# A New Marker For The Diagnosis Of Sepsis: Presepsin

Mehmet Agilli, Irfan Sener, Fatih Yesildal, Tevfik Honca, Ibrahim Aydin,
Emin Ozgur Akgul, Halil Yaman

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Mehmet Agilli, Irfan Sener, Fatih Yesildal, Tevfik Honca, Ibrahim Aydin, et al.. A New Marker For The Diagnosis Of Sepsis: Presepsin. Journal of Investigational Biochemistry, 2012, 1, 10.5455/jib.20120521073837. hal-04368522

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Mini Review

# A new marker for the diagnosis of sepsis: Presepsin

Mehmet Agilli, Irfan Sener, Fatih Yesildal, Tevfik Honca, Ibrahim Aydin,
Emin Ozgur Akgul, Halil Yaman

Department of Medical Biochemistry, Gulhane Military Medical Academy, Ankara, Turkey

**Received:** April 06, 2012

**Accepted:** May 21, 2012

**Published Online:** May 28, 2012

**DOI:** 10.5455/jib.20120521073837

**Corresponding Author:**
Mehmet Agilli,
Gulhane School of Medicine, Department of
Biochemistry, Ankara, Turkey
mehmetagilli@yahoo.com

**Key words:** Presepsin, sepsis, SIRS

Abstract

Sepsis is a clinical syndrome that complicates severe infection. It is characterized by the cardinal signs of inflammation (vasodilatation, leukocyte accumulation, increased microvascular permeability) occurring in tissues which are remote from the infection. The clinical definitions of sepsis are basically nonspecific, often resulting in the delay of the diagnosis. During the last decade, a variety of different molecules have been suggested as clinical biomarkers in sepsis, most of which are still in experimental stage. However, some have come into use in clinical practice and have evolved as valuable tools for diagnosis, therapy monitoring, and outcome prediction.

Presepsin, which is approximately 13 kDa, has been identified as a protein whose levels increase specifically in the blood of sepsis patients. Presepsin is thought to be a more specific and sensitive marker for the diagnosis of sepsis compared with interleukin-6 and procalcitonin (PCT). Presepsin concentrations in blood were increased faster than PCT and CRP in sepsis patients. Although there are a lot of biomarkers to diagnose sepsis, presepsin could be a new candidate for this purpose. In this mini review, we discussed a new biomarker, presepsin, and its clinical relevance

© 2012 GESDAV

INTRODUCTION

Sepsis is a clinical state, which is complicated with severe
infection and characterized with systemic inflammation and
disseminated tissue damage [1]. It would be better to explain
SIRS primarily, so that sepsis could be understood according
to this definition.

**SIRS :** SIRS is the clinical syndrome that results from a dysregulated inflammatory response to a noninfectious insult, such as an autoimmune disorder, pancreatitis, vasculitis, thromboembolism, burns, or surgery. It requires that two or more of the following abnormalities be present [2].

1. Body temperature > 38,5 or < 36 °C

2. Heart rate > 90/minute

3. Respiratory rate > 20/minute or PaCO₂ < 32 mmHg

4. Leukocyte count > 12000/mm³ or < 4000/mm³

**Sepsis:** Sepsis is the clinical syndrome that results from a dysregulated inflammatory response to an infection. It exists if two or more of the above abnormalities are present, along with either a culture-proven or visually identified infection.

Biomarkers can have an important role in the presence,
absence or severity of sepsis, and can differentiate bacterial
from viral and fungal infection, and systemic sepsis from
local infection [3, 4]. Other potential uses of biomarkers
include roles in prognosis, antibiotic therapy, evaluating the
response to therapy and recovery from sepsis, differentiating
gram-positive from gram-negative microorganisms as the
cause of sepsis, predicting sepsis complications and the
development of organ dysfunction (heart, kidneys, liver or
multiple organ dysfunction). However, the exact role of
biomarkers in the management of septic patients remains
undefined [5]. C-reactive protein (CRP) has been used for
many years but its specificity has been challenged [6].
Procalcitonin (PCT) has been proposed as a more specific [7]
and better prognostic marker than CRP, although its value has
also been challenged [8]. It remains difficult to differentiate
sepsis from other non-infectious causes of systemic
inflammatory response syndrome, and studies are being
continued to define a reliable biomarker [8].

In a review, more than 170 different biomarkers have been
assessed for potential use in sepsis, more for prognosis than
for diagnosis [9]. These biomarkers could be divided 9
subheadings according to their structure. These are;
Cytokine/chemokine biomarkers (IL-6, IL-8, IL10, e.g.), Cell
marker biomarkers (CD11b, CD14, CD64, e.g.), Receptor
biomarkers (Toll-like receptor (TLR) 2 and 4, triggering
receptor expressed on myeloid cells (TREM-1), receptor for
advanced glycation end-products (RAGE), e.g.), Coagulation
biomarkers (Antithrombin, Protein C and S, D-dimer, e.g.),
Biomarkers related to vascular endothelial damage
(Neopterin, Laminin, P-Selectin, e.g.), Biomarkers related to
vasodilatation (Elastin, Copeptin, Anandamide, e.g.),
Biomarkers of organ dysfunction (Atrial natriuretic peptide
(ANP), Brain natriuretic peptide (BNP), Protein S-100b, e.g.),
Acute phase protein biomarkers (CRP, Serum amyloid A,
Pentraxin 3, e.g.) and Other biomarkers (Neurotensin, Leptin,
Resistin, e.g.). 34 biomarkers of them were identified that
have been assessed for use specifically in the diagnosis of
sepsis; of these just five reported sensitivity and specificity
values greater than 90%. These were: CD11b, CD64, IL-12,
interferon induced protein-10 (IP-10) and phospholipase A2 -
II (PLA2-II) soluble. Importance of these five biomarkers
were; CD11b: higher values in neonates with sepsis than in
those with possible infection, CD64: higher expressions may
indicate early diagnosis of sepsis, IL-12: higher values may
indicate diagnosis of sepsis in pediatric patients, IP-10: higher
values may indicate early diagnosis of sepsis in newborns,
PLA2-II: higher values may distinguish between bacteremic
and non-bacteremic infections. But these biomarkers were
studied in a very narrow study group. For example IP-10 was
higher in neonates with sepsis and necrotizing enterocolitis
than in neonates who had only necrotizing enterocolitis [10].
Or, CD 64 had high sensitivity and specificity for the early
diagnosis of sepsis in adults, but could not reliably
distinguish viral from bacterial infections, or local infection
from systemic sepsis [11]. Actually, there are some findings
about diagnostic biomarkers but none has sufficient capability
to diagnose all etiological kinds of sepsis or specificity -
sensitivity to be routinely employed in clinical practice.
Currently, PCT and CRP have been most widely used in
clinical practice, despite their limited abilities to specify
sepsis or to predict outcome [9].

In this article, a new biomarker, which is a candidate
biomarker for early diagnosis of sepsis, namely presepsin
(sCD14-ST) is going to be mentioned.

A Newly Used Biomarker: Presepsin (sCD14-ST)

In these days, a new biomarker, presepsin or sCD14-ST, is
proposed in the field of sepsis. It was firstly defined in 2005
[12] and has been a new important marker for diagnosis and
prognosis of sepsis in recent years.

CD14 is a glycoprotein expressed on the surface membrane
of monocytes/macrophages (mCD14) and serves as a receptor
for complexes of lipopolysaccharides (LPS) and LPS binding
protein (LPBP). mCD14 co-localizes with toll-like receptor 4
(TLR4). Upon binding of the LPBP complex CD14 activates
the TLR4-specific proinflammatory signaling cascade thereby
starting the inflammatory reaction of the host against
infectious agents. The complex of LPS-LPBP-CD14 is
released into circulation by shedding of CD14 from the cell
membrane yielding soluble CD14 (sCD14). However, plasma
protease activity generates also another sCD14 molecule
called sCD14 subtype (sCD14-ST) or presepsin [13].
Although many aspects of its production in vivo are

unknown, based on the results of animal experiments, etc., it
is thought that phagocytosis in response to bacterial infection
may play a major role, and the possibility that the lysosomal
enzymes, e.g., aspartic proteases (cathepsin, etc.), are
involved in the mechanism of production is suspected based
on the results of enzyme inhibition experiments [14].

DISCUSSION

Sepsis is a leading cause of death in critically ill patients despite the use of modern antibiotics and resuscitation treatments [15]. The septic response is an intensely complex chain of events involving inflammatory and anti-inflammatory processes, humoral and cellular reactions and circulatory abnormalities [16]. The diagnosis of sepsis and evaluation of its severity is complicated by the highly variable and non-specific nature of the signs and symptoms [17]. However, the early diagnosis and stratification of the severity of sepsis is vital, in timing and specific treatment [18].

Presepsin is thought to be a new candidate biomarker for
diagnosis of sepsis. Presepsin levels of patients with sepsis
were found significantly elevated in comparison with patients
having SIRS and healthy people, in a clinical study [13] [12].
The rise in presepsin levels was found to be earlier with
respect to the rise in IL-6 and D-Dimer levels as a result of a
study by creating an animal model of bacteriemia [19]. It is
indicated that presepsin levels may be an important marker
for diagnosis of sepsis.

Shozushima et al. [20] studied presepsin and PCT levels for
diagnosis of sepsis and found presepsin more useful in
diagnosis of sepsis compared to PCT. As the cut-off value of
presepsin is determined 415 pg/ml; it was found that clinical
sensitivity was %80.1, specificity was %81. ROC analyse
was made and Area Under the Curve (AUC) of presepsin was
found higher than PCT and presepsin was thought to be more
precious in diagnosis compared to PCT. In this study, it was
found that PCT levels elevated in patients with SIRS also, but
presepsin levels elevated only in patients with sepsis.

In another clinical study, presepsin was compared with CRP,
IL-6 and PCT again. In this prospective cohort study; healthy,
local infection, SIRS, sepsis and severe sepsis groups were
compared for diagnostic performance for sepsis in 41 patients
with SIRS. When they divided the patients into an infection
group and a non-infection group and plotted the ROC curves
of each of the markers to compare presepsin with other
markers, the results showed that presepsin was the best,
followed by CRP, IL-6, and PCT. Although PCT is thought to
be one of the best markers for diagnosis of sepsis, there were
12 patients with trauma and burn in that study and so PCT
levels thought to be increased as a reflection of the severity of
the body's reaction to the traumatic stimuli in the early stage
of trauma in the absence of signs of infection [20]. Yaegashi
et al. also found same findings for diagnostic performance of
presepsin compared other biomarkers as IL-6 and PCT [12].
These studies thought that PCT was not capable enough to
distinguish sepsis and SIRS but presepsin was. Same finding
for PCT was reported in a review and they thought PCT could
not reliably differentiate sepsis from other non-infectious
causes of SIRS in critically ill adult patients. Moreover they
do not lend support to the widespread use of the PCT test in
critical care settings [8].

According to several studies, presepsin could be seen a valuable biomarker for early diagnosis for sepsis and distinguish it from non-infectious diseases. But there is no data about presepsin levels on prognosis of sepsis or therapy modification. Whereas widely used biomarkers routinely as CRP, lactate or PCT levels could be used for this purpose and could change the treatment. However presepsin is claimed to be an ideal biomarker for diagnosis sepsis and distinguish it from non-infectious diseases, PCT, CRP or lactate are each more capable to achieve prognosis, response to therapy. Combination of presepsin and several sepsis biomarkers may be more effective. For example, presepsin can be used for diagnosis and specify sepsis, and PCT or other biomarkers can be used prognosis and therapy modification, but this requires further evaluation.

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