The Journal of Maternal-Fetal & Neonatal Medicine

ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20

Comparison between presepsin and procalcitonin

in early diagnosis of neonatal sepsis

Agustin Iskandar, Maimun Z. Arthamin, Kristin Indriana, Muhammad

Anshory, Mina Hur & Salvatore Di Sommaon behalf of the GREAT Network

To cite this article: Agustin Iskandar, Maimun Z. Arthamin, Kristin Indriana, Muhammad Anshory,
Mina Hur & Salvatore Di Sommaon behalf of the GREAT Network (2018): Comparison between
presepsin and procalcitonin in early diagnosis of neonatal sepsis, The Journal of Maternal-Fetal &
Neonatal Medicine, DOI: 10.1080/14767058.2018.1475643

To link to this article: https://doi.org/10.1080/14767058.2018.1475643

Accepted author version posted online: 09

May 2018.

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COMPARISON BETWEEN PRESEPSIN AND PROCALCITONIN IN
EARLY DIAGNOSIS OF NEONATAL SEPSIS

Agustin Iskandar*, Maimun Z. Arthamin*, Kristin Indriana*, Muhammad

Anshory*, Mina Hur**and Salvatore Di Somma***; on behalf of The GREAT
Network

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*Faculty of Medicine, Brawijaya University, Malang, Indonesia; **Department of Laboratory
Medicine, Konkuk University School of Medicine, Seoul, Korea; ***Department of Medical-
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Surgery Sciences and Translational Medicine, Sapienza University of Rome, Italy

Running Title:Presepsin and Procalcitonin in Neonatal Sepsis

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Author for Correspondence:

Prof. Salvatore Di Somma MD, PhD

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Department of Medical-Surgery Sciences and Translational Medicine, Sapienza University of

Rome, Italy
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Tel: +39 348 331 6131

e-mail: salvatore.disomma@uniroma1.it
ABSTRACT

Background: Neonatal sepsis remains worldwide one of the leading causes of morbidity
and mortality in both term and preterm infants. Lower mortality rates are related
to timely diagnostic evaluation and prompt initiation of empiric antibiotic therapy.
Blood culture, as gold standard examination for sepsis, has several limitations for

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early diagnosis, so that sepsis biomarkers could play an important role in this regard.
This study was aimed to compare the value of the two biomarkers presepsin and

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procalcitonin in early diagnosis of neonatal sepsis.

Methods: This was a prospective cross-sectional study performed, in Saiful Anwar

General Hospital Malang, Indonesia.,in 51 neonates that fulfil the criteria of SIRS with
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blood culture as diagnostic gold standard for sepsis

Results:At ROC curve analyses, Using a presepsin cutoff of 706,5 pg/mL, the
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obtained AUCs were: sensitivity= 85.7%, specificity= 68.8%, positive predictive
value= 85.7%, negative predictive value = 68.8%, positive likelihood ratio = 2.75,
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negative likelihood ratio= 0.21, and accuracy= 80.4%. On the other hand, with a
procalcitonin cutoff value of 161.33 pg/mL the obtained AUCsshowed:sensitivity=
68.6%, specificity= 62.5%, positive predictive value = 80%, negative predictive value=
47.6%, positive likelihood ratio= 1.83, the odds ratio negative= 0.5, and accuracy=
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66.7%.

Conclusions: In early diagnosis of neonatal sepsis, compared with procacitonin,

presepsin seems to provide better early diagnostic value with consequent possible faster
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therapeutical decision making and possible positive impact on outcome of neonates.

Keywords: neonatal sepsis, early diagnosis, biomarkers, presepsin, procalcitonin.

BACKGROUND

World Health Organization estimated four million neonatal deaths per year occuring in low
and middle income countries; consequently this remains an important global public health
challenge [1, 2]. Morbidity and mortality for sepsis in both term and preterm infants, varies
from 7.1 to 38 per 1,000 live births in Asia, with a greater incidence as compared to United
States and Australia, where it ranges from 6-9 per 1,000 live births [1].Based on the results

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of Indonesia Demographic and Health Survey in 2012, neonatal mortality rate accounted
for about 19 per 1,000 live births, and the complications that caused death were mostly

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represented by neonatal asphyxia, low birth weight infants, and infection [3]. Delay in starting
appropriate antibiotic treatment in these subjects is associated with worsening morbidity and
mortality [4]. Nevertheless the clinical diagnosis of sepsis in neonates could be difficult, since
the simple physical examination often cannot find objective abnormalities despite bacteriemia
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is present[5]. So that the challenge would b e to promptly identify neonates with sepsis and
initiate appropriate antimicrobial therapy [6].

Severe sepsis or septic shock in neonates may occur as a consequence of

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hyperinflammatory status and high level of proinflammatory circulating cytokines [5]and
the most widely studied biomarkers in this setting are C-reactive protein (CRP), interleukin
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(IL)-6, IL-8, procalcitonin (PCT), and tumor necrosis factor-α (TNF-α) [7]. Some of the
limitations for PCT use are represented by the presence of physiologically increasing
concentrations within the first 24 hours after birth and false positive results caused by non-
infectious conditions like respiratory distress syndrome [6]. Nevertheless, some previous
researches demonstrated the superiority of PCT to CRP in the diagnosis of neonatal sepsis [8,
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9].
Another biomarker that can aid in early diagnosis of sepsis is presepsin [10]. A meta-
analysis on persepsin showed that this biomarker may be a helpful and valuable biomarker
in early diagnosis of sepsis. However, presepsin showed a moderate diagnostic accuracy
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in differentiating sepsis from non-sepsis, which prevented it from being recommended as a

definitive test for diagnosing sepsis in isolation [11].
While meta analysis, in adult patients, comparing presepsin and PCT in early
diagnosis are still reason for research [12], in neonatal sepsis, there are already two studies
aviable comparing these two biomarkers [13, 14],;where one of the two13]showed the AUCs
for presepsin to be 0.74 and 0.76 in neonates respectively before and after 48 h of the born ,
while PCT showed AUCs 0.65 and 0.65 for the same groups [. Aim of this study was to
compare the value of presepsin and PCT in early diagnosis of neonatal sepsis.

METHODS
From May 2015 to July 2015, in hospitalized neonates with systemic inflammatory response
syndrome (SIRS) criteria and suspicion of sepsis, at the Perinatology Department of Saiful
Anwar Hospital, Malang, a prospective observational study with cross sectional design
was performed. The study was approved by the Ethics Committee of Faculty of Medicine,
Brawijaya University/Saiful Anwar General Hospital, Malang, according to the Declaration
of Helsinki, and informed consent to participate in the study was obtained from the patients’
parents.

The inclusion criteria were: 1) age between 0-30 days and 2) fullfilling SIRS criteria
for neonates. The SIRS criteria were applied, as possible presence of sepsis, when two or
more of symptoms including fever or hypothermia (core temperature more than 38°C or
less than 36°C), tachycardia, tachypnoea and change in blood leucocyte count were present,

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in which .Moreover mandatory criteria for inclusion were:abnormality in temperature or
leukocytosis, and these criteria were adjusted according to the consensus of definitions for

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sepsis and organ dysfunction in pediatrics [15, 16].
Based on SIRS criteria results; blood cultures were obtained in study subjects as the
gold standard for confirming the diagnosis of neonatal sepsis. Blood was taken from studied
subjects at the same time for culture and biomarker analysis but there was limitation for
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several subjects, in which the blood samples were taken in slightly different timing,due to
blood volume restrictions caused by venous puncture in neonates. Blood cultures were taken
from two different places and stored in BD Bactec™Peds Plus™ medium (Becton, Dickinson
and Company, New Jersey, USA). Patient blood was then included into the culture medium
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and analyzed using VITEK2 system, (bioMérieux.Inc, Marcy-l'Étoile, France) to determine
the microorganisms presence and antibiotic sensitivity. Presepsin levels were measured by a
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chemiluminescent enzyme immunoassay (CLEIA) method using the immunoassay analyzer

PATHFAST (Mitsubishi Chemical Medience Corporation, Tokyo, Japan)[17].PCT levels
were measured by enzyme linked immunosorbent assay (ELISA) (Elabscience Biotechnology
Corporation, Guangdong, China)[18].
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Statistical analysis
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Data were analyzed using IBM SPSS Statistic version 20 (IBM, New York, USA). The
normality of the data was analyzed using Kolmogorov-Smirnov test, and the difference
between presepsin and PCT levels in positive and negative culture group were analyzed
using Mann-Whitney test (non-parametric) or T test (parametric) with a Pvalue less than 0.05
considered statistically significant.

Diagnostic test values of presepsin and PCT were analyzed using reveiver operating
characteristic (ROC) curves. From the ROC curve results, we obtained area under the
curve (AUC) data. Data on clinical criteria adjudication for: SIRS, presepsin, PCT, and a
combination of both biomarkers as a diagnostic tool for neonatal sepsis were also analyzed
using the ROC curves. The sensitivity, specificity, positive and negative predictive values,
positive and negative likelihood ratios, and accuracy were also analyzed using 2x2 table.
RESULTS

Fifty-one consecutive neonates were enrolled in this study. In 35 patients positive blood
cultures were detected, while 16 patients had negative blood cultures. Based on the onset of
sepsis, 65.7% of neonates with positive blood cultures were diagnosed as having late onset
sepsis. The detailed characteristics of patients are shown in Table 1. The patient outcomewas
distinguished into three groups: 21.6%(11) patients death, 49%(25) patientswith clinical
improvement, and 29.4%(15) patients autonomously discharged or refused to continuemedical
treatment.The bacteria that, on the basis of cultural positive tests , caused neonatal sepsis are
shown in Table 2.

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Presepsin and PCT concentrations in the group of positive and negative cultures
are shown in Figure 1.Presepsin concentrations showed significant differences between

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positive and negative culture groups (P = 0.026), while PCT concentrations were not different
between the two groups (P = 0.758) (Fig. 1).In ROC curve analyses, the obtained AUCs were
respectively: 61.4% for SIRS clinical criteria, 75.8% for presepsin, 59.9% for PCT, and 26.3%
for the combination of presepsin and PCT (Figure 2).
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With presepsin cutoff values of 706.5 pg/mL, selected through the intersection curve
between sensitivity and specificity, the sensitivity and specificity were: 85.7% and 68.7%,
respectively (Table 3).
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DISCUSSION

It is well known that blood culture, as the gold standard examination for sepsis, has many
limitations due to: small sample volume, low bacterial density, contamination of cultures or
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suppression of bacterial growth as consequence of previous antibiotic treatment [19]. From

results of our study, this was confirmed also for neonates since blood culture examination
resulted with lower number of bacterial colonies (≤ 4 CFU/mL) and with younger infants
presenting with a colony count of less than 10 CFU/mL [6].
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Number of ositive cultures resulted to be greater in male neonates compared to female

neonates, although the difference wan not statistically significant (Table 1), with the ratio 4:3.
This finding was similar to a previous study where 37 male neonates out of 64 total neonates
showed positive culture [20]. The higher incidence of neonatal sepsis in male than in female
neonates has been associated with x-linked immunoregulatory genes [20].
Other factors that could be linked to the incidence of neonatal sepsis have been
attributed to prematurity and low birth weight [21]. In our study, the characteristics of birth
weight and neonates maturity (gestational age) seems to differ within positive and negative
cultures groups although not significant (Table 1).
From our study data, the results on bacteria presence obtained from blood cultures
showed: Gram-negative in 62.9% (n = 22), Gram-positive in 31.4% (n = 11), and fungi in
5.7% (n = 2) of cases. Coagulase negative Staphylococcus and Enterobacter gergoviae were
the most common bacteria found in patients with early onset sepsis,whereas in patients with
late onset sepsis, Klebsiella pneumonia was the most common represented bacteria followed
by Coagulase negative staphylococcus. These data are consistent with the literature reports, in
which gram-negative bacteria represent the main cause of neonatal sepsis [22].
From our study results, the value of the AUC from ROC analysis for presepsin ability
to detect the early occurrence of sepsis was = 75.8% providing a fairly good value of this
biomarker for neonatal sepsis early diagnosis. On the other side the AUC value of PCT
was lower (59.9%, p = 0.15). These results were consistent with the results obtained in a
Japanese adult cohort, where in diagnosing sepsis patients,presepsin showed an AUC of
84.5%, greater than the one of PCT: 65.2% [23]. The greater advantage in using presepsin, as
a better diagnostic biomarker compared to PCT to predict sepsis in neonates,could be linked
to the differences in the synthesis processbetween the two biomarkers. Presepsin is produced
by LPS/LBP-CD14 complex that is released into the circulation, then hydrolyzed by protease
plasma and is secreted by monocytes after phagocytosis. However, presepsin secretion

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is not induced by the stimulation of physiologic activating agents such aspeptidoglycan
(PGN), lipopolysaccharide (LPS), and TNF-α [24, 25]. The results of research using rabbit

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granulocyte cells showed that stimulation by interferon (IFN)-γ, N-formyl-methionine-
leucine-phenylalanine (fMLP), and phorbol myristate acetate (PMA) could not induce the
secretion of presepsin (sCD14-ST) [26].
Meanwhile, PCT could be directly stimulated by the toxin and LPS released by
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microbes or induced by proinflammatory cytokines such as IL-1b, IL-6, TNF-α indirectly
[27]. PCT levels could be nonspecifically increased without massive bacterial infection in
conditions of stress, such as trauma or surgery. In these settings, PCT could moderately
increase and could show a rapid decrease in follow-up. Conversely, false-negative level of
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PCT could be found at the very beginning of infection or local infection and may show an
increase in follow-up in case of progression of the infection [28]. In accordance with our
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results, in other studies comparing presepsin, PCT, and CRP in adult patients with SIRS, the
diagnostic value of presepsin was also greater than those of PCT and CRP [29, 30].
Although we used different laboratory methodology for assessing PCT level compared
with automated analyzer with CLEIA, we should outline that the cost of the methodology
we used for presepsin determination would be less expensive than PCT with CLEIA.
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Nevertheless in evaluating the difference comparing presepsin and PCT in adults, it was
shown that presepsin had a greater prognostic value than PCT also when PCT was analyzed
using CLEIA [31]. Moreover, another study comparing the diagnostic value of PCT and
presepsin using enzyme linked fluorescent assay (ELFA) confirmed the superiority of
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presepsin to PCT [29].

In our research, we found five patients who showed elevated levels of presepsin with
negative blood cultures. There are several things that can cause false-positive test results using
presepsin. One of the possible causes is the presence of dead bacteria in the bloodstream that
can induce secretion of presepsin by monocytes. This possibility is supported by a study in
human monocytes after incubation with Escherichia coli and Staphylococcus epidermidis.
E. coli, which was killed by heating (95°C for 5 min) also induced presepsin secretion by
monocytes, so it can be concluded that presepsin was induced by alive or died bacteria [25].
Other possible causes are represented by sensitivity of blood cultures in neonates that is
generally considered between 50 - 67%. Furthermore, false-negative results on the blood
culture can be caused by the low number of live bacteria present in the sample, transient
bacteremia, or antibiotics treatment presence before sampling including maternal antibiotic
administration during intrapartum [32, 33].
 Two of the 35 subjects with positive blood culture results showed the presence of
fungi linked with the increased levels of presepsin above the cutoff. This is consistent with
literature data that show how presepsin may increase in patients with fungal infection [33].
The low number of enrolled patients in the study could be considered the main
limitations of it. Therefore, we suggest that further researches, in a greater cohort of similar
patients, should be done in order to confirm our preliminary results.
Although both evaluated biomarkers were performed using immunoassay methods,
we cannot exclude that, using an automated analyzer for PCT detection with CLEIA, different
results could have been obtained. As consequence, further studies, comparing PCT and
presepsin using CLEIA for PCT evaluation should be performed in order to confirm our
results.
The analysis on the role of Presepsin as a prognostic biomarker was not performed in

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our study, therefore, further studies are needed to compare the value of Presepsin and PCT as
a prognostic biomarker in neonatal sepsis.

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CONCLUSION
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From our used technical methods, it seems that, in early diagnosis of neonatal sepsis, the
biomarker presepsin could perform better than PCT. Consequently, presepsin could be
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considered as biomarker of choice for early diagnosis of neonatal sepsis, despite some
limitations such as: relatively low specificity, increased levels seen in infants with dead
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bacteria in the blood stream, lack of a standardized range or cutoff value. Furthermore we
need to ouline that there exist also other new tests and tools for early diagnoses of neonatal
sepsis like liposaccharide binding protein and the sepsis risk calculator. In the future, with
some improvement, this biomarker can be used as a routine tool in this setting in order to
provide the chance to clinicians for faster and more appropriate therapeutical decisions
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making with the aim of improving neonates survival.

DECLARATION OF INTEREST
The authors confirm that there are no known conflicts of interest associated with this publication
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and there has been no significant financial support for this work that could have influenced its
outcome.
AKNOWLEDGEMENT
This research was partially supported by Saiful Anwar General Hospital of Malang and PT.
Dimensi Citra Semesta. We thank our colleagues from Neonatology Division of Pediatric
Department who provided insight and expertise that greatly assisted the research.

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Table 1.Demographic and clinical features of the neonates

Characteristics Positive Negative P

blood culture blood culture

Gender 20 (71.4%) 8 (28.6%) 0.634

Male, n (%) 15 (65.2%) 8 (34.8%)
Female, n (%)

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Age (days), median (IQR) 8.0 (8) 7.5 (10) 0.737

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Leucocyte (x103/L), median (IQR) 19.5 (20.59) 11.68 (11.63) 0.973

Heart rate (x/min), mean (SD) EP

152.3 (15.13) 149.75 (17.97) 0.624

Respiratory rate (x/min), mean (SD) 61.37 (7.46) 63.06 (8.11) 0.485
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Temperature (°C), median (IQR) 36.7 (1.7) 37.6 (3.0) 0.297
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Birth weight (g), n (%) 4 (57.1%) 3 (42.9%) 0.849

< 1,500 g 15 (75.0%) 5 (25.0%)
1,500 – 2,500 g 16 (66.7%) 8 (33.3%)
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> 2,500 g

Maturity, n (%) 18 (66.7%) 9 (33.3%) 0.749

Preterm (<37 weeks gestational age) 17 (70.8%) 7 (29.2%)
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Full term

Outcome, n (%) 16 (64.0%) 9 (36.0%) 0.027

Clinically Improved 14 (93.3%) 1 (6.7%)
Autonomous Discharge 5 (45.5%) 6 (54.5%)
Death

Onset of sepsis, n (%) 0.203

Early onset (<4 days) 11 (57.9%) 8 (42.1%)

Late onset (≥4 days) 24 (75%) 8 (25%)

Abbreviations: n, number; IQR, interquartile range; SD, standard deviation.

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Table 2.The types of bacteria in blood culture

Culture Results Onset of Sepsis Percentage

Early Onset Late Onset

Gram Positive

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Staphyloccus coagulase negative 5 6 31.3%

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Gram Negative

Klebsiella pneumonia 1 7 22.9%

Enterobacter gergoviae 4 EP 4 22.9%

Salmonellaarizonae - 2 5.7%
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Serratia marcescens - 2 5.7%
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Serratia rubidoea - 1 2.9%

Escherichia coli - 1 2.9%

Fungi
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Yeast like fungi 1 1 5.7%

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Table 3.Diagnostic value of presepsin and procalcitonin

Diagnostic Value Presepsin Procalcitonin

% (95% CI) % (95% CI)

Sensitivity 85.7 (74.2-97.3) 68.6 (53.2-84.0)

Specificity 68.8 (46.0-91.5) 62.5 (38.8-86.2)

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Positive predictive value 85.7 (74.1-97.3) 80 (65.7-94.3)

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Negative predictive value 68.8 (46.0-91.5) 47.6 (26.3-69.0)

Positive likelihood ratio 2.75 (1.3-5.7) EP 1.83 (0.93-3.57)

Negative likelihood ratio 0.21 (0.09-0.5) 0.50 (0.27-0.93)

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Accuracy 80.4% 66.7%
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Figure legends

Fig. 1. The result of independent sample t test in presepsin and procalcitonin level. Presepsin
showed significant differences between positive and negative culture groups, while PCT was
not significant between two groups

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Fig. 2. ROC curves of presepsin and procalcitonin. The largest AUC was for presepsin rather
than procalcitonin, The combination between these two biomarkers even gave lower AUC

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than these biomarkers alone.

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 Figure 1.

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Figure 2.

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Table 1.Demographic and clinical features of the neonates
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Characteristics Positive Negative P
blood culture blood culture

Gender 20 (71.4%) 8 (28.6%) 0.634

Male, n (%) 15 (65.2%) 8 (34.8%)
Female, n (%)

Age (days), median (IQR) 8.0 (8) 7.5 (10) 0.737

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Leucocyte (x103/L), median (IQR) 19.5 (20.59) 11.68 (11.63) 0.973

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Heart rate (x/min), mean (SD) 152.3 (15.13) 149.75 (17.97) 0.624

Respiratory rate (x/min), mean (SD) 61.37 (7.46) 63.06 (8.11) 0.485

Temperature (°C), median (IQR)

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36.7 (1.7) 37.6 (3.0) 0.297

Birth weight (g), n (%) 4 (57.1%) 3 (42.9%) 0.849

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< 1,500 g 15 (75.0%) 5 (25.0%)
1,500 – 2,500 g 16 (66.7%) 8 (33.3%)
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> 2,500 g

Maturity, n (%) 18 (66.7%) 9 (33.3%) 0.749

Preterm (<37 weeks gestational age) 17 (70.8%) 7 (29.2%)
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Full term

Outcome, n (%) 16 (64.0%) 9 (36.0%) 0.027

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Clinically Improved 14 (93.3%) 1 (6.7%)

Autonomous Discharge 5 (45.5%) 6 (54.5%)
Death

Onset of sepsis, n (%) 0.203

Early onset (<4 days) 11 (57.9%) 8 (42.1%)

Late onset (≥4 days) 24 (75%) 8 (25%)

Abbreviations: n, number; IQR, interquartile range; SD, standard deviation.

Table 2.The types of bacteria in blood culture

Culture Results Onset of Sepsis Percentage

Early Onset Late Onset

Gram Positive

Staphyloccus coagulase negative 5 6 31.3%

Gram Negative

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Klebsiella pneumonia 1 7 22.9%

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Enterobacter gergoviae 4 4 22.9%

Salmonellaarizonae - 2 5.7%

Serratia marcescens -
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Serratia rubidoea - 1 2.9%

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Escherichia coli - 1 2.9%
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Fungi

Yeast like fungi 1 1 5.7%

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Table 3.Diagnostic value of presepsin and procalcitonin

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 Diagnostic Value Presepsin Procalcitonin

% (95% CI) % (95% CI)

Sensitivity 85.7 (74.2-97.3) 68.6 (53.2-84.0)

Specificity 68.8 (46.0-91.5) 62.5 (38.8-86.2)

Positive predictive value 85.7 (74.1-97.3) 80 (65.7-94.3)

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Negative predictive value 68.8 (46.0-91.5) 47.6 (26.3-69.0)

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Positive likelihood ratio 2.75 (1.3-5.7) 1.83 (0.93-3.57)

Negative likelihood ratio 0.21 (0.09-0.5) 0.50 (0.27-0.93)

Accuracy 80.4%
EP 66.7%
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Figure 1.
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 Figure 2.

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11