Biomedicine & Pharmacotherapy 111 (2019) 649–656

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Presepsin: A promising biomarker for the detection of bacterial infections T

a,b,c a,b,d,⁎
Mohammad Yousef Memar , Hossein Bannazadeh Baghi
a
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
b
Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
c
Students’ Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
d
Department of Microbiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

A R T I C LE I N FO A B S T R A C T

Keywords: Appropriate recognition of bacterial infections in health care setting is the basis for effective treatment and
Biomarker control of infectious diseases. The positivity rate of traditional methods is low and is influenced by quality and
Diagnosis quantity of specimens, patient antibiotic administration, severity of infection, and laboratory sufficiency.
Infections Currently, there are novel non-culture-based techniques that are being accomplished to improve the identifi-
Presepsin
cation of infections. Several immunologic biomarkers have been assessed to develop the best indicator of in-
Sepsis
fections. Presepsin is an immunologic biomarker which has been demonstrated as new, emerging, early indicator
for the detection of different infections. The biological function of presepsin is not well known. However, it is
believed that it may be a regulatory molecule of the adaptive immune system and also a stimulator of monocyte
phagocytosis. The early increased levels of presepsin during the sepsis and other bacterial infections have made
it an attractive indicator for laboratory testing. Several studies have investigated the capacity of presepsin for use
in clinical settings. The aim of the present study was review the clinical application of presepsin in diagnosis and
prediction of infections. To achieve this objective, the documents on diagnostic and clinical assessment were
evaluated in PubMed and Scopus databases regarding the use of presepsin as indicators of infections.

1. Introduction prognosis of infections. To achieve this objective, the papers on diag-

nostic, prognostic and clinical assessment were evaluated in PubMed
Infections are demonstrated by signs and symptoms that overlapped and Scopus databases regarding the use of presepsin as indicators of
with other acute disorders in certain cases. The identification of bac- infections.
terial infections from other diseases is clinically critical, but often also
very challenging. This incomplete understanding may lead to un- 2. Presepsin
necessary antibiotic therapy, which is a principle cause of antibiotic
resistance [1–3]. Traditional techniques for the detection of infections Survival from infections can be influenced by the capacity of the
such as culture-based approaches, biochemical methods, and antibody- host immune system in identified microbial pathogens and triggering
based detection and molecular techniques often need sophisticated an immediate and effective response [11,12]. This mechanism is di-
equipment and highly proficient operators; therefore, their analysis cost vided into an innate and an adaptive system [13,14]. In contrast to
is very high [4,5]. Consequently, there is a continuous requirement for adaptive systems, innate mechanisms depend on an immediately re-
the simple, reliable, manageable, fast, sensitive, and cost-effective sponse, an effective pathway and mediators such as antimicrobial
point-of-care analyses [5]. Recently, several immunologic biomarkers peptides, alternative complement systems, and phagocytosis. The acti-
have been assessed in order to develop the best indicator of infections vation of innate immunity responses need the recognition of the pa-
[6–8]. Soluble CD14 subtype (sCD14-ST), known as presepsin, is a thogens by different receptors at the cellular surface of immune effector
biomarker which has been demonstrated as a new, emerging, early cells particularly monocytes/macrophages [13,15,16]. These receptors
indicator for the detection of different infections [7,9]. Presepsin is are innately pre-determined, and they identify a wide range of antigens
elevates in response to bacterial infections and is decreased after known as pathogen-associated molecular patterns (PAMPs) on the
healing or efficient treatment [6,10]. The aim of the present study was surface of most microbial pathogens [17]. After recognition, effector
to review the clinical application of presepsin in diagnosis and cells are stimulated in a direct pathway without any preceding

⁎
Corresponding author at: Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, 5166/15731, Tabriz, Iran.
E-mail addresses: [email protected], [email protected] (H.B. Baghi).

https://doi.org/10.1016/j.biopha.2018.12.124
Received 13 October 2018; Received in revised form 28 December 2018; Accepted 30 December 2018
0753-3322/ © 2018 Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
M.Y. Memar, H.B. Baghi Biomedicine & Pharmacotherapy 111 (2019) 649–656

multiplication. Therefore, innate immune system provides an instant presepsin with appropriate sensitivity and specificity [31]. Firstly, a
and protective response to invasive pathogens [17,18]. CD14 is a traditional two-step sandwich enzyme-linked immunosorbent assay
member of Toll-like receptor (TLR), that has the ability to identify (ELISA) was used for the detection of presepsin by the recombinant
several groups of ligands of both Gram positive and Gram negative CD14 (S286C) as standard within 4 h. This assay was not appropriate
pathogens, such as lipids, peptidoglycan and other surface patterns and lacked the speed and accuracy that is essential for routine presepsin
[19,20]. The best studied ligand is lipopolysaccharide (LPS) of Gram assessments in intensive care units (ICU) [32]. A few years later, a one-
negative bacteria. To be potentially recognized, LPS needs the asso- step ELISA assay developed and was evaluated using recombinant
ciation of Lipoprotein Binding Protein (LBP) which presents LPS to presepsin and two new antipresepsin antibodies: F1106-13-3 mono-
CD14. CD14 is a coreceptor which is constitutively expressed at the clonal antibody as capture antibody and S68 polyclonal antibody as the
surface of monocyte/macrophage [21,22]. CD14 plays an important recognition antibody. As a result, the total analysis time was reduced
role in the presentation of LPS to TLR and actively contributes to in- from 4 h to 1.5 h, and the dynamic range of the one-step ELISA assay
tracellular signals and promotes the expression of genes responsible for was changed to 0.05–3.00 ng/mL (compared to 3–150 ng/mL with the
the immune response such as cytokines production by effector cells two-step assay) [32]. A novel, highly-sensitive, fully automated PAT-
[23,24]. The complex CD14-LPS-LBP stimulates signals [25,26]. So- HFAST presepsin measurement system, based on the chemiluminescent
luble subtypes of CD14 are released and are detectable in the general enzyme immunoassay (CLEIA) principle, has been developed to ana-
circulation [27,28]. CD14 has two forms: membrane-bound CD14 lyzing the entire blood samples that provides its result within 17 min.
(mCD14) and soluble CD14 (sCD14). The sCD14 is found in plasma, and This approach is applicable for use in the Emergency Department (ED),
is produced by mCD14 fall-off or cell secretion. sCD14 is cleaved by ICU, and the surgical wards. No interference of presepsin has been
cathepsin D and other proteases in plasma or in the phagolysosome and detected with other analytes such as bilirubin, hemoglobin, lipids, tri-
the N-terminal fragments of 13 kDa constitutes sCD14 subtype (sCD14- glyceride, or rheumatoid factors [33]. Determination of a normal range
ST) which has been named presepsin. The complex of CD14-LPS-LBP is is essential for the development of a biomarker as a diagnostic tool.
submitted to an enzymatic processing that needs cathepsin D. Presepsin [26]. An effective breakpoint for diagnosis procedure at the 95th per-
is released in the general circulation by proteolysis and exocytosis centile value has been suggested for most of the traditional biomarkers.
(Fig. 1). Whereas the biological function of presepsin is not well de- This value can be detected with enough statistical confidence (> 95%
scribed, it is demonstrated that it has lost its capacity to bind LPS. CI) only if the studied population is > 300 volunteers. This detection
However, presepsin has been reported as a regulatory molecule. should be established for the clinical use of presepsin in infections di-
[26,29]. Plasma levels of presepsin can be considered as an indicator of agnosis [26]. Presepsin levels have been demonstrated to be re-
activated innate immune effector cells in response to invasive patho- markably elevated in patients with a bacterial infection when compared
gens. The secretion of presepsin has been reported as a stimulus of to non-infective patients according to the site or blood culture. It has
monocytes phagocytosis [26,30]. Therefore, recognition of presepsin is higher levels in patients with Gram-negative bacterial infections than
predictable even in healthy non-infective individuals. The concept for patients with Gram-positive infections. In addition, patients with ab-
presepsin proposes that its levels should be measureable in non-in- dominal or urinary tract infections had higher baseline presepsin levels
fective individuals, increase the early steps of bacterial infections, and than patients with lung infections [38].
its levels should be dependent on the intensity of the innate immune
induction [26].
4. Sepsis diagnosis and prognosis by presepsin

3. Measurement of presepsin According to the results of several multicenter prospective studies,

presepsin levels are significantly higher in patients with systemic bac-
An presepsin assay kit using antibody and a special sandwich terial infections than in those with nonbacterial infections [28,39–41].
technique is useful for qualitative and quantitative measurement of The cutoff value of 600 ng/L has been reported for the discrimination of

Fig. 1. The mechanism of presepsin production. LBP: Lipoprotein Binding Protein, LPS: lipopolysaccharide, TLR: Toll-like receptor. CD14 exists in two forms,
membrane CD14 (mCD14) and soluble CD14 (sCD14). Soluble CD14-subtype (sCD14-ST), or Presepsin, is produced by circulating plasma proteases effect on sCD14.
The molecular complex CD14-LPS-LBP is internalized into a phagolysosome. CD14-LPS-LBP is exposed to an enzymatic processing that needs cathepsin D. CD14
proteolysis and internalization processes release a small soluble peptid fragment. The product of CD14 cleavage has been named soluble CD14subtype (sCD14-ST) or
presepsin that is released in the general circulation by proteolysis and exocytosis.

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M.Y. Memar, H.B. Baghi Biomedicine & Pharmacotherapy 111 (2019) 649–656

bacterial and nonbacterial sepsis by presepsin with the sensitivity and and subsequent mortality in ICU [38,47]. Table 1 is the overview of
specificity of 87.8% and 81.4%, respectively [39]. At the cutoff value of different performance efficiency of presepsin as indicator in different
670 ng/L for presepsin, sensitivity and specificity has been reported as types of infections.
70.3% and 81.3%, respectively while at a cutoff value of 864 ng/L,
sensitivity and specificity were 71.4% and 63.8% [42]. Using a cutoff of
5. Presepsin for the detection of Pneumonia
600 ng/L, presepsin levels are not significantly different between pa-
tients with Gram-positive and Gram-negative bacterial infections and
Bacterial pathogens are the common cause of CAP; thus, early and
also between the blood culture-positive and -negative groups [39].
accurate identification of etiology is critical for appropriate treatment
However, at a concentration at baseline of 946 ng/L, higher levels of
of CAP. [48,49]. The accuracy of presepsin assessment has been re-
presepsin have been reported in patients with Gram-negative bacterial
ported in the diagnosis of CAP (Table 1). In an observational pro-
infections, than in patients with Gram-positive infections [38]. The
spective study, presepsin assay with a cutoff at 588 ng/L shows sensi-
presepsin values (mean ± standard deviation) have been reported for
tivity, specificity, positive predictive value (PPV) and negative
the healthy, SIRS, and sepsis group as 258.7 ± 92.53 ng/L,
predictive value (NPV) of 81%, 80%, 94% and 52%, respectively in
430.0 ± 141.33 ng/L, 1508.3 ± 866.6 ng/L, respectively [42]. The
diagnosis of CAP [50]. Presepsin levels have been reported in pul-
presepsin levels are significantly higher in sepsis patients than in SIRS
monary tuberculosis to be higher than the healthy control individual
cases [42]. According to the results of the meta-analysis, presepsin has
(218.0 [146.0, 368.0] ng/L versos 128.0 [101.5, 176.5] ng/L) and
found to have a higher sensitivity and specificity in the diagnosis of
lower than bacterial community acquired pneumonia (128.0 [101.5,
sepsis and may be a helpful and valuable biomarker in early diagnosis
176.5] ng/L versos 532.0 [364.0, 852.3] ng/L). Compared with both
of sepsis [43]. However, presepsin showed a moderate diagnostic ac-
Gram positive and Gram negative bacteria, Mycobacterium tuberculosis
curacy in differentiating sepsis from non-sepsis which prevented it from
induces a limited increase in presepsin levels. At the cut-off value of
being recommended as a definitive test for diagnosing sepsis in isola-
401 ng/L, presepsin demonstrated sensitivity, specificity, PPV and NPV
tion, but the results should be interpreted cautiously [44]. Change in
of 70.8%, 83.5%, 89.4% and 59.3% in the discrimination between ac-
presepsin levels may be an appropriate indicator for monitoring anti-
tive pulmonary tuberculosis and bacterial CAP. Presepsin combined
biotic therapy that improve the prognosis and increase the survival rate
with CURB-65 score (confusion, serum urea > 7 mmol/l, respiratory
in severe sepsis or septic shock cases. Presepsin levels tended to reduce
rate ≥ 30/min, systolic blood pressure < 90 mm Hg and/or diastolic
on day 7, in patients with positive blood cultures and appropriate an-
blood pressure ≤ 60 mm Hg, and age ≥ 65 y) remarkably improved the
tibiotic therapy. However, it elevated in those with positive blood
discrimination capacity between active pulmonary tuberculosis and
cultures and inappropriate antibiotic therapy [38,45]. Most of the in-
bacterial CAP, that is essential for early identification and the de-
appropriate empirical antibiotic therapy was related to infections
termination of the appropriate initial therapy [48]. Plasma presepsin
caused by multidrug-resistant bacteria [46]. Elevated presepsin levels
concentration has been demonstrated to be significantly higher in se-
on day 1 may be associated with acute kidney injury and renal re-
vere CAP than in CAP cases (689.0 [395.5–1225.5] pg/mL vs 400.0
placement, a longer ICU stay, longer mechanical ventilation and time
[231.5–691.5] pg/mL). The median Presepsin level has been reported
for discontinuation of vasopressor or inotropic agents, as well as a
more in the non-survivors than survivors in CAP and severe CAP pa-
longer duration, a lower degree of resolution of the primary infection
tients at the 28-day follow-up (699.0 [373.0–1250.0] pg/mLvs 410.5

Table 1
Different performance efficiency of presepsin as indicator in different type of infections.
Infection Cutoff (ng/L) Sen Spe PPV NPV (%) Setting Study Ref
(%) (%) (%) Population

Sepsis 907 69.7 83.3 88.5 60.0 ICU 76 [91]

Sepsis 686 46.5 91.3 ND ND ED 223 [65]
207 95.5 21.7 ND ND
Sepsis 670 70.3 81.3% ND ND ICU 247 [92]
864 71.4 63.8% ND ND
Sepsis 729 81.1 63.0 30.0 94.4 ED 226 [66]
Sepsis 600 85.96 72.09% ND ND CCU 21 [90]
Sepsis 600 78.95 61.90 ND ND ED 106 [36]
Sepsis 542 77.3 76.4 72.3 80.7 Burn 37 [37]
Sepsis 430 87.7 82.2 88.9 80.4 ED 118 [45]
Sepsis 466 90 55 82 71 ICU 100 [50]
CAP 401 70.8 83.5 89.4 59.3 ED 408 [48]
CAP 588 81 80 94 52 ICU 58 [50]
Sever CAP 498.5 63.4 64.4 51.5 74.7 ED 214 [49]
ARDS 468.5 72.6 57.8 88.4 32.4 ED 125 [49]
DIC 591.5 64.0 65.5 25.6 90.8 ED 89 [49]
Meningitis 625 84.2 82.1 86.5 79.3 S,ICU 18
Systemic Infections 221.5 92.31 77.7 70 94 RA 151 [52]
300 73.08 88.8 76 84
400 46.15 97.7 92 75
500 34.62 100 100 73
Pyelonephritis 200 0.92 0.51 93 49 ED 312 [85]
300 78 83 97 36
320 76 87 98 35
340 74 94 99 35
350 71 94 99 33
SSI 702 72 66 ND ND Cardiac Surgery 51 [93]

AbbreviationARDS: Acute Respiratory Distress SyndromeCAP: Community-acquired pneumoniaCCU: Cardiac Care UnitDIC: disseminated intravascular
coagulationED: Emergency DepartmentICU: intensive care unitND: none definedNPV: negative predictive valueRA: rheumatoid arthritisPPV: positive predictive
valueS: surgerySen: sensitivitySpe: specificitySSI: surgical site infection.

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[242.3–697.0] pg/mL). CAP patients with plasma presepsin levels sensitivity, specificity, PPV and NPV of presepsin to diagnosis in the
higher than a cutoff of 556.0 pg/mL have shown significantly lower first 24 h from ICU admission allowing a better management of septic
survival rates, compared to patients with levels lower than this cutoff patients (diagnostic and prognostic) both in severe sepsis and septic
(50.0% vs 76.6%) [49]. The highest sensitivity (54%) and highest shock were reported as 81.9%, 96.5%, 82.4% and 96.3%, respectively
specificity (81%) of presepsin levels, in tracheal aspirate for diagnosing [63]. Liu et al reported plasma presepsin levels to be a promising in-
early onset neonatal pneumonia, have been reported to have a cutoff of dicator for diagnosing sepsis and predicting severity of sepsis, septic
511 ng/L and 768.5 ng/L, respectively. Therefore, additional studies, shock and 28-day mortality in septic patients in the ED. According to
primarily on a larger population, are needed to confirm or discard the their study, a cutoff of 449 ng/L, presepsin predicting severity sepsis
claims considering the use of this marker [51]. with sensitivity of 82.4%, specificity of 72.4%, PPV of 71.3%, NPV of
83.2% with the predictive accuracy of 77.0%. At a presepsin cutoff of
6. Presepsin for the detection of other infections 550 ng/L, septic shock has been predictable with the sensitivity, spe-
cificity, PVV and NPV of 85.7%, 63.6%, 28.5% and 96.3%, respectively
Direct Cerebral Spinal Fluid (CSF) assessment gives data of bacterial and the predictive accuracy of 66.8%. Presepsin also has been de-
meningitis in only 50–80% of cases [40]. It is well known that other monstrated as an indicator of 28-day mortality by these researchers at
techniques applied for identification, such as Polymerase Chain Reac- the cutoff of 556 ng/L with the sensitivity of 62.2%, specificity of
tion (PCR), immunological, and biochemical methods have their own 66.8%, PPV of 48.3%, NPV of 78.0% and the predictive accuracy of
restrictions. presepsin in CSF has been reported as an applicable diag- 65.3% [40]. A single-center, prospective observational study reported
nostic biomarker in the detection of meningitides and in the case of the differentiation between SIRS and sepsis at presentation in the ED
meningitis and ventriculitis in children with a cutoff of 625 pg/ml with a high discriminatory power, sensitivity of 61% and specificity of
which indicated an 84.2% and 82.1% of sensitivity and specificity, re- 100% at a presepsin cutoff of 581 ng/L [64]. The performance of pre-
spectively (compared to 77.4% sensitivity and 77.3% specificity for sepsin, for identify of infection, is depended on the considered cutoff. In
leukocytes in CSF) [6]. the cutoff 273 ng/L, the performance of presepsin was reported with
Although early identification of infections in rheumatoid arthritis sensitivity of 95.5%, specificity of 21.7% for diagnosis of infection in
patients is remarkably essential for the treatment, it can be a proble- the ED, however using the cutoff of 686 ng/L in the same study these
matic assignment. For many cases, a physical assessment may not values were reported as 46.5% and 91.3%, respectively. The sensitivity
provide a deterministic diagnosis. A higher concentration of presepsin of 97.1% and 67.1% and specificity of 16.9% and 80.8% for the diag-
has been reported in the non-infected group of rheumatoid arthritis, nosis of sepsis in the ED were reported by using of 312 ng/L and
compared to in the healthy control group (25). Presepsin may be va- 849 ng/L, respectively [65]. In the cutoff of 729 ng/L the sensitivity,
luable in the identification of infections in rheumatoid arthritis patients specificity, PPV and NVP of 81.1%, 63%, 30% and 94.4%, respectively
other biomarkers [52]. In rheumatoid arthritis cases, presepsin is a were reported for the diagnosis of SIRS in the ED [66]. Different value
promising novel marker for the diagnosis of bacterial infections re- reported by different studies may be due to the heterogeneity estab-
gardless of rheumatoid arthritis disease activity [53]. Different sensi- lished in the included studies, with possible sources such as the study
tivity and specificity for presepsin has been reported in the detection of strategy (prospective or not), clinical setting (emergency department,
infection in rheumatoid arthritis patients. The highest levels of sensi- ICU), type of patients, reference for sepsis criteria and even the type of
tivity (92.31%) and specificity (100%) were observed in cutoff values of sample (plasma, serum or whole blood) for the measurement of pre-
221.5 ng/L and 500 ng/L, respectively [52]. In another study, presepsin sepsin. An advantage of the determination of presepsin is also its power
levels for bacterial infection in rheumatoid arthritis patients had a to predict the severity of bacterial infections. In addition, the mea-
cutoff value of 278 ng/L, and sensitivity and specificity were reported surement of presepsin can be performed by an easy process that takes
as 79.2% and 80.6%, respectively [53]. Surgical Site Infections (SSIs) less than 17 min in ICU and ED [62].
can increase the costs and duration of hospitalization. Moreover, SSIs
can cause a higher risk of morbidity and lower life quality in surgical 8. Presepsin: the marker of pediatric bacterial infection
patients [54,55]. Patients who develop major infections after cardiac
operations show a five-fold increase in presepsin. In all patients, the Rapid identification and treatment of pediatric bacterial infections
presepsin levels on post-surgery day 0, post-surgery day 1 and post- are important in treatment choices and outcomes, and proves to be a
surgery day 2 have been reported as significantly more elevated than challenge even for highly experienced pediatricians [8,67]. The appli-
the baseline (176 [123–275] ng/L) with the levels of 220 (166–445), cation of presepsin has been investigated for diagnosis of several severe
328 (210–581) and 310 (202–368) ng/L, respectively [56]. The pre- infections of children such as late-onset sepsis (LOS) in preterm new-
sepsin level of 300 ng/L, one week after surgery, has been suggested to borns, early-onset sepsis (EOS), meningitides and pneumonia in pre-
be used as a novel indicator for suspected SSIs [57]. Further prospective term newborns, pediatric oncology patients, critically ill children and
studies with larger and more diverse populations are needed to validate febrile neutropenic pediatric patients with hematological malignancies
the presepsin level for detection of SSIs. [6,41,68–77]. The performance efficiency of presepsin in pediatric
bacterial infections, which are reported by different studies, were
7. Presepsin for ICU and ED patients summarized in Table 2. Mean presepsin levels of 649 ng/L have been
reported in healthy term neonates and 720 ng/L in preterm neonates
Sepsis is a common reason of mortality during major processes of without clinical signs or symptoms of infection [28]. The reference le-
ICU and ED [36]. The important issue associated with sepsis in ICU n vels of presepsin in neonates without symptoms of infection have been
and ED is an appropriate identification of etiology [58,59]. Presepsin observed to be considerably higher than those shown in healthy adults.
has been reported by several studies as an appropriate indicator for the The triggering of the innate immune system happens after birth due to
detection of likely infections in cases that required ICU and ED the transition from the generally sterile intra-uterine condition to an
(Table 1). The sensitivity and specificity of presepsin for the prediction environment that is rich in foreign antigens could partly describe the
of infection in the ICU sepsis patients have been reported as 84.6% and higher concentrations of presepsin reported in normal neonates com-
62.5%, respectively and are significantly associated with APACHE II pared to healthy adults. After birth, the skin and gut of neonates are
score value (p-value = 0.016) [62]. At a cutoff value of 466.5 ng/L quickly colonized with bacterial flora, which is a continuous motivation
sensitivity and specificity of presepsin, to severe sepsis and septic shock for the innate immune system. In addition, it is recognized that TLR role
diagnosis in ICU patients, were 90% and 55%, respectively, with a PPV and reactivity are well established in neonates. When compared to
of 82% and NPV of 57% [50]. At a cutoff value of 101.6 ng/L, healthy adults, preterm and full-term neonates express considerably

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Table 2
The performance efficiency of presepsin in the diagnosis of pediatric bacterial infections.
Infection Gestational Age Postnatal Age Population Cutoff Sen Spe PPV NPV Setting Ref
(week) (ng/L) (%) (%) (%) (%)

LOS 32≤ 4 - 30 days 82 800.5 67 100 100 74 ICU [41]

EOS < 34 1 day 70 453 66 84 82 65 ICU [80]
LOS 32≤ 4 to 60 days 40 885 94 100 100 95 ICU [79]
EOS < 39 first 72 hours 69 539 80 75 91 59 ICU [76]
sepsis – 1.5 – 18.9 years 55 299 84 58 37 93 Oncology [73]
sepsis < 35 ND 65 548 100 81.2 ND ND ICU [75]
sepsis < 37 8 day 51 706.5 85.7 68.8 85.7 68.8 Perinatology [68]
sepsis – 3 to 15 years 60 951 93.8 100 ND ND Oncology [71]
1014 100 85.7 ND ND

AbbreviationEOS: early- onset sepsis, ICU: intensive care unit, LOS: late- onset sepsis, ND: none defined, NPV: negative predictive value, PPV: positive predictive
value, Sen: sensitivity, Spe: specificity.

Table 3
The performance efficiency of presepsin in comparison to other biomarkers.
Biomarker Cutoff* Sen Spe PPV NPV AUC Infections Study Setting Main finding ref
(%) (%) (%) (%) population

Presepsin 686 46.5 91.3 ND ND 0.775 Sepsis 223 ED PCT: the highest diagnostic accuracy for infection [65]
237 95.5 21.7 ND ND PCT and presepsin: similar performance to identifying sepsis
CRP 60 80.5 65.2 ND ND 0.588
20 94 30.4 ND ND
PCT 0.22 77.5 95.7 ND ND 0.815
0.19 83.5 87.0 ND ND
Presepsin 729 81.1 63.0 30.0 94.4 0.750 SIRS 225 ED Presepsin: similar diagnostic accuracy to PCT [66]
CRP 105 62.2 51.9 20.2 87.5 0.602
PCT 0.45 81.1 63.0 30.0 94.4 0.787
Presepsin 542 77.3 76.4 72.3 80.7 0.834 Sepsis 37 Burn Presepsin: similar diagnostic efficiencies to PCT, both were [37]
CRP 65 91.6 58.2 62.1 90.2 0.819 superior to CRP
PCT 0.759 75.7 78.6 73.6 80.3 0.847
Presepsin 600 78.95 61.90 ND ND 0.701 Sepsis 106 ED PCT: a better diagnostic accuracy than presepsin. [36]
PCT 0.18 95% 75.90 ND ND 0.875
Presepsin 2455 76.5 53.7 ND ND 0.684 Sepsis 157 ICU Presepsin, galectin-3, and sST2: better than PCT for the prediction [47]
PCT 0.16 100.0 10.57 ND ND 0.513 ED of 30-day mortality
Galectin-3 28.4 91.2 56.9 ND ND 0.776 Galectin-3: the strongest risk predictor of 30-day mortality
sST2 215.2 73.5 57.7 ND ND 0.673
Presepsin 957.5 94.7 85.7 90.0 92.3 0.891 Sepsis 76 ICU Presepsin: similar diagnostic accuracy to PCT, significantly better [91]
CRP 97.0 47.4 64.3 64.3 47.4 0.445 than CRP
PCT 2.60 8.9 100.0 100.0 77.8 0.932
Presepsin 299 0.84 58 37 93 0.489 Sepsis 33 PO Presepsin: slightly better for prediction of clinical signs of sepsis [73]
CRP 49.4 50 71 35 82 0.570
PCT 0.68 67 80 50 89 0.798
IL-6 106 81 61 42 90 0.674
Presepsin 466 90 55 82 71 0.748 Sepsis 144 ICU Presepsin: not superior to that of PCT [50]
PCT 0.5 80 59 82 57 0.808
Presepsin 588 81 80 94 52 0.858 Pneumonia
PCT 0.5 69 80 93 40 0.793
Presepsin 706.5 85.7 68.8 85.7 68.8 0.804 Sepsis 51 Pediatric Presepsin seems to provide better early diagnostic [68]
PCT 161.3 68.6 62.5 80 47.6 0.667

AbbreviationAUC: Area under the curve, CRP: C-reactive protein, ED: Emergency Department, ICU: intensive care unit, IL-6: interleukin-6, ND: none defined, NPV:
negative predictive value, PCT: procalcitonin, PO: pediatric oncology, PPV: positive predictive value, Sen: sensitivity, Spe: specificity, sST2: soluble suppression of
tumorigenicity- 2.
* ng/L for Presepsin and IL-6, ng/mL for sST2 and galectin-3, mg/L for CRP, μg/L for PCT.

higher levels of TLR4 on peripheral blood monocytes, both at baseline [76]. At a cut-off of 788 ng/L, the sensitivity of 93% and specificity of
and following LPS prompt. Considerably higher CD14 expression at 100% were recorded for presepsin in the diagnosis of early-onset sepsis
baseline and following LPS induction have been demonstrated in full- in preterm newborns [80]. In contract to PCT, presepsin is not affected
term neonates compared to healthy adults [28,78]. by gestational age in healthy infants [28,76,79]. The better sensitivity
Different performance efficiency of presepsin reported at different and NPV have been reported for presepsin, in comparison to CRP and
cutoff values in the pediatric settings (Table 2). At the cutoff of 885 ng/ PCT in diagnosing neonatal sepsis [70].
L, presepsin demonstrated a sensitivity of 94% and specificity of 100%,
for the detection of LOS in preterm newborns [79]. At a cut-off value of
9. Presepsin compared to other immunologic biomarkers for
800.5 ng/L, presepsin showed 67% sensitivity and 100% specificity in
diagnosis and prognosis of infections
the detection of LOS in preterm infants and gradually reduced during
treatment [41]. Diagnostic values of presepsin in the detection of EOS
In this comparative evaluation the diagnostic and prognostic effi-
have been reported. Presepsin levels in the EOS are higher than the
ciency of presepsin and other biomarkers has been investigated in dif-
healthy control group. At a cutoff of 539 ng/L, the sensitivity and
ferent groups of patients. Controversial results of presepsin efficiency,
specificity of presepsin has been reported as 80% and 75%, respectively
compared to other biomarkers of sepsis, have been reported. Presepsin

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M.Y. Memar, H.B. Baghi Biomedicine & Pharmacotherapy 111 (2019) 649–656

with a cutoff of 2455 ng/L has been reported to be better than PCT, in the gold standard of infection detection and immunologic biomarkers
the prediction of 30-day mortality of sepsis (AUC of 0.684 versus should be used in addition to culture [76]. Further investigations are
0.513), and to be higher in non-survivors than in survivors [47]. At the required to define the effect of steroid usage on presepsin levels.
cutoff of 413 ng/L presepsin has been shown to be higher in AUC than
in PCT (0.705 versus 0.630) and lower than CRP (0.705 versus 0.734) 11. Conclusion
in the detection of bacterial infections for patients admitted to hospital
ICU [62]. AUC-ROC% values for diagnosis of burn sepsis have been An advantage of the assessment of presepsin is its capacity to predict
reported to be 83.4% for presepsin, 84.7% for PCT, 81.9% for CRP and the severity of a bacterial infection. In addition, the measurement of
50.8% for WBC. For burn sepsis patients, significantly changed pre- presepsin can be done by an easy procedure that takes less than 17 min.
sepsin, CRP and WBC, but not PCT, levels were reported on the first day To increase the accuracy, presepsin could be used in combination with
of sepsis compared to previous days [37]. Neonatal sepsis, when com- other markers and standard methods of infection diagnosis. The dif-
pared to PCT, presepsin has been shown to be a better early diagnostic ferent performance efficiency values may be due to the heterogeneity
efficiency for faster therapeutic decision making and possible positive established in the included studies, with possible sources such as the
impact on the outcome [68]. Other multicenter prospective studies study strategy (prospective or not), clinical setting (ED, ICU), type of
reported a higher diagnostic accuracy of PCT than presepsin (AUCs of patients (adults or neonate), reference for sepsis criteria and even the
0.875 for PCT and 0.701 for presepsin) for sepsis in the ED. Mean type of sample (plasma, serum or whole blood) for measurement of
presepsin levels were considerably more elevated in non -survivor presepsin. Further prospective studies with larger and more diverse
septic patients (60-day mortality) than in survivors. However, a sig- populations are required to establish the cut of presepsin for the diag-
nificant relationship has not been observed between PCT and survival nosis and prognosis of infections. The knowledge of conditions, that
[36]. The role of the immunologic biomarkers in monitoring infection is influence the levels of presepsin, can reduce the false positive rate of
examined by the analysis of serial measurements, which was performed infection diagnosis and inappropriate treatments. Future studies are
at admission time (T0) and at different times after admission with necessary, for the identification of these conditions and the determi-
twenty-four hour intervals (T1 and T2). Presepsin levels were reported nation of cutoff values for the detection of different types of infections
to be considerably higher at T0 than at T1 and T2, but PCT levels were in different groups of patients would also be effective in the clinical
higher at T2. The performance efficiency of presepsin in comparison to application of this biomarker.
other immunologic biomarkers, which were reported by different stu-
dies, was summarized in Table 3. Presepsin levels are increased prior to Conflict of interest
PCT and CRP. [8,36,81]. According to the results of the meta-analysis,
presepsin has been shown to be an appropriate marker for the diagnosis There is no conflict of interest.
of sepsis in PCT or CRP. As the only diagnostic approach, presepsin is
not appropriate to rule out or confirm sepsis, and its diagnostic value Acknowledgments
should be considered with the other sepsis characterizations
[10,82,83]. Presepsin in combination with IL-6 has been shown to in- This project was supported by Immunology Research Center, Tabriz
crease sensitivity in comparison to only using presepsin in the detection University of Medical Sciences. The authors would like to also thank the
of sepsis in pediatric hemato-oncological patients. Presepsin in combi- Clinical Research Development Unit, Shohada Hospital, Tabriz
nation with PCT and CRP have not shown better accuracy than only University of Medical Sciences for their kind support.
presepsin in the detection of sepsis in these patients [73]. The combi-
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