 infants with
diagnosis of clinical sepsis.3) group C,
61 infants with probable infection and
negative blood culture and 4) group D,
44 infants without clinical and laboratory
symptoms of infection in first 72 h of life.

333
334
predictive value and 92.50% accuracy. The results showed
that IL6 has maximum sensitivity and specificity compared
with other septic markers (CRP, Micro-ESR). It was also
found that IL6 level is increased in patients with sepsis and
its’ increase rate is depended on the severity of sepsis.18 In
the study of Arani et al., (2013), infants were divided into
three groups: Group 1) infants who were hospitalized with
positive blood culture. Group 2) infants who were hospi-
talized with negative blood culture and susceptible to
neonatal sepsis. Group 3) healthy and term infants with
similar age and weight who were hospitalized due to
jaundice (control group). The average plasma level of IL6
for sepsis group with signs and symptoms of sepsis and
positive blood culture was 1545.65 pg/ml and it was
14.79 pg/ml with sepsis sign and symptoms but with nega-
tive blood culture (susceptible to sepsis group) and
11.04 pg/ml in control group. Comparison of tests showed
that there is a significant difference between IL6 levels in
the three groups (p Z 0.001).19 Basu et al., (2012) checked
87 infants with risk factors of neonatal sepsis before birth
for 72 h in terms of sepsis. Sensitivity and specificity of IL6
with 40.5 pg/ml cutoff was respectively 92.3% and
90.48%.20 In a study by Kumar et al. (2016), IL6 with a
turning point of 181 pg/ml had sensitivity, specificity, pos-
itive predictive value and negative predictive value of
80.1%, 85.7%, 84.6% and 81.8% respectively.21 In a study by
Khaled Noor et al., (2008), IL6 had 55.6% sensitivity and
83.3% specificity in diagnosis of neonatal sepsis. IL6 had
100% sensitivity, 47.61% specificity, 12% positive predictive
value, 100% predictive value and 51.11% accuracy
compared with CRP.9 In the study of Buck et al., (1994), IL6
was more sensitive than CRP in diagnosis of neonatal sepsis
at the time of admission (73% towards 58%).22 Adib et al.,
(2007) reported sensitivity, specificity, positive predictive
value and negative predictive value of IL6 (with 30 pg/ml
cutoff) respectively 78%, 95%, 100% and 87% for diagnosis of
neonatal sepsis.23 Gharehbaghi et al. (2015), in a prospec-
tive study reviewed 141 preterm infants at 26e35 weeks in
terms of the relation between early sepsis and increasing
the levels of CRP and IL6 in plasma of umbilical cord. They
reported the turning number of 18 pg/ml, 72% sensitivity
and 55% specificity for diagnosis of early sepsis.24
The average values of IL6 in the proposed studies
showed that an IL6 above 68 pg/ml has 85% sensitivity and
80% specificity.
3.5. Articles related to the assessment of IL8
(1 item)
Boskabadi et al., (2010) in their study reported sensitivity,
specificity, positive predictive value and negative predic-
tive value for IL8 boundary limit above 60 pg/ml respec-
tively 95%, 10%, 97% and 10%.25
3.6. Articles related to the assessment of IL10 (1
item)
Boskabadi et al., (2011) showed that the values above
14 pg/ml of IL10 has sensitivity, specificity, positive pre-
dictive value and negative predictive value of respectively
77.7%, 87.8%, 73.6% and 90%.16
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H. Boskabadi, M. Zakerihamidi
3.7. Articles related to the assessment of combined
interleukins (6 articles)
Zhao et al., (2015) evaluated the importance of IL6 and IL8
in diagnosis of neonatal sepsis. IL6 with 32 pg/ml boundary
limit had sensitivity, specificity and accuracy of respec-
tively 87.8%, 79.6% and 81.6% for diagnosis of neonatal
sepsis. IL8 with 54 pg/ml boundary limit had 77.6% sensi-
tivity, 63.8% specificity and 67.2% accuracy for diagnosis of
neonatal sepsis. Combination of IL6 and IL8 had also
sensitivity, specificity and accuracy of respectively 71.4%,
86.2% and 82.6%.26 El-Sonbaty et al., (2016) conducted a
study to assess IL6, TNF, CRP and IL1 to confirm or reject
the diagnosis of neonatal sepsis in the early stages before
receiving antibiotics in Greece. CRP with 12 pg/ml
boundary limit had 91% sensitivity and 100% specificity,
TNF above 113.2 pg/ml had 83% sensitivity and 100%
specificity, IL6 above 16.8 pg/ml had 100% sensitivity and
47% specificity and IL1 above 15 pg/ml had 100% sensitivity
and 47% specificity for infection diagnosis before starting
treatment with antibiotics. According to the results of the
study, TNF and CRP markers were superior towards
determining the amount of IL6 and IL1 values in sepsis
diagnosis.27 Bender et al., (2008) evaluated early and late
markers for diagnosis of neonatal sepsis in Denmark.
Levels of IL6, IL8, IL10, IL18, TNF-a, and INF-y, procalci-
tonin (PCT) and CRP were measured in a 8-hour intervals
(at 0, 8, 16, 24, 48 and 72 h after suspicion of neonatal
sepsis). IL8, IL10 and IL6 were from new markers and PCT,
I/T and CRP were from old markers of diagnosis of neonatal
sepsis. PCT above 25 pg/ml for diagnosis of neonatal sepsis
had 70% sensitivity and 86% specificity. IL6 above 250 pg/
ml had 71% sensitivity and 88% specificity; IL8 above
900 pg/ml had 50% sensitivity and 88% specificity; IL10
above 40 pg/ml had 43% sensitivity and 87% specificity. The
ratio of immature neutrophils to total (I/T) above 0.35 had
59% sensitivity and 88% specificity. The results of TNF, IL18
and INF couldn’t predict neonatal sepsis. In this study, PCT
and CRP were late diagnostic marker for neonatal sepsis.
Thus, combination of IL6 with PCT is a good way to eval-
uate neonatal sepsis at susceptible time of infection. The
old primary marker (I/T) is effective almost as much as
IL6. Combination of an early marker and a late marker may
reduce paraclinical diagnostic time.28 Campos et al.,
(2010) evaluated the serum levels of cytokine and clinical
and laboratory parameters. IL6, IL10, IL1ß and TNF-a were
measured by ELISA method. Although not much changes
were created in the values of these cytokines during the
study, but, infants having the highest levels of cytokines
during sepsis already had their increased levels in umbili-
cal cord blood which their levels were already high up to
96 h after sepsis diagnosis. Clinical and laboratory pa-
rameters between infants with sepsis varied widely.
Abnormal parameters persisted throughout the infectious
process in infants with high levels of cytokines at birth.29
Boskabadi et al. (2013) in a study assessed the serum
levels of interleukins 6, 8 and 10 as diagnostic markers for
infant infection and mortality. The study results showed
that there is a significant statistical difference between
the two groups of subject and control in terms of serum
levels of IL8, IL6 and IL10. IL6 with 10.85 pg/ml is proposed
Neonatal sepsis by measuring ILs 335

for differentiating the two groups of subject and control
and 78.2 pg/ml for prediction of neonatal death. IL8 with
60.05 pg/ml is valuable for differentiating specified
infection from unspecified. In this study, however, IL10
level in the subject model was more than the control
group; but it was not helpful as IL6 and IL8 in predicting
and diagnosing neonatal infection. Measuring IL8, IL6 and
IL10 in infants suspected of having sepsis with mentioned
boundary limit values may predict neonatal sepsis and
prevent receiving unnecessary antibiotics. The re-
searchers concluded that simultaneous assessment of IL8,
IL6 and IL10 can improve sensitivity and specificity of
diagnosis of neonatal sepsis. These combined markers had
89% sensitivity and 100% specificity in differentiating sub-
ject and control groups.15 Ganesan et al., (2016) evaluated
IL6, CRP and hs-CRP as primary markers of neonatal sepsis.
CRP above 13.49 mg/l had 80% sensitivity and 65.70%
specificity. IL6 above 51.29 pg/ml had 100% sensitivity and
62.86% specificity and hs-CRP had 90% sensitivity and
32.86% specificity. Combination of IL6 and CRP had 100%
sensitivity and 75.71% specificity.30 Table 1 has provided
the summary of articles.
According to the results of conducted studies, IL6 more
than 72 pg/ml had 85% sensitivity and 82% specificity, IL8
more than 269.51 pg/ml had 80% sensitivity and 50% spec-
ificity and IL10 more than 27 pg/ml had 60% sensitivity and
87% specificity in diagnosis of neonatal sepsis. According to
the results of conducted studies, combined interleukins
more than 186.83 pg/ml had 75.63% sensitivity and 71.49%
specificity. Hence, among diagnostic interleukins for
neonatal sepsis, IL6 has the highest average of sensitivity
(85%) and IL10 has the highest specificity (78%) (Table 2).
4. Discussion
This study was done to evaluate the diagnosis or prediction
of neonatal sepsis using interleukins. In this regard, 15 ar-
ticles were obtained through searching databases. 7 arti-
cles had reviewed IL6, 6 articles had evaluated combined
interleukins, 1 article had reviewed IL8 and 1 article had
examined IL10. Most studies of diagnosis of neonatal studies
(33.33%) are conducted in Iran and then in India (26.67%)
and most studies (53.34% of articles) had reviewed the ef-
fect of IL6 on diagnosis of neonatal sepsis.
Neonatal sepsis is a global problem with very important
mortality, complications and consequences. Diagnosis of
neonatal sepsis may be delayed due to nonspecific symp-
toms and lack of positive blood culture in the early stages
of sepsis. So, unnecessary treatment with antibiotics may
be started before confirming sepsis diagnosis. Thus, the
cost of treatment will be increased and resistance to an-
tibiotics will also be created.31 Early diagnosis of neonatal
sepsis is still considered as a major laboratory and medical

Table 2 The average of ILs diagnostic value regarding neonatal sepsis.

Biomarker Boundary Sensitivity Specificity Boundary Sensitivity Specificity Average of Average of Average of
values values values range range (%) range5 boundary sensitivity specificity
(pg/ml) limit
IL6 32 87.8% 79.6% 10e100 71e100% 47-95% 67.31 84.10% 79.25%
100 95.83% 87.5% pg/ml pg/ml
40.5 92.3% 90.48%
16/8 100% 47%
181 80/1% 85.7%
10 55.6% 83.3%
250 71% 88%
10/85 92/5% 97/3%
51.29 100% 62.86%
30 78% 95%
18 72% 55%
IL8 54 pg/ml 77.6% 63.8% 54e900 50-95% 10-88% 269.51 79.8% 51.45%
900 pg/ml 50% 88% pg/ml pg/ml
64/05 pg/ 93/7% 44%
m 95% 10%
60 pg/ml
IL10 14 pg/ml 77.7% 87.8% 14e40 43e77.7% 87e87.8% 27 pg/ml 60.35% 87.4%
40 pg/ml 43% 87% pg/ml
IL6, IL8, IL6: 10/85 IL6:92/5% IL6:97/3% 15e900 43e100% 47-88% 186/83 75/63% 71/49%
IL1, IL8:4/05 IL8: 93/7% IL8: 44% pg/ml pg/ml
IL10 IL6:32 IL6:87.8% IL6:79.6%
IL8:54 IL8:77.6% IL8: 63.8%
IL6:16/8 IL6:100% IL6:47%
IL1:15 IL1: 100% IL1: 47%
IL8:900 IL6:71% IL6:88%
IL6:250 IL8:50% IL8:88%
IL10: 40 IL10: 43% IL10: 87%

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336
challenge due to non-specific clinical signs, lack of standard
boundary limit values of sepsis markers and difficulty of
differentiating it from non-infectious conditions such as
respiratory distress syndrome.6 So, a reliable test is
required for diagnosis of neonatal sepsis. Because, delay in
beginning treatment with antibiotics can lead to early
death during the hours of onset of symptoms of infection.32
Despite that blood culture is a gold standard for diagnosis of
neonatal sepsis, but, it is not actually helpful in early
diagnosis of neonatal sepsis. IL-assessment has been
approved in recent studies in order to reduce the time of
diagnosis and increase the accuracy of diagnostic tests in
the early of infection. Increasing cytokines may be created
in normal status after childbirth and this can limit the
application of cytokines as a diagnostic marker in newborns
care section especially immediately after childbirth. Also,
there are numerous other variables such as hypoxia, fetal
distress, and premature, steroid use before calving and
meconium aspiration which increase cytokines levels and
limit their application in diagnosis of early neonatal
sepsis.33 Chemokine and pro-inflammatory cytokines are
essential for host defense against microbial infection, but,
increase of activated pro-inflammatory mediators can
cause harmful results and lead to extensive damages of
small blood vessels, dysfunction of multiple organs and
death.34
Several interleukins with different boundary limit,
sensitivity and specificity were evaluated for diagnosis of
neonatal sepsis. But, neonatal sepsis is still a major chal-
lenge in medicine of newborns due to the lack of a standard
in the values of boundary limit of interleukins. IL6 is used in
most studies for diagnosis of neonatal sepsis.
IL6 is a marker that recently has been taken into
consideration for early diagnosis of neonatal sepsis. IL6 is
created by monocytes, endothelial cells, fibroblasts and
lymphocytes T and B and is much more sensitive than CRP.
But, it cannot be used for sepsis as a single marker due to
its’ short half time.6,35 The study results of Buck et al.,
showed that IL6 level reach its’ pick at the time of admis-
sion and is non-quantifiable after 24 h. Since IL6 has a vital
role in inducing the creation of CRP in liver, there is the
hypothesis that this cytokine is identified in the blood in
earlier levels of bacterial infection compared with CRP.22
The results of the studies showed that the average of
serum level of IL6 in infants with sepsis is higher than
healthy infants.15,36e38 So, IL6 can be applied as an
important marker for early neonatal sepsis in neonates care
sections.39 Since studies on adults with sepsis have shown
that increasing IL6 level is along with higher mortality, it
seems that this mediator is important in pathogenesis of
sepsis.40 One advantage of IL6 assessment is that its’ level is
increased at the onset of infection, while CRP reaches its’
maximum concentration with delay. IL6 of umbilical cord
blood is a better predictor for starting treatment immedi-
ately after birth in infants having risk factors of infection
before birth compared with CRP. So, increasing concen-
tration of IL6 and CRP is a risk factor of preterm delivery
before 32 weeks.41 IL6 has the highest sensitivity (89%) and
negative predictive value (91%) at the onset of infection
compared with other chemical makers such as TNF and
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H. Boskabadi, M. Zakerihamidi
CRP.22 Hu et al., (2015) evaluated the diagnostic value of
IL6 for neonatal sepsis using meta-analysis and reviewed 33
studies including 3135 infants. Sensitivity and specificity of
IL6 for diagnosis of neonatal sepsis was calculated respec-
tively 79% and 83%.42 Shahkar et al., (2011) conducted a
systematic review and evaluated the role of IL6 to predict
neonatal sepsis using meta-analysis method. They reviewed
13 studies including 353 infants with sepsis and 691 infants
of control group. Sensitivity and specificity of IL6 were
respectively 79% and 84%. According to the results of this
study, IL6 is a valid marker for prediction of neonatal sepsis
and can be applied for sepsis early diagnosis in neonates
care units.35 Based on the results of studies, IL6 higher than
68 pg/ml has 85% sensitivity and 80% specificity. IL8 is a
valid and primary predictive marker for neonatal infection
which is relevant with severity of infection.39
IL8 is a pro-inflammatory cytokine which is often created
by monocytes, macrophages and endothelial cells and
causes the release, activation and chemotaxis of neutro-
phils and its’ level is increased in early stages of neonatal
bacterial infections.43 It is so that based on the results of a
study, IL8 concentration in died infants with sepsis is
increased 3.3 times compared with survived infants.25
Boskabadi et al., in their study showed that serum con-
centration of IL8 in infants with confirmed sepsis is signifi-
cantly higher than in healthy infants before blood culture
become positive. Also, the serum level of this marker in the
infants with sepsis who died was much higher than survived
infants. Sensitivity, specificity, positive predictive value
and negative predictive value for IL8 was respectively 95%,
10%, 97% and 10% and for CRP, it was respectively 83%, 86%,
83% and 69%. Boundary limit of IL8 was above 60 pg/ml and
boundary limit of CRP was above 6 pg/ml.25 Results of a
study showed that IL8 in diagnosis of definite infection is
more effective than IL6 and IL10.15 IL8 above 60 pg/ml as
an accurate marker is considered with a sensitivity of 80 to
91% and a specificity of 76 to 100%.43 In a study, IL8 with
54 pg/ml boundary limit had 77.6% sensitivity, 63.8% spec-
ificity and 67.2% accuracy for diagnosis of neonatal sepsis.26
In the study of Kocabaset al, the increase of IL8 in early and
late neonatal sepsis had 80 to 91% sensitivity and 100%
specificity.44 Zhou et al., (2015) in a meta-analysis study
reviewed the role of IL8 in diagnosis of neonatal sepsis. 8
studies including 548 infants entered the study. IL8 had
moderate accuracy for diagnosis of neonatal sepsis.45 IL8
above 269.51 pg/ml had 80% sensitivity and 50% specificity
in sepsis diagnosis.
IL10 is an early predictive marker for neonatal infection
and its’ high values are relevant to very severe infection.
Gram-negative infections are associated with higher con-
centrations of IL10 compared with Gram-positive in-
fections. Boskabadi et al., showed that quantitative
measurement of IL10 can help the neonates’ specialists to
predict the infection severity. In addition, IL10 values in
died infants was higher than survived infants.16 IL10 above
27 pg/ml had 60% sensitivity and 87% specificity in diagnosis
of neonatal sepsis.
Various markers such as IL6, PCT, CRP and IL8 are applied
both for early diagnosis (24e48 h) of neonatal sepsis and for
controlling antibiotic treatment due to not having delay in
Neonatal sepsis by measuring ILs
diagnosis compared with time consuming results of blood
culture.46 IL6, IL8 and oxidative parameters in umbilical cord
blood can predict neonatal sepsis in neonates with known
risk factors.47 IL6 and IL8 increase in inflammatory responses
and values of these factors will be changed based on the
severity of infection. In a study, combination of IL6 and IL8
had 71.4% sensitivity, 86.2% specificity and 82.6% accuracy.
Diagnostic value of IL6 was more than IL8. Combination on
IL6 and IL8 can increase the diagnostic accuracy of neonatal
sepsis.26 Simultaneous assessment of IL6, IL8 and IL10 can
improve sensitivity and specificity of early diagnostic of
neonatal sepsis. These combined markers have 89% sensi-
tivity and 100% specificity in differentiation of subject and
control groups.15 In the study of Franz et al., combination of
IL8 and CRP for early diagnosis of neonatal sepsis had 91%
sensitivity and 73% specificity.48
According to the results of conducted studies, combined
interleukins above 186.83 pg/ml have 75.63% sensitivity and
71.49% specificity.
One of the strengths of this study is that it was found
within the searches that this study is the only study which
has examined the role of interleukins in diagnosis of
neonatal sepsis. Limitations of this study include lack of
access to all articles and unpublished reports, lack of cor-
rect and quality and usable report of some articles, limited
number of articles in the field of each interleukin and
impossibility of accurate judgment about their effect, lack
of measuring variables with same method, lack of similar
definition for subject group in studies and lack of a standard
in boundary limit of interleukins.
5. Conclusion
Wide effort has been done in order to find studies related to
diagnosis and prediction of neonatal sepsis. The found
studies were different in terms of methodology, method,
boundary limit of interleukins and diagnostic value of in-
terleukins. The results of the studies showed that IL6, IL8
and IL10 are primary markers for diagnosis of neonatal
sepsis. IL8 above 269.51 pg/ml had 80%sensitivity and 50%
specificity in sepsis diagnosis. IL10 above 27 pg/ml had 60%
sensitivity and 87% specificity in diagnosis of neonatal
sepsis. Based on the results of studies, IL6 above 68 pg/ml
had 85% sensitivity and 80% specificity. However, IL6 had
the most sensitivity and IL10 had the most specificity for
sepsis diagnosis.
Combination of IL6 with other interleukins and diag-
nostic markers will have higher sensitivity and specificity
due to its’ short half time. Despite primary diagnostic
markers of neonatal sepsis, this disease is yet a major
challenge in newborn medicine; it may be due to not having
standard values of boundary limit of interleukins and high
cost of testing. Therefore, it is helpful to conduct extensive
studies to identify more interleukins and standardize the
values of boundary limit of interleukins in early diagnosis of
neonatal sepsis.
Conflict of interest
The authors declare no conflict of interest.
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337
Acknowledgement
Hereby, the authors of the article appreciate the Deputy of
Research, Research Director and other officials and all
people who helped us in this project.
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