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Diagnostic and Prognostic Potential of

Presepsin in Emergency Department Patients
presenting with Systemic Inflammatory
Response Syndrome

Article in Journal of Infection December 2014

Impact Factor: 4.44 DOI: 10.1016/j.jinf.2014.07.024

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8 authors, including:

Jasmin Rabensteiner Martin Hoenigl

Medical University of Graz Medical University of Graz
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Josko Osredkar Florian Prller

Ljubljana University Medical Centre Medical University of Graz
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Available from: Martin Hoenigl

Retrieved on: 01 June 2016
Journal of Infection (2014) 69, 627e632
LETTERS TO THE EDITOR
Diagnostic and prognostic
potential of presepsin in
Emergency Department patients presenting
with systemic inflammatory response
syndrome
Dear Sir,
We read with interest the paper by ten Oever et al. who
evaluated a number of biomarkers for the discrimination
between bacterial and viral lower respiratory tract
infections.1
C-reactive protein (CRP), procalcitonin (PCT) and
interleukin-6 (IL-6) are widely used in clinical routine as
biomarkers in infectious and inflammatory conditions. PCT is
considered the most promising biomarker in this field and has
demonstrated superior diagnostic accuracy for bloodstream
infection (BSI) when compared to other biomarkers.2,3 How-
ever, normal PCT levels below 0.5 ng/L and even below
0.1 ng/L have been reported in systemic inflammatory
response syndrome (SIRS) patients with BSI.4 Presepsin is a
new and promising biomarker for early detection of bacterial
sepsis.5,6 To date, few studies evaluated the role of presepsin
in predicting the presence of bacteremia.7,8
In this semiprospective observational study we assessed
diagnostic and prognostic potential of presepsin in SIRS
patients with suspected BSI on admission to the Emergency
Department (ED). 300 patients were consecutively included
between March and October 2012 at the University Hospital of
Graz, Austria, until the number of each causative pathogen
and negative controls reached each 100 for Gram-positive and
Gram-negative bacteremia, 50 for candidemia and 50 for
controls (i.e. patients with SIRS but negative blood culture).
As Candida spp. were isolated rarely we decided to include
additional patients with bacteremia or negative blood culture
to reach the anticipated number of 300 patients. Presepsin,
PCT, IL-6, and CRP were determined from blood samples
collected simultaneously with blood cultures and before initi-
ation of antiinfective therapy, as described previously.3 Pre-
sepsin was retrospectively determined from plasma samples
that were aliquoted, frozen and stored at
80  C immediately
after collection. Analysis was performed at the Institute of
Clinical Chemistry and Biochemistry, University Medical
Centre of Ljubljana, Slovenia. Presepsin was measured on a
PATHFAST
Immunoanalyzer system using the commercially
available chemiluminescent enzyme immunoassay (Mitsubishi
Chemical Europe, Duesseldorf, Germany).
www.elsevierhealth.com/journals/jinf
This study was approved by the ethics committee of the
Medical University of Graz, Austria (EC-number 21e469 ex
09/10). Statistical analysis was performed using SPSS,
version 20 (SPSS Inc., Chicago, IL, USA). Receiver operating
characteristics (ROC) curve analysis was performed for bio-
markers and combinations. Area under the curve (AUC)
values were displayed including 95% confidence interval (CI).
Baseline characteristics, mortality rates and blood cul-
ture results are presented in Table 1. For presepsin
(p Z 0.012), PCT (p < 0.001), and IL-6 (p Z 0.022) signifi-
cant higher plasma levels were found in patients with BSI.
This was not the case for CRP (p Z 0.051). ROC curve anal-
ysis revealed AUCs of 0.605 (95%CI 0.522e0.688) for presep-
sin, 0.687 (95%CI 0.612e0.763) for PCT, 0.599 (95%CI
0.519e0.678) for IL-6 and 0.582 (95%CI 0.498e0.667) for
CRP for prediction of BSI. Detailed results of biomarker
levels related to BSI caused by different pathogens are de-
picted in Table 2. The potential of the four biomarkers for
prediction of bacteremia revealed AUCs of 0.6 (95%CI
0.517e0.684) for presepsin, 0.693 (0.617e0.768) for PCT,
0.604 (0.524e0.685) for IL-6 and 0.586 (0.502e0.670) for
CRP. Only PCT showed a significant difference between
Gram-positive and Gram-negative blood culture results
with higher levels in the latter (p Z 0.008). When the
two most frequent causes of BSI Staphylococcus aureus
and Escherichia coli were compared no significant differ-
ences were found for either of the parameters. Presepsin
was significantly higher (p Z 0.038) in patients with candi-
demia compared to patients with negative blood culture re-
sults. ROC curve analyses revealed an AUC for presepsin of
0.7 (95%CI 0.539e0.86), PCT 0.652 (0.487e0.816), IL-6
0.505 (0.31e0.7) and CRP 0.553 (0.401e0.705) for differen-
tiation between candidemia and negative blood culture.
ROC curve analysis for prediction of ICU admission, 48 h-,
30-day- and 90-day mortality, revealed the following AUCs:
0.645 (95%CI 0.565e0.725), 0.619 (0.442e0.795), 0.65
(0.557e0.742) and 0.659 (0.581e0.737) for presepsin;
0.612 (95%CI 0.529e0.694), 0.709 (0.557e0.861), 0.583
(0.497e0.668) and 0.577 (0.502e0.653) for PCT; 0.597 (95%
CI 0.506e0.689), 0.685 (0.532e0.838), 0.547 (0.445e0.648)
and 0.516 (0.429e0.603) for IL-6; 0.561 (95%CI 0.487e0.634),
0.61 (0.476e0.744), 0.583 (0.501e0.665) and 0.574
(0.501e0.647) for CRP. Cut-off values for presepsin regarding
30-day mortality were calculated with Youdens index,
revealing a cut-off of 1379 pg/mL with a sensitivity of 56%,
and a specificity of 63%.
Diagnostic potential of presepsin was markedly lower
when compared to previous studies that reported AUCs of
628 Letters to the Editor

Table 1 Baseline characteristics, mortality rates and blood culture results and of the study population (n Z 300).
Overall study population Bacteremia Candidemia Negative blood culture
n 300 226 (75) 15 (5) 59 (20)
Age e years (mean SD) 67 14 68 13 63 11 66 17
Female sex e no. (%) 133 (44) 105 (47) 8 (53) 20 (34)
Underlying conditions e no. (%)
Cardiovascular disease 150 (50) 110 (49) 7 (47) 33 (56)
Malignancies 62 (21) 49 (22) 5 (33) 8 (14)
Hematological disease 47 (16) 36 (16) 2 (13) 9 (15)
Neutropenia (<0.05 3 109) e no. (%) 26 (9) 22 (10) 1 (7) 3 (5)
Impaired renal function (Glomerular 140 (47) 114 (50) 5 (33) 21 (36)
filtration rate <60 mL/min) e no. (%)
Admission to ICU- no. (%) 62 (21) 48 (21) 6 (40) 8 (14)
Mortality e no. (%)
Within the first 48 ha 11 (4%) 8 (4) 1 (7) 2 (3)
Within the first 30 daysa 46 (15%) 40 (18) 2 (13) 4 (7)
Within the first 90 daysa 62 (21%) 54 (24) 3 (20) 5 (8)
Causative pathogens e no (%)
Gramepositive bacteria 102 (34)
Staphylococcus aureus 55 (54)
Coagulase-negative Staphylococcib 23 (22)
Streptococcus spp. 15 (15)
Enterococcus spp. 7 (7)
Othersc 2 (2)
Gramenegative bacteria 124 (41)
Escherichia coli 93 (75)
Pseudomonas spp. 10 (8)
Othersd 21 (17)
Fungi 15 (5)
Candida albicans 13 (86)
Candida parapsilosis 1 (7)
Issatchenkia orientalis 1 (7)
ICU: Intensive Care Unit.
a
After drawing of blood for laboratory testing and blood culture.
b
Patients were included in the study if more than 2 blood culture bottles were positive with the identical Coagulase-negative Staph-
ylococcus spp.
c
Micrococcus spp. (1), Listeria innocula (1).
d
Klebsiella spp. (10), Enterobacter spp. (6), Stenotrophomonas spp. (2), Acinetobacter spp. (1), Citrobacter spp. (1), Proteus spp. (1).

0.75 and 0.701 for prediction of BSI and sepsis/septic shock
in ED SIRS patients.6,7 Potential explanations for differing
findings include the markedly lower number of bacteremic
patients that were investigated in those studies. As in our
study, PCT exhibited higher AUCs for prediction of BSI
than presepsin.6,7 Our results indicate that presepsin levels
may be highly elevated in patients with candidemia. As the
number of patients with candidemia included in this study
was comparatively small (n Z 15) further studies are
needed to evaluate the diagnostic potential of presepsin
for candidemia.
While PCT had the highest prognostic potential for 48-h
mortality, presepsin was found a promising prognostic
marker in particular for 30- and 90-day mortality and
admission to ICU, where presepsin revealed higher AUCs
when compared to the other biomarkers. This is in
accordance to the literature where presepsin determined
at the ED was significantly higher in septic non-survivors (60
day mortality) compared to survivors.6 In another trial,
presepsin revealed higher AUCs compared to PCT for 28-
day and 90-day survival in patients with severe sepsis and
septic shock (AUCs 0.72 and 0.66 for presepsin versus 0.59
and 0.55 for PCT).9
In this study a cut-off value for presepsin of 1379 pg/
mL was calculated for prediction of 30-day mortality.
Masson et al. previously calculated a cut-off level of
1631 pg/mL for 28- and 90-day survival in ICU patients
with severe sepsis or septic shock.9 Diagnostic cut-off
values have been markedly lower: 600 pg/mL has been
suggested for differentiation between patients with sus-
pected but culture-negative sepsis and those with
culture-proven sepsis8 and 729 pg/mL for differentiation
between SIRS patients with bacteremia and those
without.7
In conclusion, presepsin may be useful for prediction of
30- and 90 day mortality as well as ICU-admission in
patients with SIRS at the ED while PCT was the most
promising diagnostic biomarker for BSI.
Letters to the Editor 629

Funding

Table 2 Levels of biomarkers (median and interquartile range [IQR]) in patients with and without BSI, admitted/not admitted to ICU, and patients that died with 30 days and

survived on day

(IQR 88.4e753)
(IQR 629e2231

(IQR 0.2e4.4)

(IQR 42e225)
30 (n Z 243)
Patients that died Patients that
No current funding sources for this study.

1049

192

101
0.9
Acknowledgments

(IQR 860e6068)

(IQR 108e1549)
within 30-days

We thank Christina Strempfl, Bernadette Neuhold and

(IQR 0.4e9.4)

(IQR 61e233)
Verena Posch for their support in the microbiologic labora-
to ICU (n Z 238) (n Z 46)

tory.
1624

237

174
1.7

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(IQR 60e190)

4. Hoenigl M, Raggam RB, Wagner J, Prueller F, Grisold AJ,

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Lupia E, et al. Role of presepsin for the evaluation of sepsis
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(IQR

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Jasmin Rabensteinera
79

Section of Infectious Diseases and Tropical Medicine,

(pg/mL)

(pg/mL)
(ng/mL)
Presepsin

Department of Internal Medicine, Medical University of

(mg/L)

Graz, Austria
PCT

CRP
IL-6

a
Contributed equally to the work.
630
Miha Skvarca
Institute of Microbiology and Immunology, Medical Faculty
Ljubljana, University of Ljubljana, Slovenia
Martin Hoenigl*
Section of Infectious Diseases and Tropical Medicine,
Department of Internal Medicine, Medical University of
Graz, Austria
Division of Pulmonology, Department of Internal Medicine,
Medical University of Graz, Austria
Division of Infectious Diseases, Department of Medicine,
University of California, San Diego, San Diego, CA, USA
Josko Osredkar
Institute of Clinical Chemistry and Biochemistry, Univer-
sity Medical Centre of Ljubljana, Ljubljana, Slovenia
Florian Prueller
Clinical Institute of Medical and Chemical Laboratory Di-
agnostics, Medical University of Graz, Austria
Matthias Reichsoellner
Section of Infectious Diseases and Tropical Medicine,
Department of Internal Medicine, Medical University of
Graz, Austria
Robert Krause
Section of Infectious Diseases and Tropical Medicine,
Department of Internal Medicine, Medical University of
Graz, Austria
Reinhard B. Raggam
Clinical Institute of Medical and Chemical Laboratory Di-
agnostics, Medical University of Graz, Austria
*Corresponding author. Section of Infectious Diseases and Tropical
Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036-
Graz, Austria. Tel.: 43 316 385 81319; fax: 43 316 385 14622.
E-mail address: martin.hoenigl@medunigraz.at
Accepted 31 July 2014
http://dx.doi.org/10.1016/j.jinf.2014.07.024
2014 The British Infection Association. Published by Elsevier Ltd.
All rights reserved.
A Cluster of Hepatitis A cases with a novel
sequence in South East England, 2013e14
To the Editor
In this journal, Nielsen and colleagues reported on risk
factors for travel-related Hepatitis A virus (HAV) infection
in Denmark.1 In England and Wales the incidence of HAV
infection has been falling over many years; only 283
confirmed HAV infections were reported in 2013.2 In the
UK pre-exposure immunisation is only recommended for
Letters to the Editor
individuals at high risk such as those travelling to endemic
countries and men who have sex with men (MSM);
post-exposure vaccination is recommended for household
contacts of confirmed HAV cases.3 As in other European
countries, travel is the predominant risk factor, with 88
(51%) of 171 confirmed cases with samples referred to the
Public Health England reference laboratory in 2013 associ-
ated with foreign travel.2
As England has been a low endemicity country for some
years, a high proportion of younger people are seronegative
for IgG antibody to HAV4 and therefore susceptible to infec-
tion from consumption of contaminated food or water, or
faeco-oral transmission from an infected person.
We report a cluster of HAV cases in South East England in
2014 with a novel virus. Cases were identified from
genotyping and sequencing of RNA from specimens
routinely referred to the national reference laboratory
(Virus Reference Department, Public Health England, Col-
indale). The cluster was defined as HAV cases resident in
South East England with onset dates from 1st December
2013 and sharing the same novel Genotype IA sequence.
Following the identification of this cluster, hospital labora-
tories in England were contacted to request that any
remaining specimens from recent HAV IgM positive cases
be forwarded for confirmation, genotyping and sequencing
of a 505 bp fragment of the VP1/2PA junction. The cluster
sequence was compared to others identified by Public
Health England in 2014, and the ten most closely related
sequences from the international, open-access online
sequence repository, Genbank.5 Cases were included if
they were found to have the cluster strain on sequencing.
Enhanced questionnaires were administered to cases, to
identify potential sources of infection, such as travel, food
and sexual exposures. Cases were described by age, sex,
date of onset and potential exposures.
We identified 6 cases with the cluster sequence,
including a suspected secondary transmission within a
household. Five cases (83%) were male, and the median
age was 38.5 years (range 6e64 years). Onset of symptoms
ranged from 28th December 2013 to 3rd March 2014. No
further cases with the cluster sequence have been identi-
fied since. All cases recovered. Investigation of food, travel
and sexual exposures did not identify any common expo-
sures between the cases despite detailed questioning.
Household contacts of cases received post-exposure pro-
phylaxis as per national guidance.3 One case attended a pri-
mary school and since no external source could be
identified, children in the same class were vaccinated to
prevent further transmission due to the possibility of one
or more asymptomatic case in the school.
The outbreak sequence was genotype 1A and was
identified in all 6 cases; this sequence was closely related
to others previously identified from South America (Fig. 1).
Only one additional case with the same sequence had been
previously seen in England; this case was in a different re-
gion and preceded this cluster by more than six months.
The follow-up of HAV IgM positive cases for genotyping
and sequencing identified an additional HAV case in another
part of England where there was one-base pair difference
to the cluster sequence. However, follow-up of food and
travel exposures for these additional cases did not identify