procalcitonin fails to predict bacteremia in sirs patients: a cohort study

SHORT COMMUNICAT ION

Procalcitonin fails to predict bacteremia in SIRS patients:a cohort study

M. Hoenigl,1,2 R. B. Raggam,3 J. Wagner,1 F. Prueller,3 A. J. Grisold,4 E. Leitner,4 K. Seeber,1

J. Prattes,1 T. Valentin,1 I. Zollner-Schwetz,1 G. Schilcher,5 R. Krause1

SUMMARY

Background: Procalcitonin (PCT) has previously been proposed as useful mar-

ker to rule out bloodstream-infection (BSI). The objective of this study was to

evaluate the sensitivity of different PCT cut-offs for prediction of BSI in patients

with community (CA)- and hospital-acquired (HA)-BSI. Methods: A total of

898 patients fulfilling systemic-inflammatory-response-syndrome (SIRS) criteria

were enrolled in this prospective cohort study at the Medical University of

Graz, Austria. Of those 666 patients had positive blood cultures (282 CA-BSI,

384 HA-BSI, enrolled between January 2011 and December 2012) and 232

negative blood cultures (enrolled between January 2011 and July 2011 at the

emergency department). Blood samples for determination of laboratory infection

markers (e.g. PCT) were collected simultaneously with blood cultures. Results:

Procalcitonin was significantly (p < 0.001) higher in SIRS patients with bactere-

mia/fungemia than in those without. Receiver operating characteristic curve

analysis revealed an area under the curve (AUC) value of 0.675 for PCT (95%

CI 0.636–0.714) for differentiating patients with BSI from those without. AUC

for IL-6 was 0.558 (95% CI 0.515–0.600). However, even at the lowest cut-

off evaluated (i.e. 0.1 ng/ml) PCT failed to predict BSI in 7% (n = 46) of

patients. In the group of patients with SIRS and negative blood culture 79%

(n = 185) had PCT levels > 0.1. Conclusion: Procalcitonin was significantly

higher in patients with BSI than in those without and superior to IL-6 and

CRP. The clinical importance of this is questionable, because a suitable PCT

threshold for excluding BSI was not established. An approach where blood cul-

tures are guided by PCT only can therefore not be recommended.

What’s knownEarly diagnosis and appropriate treatment of

bloodstream-infection (BSI) are the key factors in

order to increase survival. Procalcitonin (PCT) has

previously been proposed in numerous studies as

useful marker to guide antimicrobial therapy in

patients hospitalised for community-acquired (CA)

infections. Some smaller studies have also suggested

that PCT might be useful to rule out BSI in the

emergency department and therefore may guide

bloodcultures.

What’s newWe found that even at the lowest cut-off evaluated

(i.e. 0.1 ng/ml) PCT could not predict BSI in 7%

(n = 46) of patients (30 patients with hospital-

acquired and 16 with CA-BSI). In the group of

patients with SIRS and negative blood culture 79%

(n = 185) had PCT levels > 0.1. Driven from the

results of our study cohort an approach where blood

cultures are guided by PCT only can therefore not be

recommended.

Introduction

Despite advances in therapy and supportive care,

bloodstream-infection (BSI) still represents a major

cause of morbidity and mortality (1). Early diagno-

sis and appropriate treatment of BSI are the key

factors in order to increase survival (2). Procalcito-

nin (PCT) has recently been proposed as useful

marker to rule out BSI in the emergency

department and to guide antimicrobial therapy

in patients hospitalised for community-acquired

(CA) infections (3–5). The objective of this

study was to evaluate the sensitivity of different

PCT cut-offs for prediction of bacteremia in

systemic-inflammatory-response-syndrome (SIRS)

patients with CA and those with hospital-

acquired (HA)-BSI.

Patients and methods

A total of 898 patients (all adults above 18 years of

age) fulfilling SIRS criteria as described previously

(6) were enrolled in this prospective cohort study at

the Medical University of Graz, Austria. Of those 666

patients had positive blood cultures and were

enrolled between January 2011 and December 2012.

In 282 of the included 666 patients, the positive

blood cultures were collected at the emergency

department (not admitted during the last 5 days

before presentation). These patients were therefore

assigned to the CA-BSI group. Another 384 patients

had been hospitalised for at least 48 h at the time

the positive blood cultures were collected. These

patients were therefore assigned to the HA-BSI

group. Of 898 patients, 232 had negative blood cul-

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1278ª 2014 John Wiley & Sons Ltd

Int J Clin Pract, October 2014, 68, 10, 1278–1281. doi: 10.1111/ijcp.12474

1Section of Infectious Diseases

and Tropical Medicine,

Department of Internal

Medicine, Medical University of

Graz, Graz, Austria2Division of Pulmonology,



Graz, Graz, Austria3Clinical Institute of Medical

and Chemical Laboratory

Diagnostics, Medical University

of Graz, Graz, Austria4Institute of Hygiene,

Microbiology and Environmental


Graz, Graz, Austria5Division of Nephrology,



Graz, Graz, Austria

Correspondence to:

Martin Hoenigl, Section of

Infectious Diseases and Tropical


Graz, Auenbruggerplatz 15, A-

8036, Graz

Tel.: + 4331638581319

Fax: + 4331638514622

Email: martin.hoenigl@medunigraz.

at

and

Robert Krause, Section of Infectious

Diseases and Tropical Medicine,

Medical University of Graz,

Auenbruggerplatz 15, A-8036 Graz

Tel.: + 4331638581796

Fax: + 4331638514622

Email: robert.krause@medunigraz.

at

Disclosures

All authors declare that they

have no conflicts of interest. I

hereby verify that all authors

had access to the data and a

role in writing the manuscript.

tures and were enrolled between January 2011 and

July 2011. The group consisted of patients that had

presented with SIRS with subsequent collection of

blood cultures at the emergency department. All

these patients had not received antibacterial therapy

at least 5 days prior to collection of the blood cul-

tures and subsequently had negative blood culture

results.

Three pairs of blood cultures per patient were col-

lected simultaneously, placed in the BACTECs blood

culture systems (Becton Dickinson, Cockeysville,

MD) and incubated for a maximum of 5 days as

described previously (7). If coagulase negative staph-

ylococci (CoNS) or gram-positive rods were detected

two or more positive blood culture bottles from a

blood culture set drawn by one venous puncture

growing the same organism were required for a case

to count as true bacteremia; cases that did not meet

this requirements were excluded because of possible

contamination. For the remaining bacterial/fungal

pathogens one positive blood culture bottle was

defined as sufficient evidence of bacteremia/fung-

emia. Blood samples for determination of laboratory

infection markers were collected simultaneously with

the initial blood cultures. For determination of PCT,

the high sensitive Elecsys BRAHMS PCT test kit

(ThermoFisher, Henningsdorf, Germany), with a

detection limit of 0.02 ng/ml (analytical sensitivity)

and a test linearity ranging from 0.02 to 100 ng/ml

(analytical measuring range) on a Cobas 8000 system

(Roche Diagnostics, Rotkreuz, Switzerland) was used.

PCT values below 0.02 ng/ml were given as

< 0.02 ng/ml and values exceeding > 100 ng/ml were

diluted 1:4. Directly after patient enrolment determi-

nation of C-reactive protein (CRP), Interleukin (IL)-

6, and creatinine (from serum samples) was

performed on the fully automated analyzer Cobas

8000 system (reagents all Roche Diagnostics).

For calculation of sensitivities for BSI detection

PCT cut-offs > 0.1, > 0.4 and > 0.5 ng/ml and IL-6

cut-off >10 pg/ml were used. Cut-offs were chosen

consistent with previously published literature

(3,4,7,8).

Statistical analysis was performed using SPSS,

version 20 (SPSS Inc., Chicago, IL). Patient groups

were compared using Mann–Whitney U test. The p-

values of the Mann–Whitney U tests were not cor-

rected for multiple comparisons and are therefore

only descriptive. Receiver operating characteristics

(ROC) curve analysis was performed for PCT and

IL-6. Area under the curve (AUC) values were dis-

played including 95% confidence interval (CI). Cor-

relation between PCT and duration of hospitalisation

was calculated using Spearman-Rho correlation

analysis. The study protocol was approved by the

local ethics committee, Medical University Graz,

Austria (Ethical committee EC-number 21-469 ex

09/10; Clin.Trials.gov. number NCT01359891).

Results

Demographical data as well as laboratory parameters

in SIRS patients with BSI and those without are

depicted in Table 1. While PCT and IL-6 were signif-

icantly higher in patients with BSI than in SIRS

patients without, no differences were found for CRP

and creatinine. ROC curve analysis revealed an AUC

value of 0.675 for PCT (95% CI 0.636–0.714) for dif-ferentiating patients with BSI from those without.

AUC for IL-6 was 0.558 (95% CI 0.515–0.600).Overall, 263/666 patients had bacteremia caused by

Staphylococcus aureus (n = 82) or Escherichia coli

(n = 181). Median PCT for these 263 patients was

1.64 ng/ml (IQR 0.42–10.87) and therefore markedly

higher than in 83 patients with bacteremia caused by

CoNS (median 0.37, IQR 0.16–0.95). ROC curve

analysis for PCT to predict S. aureus or E. coli bac-

teremia (vs. negative blood culture results) revealed

an AUC of 0.719 (95% CI 0.675–0.764; AUC for

IL-6 0.601) while AUC for prediction of CoNS bac-

teremia was 0.507.

While no significant correlation was found

between PCT and duration of hospitalisation

(p = 0.192, Spearman-Rho) in the overall study col-

lective, there was a significant correlation in the sub-

groups of CA-BSI (p < 0.001, Spearman-Rho, higher

PCT correlated with longer hospitalisation) and

HA-BSI (p = 0.001). In the latter higher PCT

(> 0.5 ng/ml) correlated with significantly shorter

duration of hospitalisation (p = 0.021), since many

of these patients (high PCT and HA-BSI) died, while

no difference was found when using the 0.1 ng/ml

PCT cut-off.

Sensitivity of PCT for prediction of BSI (cut-off

> 0.5 ng/ml) was 64% (CA-BSI 70%, HA-BSI 60%;

BSI caused by S. aureus or E. coli 68.8%). The sensi-

tivity increased slightly at a cut-off > 0.4 ng/ml

(69%; CA-BSI 76%, HA-BSI 64%) and markedly at

> 0.1 ng/ml (93%; CA-BSI 94%, HA-BSI 92%; BSI

caused by S. aureus or E. coli 94.7%).

At the time of blood culture sampling, PCT was

≤ 0.1 ng/ml in a total of 46 patients with BSI (31

males, 15 females, median age 63 years, median

duration of hospitalisation 11 days). Sixteen of these

46 patients had CA-BSI. Detected pathogens included

CoNS (n = 8), E. coli (n = 3), S. aureus (n = 3), and

others (n = 2). Two of these 16 patients had to be

admitted to the ICU, one patient died because of

septic shock within 24 h, all others survived at day

90 after admission. The remaining 30/46 patients had

ª 2014 John Wiley & Sons LtdInt J Clin Pract, October 2014, 68, 10, 1278–1281

Procalcitonin: useful to rule out blood stream infection? 1279

HA-BSI caused by S. aureus (n = 6), Enterococcus

spp. (n = 5), Pseudomonas spp. (n = 4), CoNS

(n = 4), E. coli, Streptococcus spp., Klebsiella pneumo-

niae, Candida spp. (n = 2 each), and others (n = 3).

In three out of these 30 patients blood cultures were

drawn at ICU while two had to be admitted to ICU

because of septic shock within 3 days after blood cul-

tures had been drawn. All but two patients survived

at day 90. IL-6 was above 10 pg/ml in 44/46 (96%)

of patients with BSI and low PCT (≤ 0.1 ng/ml).

Sensitivity for IL-6 (cut-off 10 pg/ml) for predic-

tion of BSI was 99.6%. Three patients with BSI had

IL-6 levels ≤ 10 pg/ml.

With regard to patients with SIRS and negative

blood culture result (n = 233, had not received anti-

bacterial therapy at least 5 days prior to collection of

the blood cultures), 185 (79%) had PCT levels

> 0.1 ng/ml and 227 (97%) IL-6 levels > 10 ng/ml.

Discussion

We evaluated PCT for prediction of BSI in 666

patients with BSI and found that PCT was signifi-

cantly higher in patients with bacteremia/fungemia

than in those without and proved to be superior to

IL-6 and CRP. However, even at the lowest cut-off

evaluated (i.e. > 0.1 ng/ml) PCT could not predict

BSI in 7% (n = 46) of patients.

A biomarker that convincingly rules out BSI0smight be useful to guide blood culturing and select

patients that may benefit from blood cultures. PCT

has been proposed by a number of studies with

smaller patient collectives to have the potential of

ruling out BSI in the emergency department and in

patients hospitalised for CA-infections (3–5,8). While

in one study, a serum PCT level of < 0.4 ng/ml has

been reported as an accurate cut-off to rule out BSI

in 22 patients hospitalised with CA-BSI (4), recent

studies have proposed a distinctive lower cut-off of

0.1 ng/ml at emergency departments (3,8). Also in

the latter studies, however, the number of bacteremic

patients was small. With regard to the poor specific-

ity of the currently proposed cut-offs our results are

in accordance with previously published studies

(7,8).

This study has some limitations which mostly

relate to the blood culture negative cohort

(n = 232) that had been enrolled during the first

months of the study only. Reliable calculation of

positive and negative predictive values was there-

fore not possible.

Nevertheless, our results clearly point out that

PCT is a promising marker for prediction of BSI.

However, our data also indicate that PCT – even at

a very low cut-off – may not only fail to predict BSI

in one of 15 patients, but may also be an unspecific

predictor of BSI resulting positive in about 80% of

patients with clinical suspicion of BSI but subsequent

negative blood culture results. At our institution, a

PCT guided approach for the decision whether to

obtain blood cultures or not (with a PCT cut-off of

0.1 ng/ml) would have resulted in a 20% decrease in

blood cultures obtained unnecessarily in patients

without BSI, but conversely would have missed 7%

of patients with BSIs. Considering (i) the potential

of prolonged hospitalisations, morbidity and mortal-

ity because of delayed diagnosis in BSI patients with

low PCT and (ii) the fact that PCT may reduce neg-

ative blood cultures by 20% only, an approach for

blood cultures guided by PCT only may not seem

feasible.

Acknowledgements

The study was conducted as part of our routine

work. No extra funding obtained.

Table 1 Demographical data, duration of hospitalisation and laboratory parameters (medians and IQRs displayed) of

SIRS patients with BSI and those without

BSI (n = 666)*

Negative blood

cultures (n = 232)*

p-value

(if significant)

Age (years) 66 (IQR 54–76) 68 (IQR 51–77)

Sex (f/m) 284/382 95/137

Procalcitonin (ng/ml) 1.06 (IQR 0.31–7.6) 0.29 (IQR 0.12–1.30) < 0.001

Interleukin-6 (pg/ml) 223 (IQR 82–840) 174 (76–401) 0.01

C-reactive protein (mg/l) 108 (IQR 50–201) 108 (IQR 40–210)

Serum creatinine (mg/dl) 1.25 (IQR 0.89–2.30) 1.16 (IQR 0.91–1.74)

Days hospitalised after collection

of positive blood culture (days)

13 (IQR 8–21) 8 (IQR 5–11) < 0.001

BSI, blood stream infection; f, female; IQR, inter quartile range; m, male. *All data available from all included patients.


1280 Procalcitonin: useful to rule out blood stream infection?

Author contributions

Martin Hoenigl, Robert Krause, and Reinhard B Rag-

gam concepted and designed the study, analysed the

data, drafted the manuscript and supervised Jasmin

Wagner, Katharina Seeber and J€urgen Prattes. Jasmin

Wagner, J€urgen Prattes, Gernot Schilcher and Martin

Hoenigl collected the extensive laboratory and clinical

data. Reinhard Raggam and Florian Prueller were

responsible for measurement of biomarkers in the

laboratory. Andrea J Grisold and Eva Leitner contrib-

uted cases of bacteremia diagnosed at the Institute of

Hygiene. Jasmin Wagner, Ines Zollner-Schwetz and

Thomas Valentin made major contributions in inter-

pretation and analysis of the data and critically revised

of the intellectual content together with Florian Pruel-

ler, Andrea J Grisold, Eva Leitner, Katharina Seeber,

Gernot Schilcher and J€urgen Prattes. All contributing

authors approved the final version to be published.

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Paper received December 2013, accepted May 2014


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procalcitonin fails to predict bacteremia in sirs patients: a cohort study

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