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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


3 59

8 authors, including:

Jasmin Rabensteiner Martin Hoenigl

Medical University of Graz Medical University of Graz


Josko Osredkar Florian Prller

Ljubljana University Medical Centre Medical University of Graz


Available from: Martin Hoenigl

Retrieved on: 01 June 2016
Journal of Infection (2014) 69, 627e632


Diagnostic and prognostic This study was approved by the ethics committee of the
potential of presepsin in Medical University of Graz, Austria (EC-number 21e469 ex
Emergency Department patients presenting 09/10). Statistical analysis was performed using SPSS,
with systemic inflammatory response version 20 (SPSS Inc., Chicago, IL, USA). Receiver operating
syndrome 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-
Dear Sir, 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-
We read with interest the paper by ten Oever et al. who cant higher plasma levels were found in patients with BSI.
evaluated a number of biomarkers for the discrimination This was not the case for CRP (p Z 0.051). ROC curve anal-
between bacterial and viral lower respiratory tract ysis revealed AUCs of 0.605 (95%CI 0.522e0.688) for presep-
infections.1 sin, 0.687 (95%CI 0.612e0.763) for PCT, 0.599 (95%CI
C-reactive protein (CRP), procalcitonin (PCT) and 0.519e0.678) for IL-6 and 0.582 (95%CI 0.498e0.667) for
interleukin-6 (IL-6) are widely used in clinical routine as CRP for prediction of BSI. Detailed results of biomarker
biomarkers in infectious and inflammatory conditions. PCT is levels related to BSI caused by different pathogens are de-
considered the most promising biomarker in this field and has picted in Table 2. The potential of the four biomarkers for
demonstrated superior diagnostic accuracy for bloodstream prediction of bacteremia revealed AUCs of 0.6 (95%CI
infection (BSI) when compared to other biomarkers.2,3 How- 0.517e0.684) for presepsin, 0.693 (0.617e0.768) for PCT,
ever, normal PCT levels below 0.5 ng/L and even below 0.604 (0.524e0.685) for IL-6 and 0.586 (0.502e0.670) for
0.1 ng/L have been reported in systemic inflammatory CRP. Only PCT showed a significant difference between
response syndrome (SIRS) patients with BSI.4 Presepsin is a Gram-positive and Gram-negative blood culture results
new and promising biomarker for early detection of bacterial with higher levels in the latter (p Z 0.008). When the
sepsis.5,6 To date, few studies evaluated the role of presepsin two most frequent causes of BSI Staphylococcus aureus
in predicting the presence of bacteremia.7,8 and Escherichia coli were compared no significant differ-
In this semiprospective observational study we assessed ences were found for either of the parameters. Presepsin
diagnostic and prognostic potential of presepsin in SIRS was significantly higher (p Z 0.038) in patients with candi-
patients with suspected BSI on admission to the Emergency demia compared to patients with negative blood culture re-
Department (ED). 300 patients were consecutively included sults. ROC curve analyses revealed an AUC for presepsin of
between March and October 2012 at the University Hospital of 0.7 (95%CI 0.539e0.86), PCT 0.652 (0.487e0.816), IL-6
Graz, Austria, until the number of each causative pathogen 0.505 (0.31e0.7) and CRP 0.553 (0.401e0.705) for differen-
and negative controls reached each 100 for Gram-positive and tiation between candidemia and negative blood culture.
Gram-negative bacteremia, 50 for candidemia and 50 for ROC curve analysis for prediction of ICU admission, 48 h-,
controls (i.e. patients with SIRS but negative blood culture). 30-day- and 90-day mortality, revealed the following AUCs:
As Candida spp. were isolated rarely we decided to include 0.645 (95%CI 0.565e0.725), 0.619 (0.442e0.795), 0.65
additional patients with bacteremia or negative blood culture (0.557e0.742) and 0.659 (0.581e0.737) for presepsin;
to reach the anticipated number of 300 patients. Presepsin, 0.612 (95%CI 0.529e0.694), 0.709 (0.557e0.861), 0.583
PCT, IL-6, and CRP were determined from blood samples (0.497e0.668) and 0.577 (0.502e0.653) for PCT; 0.597 (95%
collected simultaneously with blood cultures and before initi- CI 0.506e0.689), 0.685 (0.532e0.838), 0.547 (0.445e0.648)
ation of antiinfective therapy, as described previously.3 Pre- and 0.516 (0.429e0.603) for IL-6; 0.561 (95%CI 0.487e0.634),
sepsin was retrospectively determined from plasma samples 0.61 (0.476e0.744), 0.583 (0.501e0.665) and 0.574
that were aliquoted, frozen and stored at 80  C immediately (0.501e0.647) for CRP. Cut-off values for presepsin regarding
after collection. Analysis was performed at the Institute of 30-day mortality were calculated with Youdens index,
Clinical Chemistry and Biochemistry, University Medical revealing a cut-off of 1379 pg/mL with a sensitivity of 56%,
Centre of Ljubljana, Slovenia. Presepsin was measured on a and a specificity of 63%.
PATHFAST Immunoanalyzer system using the commercially Diagnostic potential of presepsin was markedly lower
available chemiluminescent enzyme immunoassay (Mitsubishi when compared to previous studies that reported AUCs of
Chemical Europe, Duesseldorf, Germany).
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.
After drawing of blood for laboratory testing and blood culture.
Patients were included in the study if more than 2 blood culture bottles were positive with the identical Coagulase-negative Staph-
ylococcus spp.
Micrococcus spp. (1), Listeria innocula (1).
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 presepsin revealed higher AUCs compared to PCT for 28-
in ED SIRS patients.6,7 Potential explanations for differing day and 90-day survival in patients with severe sepsis and
findings include the markedly lower number of bacteremic septic shock (AUCs 0.72 and 0.66 for presepsin versus 0.59
patients that were investigated in those studies. As in our and 0.55 for PCT).9
study, PCT exhibited higher AUCs for prediction of BSI In this study a cut-off value for presepsin of 1379 pg/
than presepsin.6,7 Our results indicate that presepsin levels mL was calculated for prediction of 30-day mortality.
may be highly elevated in patients with candidemia. As the Masson et al. previously calculated a cut-off level of
number of patients with candidemia included in this study 1631 pg/mL for 28- and 90-day survival in ICU patients
was comparatively small (n Z 15) further studies are with severe sepsis or septic shock.9 Diagnostic cut-off
needed to evaluate the diagnostic potential of presepsin values have been markedly lower: 600 pg/mL has been
for candidemia. suggested for differentiation between patients with sus-
While PCT had the highest prognostic potential for 48-h pected but culture-negative sepsis and those with
mortality, presepsin was found a promising prognostic culture-proven sepsis8 and 729 pg/mL for differentiation
marker in particular for 30- and 90-day mortality and between SIRS patients with bacteremia and those
admission to ICU, where presepsin revealed higher AUCs without.7
when compared to the other biomarkers. This is in In conclusion, presepsin may be useful for prediction of
accordance to the literature where presepsin determined 30- and 90 day mortality as well as ICU-admission in
at the ED was significantly higher in septic non-survivors (60 patients with SIRS at the ED while PCT was the most
day mortality) compared to survivors.6 In another trial, promising diagnostic biomarker for BSI.
Letters to the Editor 629


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.




(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)




(IQR 606e2165)

(IQR 0.2e3.8)

(IQR 86e661)

(IQR 42e225)
Patients admitted Patients not

1. ten Oever J, Tromp M, Bleeker-Rovers CP, Joosten LA,


Netea MG, Pickkers P, et al. Combination of biomarkers for

the discrimination between bacterial and viral lower respira-

tory tract infections. J Infect 2012 Dec;65(6):490e5.



2. Hoenigl M, Raggam RB, Wagner J, Valentin T, Leitner E,

Seeber K, et al. Diagnostic accuracy of soluble urokinase plas-
to ICU (n Z 62)

minogen activator receptor (suPAR) for prediction of bacter-

(IQR 882e4758)

(IQR 110e4321)
(IQR 0.4e13.1)

(IQR 61e229)

emia in patients with systemic inflammatory response

syndrome. Clin Biochem 2013 Feb;46(3):225e9.
3. Raggam RB, Wagner J, Pruller F, Grisold A, Leitner E, Zollner-
Schwetz I, et al. Soluble urokinase plasminogen activator re-



ceptor predicts mortality in patients with systemic inflamma-

tory response syndrome. J Intern Med 2014 Mar 19. http://
(IQR 804e3027)

(IQR 0.2e10.2) [Epub ahead of print].

(IQR 60e190)

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

(IQR 50e26)

Leitner E, et al. Procalcitonin fails to predict bacteremia in

(n Z 15)

SIRS patients: a cohort study. Int J Clin Pract 2014 Jun 4.

2293 [Epub ahead of print].



5. Okamura Y, Yokoi H. Development of a point-of-care assay sys-

tem for measurement of presepsin (sCD14-ST). Clin Chim Acta
(IQR 777e2654)

(IQR 0.5e12.1)

(IQR 95e1313)

2011 Nov 20;412(23e24):2157e61.

(IQR 55e235)

6. Ulla M, Pizzolato E, Lucchiari M, Loiacono M, Soardo F, Forno D,

(n Z 124)

et al. Diagnostic and prognostic value of presepsin in the man-

agement of sepsis in the emergency department: a multicenter



prospective study. Crit Care 2013 Jul 30;17(4):R168.


7. Romualdo LG, Torrella PE, Gonzalez MV, Sanchez RJ,

(IQR 670e2422)

Holgado AH, Freire AO, et al. Diagnostic accuracy of presep-

(IQR 105e600)

(IQR 0.2e3.8)

(IQR 42e222)

sin (soluble CD14 subtype) for prediction of bacteremia in


patients with systemic inflammatory response syndrome in

(n Z 102)

the Emergency Department. Clin Biochem 2014 May;





8. Pizzolato E, Ulla M, Galluzzo C, Lucchiari M, Manetta T,

Lupia E, et al. Role of presepsin for the evaluation of sepsis
500e1722) (IQR 713e2618)

in the emergency department. Clin Chem Lab Med 2014

(IQR 102e942)
Positive blood

(IQR 0.3e8.3)

(IQR 51e228)

Jun 4. pii: /j/cclm.ahead-of-print/cclm-2014-0199/cclm-

(n Z 241)


[Epub ahead of print].



9. Masson S, Caironi P, Spanuth E, Thomae R, Panigada M,



Sangiorgi G, et al. Presepsin (soluble CD14 subtype) and procal-

citonin levels for mortality prediction in sepsis: data from the
Biomarkers Negative blood


Albumin Italian Outcome Sepsis trial. Crit Care 2014 Jan 7;



(n Z 59)
those who survived.






Jasmin Rabensteinera

Section of Infectious Diseases and Tropical Medicine,



Department of Internal Medicine, Medical University of


Graz, Austria


Contributed equally to the work.
630 Letters to the Editor

Miha Skvarca individuals at high risk such as those travelling to endemic

Institute of Microbiology and Immunology, Medical Faculty countries and men who have sex with men (MSM);
Ljubljana, University of Ljubljana, Slovenia post-exposure vaccination is recommended for household
contacts of confirmed HAV cases.3 As in other European
Martin Hoenigl*
countries, travel is the predominant risk factor, with 88
Section of Infectious Diseases and Tropical Medicine,
(51%) of 171 confirmed cases with samples referred to the
Department of Internal Medicine, Medical University of
Public Health England reference laboratory in 2013 associ-
Graz, Austria
ated with foreign travel.2
Division of Pulmonology, Department of Internal Medicine, As England has been a low endemicity country for some
Medical University of Graz, Austria years, a high proportion of younger people are seronegative
for IgG antibody to HAV4 and therefore susceptible to infec-
Division of Infectious Diseases, Department of Medicine, tion from consumption of contaminated food or water, or
University of California, San Diego, San Diego, CA, USA faeco-oral transmission from an infected person.
Josko Osredkar We report a cluster of HAV cases in South East England in
Institute of Clinical Chemistry and Biochemistry, Univer- 2014 with a novel virus. Cases were identified from
sity Medical Centre of Ljubljana, Ljubljana, Slovenia genotyping and sequencing of RNA from specimens
routinely referred to the national reference laboratory
Florian Prueller (Virus Reference Department, Public Health England, Col-
Clinical Institute of Medical and Chemical Laboratory Di- indale). The cluster was defined as HAV cases resident in
agnostics, Medical University of Graz, Austria South East England with onset dates from 1st December
Matthias Reichsoellner 2013 and sharing the same novel Genotype IA sequence.
Section of Infectious Diseases and Tropical Medicine, Following the identification of this cluster, hospital labora-
Department of Internal Medicine, Medical University of tories in England were contacted to request that any
Graz, Austria remaining specimens from recent HAV IgM positive cases
be forwarded for confirmation, genotyping and sequencing
Robert Krause of a 505 bp fragment of the VP1/2PA junction. The cluster
Section of Infectious Diseases and Tropical Medicine, sequence was compared to others identified by Public
Department of Internal Medicine, Medical University of Health England in 2014, and the ten most closely related
Graz, Austria sequences from the international, open-access online
Reinhard B. Raggam sequence repository, Genbank.5 Cases were included if
Clinical Institute of Medical and Chemical Laboratory Di- they were found to have the cluster strain on sequencing.
agnostics, Medical University of Graz, Austria Enhanced questionnaires were administered to cases, to
identify potential sources of infection, such as travel, food
*Corresponding author. Section of Infectious Diseases and Tropical and sexual exposures. Cases were described by age, sex,
Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036- date of onset and potential exposures.
Graz, Austria. Tel.: 43 316 385 81319; fax: 43 316 385 14622. We identified 6 cases with the cluster sequence,
E-mail address: 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
Accepted 31 July 2014 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-
2014 The British Infection Association. Published by Elsevier Ltd. sures between the cases despite detailed questioning.
All rights reserved. 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
A Cluster of Hepatitis A cases with a novel or more asymptomatic case in the school.
sequence in South East England, 2013e14 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).
To the Editor Only one additional case with the same sequence had been
previously seen in England; this case was in a different re-
In this journal, Nielsen and colleagues reported on risk gion and preceded this cluster by more than six months.
factors for travel-related Hepatitis A virus (HAV) infection The follow-up of HAV IgM positive cases for genotyping
in Denmark.1 In England and Wales the incidence of HAV and sequencing identified an additional HAV case in another
infection has been falling over many years; only 283 part of England where there was one-base pair difference
confirmed HAV infections were reported in 2013.2 In the to the cluster sequence. However, follow-up of food and
UK pre-exposure immunisation is only recommended for travel exposures for these additional cases did not identify