7 5

6
Reduction of risk for mortality and morbidity in suspected sepsis in 15 minutes

12

9 3
15min
6

Time is survival
PreSEPSIN: The Sepsis Biomarker
A short monograph
Automated quantitative POC method
From 100 l whole blood or plasma in 15 minutes
For early monitoring of effectiveness of antibiotic treatment
Superior prognostic value for risk assessment of patients
Excellent performance demonstrated in numerous studies
Multi marker testing with other analytes possible
Contents
Sepsis 4
Mortality and Morbidity 4
Sepsis incidence and costs increase dramatically 5
Diagnosis of sepsis: time is survival 5
Presepsin: the innovative early biomarker for sepsis 6
Measurement of Presepsin 6
Normal range and kinetics 6
Presepsin: a specific and early diagnostic biomarker for sepsis 7
Presepsin and severity of the septic process 8
Presepsin in the Emergency Room (ER) 8
Presepsin as a predictor for infections in surgery 10
Presepsin as a prognostic marker 10
Presepsin and Monitoring 11
Sepsis and disseminated intravascular coagulation 12
Presepsin in children and neonates 12
Conclusions 13
Literature 14
Sepsis Definition of different stages of sepsis
Systemic The systemic inflammatory response is
Sepsis is a complex whole-body inflammatory state caused inflammatory manifested by two or more of the following
by severe infection by bacteria, fungi or other micro- response conditions:
syndrome (1) Body temperature < 36 C or > 38 C
organisms. Severe sepsis is accompanied by single or multiple
(SIRS) (hypothermia or fever)
organ dysfunction or failure, often leading to death. Cyto-
kines and other substances of the innate immune system are (2) H
 eart rate >90 beats per minute
released into the blood to combat the infection. This results (3) R
 espiratory rate >20 breaths per minute
in a systemic inflammatory state with formation of thrombi, (tachypnea or hypocapnia due to
bleeding and leaky vessels. It proceeds finally in impaired hyperventilation)
blood flow which damages the organs by depriving them of (4) W
 hite blood cell count < 4,000 cells/mm3
nutrients and interferes with oxygen supply. or > 12,000 cells/mm3
The severity of organ damage and sepsis is often estimated
from clinical risk stratification scores such as the Sequential Sepsis SIRS in response to a confirmed infectious
Organ Failure Assessment (SOFA) Score 1, APACHE II (Acute process. Infection can be suspected or proven.
Physiology and Chronic Health Evaluation II) 2, or MEDS
(Mortality in Emergency Department Sepsis).3 Severe sepsis Sepsis with organ dysfunction, hypoperfusion,
or hypotension.

Septic shock Sepsis with arterial hypotension or hypoperfusion

Parasites
and abnormalities in spite of adequate fluid
Pancreatitis
Others resuscitation.
Bacteria
Trauma Bone et al, Chest. 1992
Post-
surgery
INFECTION SEPSIS SIRS
Viruses Burns

Fungi
Mortality and Morbidity
Others

Death is common among sepsis patients, with a large pro-

portion non surviving within the first month of diagnosis.5
Mortality in patients with severe sepsis can be up to more
than 50%.6 Survivors are often strongly disabled and require
long rehabilitation treatment.7 Especially elderly survivors
of severe sepsis are up to three times as likely to develop
persistent cognitive and functional impairments.8

4
Sepsis incidence and costs
increase dramatically Sepsis cases per 100.000 population (EU/US)

400
More than 18 million cases of severe sepsis are reported
worldwide each year. Incidence increases strongly with a
300
rate of 1.5%/year.5 Hospitalizations for sepsis have more than
doubled over the last 10 years. 9 Sepsis occurs in 12% of
200
all hospitalizations and accounts for as much as 25% of
intensive-care unit (ICU) bed utilization. Recent US data 12
100 11 1
suggest the annual cost of hospital care for patients with 10 2
septicemia is USD 14 billion.10 Incidence and cost aspects 9 3 12
seem to be even worse in Europe.11 0
Sepsis Stroke 8
Cancer 15min 4
Heart HIV10
11 1
2
7 5
6 9 3
8 15min 4
Diagnosis of sepsis: 7
6
5

time is survival 12 12

About 20-40% of sepsis patients develop sepsis already out- Time is survival 9 3 9 3
side the hospital. The mainstay of sepsis treatment is a rapid 15min 15min
diagnosis and early goal directed therapy.12 By the time 100
6 6
physicians realize a patient is septic, it can be too late for
starting therapy with broad-range antimicrobials, fluids, 75
Patients (%)

medication for stabilizing the circulation, and other steps.

Clinical symptoms such as increased pulse or breathing rate, 50

raised body temperature or laboratory parameters such as

25
white blood cell count or lactate have only limited specifi-
city. About one third of patients with severe sepsis do not
0
show positive blood cultures 13 and with current methods 0 1 2 3 4 5 6 7 8 9 10 11 12 24 36
Hours
results would take too long. For every hour delay in the
Mortality Effective antibiotic treatment
administration of appropriate antibiotic therapy there is an
Modified from World Sepsis Day by lindgruen-gmbh.com
associated 7% rise in mortality.14 The problem of increased
bacterial resistance is problematic, prolonging length of stay
and duration of mechanical ventilation. Therefore moni
toring any therapeutic measures that have been taken is
highly important.
A rapid and reliable point of care test for detection of sepsis
and its differentiation from SIRS that is applicable directly
in the ICU or ER and that allows monitoring is a major step
forward.

5
Presepsin: the innovative early
biomarker for sepsis
Presepsin is a specific 13 kDa fragment derived from CD14, a
55 kDa membrane glycoprotein of monocytes, macrophages
and polymorph nuclear neutrophils. CD14 serves as a recep-
tor for complexes of bacterial lipopolysaccharides (LPS) and
LPS binding protein (LPB). It can bind to peptidoglycan and
other surface structures in both Gram-positive and Gram
negative bacteria.15
The toll-like receptor 4 (TLR4, CD 284) and/or toll-like
receptor 2 specific pro-inflammatory signaling cascade is
activated inducing a series of signal transduction pathways
that result in a systemic inflammatory response.
Hypothetical mechanism of Presepsin secretion
Cell surface
membrane TLR4
Monocyte
sCD14
MD2 activation
LPS-LBP
Phagocytosis
mCD14 complex
LPS-LBP Pr
ot
complex eo
ly
s is
Pr
o Result in 15 min
13 kDa
sCD14-ST
(Presepsin)
Lysosomal proteases
(e.g. cathepsin D)
mCD14: membrane CD14; sCD14: soluble CD14; sCD14-ST: soluble CD14 subtype
(=Presepsin); LPS: lipopolysaccharide; LBP: lipopolysaccharide binding protein, TLR4:
toll-like receptor 4; MD2: Co-Protein of TLR4.
The fragment soluble CD14 (sCD14) is shed from the cell
membrane into the circulation where it is further fragmented
by proteases such as cathepsins or during phagocytosis to
sCD14 subtype (sCD14-ST) or Presepsin16. In healthy persons,
Presepsin is found in very low concentrations. However in
patients with sepsis, direct involvement of bacterial LPS and
probably phagocytosis, increased values of Presepsin are
found already at a very early stage, even before IL-6 rises.17,18
The plasma half live has been reported to be 4-5h.6
Measurement of Presepsin
Presepsin can easily be measured from whole blood or
plasma with the compact PATHFAST TM analyzer at the point of
care or in the lab.19 The PATHFAST TM Presepsin immunoassay is
based on chemiluminescence and shows excellent precision.
The fully automated procedure takes just 15 minutes and
it requires only 100 l of EDTA- or heparin-anticoagulated
blood, or plasma. This makes the method ideal also for
pediatric samples. In whole blood samples the effect of
hematocrit is automatically corrected. There is excellent
correlation between whole blood and plasma results.19,23
Running a test on PATHFAST is very simple and does not
require special operator skills. Reliable results at the point
of care are a prerequisite for patient risk stratification
12 and
11 1
initiation of immediate targeted therapy. 10 2
In addition to Presepsin, PATHFAST offers 9 several 3other
STAT assays with relevance in sepsis such8 as 15D-Dimer,
min 4 NT- 1
proBNP, hs-cTnI, CK MB and hsCRP. All assays 7 are5provided
6 9
in economical precalibrated unit-dose cartridges. Up to six 8
samples can be tested in parallel in one run following in
3 simple steps.
12
55 kDa 9 3 9
sCD14 15min
+ 6
Step 1 Insert cartridge
Step 2 Load sample
is
ys Step 3 Press START
ol
te
Normal range and kinetics
The normal range of Presepsin in healthy adults is usually
very low with values up to around 320 pg/ml (upper
reference limit stated by the manufacturer).19 Similar values
were found in several other studies.23,34 In a small study the
mean Presepsin blood level in 26 preterm newborns was
643 pg/ml and a median value of 578pg/ml.20
However, there is evidence that in elderly patients or
patients with impaired renal function (which is frequently
found in elderly patients) there is an increase of values,
at least in patients that had no signs of infections.21 This
may be related to bioaccumulation of Presepsin (13 kDa)
due to reduced nephrotic mass, similar as described for
Procalcitonin (PCT).22 Therefore interpretaton of results
should consider the actual renal function of the patient.
In a rabbit cecal ligation and puncture (CLP) model, along
with occurrence of blood bacteria, Presepsin levels were
elevated even earlier than IL-6, and much earlier than PCT,
with a peak at about 3h after onset of the infection and a
decline after 4-8 hours.18 In survivors, Presepsin declines
after a few hours whereas it remains elevated in those who
died.
6
Presepsin: a specific and early
diagnostic biomarker for sepsis
The levels of Presepsin are significantly higher in septic
patients than in patients with SIRS or apparently healthy indi-
viduals. This has been demonstrated in several recent studies
in various countries and various groups of patients and in
infections cause by either Gram-positive or Gram-negative
infections or mixed infections.17,23,24,25,26,27,28,29,30,31,32,33,34,27,35
The following table summarizes recent studies in which
Presepsin has been often compared with other biomarkers.

Patients Results (AUC- values of ROC curves) Conclusions Reference

859 consecutive Presepsin: 0.784 Presepsin is effective and superiorover PCT Liu et al,
patients with at PCT: 0.724 for diagnosing sepsis, and predicting severe 2014 27
least two criteria sepsis, septic shock and 28-day mortality in
Presepsin in combination with APACHE II
for SIRS septic patients in the ED.
score: 0.858
Combination of Presepsin with clinical
Presepsin in combination with MEDS score:
scores enhances the diagnostic efficacy.
0.875

226 patients Presepsin: 0.750 Presepsin is significantly higher in patients Romualdo et al,
with SIRS (37 with PCT: 0.787 with bacteremia and may be useful for ruling 2014 37
positive and 189 out bacteremia in patients with SIRS.
CRP: 0.602
with negative
blood culture)

106 patients, with Presepsin: 0.701 Presepsin is useful in the early diagnosis Ulla et al,
suspected sepsis PCT: 0.875 of infection and showed a significant 2014 29
or septic shock prognostic value. Mean Presepsin values
were significantly higher in non survivors
(60 day mortality) than in survivors.
No correlation of PCT and survival.

37 patients Presepsin: 0.834 Presepsin had comparable performance Madenci et al,

with burns PCT: 0.847 as PCT in burn patients. No correlation of PCT 2014 33
and survival.
CRP: 0.819
WBC: 0.508

30 patients Presepsin: 0.996 Discrimination of SIRS from sepsis: Presepsin Vodnik et al,
with SIRS and PCT: 0.912 values were significantly higher in patients 2014 34
30 patients with sepsis than the SIRS group. Presepsin was
CRP: 0.857
with sepsis a significantly sensitive indicator of sepsis and
WBC: 0.777 useful marker for the rapid diagnosis of sepsis.

207 suspected Presepsin: 0.908 Presepsin and PCT showed similar diagnostic Endo et al,
sepsis patients, PCT: 0.905 power by AUC analysis. 2012 30
multicentric study

140 patients with Presepsin: 0.878 Compared to PCT Presepsin is efficient in the Spanuth et al,
suspected sepsis APACHE II: 0.815 diagnosis and risk stratification of sepsis. 2012 25

PCT: 0.668 Presepsin values increased significantly in

the first 72 hours in patients with poor out-
come, while values decreased in survivors

41 patients Presepsin: 0.908 Presepsin is superior over PCT, CRP and IL-6. Shoshuzima et al,
and 128 healthy PCT: 0.652 CRP: 0.815 IL-6:0.672 2011 23
subjects

231 SIRS and sepsis Presepsin: 0.817 The Presepsin concentration was a signifi- Yaegashi et al,
patients PCT: 0.744 cantly more sensitive indicator of sepsis than 2005 17
the concentrations of other biomarkers tested.

7
Presepsin and severity of the Presepsin in the Emergency
septic process Room (ER)
Shozushima et al found in a group of patients with signs of A large study in China with 859 consecutive patients ad-
SIRS that the concentration of Presepsin was 333.5 pg/mL mitted to the emergency unit with at least two criteria for a
in the SIRS group, 721 pg/mL in the local infection group, systemic inflammatory response investigated the relationship
817.9 pg/mL in the sepsis group, and 1992.9 pg/mL in the between the Presepsin levels at admission in the emergency
ROC Curve
severe sepsis group. The blood concentration of Presepsin department with the severity of disease.
among the groups increased sequentially.
ROC Curve
Staging the severity of sepsis with Presepsin ROC curve analysis of 185 patients
P<0.01 P<0.05 P<0.01 P<0.01 1.0 ROC curve analysis
10000
1992.91509.2
10000 of patients with
1322.41286.8
866.1823.4 n=22 or without bacterial
n=59 0.8
P<0.05 P<0.05
1.0 infections for the
817.9572.7
diagnosis of sepsis
721.0611.3 indicates higher AUC
Presepsin (pg/ml)

Presepsin (pg/ml)

0.6

Sensitivity Sensitivity
430.4268.9
n=23 0.8 values for Presepsin.
1000 1000
294.2121.4
333.5130.6 0.4
0.6 n=185

0.2 Presepsin
0.4 PCT
Reference Line
n=185
0.0 Presepsin
100 100 0.2 0.0
Normal SIRS Local Sepsis Severe 0 10 11 20 >21 0.2 0.4 0.6
PCT 0.8 1.0
infection sepsis APACHE II score 1-Specifity
Reference Line
1.0
0.0
Shozushima et al, 2011 (23) Liu et al, 2013
0.0
(27) 0.2 0.4 0.6 0.8 1.0
1-Specifity
Though blood culture is not always positive in sepsis patients, 0.8
rate (Sensivity)

1.0 ROC curve analysis

it is still an important assay to compare the performance of of various biomarkers
0.6
for predicting severe
sepsis biomarkers. In a study with patients with either Gram- 0.8 sepsis.
(Sensivity)

positive or Gram-negative bacterial or with fungal infections

positive

0.4
with positive blood cultures, Presepsin levels were only 0.6
Presepsin (pg/mL)
rate

significantly different between sepsis/infections and severe PCT (ng/mL)

True

0.2
True positive

IL-6 (pg/mL)
infections groups, respectively. Presepsin levels reflected 0.4
No discrimination
Presepsin (pg/mL)
the blood culture test and the severity of the clinical course 0.0 PCT (ng/mL)
0.2 0.0
more than other biomarkers such as IL-6 or PCT. A ROC-curve 0.2 0.4 0.6 0.8
IL-6 (pg/mL)
False positive rate (1-Specificity)
No discrimination
1.0

analysis showed superior performance of Presepsin over PCT

0.0
and for both markers a clearly superior performance over IL-6.36 0.0 0.2 0.4 0.6 0.8 1.0
False positive rate (1-Specificity)

Comparison of Presepsin, PCT and IL-6 in patients with Endo et al, 2012 (6)
systemic infection, localized bacterial infections and non-
infectious diseases

Presepsin PCT 30 IL-6

10000 1000 1000000

100000
100

10000
Presepsin (pg/mL)

1000 10
PCT (ng/mL)

IL-6 (pg/mL)

1000
1
100
100 0.1
10

0.01 1

10 0.001 0.1
Systemic Localized Non- Systemic Localized Non- Systemic Localized Non-
bacterial bacterial infectious bacterial bacterial infectious bacterial bacterial infectious
infection infection disease infection infection disease infection infection disease

8
A clear relationship between Presepsin levels and the Presepsin levels and severity of disease
There is a high
different stages of sepsis severity was found while for PCT 1200 P<0.0001
correlation between
a major increase of concentration is only seen in the most 1000
Presepsin levels and
1200 severity of sepsis on

Median Presepsin (pg/mL)

severe form of septic shock. The ROC analysis showed a P<0.0001
P<0.0001
admission of patients
higher AUC value for Presepsin (0.84) as compared to PCT 800
1000 to the ER.

Median Presepsin (pg/mL)

(0.741) or the clinical scores such as MEDS (0.818), or APACHE 600
P<0.0001
800
II (0.744). Combing of either score with Presepsin slightly
P<0.0001
enhanced the predictive power of Presepsin alone. There- 400
600
P<0.0001
fore Presepsin can be used for early risk stratification and for 200 P<0.0001
400
early decision for targeted therapy when required. A drop of P<0.0001
0
Presepsin during the course of sepsis may show a response 200
Control SIRS Sepsis Severe Septic
(n=100) (n=179) (n=372) sepsis shock
to successful therapy and hence the test may have potential 0 (n=210) (n=98)
as a monitoring tool.27 Control SIRS Sepsis Severe Septic
Liu et al, 2013(n=100)
(27) (n=179) (n=372) sepsis shock
(n=210) (n=98)
1.0
Biomarkers and clinical scores ROC-curves of biomarkers and clinical scores
1.0 ROC-curves of
0.8
various markers,
2500 clinical scores or
0.8
0.6
combination.
Sensitivity

2000

0.6
0.4 Presepsin
Sensitivity

1500 PCT
MEDS
0.4 Presepsin
APACHE II
0.2
1000 PCT
MEDS+Presepsin
MEDS II+Presepsin
APACHE
APACHE IILine
Reference
0.2
0.0
500 MEDS+Presepsin
0.0 0.2 0.4 0.6APACHE0.8 1.0
II+Presepsin
1-SpecificityReference Line
0 0.0
Presepsin MEDS (x100) APACHE II (x100) PCT 0.0 0.2 0.4 0.6 0.8 1.0
1-Specificity
Control SIRS Sepsis Severe Sepsis Septic Shock

Liu et al, 2013 (27)

The relationship between sepsis biomarkers and clinical
scores were compared and the clinical score values were
tentatively multiplied by 100 in order to get a comparable
scale, PCT is shown in pg/ml.
A Spanish study investigated the performance of Presepsin
as a predictor of bacteremia for the early detection of
blood-stream infections in 226 patients admitted to the
emergency department with SIRS. A negative predictive
value for Presepsin of 94.4% was found when using a
cut-off value of 729 pg/ml.37

9
Presepsin as a predictor for
infections in surgery
Novelli evaluated the analytical and clinical performance A ROC curve analysis showed superior prognostic accuracy
of the PATHFAST Presepsin assay system for early diagnosis for Presepsin as compared to PCT, and addition of Presepsin
of infection in 70 adult patients, including 35 cadaveric to the clinical APACHE II score could increase the AUC-value
organ transplant recipients and 35 abdominal surgery from 0.815 to 0.905. Improvements of adding Presepsin
patients with a mean age of 56.1 years. Presepsin was also other clinical scores was shown as well, e.g. for MEDS
tested at 48 hours after surgery together with blood from 0.819 to 0.936. The negative predictive value of
cultures and demonstrated 100% sensitivity to show the Presepsin alone was 98.5% (PCT: 92.4%), showing a high
presence of infection, confirmed by positive blood cultures.28 potential to rule out sepsis with a single assay.

Presepsin as a prognostic Presepsin values and mortality

Presepsin values
Mortality of quartiles of either Presepsin (left)
marker 40 n=140
or PCT
Mortality of quartiles of (right)
either presepsin (left)
or PCT (right)
and mortality of
sepsis patients in ER
(adapated from
40
35 Spanuth et al, 2012)
In a study in Italy on 100 patients with sepsis (50 decedents 35
(%) (%)
30
and 50 survivors), the level on day 1 and the evolution of Pre- 30
Mortality

25

sepsin levels over time was significantly higher in decedents

Mortality

25
20

than in survivors whereas PCT was not different in the two 20

15
15
groups except from day 7. Presepsin was the only variable 10
105
independently associated with ICU and 28-day mortality and
50
showed better prognostic accuracy than PCT in the range of 0 Presepsin or PCT, quartiles
SOFA score (area under the curve (AUC) from 0.64 to 0.75 vs.
AUC 0.53 to 0.65).38
Median values of survivors and non-survivors
Comparison between Presepsin and PCT Median values
(Presepsin and PCT,
Presepsin PCT 2070 both in pg/ml) of
PCT
6000 60 survivors and non
** (pg/ml) 1840 survivors (adapated
from Spanuth et al,
** 2012)
4000 ** 40 2124
Presepsin
pg/ml

g/ml

2523 2551 (pg/ml) 823

2269
18.5
2000 20
1184 1253
974 10.8 10.8 Non-Survivors Survivors
7.2
*
1.9 0 500 1000 1500 2000 2500
0.9
0 0 Concentration (pg/ml)
Day1 Day2 Day7 Day1 Day2 Day7

Two-way ANOVA Survival p=0.004 Two-way ANOVA Survival p=0.50

Time p=0.22 Time p<0.0001
Interaction p=0.03 Interaction p=0.13
ROC-curve analysis for Presepsin
ROC-curve analysis
Comparison between Presepsin (left) and PCT (right) in patients with severe sepsis or 100 revealed an AUC of
septic shock. Masson et al, 2014 (31) 0.878 for Presepsin
for 30 days survival
80

A German study on 140 patients admitted to the emergency

department with signs or suspicion of sepsis showed a clear 60
Sensitivity

and statistically highly significant (p<0.0001) relationship

40
between Presepsin concentrations and mortality, while AUC
Presepsin 0.878
this relationship was not found for PCT. APACHE II 0.815
20
The median Presepsin values at admission for survivors PCT 0.661

was 823 pg/ml and 2124 pg/ml (p<0.0001) for non-survivors 0

whereas the PCT values showed no significant 0 20 40 60 80 100
100-Specifity
difference (p=0.7452) with 1.84 ng/ml and 2.07 ng/ml.
Spanuth et al, 2012 (25)

8000 Presepsin
7000
10
6000

5000
4553
L
 80

60

Sensitivity
40
AUC
Presepsin 0.878
APACHE II 0.815
20
PCT 0.661

Presepsin and Monitoring 0

0 20 40 60 80 100
100-Specifity
In a recent multicentric study Presepsin and other bio- Mean values of Presepsin and PCT over time
markers used in sepsis were investigated in sepsis patients in non-survivors and survivors
over the clinical course. All markers declined over time in Course of mean
8000 Presepsin values of Presepsin
patients with predicted favorable outcome according to 7000 and PCT (error
SOFA or APACHE II score. Unlike other biomarkers, only bars: 95% CI) in
6000 non-survivors
Presepsin values showed a tendency to stay elevated in (30 days, red line)
5000
the group of patients with unfavorable outcome.26 4553 and survivors

pg/mL
4000 3506 (blue line).

Course of biomarkers over time 3000 3094

p=0.0002 p<0.0001 p=0.0002
2000
Presepsin PCT 1135
1203 1009
10000
P<0.0001
1000
P<0.0001 P<0.0001 1000
P<0.01 P<0.01 P<0.01 P<0.0001 P<0.01 P<0.0001
0
100
At admission 24 hours 72 hours
Presepsin (pg/mL)

PCT (ng/mL)

10
1000 80 PCT
1

0 60

100 0
D0 D3 D7 D0 D3 D7 D0 D3 D7 D0 D3 D7 40
ng/mL

31.8
Favorable Unfavorable Favorable Unfavorable 23.3

20 22.1
IL-6 CRP p=0.39 p=0.03 p=0.043

P<0.0001 P<0.0001 P=0.0001 P<0.01 6.6

1000 6.2
1000000 4.4
P<0.0001 P<0.001 P<0.0001 P<0.0001 P<0.0001 P<0.0001 0
100000
100
-20
CRP (mg/dL)
IL-6 (pg/mL)

10000
At admission 24 hours 72 hours
1000 10

100 Spanuth et al, 2012 (25)

1
10

1 0 The specific advantage of Presepsin over other biomarkers

D0 D3 D7 D0 D3 D7 D0 D3 D7 D0 D3 D7
Favorable Unfavorable Favorable Unfavorable
becomes also visible from time courses of individual
patients.
Presepsin PCT
Endo et al, 2014 (26)
P<0.0001
10000 1000
P<0.0001 P<0.0001 Therefore Presepsin is a parameter that helps to guide
P<0.01 P<0.01 P<0.01 P<0.0001 P<0.01 P<0.0001 therapy in sepsis as shown in a time course of a burn patient
100
A clear difference in the development of Presepsin and who developed a sepsis after hospitalization. Effectiveness
Presepsin (pg/mL)

PCT (ng/mL)

PCT values during the course 10of treatment could be of antibiotic

SIRStreatment Sepsis
is shown at day 13.
1000
demonstrated in 140 patients with 1 sepsis who got anti-
microbial treatment after diagnosis 0
of sepsis. Presepsin Biomarker level of a burn patient
showed a clear trend towards lower values in survivors
SIRS Sepsis
over 100theD0 period from 0 72 h 0observation
D3 D7 D0 D3 D7 D0 D3 D7 D0 D3 D7
time while
Presepsin
non-survivors
Favorable reached very high values.
Unfavorable Favorable In contrast,
UnfavorablePCT
PCT
2000 7000
thoughIL-6 also much higher in non-survivors showed only a IL-6
PCT (ng/mL) / CRP (mg/l) x 10

CRP 1800 CRP 6000

marginal
1000000 decline
P<0.0001
after 24 hours in1000
P<0.0001
the survivors.
P<0.01 P<0.0001
1600
Presepsin (pg/mL)

P<0.0001 P<0.01 P<0.0001 P<0.001 P<0.0001 P<0.0001

1400 positive 5000
100000 blood culture
100 1200 4000
CRP (mg/dL)
IL-6 (pg/mL)

10000 1000
800 3000
1000 10
600 2000
100
400
1 1000
10 200
0 0
1 0
0 2 4 6 8 10 12 14 16 18 20
D0 D3 D7 D0 D3 D7 D0 D3 D7 D0 D3 D7 Days
Favorable Unfavorable Favorable Unfavorable
PMX-DHP
Shozushima et al, 2011 (23)
Presepsin
33
APACHE II score
3000 30 15
SOFA score
Presepsin (ng/mL)

APACHE II score

SOFA score

2000 20 10
11

1000 10 5
Sepsis and disseminated
intravascular coagulation
A large proportion of sepsis patients develops severe, some-
times lethal coagulation problems. In a study in which 11
biomarkers were tested in 82 patients with suspected sepsis AUC values of various biomarkers
admitted to the emergency unit, an optimal panel of in neonatals with and without infections
markers for the detection of disseminated coagulation (DIC)
and sepsis was the combination of Presepsin and protein C
with an AUC- value of 0.913 for sepsis and 0.88 for DIC.39 CRP

Presepsin in children and PCT

neonates PSP

In neonates, early diagnosis of sepsis increases the chances

0,0 0,2 0,4 0,6 0,8 1,0
for an early and specific treatment and hence for survival.
Day 3 Day 2 Day 1
There is initial evidence that presepsin may be useful in this
condition. AbdElazziz, 2013 (40)
A study of 188 newborns with suspected infections,
Presepsin and other biomarkers were measured on three Presepsin concentration in septic newborns
subsequent days. Presepsin and PCT were able to differen- and newborns without infection
tiate between bacterial infection (n=102) and SIRS or other 2400

non-bacterial infection (n=64) while CRP was clearly less 2200

effective. 2000

ROC analysis demonstrated that Presepsin showed advan- 1800

Presepsin (pg/mL)

1600
tages over PCT. It increased earlier, was more sensitive and
1400
more specific than PCT (see figure). The cut-off value for 1200
Presepsin (781 pg/ml) was consistent on all three days. 1000
PCT showed a dynamic cut-off (day 1:0.5ng/ml, day 2 and 3: 800

1.0 ng/ml) that aggravates diagnosis. 600

In a different study, the mean presepsin concentration in 400

Group I Group II
early onset of septic newborns was 1772 1009 pg/ml while Srednia
it was 556 158 pg/ml in healthy newborns. The value found Kwiatkowska-Gruca M et al, 2013
SredniaBlad std (41)
Srednia1,96*Blad std
in healthy newborns in this study is very similar to the value
found in a previous study on preterm newborns.20

12
 Conclusions
Presepsin is a reliable, specific and sensitive biomarker for
sepsis and is a valuable tool for the very early diagnosis of
sepsis by Gram-positive and Gram-negative bacteria and fungi.
Presepsin rises earlier than other biomarkers and does not show
unspecific increases.
Presepsin values help to stratify the severity of the septic disease
with excellent correlation to APACHE II and SOFA scores.
Presepsin exceeds the prognostic power of other sepsis
biomarkers and is specifically useful when combined with clinical
risk scores.
The time course of Presepsin can be used for monitoring:
a decline demonstrates response to therapy and predicts a
favorable outcome.

13
Literature
1 Vincent JL, Moreno R, Takala J, Willatts S, De Mendona A, Bruining
H, Reinhart CK, Suter PM, Thijs LG. The SOFA (Sepsis-related Organ
Failure Assessment) score to describe organ dysfunction/failure.
On behalf of the Working Group on Sepsis-Related Problems of the
European Society of Intensive Care Medicine. Intensive Care Med
1996;22:707-10
2 Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II:
a severity of disease classification system. Critical Care Medicine
1985; 13: 81829
3 Carpenter CR, Keim SM, Upadhye S, Nguyen HB. Best Evidence
in Emergency Medicine Investigator Group.Risk stratification of
the potentially septic patient in the emergency department: the
Mortality in the Emergency Department Sepsis (MEDS) score.
J Emerg Med. 2009;37:319-27
4 Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ
failure and guidelines for the use of innovative therapies in
sepsis. The ACCP/SCCM Consensus Conference Committee. American
College of Chest Physicians/Society of Critical Care Medicine.
Chest. 1992; 101:1644-55
5 Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J,
Pinsky MR. Epidemiology of severe sepsis in the United States:
analysis of incidence, outcome, and associated costs of care.
Crit Care Med2001;29:1303-10
6 Endo S, Takahashi G, Shozushima T, Matsumo N, Kojika M, Suzuki
Y, Inoue Y. Usefulnes of presepsin (Soluble CD 14 Subtype) as a
diagnostic marker for sepsis. JJAAM 2012;23:27-38
7 Winters BD, Eberlein M, Leung J, Needham DM, Pronovost PJ,
Sevransky JE. Long-term mortality and quality of life in sepsis:
a systematic review. Crit Care Med 2010; 38:1276-83
8 Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive
impairment and functional disability among survivors of severe
sepsis. JAMA 2010; 304:1787-94
9 World Sepsis day 2013 (http://www.world-sepsis-day.org)
10 HCUP Facts and Figures, 2006: Statistics on Hospital-Based Care
in the United States. Rockville (MD)2008. Available at: http://www.
hcup-us.ahrq.gov/reports/factsandfigures/2008/TOC_2008.jsp
11 Levy MM, Artigas A, Phillips GS, Rhodes A, Beale R, Osborn T,
Vincent JL, Townsend S, Lemeshow S, Dellinger RP. Outcomes
of the Surviving Sepsis Campaign in intensive care units in the
USA and Europe: a prospective cohort study. Lancet Infect Dis.
2012;12:919-24
12 Rivers EP, Coba V, Whitmill M. Early goal-directed therapy in severe
sepsis and septic shock: a contemporary review of the literature.
Curr Opin Anaesthesiol. 2008 ;21:128-40
13 Rangel-Frausto MS. The epidemiology of bacterial sepsis. Infect Dis
Clin North Am 1999; 13:299-312 org/10.1016/S0891-5520(05)70076-3
14 Kumar A, Roberts D, Wood KE, et al. Duration of hypotension
before initiation of effective antimicrobial therapy is the critical de-
terminant of survival in human septic shock. Crit Care Med. 2006;
34:1589-96
15 Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC. CD14,
a receptor for complexes of lipopolysaccharide (LPS) and LPS
binding protein. Science. 1990;249(4975):1431-3
16 Shirakawa K, Naitou K, Hirose J, Takahashi T, Furusako S. Presepsin
(sCD14-ST): development and evaluation of one-step ELISA with
a new standard that is similar to the form of presepsin in septic
patients. Clin Chem Lab Med. 2011;49:937-9
17 Yaegashi Y, Shirakawa K, Sato N, Suzuki Y, Kojika M, Imai S, Takahashi
G, Miyata M, Furusako S, Endo S. Evaluation of a newly identified
soluble CD14 subtype as a marker for sepsis. J Infect Chemother.
2005;11:234-8
18 M Nakamura, T Takeuchi, K Naito, K Shirakawa, Y Hosaka, F Yamasaki,
S Furusako. Early elevation of plasma soluble CD14 subtype, a novel
biomarker for sepsis, in a rabbit cecal ligation and puncture model.
Critical Care March 2008 Vol 12 Suppl 2, P194
19 Okamura Y, Yokoi H. Development of a point-of-care assay system
for measurement of presepsin (sCD14-ST). Clin Chim Acta.2011;
412:2157-61
20 Mussap M, Puxeddu E, Burrai P, Noto A, Cibecchini F, Testa M,
Puddu M, Ottonello G, Dess A, Irmesi R, Gassa ED, Fanni C, Fanos V.
Soluble CD14 subtype (sCD14-ST) presepsin in critically ill preterm
newborns: preliminary reference ranges. J Matern Fetal Neonatal
Med. 2012 Oct;25(Suppl 5):51-3
21 
Chenevier-Gobeaux C, Trabattoni E, Roelens M, Borderie D,
Claessens YE. Presepsin (sCD14-ST) in emergency department: the
need for adapted threshold values? Clin Chim Acta. 2014;427:34-6
22 Chenevier-Gobeaux C, Trabattoni E, Elfassy Y, Picard C, Gurin S,
Borderie D, Claessens YE. Decisional procalcitonin thresholds are
not adapted to elderly patients admitted to the emergency room.
Biomarkers. 2012;17:477-81
23 Shozushima T, Takahashi G, Matsumoto N, Kojika M, Okamura Y,
Endo S. Usefulness of presepsin (sCD14-ST) measurements as
a marker for the diagnosis and severity of sepsis that satisfied
diagnostic criteria of systemic inflammatory response syndrome.
J Infect Chemother. 2011;3:764769
24 Mussap M, Noto A, Fravega M, Fanos V. Soluble CD14 subtype
presepsin (sCD14-ST) and lipopolysaccharide binding protein (LBP)
in neonatal sepsis: new clinical and analytical perspectives for two
old biomarkers. J Matern Fetal Neonatal Med. 2011;3(Suppl 2):1214
25 
Spanuth E, Ebelt H, Ivandic B, Werdann K. Diagnostic and
prognostic value of presepsin (soluble CD14 subtype). Emergency
patients with early sepsis using the new assay PATHFAST. In
Advances in Climical Chemistry and Laboratory Medicine . Renz H,
Tauber R edit. Walter De Gruyter, Berlin 2012:129-133
14
26 Endo S, Suzuki Y, Takahashi G, Shozushima T, Ishikura H, Murai A, 38 Masson S, Caironi P, Spanuth E, et al. Presepsin (soluble CD14
Nishida T, Irie Y, Miura M, Iguchi H, Fukui Y, Tanaka K, Nojima T, subtype) and procalcitonin levels for mortality prediction in sepsis:
Okamura Y. Presepsin as a powerful monitoring tool for the data from the Albumin Italian Outcome Sepsis trial. Crit Care. 2014
prognosis and treatment of sepsis: a multicenter prospective study. Jan 7;18(1):R6 [Epub ahead of print]
J Infect Chemother. 2014;20:30-4
39 
Ishikura H, Nishida T, Murai A, Nakamura Y, Irie Y, Tanaka J,
27 Liu B, Chen YX, Yin Q, Zhao YZ, Li CS. Diagnostic value and Umemura T. New diagnostic strategy for sepsis-induced dis-
prognostic evaluation of Presepsin for sepsis in an emergency seminated intravascular coagulation: a prospective single-center
department. Crit Care. 2013 Oct 20;17(5):R244. [Epub ahead of print] observational study. Crit Care. 2014 Jan 20;18(1):R19 [Epub ahead of
print]
28 Novelli G, Morabito V, Ferretti G, Pugliese F, Ruberto F, Venuta F,
Poli L, Rossi M, Berloco PB. Pathfast presepsin assay for early 40 AbdElazizz H. Diagnosis of Neonatal Sepsis using different sepsis
diagnosis of bacterial infections in surgical patients: preliminary markers. 4th International Conference on Biomarkers Clinical
study. Transplant Proc. 2013;45:2750-3 Research. Philadelphia 2013, (Abstract)
29 Ulla M, Pizzolato E, Lucchiari M, Loiacono M, Soardo F, Forno D, 41 Kwiatkowska-Gruca M, Behrendt J. Sonsala A, Winiewska-Ulfik D,
Morello F, Lupia E, Moiraghi C, Mengozzi G, Battista S. Diagnostic Mazur B, Godula-Stuglik U. Presepsin (soluble CD14-ST) as a bio-
and prognostic value of presepsin in the management of sepsis marker for sepsis in neonates. Pediatria Polska, 2013; 88: 392-397
in the emergency department: a multicenter prospective study.
Crit Care. 2013;17(4):R16
30 Endo S, Suzuki Y, Takahashi G, Shozushima T, Ishikura H, Murai A,
Nishida T, Irie Y, Miura M, Iguchi H, Fukui Y, Tanaka K, Nojima T,
Okamura Y. Usefulness of presepsin in the diagnosis of sepsis in
a multicenter prospective study. J Infect Chemother. 2012;18:891-7
31 
Masson S, Caironi P, Spanuth E, Thomae R, Panigada M,
Sangiorgi G, Fumagalli R, Mauri T, Isgr S, Fanizza C, Romero M,
Tognoni G, Latini R, Gattinoni L; on behalf of the ALBIOS Study
Investigators. Presepsin (soluble CD14 subtype) and procalcitonin
levels for mortality prediction in sepsis: data from the Albumin
Italian Outcome Sepsis trial. Crit Care. 2014;18:R6
32 Popov DA, Pliushch MG, Ovseenko ST, Abramian MV, Podshche-
koldina OO, Iarustovski MB. [SCD14-ST (presepsin) level moni-
toring in cardiac surgical patients during perioperative period].
Anesteziol Reanimatol. 2013 May-Jun;(3):30-5
33 Cakr Madenci O, Yakupolu S, Benzonana N, Ycel N, Akbaba D,
Orun Kaptanaas A. Evaluation of soluble CD14 subtype
(presepsin) in burn sepsis. Burns. 2014 Jun;40(4):664-9
34 Vodnik T, Kaljevic G, Tadic T, Majkic-Singh N. Presepsin (sCD14-ST) in
preoperative diagnosis of abdominal sepsis. Clin Chem Lab Med.
2013;51:2053-62
35 
Endo S, Takahashi G, Shozushima T, Matsumoto N, Kojika M,
Suzuki Y, Inoue Y. Usefulness of Presepsin (soluble CD14 subtype)
as a Diagnostic Marker for Sepsis, JJAAM. 2012; 23:27-28
36 
Fukui Y, Okamura Y. Clinical performance of a point-of-care-
assay for measurement of presepsin in patients with bacteremia.
Crit Care 2013; 13 (Suppl.4): P58
37 Romualdo LG, Torrella PE, Gonzlez MV, Snchez RJ, Holgado AH,
Freire AO, Acebes SR, Otn MD. Diagnostic accuracy of presepsin
(soluble CD14 subtype) for prediction of bacteremia in patients
with systemic inflammatory response syndrome in the Emergency
Department. Clin Biochem. 2014;47:505-8

15
 LSI Medience Corporation Mitsubishi Chemical Europe GmbH

13-4 Uchikanda 1-chome, Chiyoda-ku, Willsttterstr. 30, 40549 Dsseldorf, Germany

Tokyo 101 - 8517, Japan Phone: +49 (0) 211 - 5 20 54 10
Phone: +81 - 3 - 67 22 - 40 80 Facsimile: +49 (0) 211 - 59 12 72
Facsimile: +81 - 3 - 67 22 - 40 81 email: Pathfast@mc-e.de

www.PATHFAST.eu