J Infect Chemother

DOI 10.1007/s10156-012-0435-2

ORIGINAL ARTICLE

Usefulness of presepsin in the diagnosis of sepsis in a multicenter

prospective study
Shigeatsu Endo • Yasushi Suzuki • Gaku Takahashi • Tatsuyori Shozushima • Hiroyasu Ishikura •

Akira Murai • Takeshi Nishida • Yuhei Irie • Masanao Miura • Hironobu Iguchi •
Yasuo Fukui • Kimiaki Tanaka • Tsuyoshi Nojima • Yoshikazu Okamura

Received: 29 March 2012 / Accepted: 13 May 2012

Ó Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2012

Abstract The clinical usefulness of presepsin for dis- with bacterial infectious disease and those with nonbacte-
criminating between bacterial and nonbacterial infections rial infectious disease. The cutoff value of presepsin for
(including systemic inflammatory response syndrome) was discrimination of bacterial and nonbacterial infectious
studied and compared with procalcitonin (PCT) and inter- diseases was determined to be 600 pg/ml, of which the
leukin-6 (IL-6) in a multicenter prospective study. Sus- clinical sensitivity and specificity were 87.8 % and 81.4 %,
pected sepsis patients (n = 207) were enrolled into the respectively. Presepsin levels did not differ significantly
study. Presepsin levels in patients with systemic bacterial between patients with gram-positive and gram-negative
infection and localized bacterial infection were signifi- bacterial infections. The sensitivity of blood culture was
cantly higher than in those with nonbacterial infections. In 35.4 %; that for presepsin was 91.9 %. Also there were no
addition, presepsin, PCT, and IL-6 levels in patients with significant differences in presepsin levels between the
bacterial infectious disease were significantly higher than blood culture-positive and -negative groups. Consequently,
in those with nonbacterial infectious disease (P \ 0.0001, presepsin is useful for the diagnosis of sepsis, and it is
P \ 0.0001, and P \ 0.0001, respectively). The area under superior to conventional markers and blood culture.
the receiver operating characteristic curve was 0.908 for
presepsin, 0.905 for PCT, and 0.825 for IL-6 in patients Keywords Presepsin
Soluble CD14-subtype

Procalcitonin
Sepsis
Infection

S. Endo (&)
Y. Suzuki
G. Takahashi
T. Shozushima

Department of Critical Care Medicine, School of Medicine, Introduction
Iwate Medical University, 19-1 Uchimaru,
Morioka 020-8505, Japan
Various biomarkers have been studied for diagnosing sepsis.
e-mail: sendo@iwate-med.ac.jp
Currently, procalcitonin (PCT) is used as a marker to diag-
H. Ishikura
A. Murai
T. Nishida
Y. Irie nose sepsis or severe sepsis and has been widely measured in
Department of Emergency and Critical Care Medicine, recent years [1–3]. Although the PCT level reflects the
Faculty of Medicine, Fukuoka University, Fukuoka, Japan
pathological states of sepsis well, it is elevated in various
M. Miura
H. Iguchi conditions, such as in severe trauma, invasive surgical pro-
Anesthesiology, Emergency and Critical Care Center, cedures, and critical burn injury, that lead to systemic
Kariya Toyota General Hospital, Kariya, Japan inflammatory response syndrome (SIRS) [4]. Thus, there is a
need for new sepsis markers with higher specificity.
Y. Fukui
K. Tanaka
T. Nojima
Department of Gastroenterological Surgery, Presepsin is a 13-kDa protein that is an truncated
Kochi Health Sciences Center, Kochi, Japan N-terminal fragment of CD14, the receptor for lipopoly-
saccharide (LPS)/LPS binding protein (LBP) complexes
Y. Okamura
[5, 6]. Presepsin was identified as a protein whose levels
Research and Development Division, Yachiyo R&D
Department, Mitsubishi Chemical Medience Corporation, increase specifically in the blood of sepsis patients. An in
Tokyo, Japan vivo study using rabbit sepsis models showed that

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presepsin levels did not increase in the LPS-induced sepsis apparent clinical manifestations or laboratory results other
model whereas elevation of presepsin levels was observed than cultures. (3) Nonbacterial infection: diagnosed with
in a cecal ligation and puncture (CLP) sepsis model [7]. It infections other than bacteria (fungi, viruses, etc.) by the
was speculated that the infectious stimulus led to the ele- physician. None of the patients categorized into this group
vation of presepsin levels. The CLP sepsis model showed was enrolled in this study. (4) Suspected bacterial infec-
that presepsin levels increased at 2 h after onset of infec- tion: physician suspected infection but cultures were neg-
tion, reached a peak at 3 h, and then gradually decreased at ative and there were no apparent clinical manifestations.
4–8 h [8]. Also, the plasma half-life of presepsin was This group of patients was excluded from statistical anal-
reportedly 4–5 h. One of the production mechanisms of ysis in this study. (5) Noninfectious disease: cultures were
presepsin is related to the phagocytosis process and negative and diagnosed by the physician as not having
cleavage of membrane CD14 with lysozomal enzymes of infection, or considered by the physician not to have an
granulocytes in an in vitro study using rabbit peritoneal infection based on apparent clinical manifestations. Sex
leukocytes [7]. Aspartate proteases, including cathepsin D, and median (range) ages of patients in each of the five
were one of the lysozomal enzymes that are related to the groups are summarized in Table 2.
production of presepsin. Presepsin does not bind to LPS.
The biological function of presepsin remains unknown [6].
It is reported that the measurement of presepsin con- Table 1 Background of patients
centrations is useful for diagnosis of sepsis, for evaluating Underlying disease n Presepsin (pg/ml)
the severity of sepsis, and also for monitoring clinical
Systemic and Noninfectious
responses to therapeutic interventions [9–12]. Multicenter localized bacterial disease
clinical studies have never been done regarding the use- infection combined
fulness of presepsin. In this study, we evaluated the clinical
n Range n Range
usefulness of presepsin for the diagnosis of sepsis in four
medical institutions. Gastroenterological 45 38 226–20,000 7 123–665
disease
Respiratory disease 27 25 187–16,764 2 301–402
Patients and methods Trauma 26 1 1,110 25 71.2–889
Circulatory disease 12 4 769–6,908 8 231–9,036
Blood samples were collected from patients admitted to the Renal disease 9 9 518–5,319 0 –
emergency room in Iwate Medical University Hospital, Burns 8 0 – 8 184–976
Fukuoka University Hospital, and Kochi Health Sciences Cerebral hemorrhage 8 0 – 8 128–465
Center or the intensive care unit in Kariya Toyota General Malignant disease 7 2 783–4,447 5 410–596
Hospital between June 2010 and June 2011. Informed Hepatobiliary disease 3 3 572–2,537 0 –
consent was obtained from all patients in accordance with Cellulitis phlegmon 3 3 845–2,674 0 –
the guidelines of each institution. Two-hundred and seven Drug poisoning 3 0 – 3 254–948
patients diagnosed with infectious disease, suspected of Others 34 30 242–12,245 4 210–1,117
having infectious disease, and diagnosed with noninfec- Total 185 115 70
tious diseases were enrolled in this study. Patients who
fulfilled at least one or more of the following diagnostic
criteria for SIRS were enrolled: (1) temperature [38 or
\36 °C, (2) heart rate [90/min, (3) respiratory rate [
20/min or PaCO2 \32 mmHg, (4) white blood cell count
Table 2 Patient demographics
[12,000 or \4,000/mm3, or immature granulocytes
C10 % [13]. Patient backgrounds are shown in Table 1. n Sex Age (years)
The patients were classified into the following five groups Male Female Median Range
according to blood culture results. (1) Systemic bacterial
infection: positive blood culture and diagnosis of bacterial Systemic bacterial infection 38 20 18 76 35–94
infection by the physician. (2) Localized bacterial infec- Localized bacterial 77 44 33 75 23–98
infection
tion: culture positive for samples other than blood (e.g.,
Nonbacterial infection 0 0 0 0 –
nasal and throat swabs, urine, cerebrospinal fluid, thora-
Suspected bacterial 22 12 10 67 31–89
coabdominal fluid, vessel catheter and wound swabs) and
infection
diagnosis of bacterial infection by the physician or bacte-
Noninfectious disease 70 46 24 66 17–92
rial infection diagnosis made by the physician based on

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Presepsin assay (Analyze-it Software, UK). A P value less than 0.05 was
considered statistically significant.
Presepsin concentration was measured with a compact
automated immunoanalyzer, PATHFAST, based on a
chemiluminescent enzyme immunoassay (CLEIA) (Mits- Results
ubishi Chemical Medience, Japan) [14, 15]. Whole blood
was collected with EDTA-2K as an anticoagulant using a Presepsin, PCT, and IL-6 levels in different
conventional blood collection tube (TERUMO, Japan) and pathological conditions
used as a sample within 4 h after collection on the
PATHFAST presepsin assay. There were 185 patients (110 men, 75 women) who ful-
filled at least one of the diagnostic criteria of SIRS on
PCT assay hospital admission. Patients were retrospectively catego-
rized into the systemic bacterial infection (n = 38), local-
PCT concentrations were measured by Elecsys BRAHMS ized bacterial infection (n = 77), and noninfectious disease
PCT assay (Roche Diagnostics, Japan) using EDTA plasma (n = 70) groups. Biomarkers including presepsin, PCT,
as a sample. and IL-6 levels in the different pathological conditions are
shown in Fig. 1. The median, minimum, and maximum
Interleukin-6 assay concentrations of the biomarkers in these three groups are
summarized in Table 3. The presepsin levels in the sys-
Interleukin-6 (IL-6) concentrations were measured using temic and localized bacterial infection groups were sig-
the Immulyze 2000 assay system (Siemens Healthcare nificantly higher than those in the noninfectious disease
Diagnostics, Japan) using EDTA plasma as a sample. group (P \ 0.0001, P \ 0.0001, respectively). There were
no significant differences in presepsin levels between
Statistical analysis the systemic and localized bacterial infection groups
(P = 0.0840) (Table 4). Patients with systemic bacterial
The Mann–Whitney U test with Bonferroni correction and and localized bacterial infection were included in the
receiver operating characteristic (ROC) curve analysis bacterial infectious disease group (n = 115). Presepsin,
were performed using Analyze-it version 2.11 software PCT, and IL-6 levels in this group were significantly higher

A 10000 B 1000 C 1000000

100 100000
Presepsin (pg/mL)

10000
PCT (ng/mL)

1000 10
IL-6 (pg/mL)

1000
1
100
100 0.1
10

0.01 1

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

Fig. 1 Distribution of presepsin (a), procalcitonin (PCT) (b), and interleukin (IL)-6 (c) in patients with systemic infections (n = 38), localized
bacterial infections (n = 77), and noninfectious disease (n = 70)

Table 3 Concentration of presepsin, procalcitonin (PCT), and interleukin (IL)-6 in patients with systemic bacterial infection, localized bacterial
infection, and noninfectious disease
Group n Presepsin (pg/ml) PCT (ng/ml) IL-6 (pg/ml)
Median Min Max Median Min Max Median Min Max

Systemic bacterial infection 38 1,579 242 20,000 15.7 0.145 426 7,387 15.0 412,000
Localized bacterial infection 77 1,168 187 16,764 3.36 0.020 373 384 2.00 1,004,000
Noninfectious disease 70 312 71 9,036 0.086 0.020 72.9 75.7 2.00 10,317

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than in the nonbacterial infectious disease group (n = 70) causing their infections. The sensitivities of presepsin,
(P \ 0.0001 for all three markers) (Fig. 2). PCT, and IL-6 in each group are shown in Table 6. The
sensitivity of presepsin was 95.5 % in the gram-positive
Diagnostic accuracy and cutoff value of presepsin assay and 77.8 % in the gram-negative bacterial infection group.
There were no significant differences in presepsin levels
The ROC curve analysis was performed to compare between the gram-positive and gram-negative bacterial
between bacterial and nonbacterial infection disease infection groups (2,881 ± 4,374 and 2,641 ± 3,709 pg/ml,
groups. The area under the ROC curve (AUC) was 0.908 respectively; P = 0.5320).
for presepsin, 0.905 for PCT, and 0.825 for IL-6 (Fig. 3).
No significant differences between presepsin and PCT were Sensitivity of presepsin, PCT, and IL-6 compared
observed in the comparison of the AUCs. When 600 pg/ml with blood culture
was used as a cutoff value for presepsin, sensitivity,
specificity, positive predicted value, and negative predicted In 99 patients of the bacterial infection disease group from
value were 87.8 %, 81.4 %, 88.6 %, and 80.3 %, respec- whom blood cultures had been obtained, sensitivity of
tively (Table 5). We suggest that this presepsin level was presepsin, PCT, and IL-6 were compared with blood cul-
optimal for the diagnosis of bacterial infections. ture (Table 7). The sensitivities were 91.9 % for presepsin,
89.9 % for PCT, 88.9 % for IL-6, and 35.4 % for blood
Sensitivity of presepsin and PCT by each causative culture. There were no significant differences in presepsin
microorganism levels between the blood culture-positive and -negative
groups (2,203 ± 1,868 and 2,705 ± 3,845 pg/ml, respec-
The patients in the bacterial infectious disease group were tively; P = 0.3231).
classified into five groups according to the microorganisms

Discussion
Table 4 Mann–Whitney U test with Bonferroni correction according
to the disease criteria
Blood culture is frequently used as the ‘‘gold standard’’
Presepsin PCT IL-6
diagnostic method for sepsis. However, it usually takes
Systemic bacterial infection vs. 0.0840 0.0311 0.0037 3–7 days to obtain the results, and culture frequently yields
localized bacterial infection low positive results. Therefore, the general practical med-
Systemic bacterial infection vs. \0.0001 \0.0001 \0.0001 ical treatment used for sepsis is based on the doctor’s own
noninfectious disease experience (empirical therapy). Because a method with a
Localized bacterial infection vs. \0.0001 \0.0001 \0.0001 short turnaround time is useful for diagnosing sepsis, the
noninfectious disease
diagnostic power of various biomarkers including presepsin,

Fig. 2 Distribution of presepsin A 10000 B 1000 C 1000000

(a), PCT (b), and IL-6 (c) in
patients with bacterial infection
100000
disease (n = 115) and 100
nonbacterial infection disease
(n = 70) 10000
1000 10
Presepsin (pg/mL)

PCT (ng/mL)

IL-6 (pg/mL)

1000
1
100

100 0.1
10

0.01
1

10 0.001 0.1
Non- Bacterial Non- Bacterial Non- Bacterial
bacterial infection bacterial infection bacterial infection
infection disease infection disease infection disease
disease disease disease

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PCT, and IL-6 was studied and compared with that of 0.382 ng/ml, respectively. The presepsin levels above the
blood culture. cutoff value in patients with chronic renal failure must be
This multicenter prospective study demonstrated the interpreted with caution; we think further study will be
presepsin assay to be as useful for the diagnosis of bacterial needed to clarify the relationship between presepsin values
infections as PCT. The cutoff value of 600 pg/ml for pre- and renal failures.
sepsin yielded the optimal sensitivity and specificity, The usefulness of presepsin for diagnosis of bacterial
87.8 % and 81.4 %, respectively. These values were sim- infections was comparable to PCT in this study, but the
ilar to those obtained with the cutoff value of 0.5 ng/ml for clinical specificity of presepsin was much higher than that
PCT (Table 5). Presepsin was false negative in 14 patients of PCT. When the cutoff value of PCT was 0.5 ng/ml, 10
and false positive in 13 patients. In the false-negative patients of the 16 false-negative patients of PCT had a
patients, 4 patients became positive in presepsin level presepsin level not less than 600 pg/ml. Eight patients of
during 7 days after registration, and 2 were local infec- 10 had a PCT level less than 0.5 ng/ml during the first
tions. In the false-positive patients, 5 patients were diag- 7 days after registration. Of the 15 false-positive patients
nosed with infections during 7 days after admission, 5 were by PCT, 7 patients had a presepsin level less than 600
trauma, and 2 were chronic renal failure. The presepsin pg/ml. Backgrounds in 4 patients of these 7 included severe
levels of 2 patients with chronic renal failure were 9,036 trauma, surgical invasive procedures, and critical burn
and 1,362 pg/ml, whereas their PCT levels were 0.525 and injury. False-positive rates of presepsin and PCT were
calculated using data from 24 patients with noninfectious
traumas enrolled in this study. The false-positive rate was
1
12.5 % (3/24) for presepsin and 25.0 % (6/24) for PCT,
0.9 indicating presepsin levels were less influenced by trauma
situations than the PCT levels.
0.8
True positive rate (Sensitivity)

Presepsin is a highly specific marker for diagnosis of

0.7 bacterial infections in comparison to other sepsis markers
0.6
because of its mechanism of production by bacterial
phagocytosis. Presepsin was secreted from granulocytes by
0.5 infectious stimuli in the previous basic study [7]. PCT
0.4
levels are increased in highly invasive conditions without
No discrimination complication by infection [1]. Even though many studies
0.3 have been reported in regard to the usefulness of PCT for
Presepsin (pg/mL)

0.2
diagnosis of sepsis, the production mechanism of PCT
PCT (ng/mL)
remains unknown. Also, a few bacterial infection cases in
0.1 IL-6 (pg/mL) which PCT levels only were not increased during 7 days
0 after registration were confirmed in this study.
0 0.2 0.4 0.6 0.8 1 The sensitivity of presepsin was 95.5 % for gram-posi-
False positive rate (1 - Specificity) tive and 77.8 % for gram-negative bacterial infections.
There were no significant differences in presepsin levels
Fig. 3 Receiver operating characteristic (ROC) curves of presepsin,
PCT, and IL-6 in patients with bacterial infectious disease and those between the gram-positive and gram-negative bacterial
with nonbacterial infectious disease infection groups. Because none of the patients infected

Table 5 Sensitivity, specificity, positive predicative value, and negative predicative value of presepsin, PCT, and IL-6 in patients with bacterial
infectious disease and those with nonbacterial infectious disease
Cutoff value Sensitivity Specificity Positive predictive value Negative predictive value
Ratio (%) n Ratio (%) n Ratio (%) n Ratio (%) n

Presepsin (pg/ml) 300 95.7 110/115 48.6 34/70 75.3 110/146 87.2 34/39
600 87.8 101/115 81.4 57/70 88.6 101/114 80.3 57/71
1,000 67.0 77/115 94.3 66/70 95.1 77/81 63.5 66/104
PCT (ng/ml) 0.5 86.1 99/115 78.6 55/70 86.8 99/114 77.5 55/71
2.0 64.3 74/115 95.7 67/70 96.1 74/77 62.0 67/108
IL-6 (pg/ml) 10 99.1 114/115 14.3 10/70 65.5 114/174 90.9 10/11
100 84.3 97/115 55.7 39/70 75.8 97/128 68.4 39/57

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Table 6 Sensitivity of
Type of infection Presepsin PCT IL-6
presepsin, PCT, and IL-6 with
respect to the type of infection 600 pg/ml 0.5 ng/ml 100 pg/ml
Ratio n Ratio n Ratio n
(%) (%) (%)

Gram-positive infection 95.5 21/22 95.5 21/22 100.0 22/22

Gram-negative infection 77.8 28/36 86.1 31/36 88.9 32/36
Mixed gram-positive and -negative 94.7 18/19 94.7 18/19 89.5 17/19
infection
Mixed bacterial and fungal infections 100.0 1/1 100.0 1/1 100.0 1/1
Unknown 89.2 33/37 75.7 28/37 67.6 25/37
Total 87.8 101/115 86.1 99/115 84.3 97/115

Table 7 Sensitivity of presepsin, PCT, IL-6, and blood culture in References

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