Procalcitonin Levels Predict Bacteremia in

Procalcitonin levels Predict Bacteremia in
Patients with community-acquired Pneumonia:

A prospective cohort trial.
Fabian Müller, Mirjam Christ-Crain, Thomas Bregenzer, Martin Krause,
Werner Zimmerli, Beat Mueller, Philipp Schuetz and for the ProHOSP Study
Group
Chest; Prepublished online March 18, 2010;

DOI 10.1378/chest.09-2920
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Page 1 of 29
Word count: abstract: 246 Main text: 2860
Procalcitonin levels Predict Bacteremia in Patients with community-acquired
Pneumonia: A prospective cohort trial.
1
Fabian Müller, MD, 1Mirjam Christ-Crain, MD, 2Thomas Bregenzer, MD, 3Martin
Krause, MD, 4 Werner Zimmerli, MD, 2*Beat Mueller, MD and 1Philipp Schuetz, MD
for the ProHOSP Study Group*
1
Department of Internal Medicine, Division of Endocrinology, Diabetes and Clinical
Nutrition, University Hospital Basel, 2 Department of Internal Medicine, Kantonsspital
Aarau, 3 Department of Internal Medicine, Kantonsspital Münsterlingen 4 Department
of Internal Medicine, Kantonsspital Liestal, Switzerland
*Corresponding author:
Beat Mueller, MD
Department of Internal Medicine,
Kantonsspital, Tellstrasse, CH-5001 Aarau, Switzerland
happy.mueller@unibas.ch
Phone +41 62 838 68 40
Fax +41 62 838 69 45
Funding sources:
This trial is supported in part by a grant from the Swiss National Science Foundation
(SNF 3200BO-116177/1), contributions from santésuisse and the Gottfried and Julia
Bangerter-Rhyner-Foundation, the University Hospital Basel, the Medical University
Clinic Liestal, the Medical Clinic Buergerspital Solothurn, the Cantonal Hospitals
Muensterlingen, Aarau and Lucerne, respectively, the Swiss Society for Internal
Medicine (SGIM), and from the Department of Endocrinology, Diabetology and
Clinical Nutrition, University Hospital Basel. BRAHMS, the manufacturer of the PCT
assay, provided all assay related material.
ClinicalTrials.gov identifier NCT00350987
1
Page 2 of 29
Competing Interest
No commercial sponsor had any involvement in design and conduct of this study,
namely collection, management, analysis, and interpretation of the data; and
preparation, decision to submit, review, or approval of the manuscript.
PS, MCC and BM received support from BRAHMS to attend meetings and fulfilled
speaking engagements. BM has served as a consultant and received research
support.
2
Page 3 of 29
Background: Guidelines recommend blood culture sampling from hospitalized

patients with suspected community-acquired pneumonia (CAP). However, the yield
of true positive results is low. We investigated the benefit of procalcitonin (PCT) on
admission to predict blood culture positivity in CAP.
Methods: This is a prospective cohort study with a derivation and validation set
including a total of 925 CAP patients with blood culture sampling upon hospital
admission.
Results: A total of 73 patients (7.9%) had true bacteremia (43/463 in the derivation
cohort, 30/462 in the validation cohort). The area under the receiver-operating-
characteristics curve of PCT in the derivation and validation cohort were similar
(0.83 (95%CI 0.78-0.89), 0.79 (95%CI 0.72-0.88). Overall, PCT was a significantly
better predictor for blood culture positivity as compared to white blood cell count, C-
reactive protein and other clinical parameters. In multivariate regression analysis,
only antibiotic pretreatment (adjusted OR 0.25, p<0.05) and PCT serum levels
(adjusted OR 3.72, p<0.001) were independent predictors. Overall, a PCT cut-off of
0.1µg/L would allow reducing the total number of blood cultures by 12.6% and still
identifying 99% of the positive blood cultures. Similarly, 0.25µg/L and 0.5µg/L cut
offs would allow reducing blood cultures by 37% and 52% and still identifying 96%
and 88% of positive blood cultures.
Conclusion: Initial PCT level accurately predicted blood culture positivity in CAP
patients. PCT measurement has the potential to reduce the number of drawn blood
cultures in the Emergency Department and to implement a more targeted allocation
of limited health care resources.
3
Page 4 of 29
Introduction
Community-acquired pneumonia (CAP) is a common and potentially life-threatening
disease which puts an enormous strain on health-care resources 1. In the diagnostic
work up of CAP patients, identification of the causative organism to target a more
favourable antibiotic therapy and to study local resistance patterns is of great value
1,2
. Current guidelines recommend drawing two sets of pre-treatment blood cultures
routinely in all hospitalized patients with CAP{Mandell, 2007 #6340} 3. Nevertheless
the benefit and cost-effectiveness of routine drawing of blood cultures is
controversial, mainly because of the low yield of positive blood cultures, which is in
the range of 3-10% in non-selected hospital admitted patients with CAP 4-10. In order
to limit blood culture sampling to high-risk patients for growth of bacteria, previous
studies have evaluated clinical and laboratory predictors for blood culture positivity
6,11-13
. However, single parameters lack sensitivity and/or specificity which prevents
6,11
its use in daily routine . Some authors have developed clinical decision rules with
6,12,13
increased prognostic accuracy . However, complexity of decision rules often
restricts a widespread adoption. Hence, there is an unmet need to identify simple
and accurate predictors for blood culture positivity in patients with CAP.
Procalcitonin (PCT) has emerged as a biomarker for bacterial infections because it

14-
correlates with the extent and severity of microbial invasion in different infections
22
. Previous trials have demonstrated that patients with bacteremic CAP have
9,14,17,22
markedly increased initial PCT concentrations , which makes PCT a
promising candidate biomarker for prediction of blood culture positivity. Herein, we
evaluated the prognostic accuracy of PCT as compared to other commonly used
clinical and laboratory parameters in a large and well defined derivation and
validation cohort of CAP patients.
4
Page 5 of 29
Material and Methods
Setting and population studied
The present study is a predefined sub-study of the previously published ProHOSP
trial and evaluated data from 925 patients confirmed with radiological CAP who were
admitted to the Emergency Department (ED) of the University Hospital Basel,
Switzerland, between 12/06 and 03/08. A detailed description of the ProHOSP study
has been published elsewhere14,23. In brief, consecutive patients with lower
respiratory tract infection (LRTI) were included in six secondary and tertiary care
hospitals in northern and central Switzerland. The aim of this randomized non-
inferiority trial was to compare two different treatment strategies using either a PCT
algorithm or an algorithm based on current guidelines for conducting antibiotic
therapy. The primary endpoint was the combined medical failure rate of patients. A
study website provided information on the evidence-based management of all

24-28
patients based on the most recent guidelines and explicitly specified the need
for X-ray confirmation of CAP and for sampling two sets of pre-treatment blood
cultures. A predefined secondary endpoint of this study was the evaluation of
prognostic parameters for outcomes and blood culture positivity.
Full ethical approval for this trial has been obtained from all local ethical committees
and all patients gave written informed consent.
Participants and Definitions
Inclusion criteria for patients were written informed consent, age ≥ 18 years and
admittance from the community or a nursing home with the main diagnosis of LRTI.
Exclusion criteria were the inability to give written informed consent, insufficient
German language skills, active illegal intravenous drug use, previous hospitalisation
5
Page 6 of 29
for LRTI within 14 days, severe immunosuppression other than corticosteroids,
accompanying chronic infection or endocarditis and most severe medical co-
morbidity where death was imminent.
LRTI was defined by the presence of at least one respiratory symptom (cough, with
and without sputum production, dyspnea, tachypnea, pleuritic pain) plus one
auscultatory finding or one sign of infection (core body temperature > 38.0°C,
shivers, white blood count > 10 G/L or < 4 G/L cells) independent of antibiotic pre-
treatment. Diagnosis of CAP was made if additionally to the LRTI criteria an
underlying infiltrate on chest radiograph was present24.
In all patients with a provisional diagnosis of CAP, two pairs of blood cultures for
both aerobic and anaerobic conditions were collected before starting antibiotic
therapy. Blood cultures were processed using an automated colorimetric detection
system (BacT/ALERT, bioMerieux, Durham, NC, USA) in three hospitals and an
equivalent blood culture system (BACTEC Becton-Dickinson, Cockeysville, Md.) in

29
the other three hospitals . If blood culture bottles indicated bacterial growth,
samples were gram stained and subcultured. The correct identification of the
pathogen was achieved according to routine laboratory procedures.
In accordance with a recently published study 6, a bacteremic episode was defined
as growth of a typical organism for CAP in at least one of four collected blood
cultures within the first 36 hours of presentation to the ED. Episodes with growth of
coagulase-negative staphylococci were assumed to be contaminants. Growth of
Streptococcus spp. other than pneumococci (n=4) and Enterobacteriaeceae (n=3)
including Serratia marcescens in the blood cultures of one patient were included in
this analysis, even though a causal relationship with CAP is not clear.
6
Page 7 of 29
Clinical examination and Laboratory data
In all patients on admission, a thorough clinical examination was performed and two
prognostic scores (Pneumonia Severity Index (PSI) and the CURB-65) were
30,31
calculated . For all patients laboratory results were collected from the routine
blood analysis including markers of infection (PCT, CRP and WBC), plasma sodium
concentration and blood urea nitrogen. CRP concentrations were determined by an
enzyme immunoassay having a detection limit of < 5 mg/dl (EMIT, Merck
Diagnostica, Zurich, Switzerland). PCT was measured using a time-resolved
amplified cryptate emission (TRACE) technology assay (Kryptor® PCT, Brahms AG,
Hennigsdorf, Germany) with a functional assay sensitivity of 0.06 µg/L.
Derivation and Validation Sets
We used the first 50% of CAP patients (n=463) as the derivation set and the second
50% (n=462) as the validation set based on the timely inclusion of patients. The
validation set was not used until the analysis with the derivation set was complete
and served as an independent test of the derived rule.
Statistical Analysis
This report adheres to the STROBE guidelines for reporting observational studies 32.
Discrete variables are expressed as counts (percentage) and continuous variables
as medians and interquartile ranges (IQR). Frequency comparison was done by chi-
square test. Two-group comparison Mann-Whitney-U test was used. To assess the
prognostic performance of different parameters to predict blood culture positivity,
univariate and multivariate regression analysis adjusted for all significant parameters
7
Page 8 of 29
were used. Thereby, logarithmic transformation was performed to obtain normal
distribution for skewed variables (i.e. PCT concentrations) and outcomes were either
positive blood cultures or negative blood cultures. Receiver-operating-characteristics
(ROC) were calculated using STATA 9.2 (Stata Corp, College Station, Tex). All
testing was two-tailed and P values less than 0.05 were considered to indicate
statistical significance.
8
Page 9 of 29
Results
Baseline parameters
The median age of the overall cohort of 925 CAP patients was 73 years (IQR 59-82)
and 59% were males. The median PSI score was 91 (IQR 66-115) and 51% of
patients were in high risk PSI classes IV and V. True positive blood cultures were
detected overall in 73 patients (43/463 in the derivation cohort and 30/462 in the
validation cohort); thus the overall rate of true positive blood cultures was 7.9%
(Figure 1). The following pathogens were detected: Streptococcus pneumoniae
n=59, Escherichia coli n=3, Haemophilus influenzae n=2, Enterobacter cloacae n=2,
Enterobacter aerogenes n=1, Streptococcus pyogenes n=1, Streptococcus
acidominimus n=1, Streptococcus mitis n=1, Pseudomonas aeruginosa n=1,
Staphylococcus aureus n=1, Serratia marcescens n=1. Three patients had
contamined blood cultures with coagulase-negative staphylococci in a single blood
culture bottle each. Table 1 shows baseline characteristics on admission of all
patients (left column) and separated according to blood culture results. Patients with
positive blood cultures were less frequently admitted from nursing facilities, had less
frequent antibiotic pretreatment and congestive heart failure, while renal dysfunction
was more frequent. Laboratory analysis showed that CRP, blood urea nitrogen and
WBC were significantly higher in patients with positive blood cultures. In addition,
patients with positive blood cultures had almost 15 fold higher PCT levels compared
to patients with negative cultures (5.8 vs 0.4 µg/L). There was no significant
difference in PCT levels in patients with Streptococcus pneumoniae as compared to
patients with other pathogens (median PCT 5.8 µg/L (IQR 2.1-21.1) vs 6.3 µg/L
(IQR 3.3-11.4), p=0.98). While, the majority of patients with positive blood cultures
had increased PCT levels, one patients with a PCT level < 0.1 µg/L, and 2 patients
9
Page 10 of 29
with a PCT level < 0.25 µg/L had growth of Streptococcus pneumoniae in blood
cultures. These three patients had an increase of PCT levels of higher than 0.25
µg/L in the follow up PCT measurement. Patients with positive blood cultures were
more frequently transferred to the ICU, but mortality was similar.
PCT compared to other parameters to predict positive blood cultures
In univariate analysis (Table 2), antibiotic pretreatment, congestive heart failure, and
systolic blood pressure were negative predictive factors for positivity of blood
cultures. In contrast, renal dysfunction, heart rate, body temperature, blood urea
nitrogen, white blood count, CRP serum levels, as well as PCT serum levels were
positive predictors for positive blood cultures. Multivariate logistic regression
analysis using all significant parameters from univariate analysis showed that only
antibiotic pretreatment (adjusted OR 0.25 (95%CI 0.08-0.76), p<0.05) and PCT
serum levels (adjusted OR 3.72 (95%CI 2.31-5.95), p<0.001) were independent
predictors for negative and positive blood cultures, respectively.
To assess the overall discriminatory ability of different parameters, we calculated
ROC curves (Figure 2). The AUC of PCT in the derivation and validation cohort
were similar (0.83 (95%CI 0.78-0.89) and 0.79 (95%CI 0.72-0.88), Table 3). With an
AUC of 0.82 (95% CI 0.78-0.87) in the overall population, PCT had the highest
diagnostic accuracy to predict positive blood cultures as compared to CRP and
other clinical and laboratory predictors. At a PCT cut-off of 0.1µg/L, sensitivity to
predict positive blood cultures was 98% and 100% in the derivation and the
validation cohort and 99% in the overall cohort. Appendix I shows sensitivity,
specificity, positive and negative likelihood ratios for all parameters.
10
Page 11 of 29
Positive and negative blood cultures within different risk categories
Blood culture positivity within different risk categories of PCT, CRP and the two
clinical risk scores (PSI and CURB-65) was assessed. Figure 3 shows percentage
of patients with positive (dark grey) and negative (light grey) blood cultures within
risk categories. In patients with a PCT value < 0.1 µg/L and between 0.1-0.25 µg/L,
only 0.9% (1/117) and 0.9% (2/224) of patients had positive blood cultures, while
16.8% (61/364) had positive results with PCT levels > 1.0 µg/L. Patients with CRP <
20 mg/dl and between 20-50 mg/dl, 3.7% and 5.9% had positive culture results.
Except for the highest risk category, the occurrence of positive cultures was
balanced in the different risk classes of both clinical risk scores.
Financial implications
We calculated potential cost-savings using different PCT cut off values. We
assumed costs of 145 US Dollars (USD) for two sets of blood culture per patient
based on institutional data of the University Hospital in Basel, Switzerland. Thus,
total costs for the whole CAP study cohort (925 patients times 145 USD) were
estimated to be 134’125 USD. Similarly, we assumed costs of 30 USD per PCT
measurement resulting in total costs of 27`750 USD for the cohort. Estimated total
costs for different PCT cut offs are presented in Table 4. Using a cut off value of 0.1
µg/L would reduce the total number of blood cultures by 12.6% (n=117), while still
identifying 99% (72 out of 73) of positive blood cultures. Similarly, using a cut off of
0.25 µg/L and 0.5 µg/L would result in 37% and 52% of blood cultures while still
identifying 96% and 88% of positive culture results, respectively.
11
Page 12 of 29
Discussion
In this large prospective multicenter study including CAP patients from the
Emergency Department, PCT proved to be the most reliable predictor of blood
culture positivity. Depending on the cut off applied, PCT levels of < 0.25 µg/L
identified patients at very low risk for bacteremic episodes and thus helps to avoid
unnecessary blood culture sampling with resulting financial benefits. Conversely,
increased PCT levels > 0.5 µg/L and especially > 1 µg/L may help to identify high-
risk patients who benefit from early and aggressive diagnostic work up and antibiotic
therapy.
Routine sampling of blood cultures in CAP patients have been a cornerstone for
epidemiological reasons, for monitoring antibiotic resistance patterns and for a
better streamlining of antibiotic therapy in individual patients1,24,27. Nevertheless, the
routine implementation of blood culture sampling in CAP has been questioned,

4-9
because of the low yield of true positive results . Consensus guidelines
encourages a more rational approach to blood culture collection without, however,

24
giving specific criteria . Thus, there is an unmet need for accurate predictors of
blood culture positivity that would increase the pre-test probability of patients and
thus the yield of blood cultures in CAP. In this context, enormous attempts have
been undertaken to correlate the levels of different biomarkers and mediators with
the presence of bacteremia19,33. Herein, PCT is a promising biomarker, because it
correlates with the extent and severity of microbial infection, because of high
specificity for bacterial etiology of LRTI and the superior clinical usefulness as
compared to other commonly used laboratory tests, namely CRP and WBC15-22,33.
This study validates a series of previous findings. In accordance with previous
studies we found that antibiotic pre-treatment is an important factor to decrease the
12
Page 13 of 29
likelihood of positive blood culture findings 6,34. In a large retrospective cohort study 6
different predictors for bacteremia in hospitalized CAP patients have been identified.
Antibiotic pre-treatment and 40°C < body temperature < 35°C were negative
predictors, while liver disease, systolic blood pressure < 90 mm Hg, heart rate ≥
125/min., blood urea nitrogen ≥ 11 mmol/L, sodium < 130 mmol/L, WBC <
5,000/mm3 or > 20,000/mm3 were positive predictors. Using this “decision support
tool” in their data would result in 38% fewer blood cultures when compared with the
standard practice and still allow identification of 88% to 89% of patients with
bacteremia 6. In our study, we validate these predictors. However, after including
PCT in multivariate analysis, only antibiotic pre-treatment and PCT remained
independent predictors. Using a PCT cut off of 0.25 µg/L in our study would allow
reducing the amount of blood culture collection by a similar amount (37%), but still
result in a higher sensitivity of 96%.

7
Waterer and colleagues reported that the yield of positive blood cultures in CAP
patients increases with increasing PSI. Thus, they concluded that blood cultures
should be limited to high risk patients in the PSI classes IV and V 7. In the present
study we found no significant correlation between PSI classes and the yield of
positive blood cultures, and only a weak association between the CURB-65 score
and likelihood of positive blood cultures. The PSI is a mortality prediction tool and is
30
mainly influenced by the age of patients . Thus, young patients with bacteremic
CAP usually have a lower PSI but still a high risk of blood culture positivity.
Based on the results of two 2 retrospective studies reporting a reduced mortality in
CAP patients who received antibiotic treatment within 4-8 hours, the time to first
antibiotic dose has recently received significant attention from a quality-of-care
perspective 24. Within the ProHOSP trial, PCT was measured using a rapid sensitive
13
Page 14 of 29
assay and an assay time of around 20 minutes 14. The test was performed on-site at
the central lab of each participating hospital and results were routinely available
around the clock within 1 hour and by the time results from routine chemistry were
available. Thus, if PCT is measured on admission in patients with suspicion of CAP,
PCT can be used for the evaluation of the patients without putting him at risk
because of time delays.
Some limitations merit consideration. First, patients with severe immunosuppression
were excluded limiting generalization. In blood cultures of seven patients we found
some pathogens that are not typically found in CAP, and might thus not be the true
cause for the diagnosed CAP. Although we excluded patients with other sites of
infection than the respiratory tract it is not entirely possible to rule out the influence
of concomitant infections. Exclusion of these patients, however, would not have
altered our results (data not shown).
In conclusion, this study suggests PCT to be an accurate parameter for predicting
bacteremia in patients with CAP. Based on the results of this study, we recommend
to draw blood cultures in CAP patients only when PCT levels are 0.25 µg/L or higher
because the likelihood for bacteremic CAP in patients with lower PCT levels is very
low. In addition, blood cultures should be considered at lower PCT level, if
antibiotics are prescribed based on validated overruling criteria especially in areas
with increased prevalence of resistant organisms. Obviously, the clinical picture of
bacteraemic infection is far too heterogeneous and complex to be reduced to a
single cut-off of any surrogate marker. Different microbes might induce distinct
responses resulting in a variable upregulation of circulating PCT levels. Still, as
demonstrated in this and other studies, the likelihood for bacterial CAP increases
gradually with increasing serum levels of PCT, making PCT a putative indicator for
14
Page 15 of 29
blood culture positivity. Thus, used in the proper context of CAP it may result in a
substantial reduction in the numbers of cultures obtained and to an optimized
allocation of our limited health care resources and in patient costs.
15
Page 16 of 29
Competing Interest
No commercial sponsor had any involvement in design and conduct of this study,
namely collection, management, analysis, and interpretation of the data; and
preparation, decision to submit, review, or approval of the manuscript.
PS, MCC and BM received support from BRAHMS to attend meetings and fulfilled
speaking engagements. BM has served as a consultant and received research
support. All other authors declare that the answer to the questions on the competing
interest form are all “No” and therefore have nothing to declare.
Contributors
MCC, BM, WZ and PS had the idea and initiated the study, FM, BM and PS
performed the analyses and drafted the manuscript. All authors amended and
commented on the manuscript and approved the final version.
Acknowledgement
We are grateful to all local physicians, the nursing staff and patients who
participated in this study. Especially, we thank the staff of the emergency room,
medical clinics and central laboratories of the University Hospital Basel, the
“Kantonsspitaeler” Liestal, Aarau, Luzern and Muensterlingen and the
“Buergerspital” Solothurn for their very helpful assistance, patience and technical
support. We thank other members of the Data Safety and Monitoring Board, namely
A.P.Perruchoud, S.Harbarth and A. Azzola and all members of the ProHOSP Study
Group, namely Robert Thomann, MD, Claudine Falconnier, MD, Marcel Wolbers,
PHD, Isabelle Widmer, MD, Stefanie Neidert, MD, Thomas Fricker, MD, Claudine
Blum, MD, Ursula Schild, RN, Katharina Regez, RN, Rita Bossart, RN, Ronald
16
Page 17 of 29
Schoenenberger, MD, Christoph Henzen, MD, Claus Hoess, MD, Heiner C. Bucher,
MD, Ayesha Chaudri, Jeannine Haeuptle, Roya Zarbosky, Rico Fiumefreddo,
Melanie Wieland, RN, Charly Nusbaumer, MD, Andres Christ, MD, Roland
Bingisser, MD, Kristian Schneider, RN, Christine Vincenzi, RN, Michael Kleinknecht,
RN, Brigitte Walz, PhD, Verena Briner, MD, Dieter Conen, MD, Andreas Huber, MD,
Jody Staehelin, MD, Aarau, Chantal Bruehlhardt, RN, Ruth Luginbuehl, RN, Agnes
Muehlemann, PhD, Ineke lambinon and Max Zueger, MD. D.Conen, MD,
M.Wieland, RN, C.Nusbaumer, MD, C.Bruehlhardt, RN, R.Luginbuehl, RN, A.Huber,
MD, B.Walz, RN, and M.Zueger, MD.
17
Page 18 of 29
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28 Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult
lower respiratory tract infections. Eur Respir J 2005; 26:1138-1180
29 Thorpe TC, Wilson ML, Turner JE, et al. BacT/Alert: an automated
colorimetric microbial detection system. J Clin Microbiol 1990; 28:1608-1612
30 Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk
patients with community-acquired pneumonia. N Engl J Med 1997; 336:243-
250
31 Lim WS, van der Eerden MM, Laing R, et al. Defining community acquired
pneumonia severity on presentation to hospital: an international derivation
and validation study. Thorax 2003; 58:377-382
32 von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of
Observational Studies in Epidemiology [STROBE] statement: guidelines for
reporting observational studies. Gac Sanit 2008; 22:144-150
33 Schuetz P, Christ-Crain M, Muller B. Procalcitonin and other biomarkers to
improve assessment and antibiotic stewardship in infections - hope for hype?
Swiss Med Wkly 2009; 139:318-326
34 Glerant JC, Hellmuth D, Schmit JL, et al. Utility of blood cultures in
community-acquired pneumonia requiring hospitalization: influence of
antibiotic treatment before admission. Respir Med 1999; 93:208-212
19
Page 20 of 29
Table 1 Baseline characteristics of the overall 925 patients with CAP separated by
positive blood cultures (n=73) and negative or contaminated blood cultures (n=852).
All Positive Negative or
blood cultures contaminated p-value
blood cultures
(n=925) (n=73) (n=852)
Demographic characteristics – no. (%)
Age (years)* 73 (59-82) 72 (56-81) 73 (59-82) 0.34
Male 544 (59) 42 (57) 502 (59) 0.82
Admitted from nursing facility 53 (6) 0 (0) 53 (6) 0.03
Antibiotic pretreatment 236 (26) 5(7) 231 (27) <0.001
Active smokers 233 (26) 25 (35) 208 (25) 0.06
Comorbidities – no. (%)
Congestive heart failure 159 (17) 6 (8) 153 (18) <0.05
Cerebrovascular disease 82 (9) 4 (6) 78 (9) 0.30
Renal dysfunction 206 (22) 27 (38) 179 (21) <0.01
Chronic lung disease 282 (30) 23 (32) 259 (30) 0.84
Chronic liver disease 22 (2) 3 (4) 19 (2) 0.31
Diabetes mellitus 162 (18) 16 (22) 146 (17) 0.30
Neoplastic disease 118 (13) 13 (18) 105 (12) 0.18
Coronary heart disease 159 (17) 6 (8) 167 (20) 0.63
Physical exam findings – no. (%)
Confusion 74 (9) 6 (9) 68 (9) 0.87
Systolic blood pressure 132 (119-148) 121 (110-142) 133 (120-150) <0.01
(mmHg)*
Pulse rate (beats/minute)* 95 (82-108) 100 (89-120) 94 (81-107) <0.01
Body temperature (C°)* 38.1 (37.2-38.9) 38.5 (37.7- 39.3) 38.0 (37.2-38.8) 0.01
Respiratory rate 20 (16-25) 22 (16-30) 20 (16-25) 0.05
(breaths/minute)*
Oxygen saturation (%)* 92 (89-95) 91 (88-96) 92 (89-95) 0.59
Auscultatory crackles 636 (71) 53 (75) 583 (71) 0.50
Laboratory data – no. (%)
C-reactive protein (mg/L)* 155 (75-252) 239 (125-403) 149 (71-247) <0.0001
Procalcitonin (µg/L))* 0.46 (0.15-2.66) 5.83 (2.24-15.6) 0.40 (0.15-2.01) <0.0001
Blood urea nitrogen (mmol/L)* 7.1 (4.9-10.5) 8.7 (6.9-12.6) 6.9 (4.8-10.4) <0.001
9
White blood count (x10 /L)* 12.1 (9.0-16.4) 14.9 (10.0-17.8) 11.9 (9.0-16.2) 0.03
Sodium (mmol/L)* 136 (133-138) 135 (133-138) 136 (133-138) 0.13
Risk assessment – no. (%)
PSI Points * 91 (66-115) 96 (73-126) 91 (66-115) 0.14
CURB65 * 2 (1-2) 2 (1-3) 2 (1-2) <0.01
Outcomes – no. (%)
Admission to ICU (patients) 83 (9) 14 (19) 69 (8) 0.001
30-day mortality 50 (5.4) 4 (5.5) 46 (5.4) 0.98
NOTE.-* median (Interquartile range); BC, blood culture, PSI, Pneumonia Severity Index;
20
Page 21 of 29
Table 2 Predictors for positive blood cultures (n=73) in univariate logistic regression
analysis of CAP patients (n=925).
Predictor Odds ratio (95% CI) P-value

Clinical history
Antibiotic pretreatment 0.20 0.08 0.50 0.001
Congestive heart failure 0.41 0.17 0.96 <0.05
Renal dysfunction 2.21 1.33 3.65 <0.01
Chronic liver disease 1.90 0.54 6.50 0.32
Clinical measurements
Systolic blood pressure (mmHg) 0.98 0.97 0.99 <0.01
<90 mmHg 2.47 0.92 6.67 0.07
Pulse rate (beats/minute) 1.02 1.01 1.03 <0.01
≥ 125/min 2.76 1.40 5.43 <0.01
Body temperature (°C) 1.32 1.06 1.65 <0.05
<35°C or ≥ 40° C 2.52 1.08 5.91 <0.05
Respiratory rate (breaths/minute) 1.02 0.99 1.04 0.18
Oxygen saturation (%) 0.98 0.95 1.02 0.45
Laboratory parameters
Sodium (mmol/L) 0.96 0.92 1.01 0.12
<130 mmol/L 1.59 0.78 3.22 0.20
Blood urea nitrogen (mmol/L) 1.06 1.02 1.09 0.001
≥11mmol/L 1.65 0.92 2.98 0.08
9
White blood count (x10 /L) 1.03 1.00 1.05 <0.05
9 9
≤ 5 x10 /L or ≥ 20 x10 /L 1.43 0.80 2.57 0.23
Markers of infection
C-reactive Protein (mg/L) 1.005 1.003 1.006 <0.001
> 20 mg/L 2.27 0.70 7.38 0.17
> 50 mg/L 1.81 0.85 3.84 0.13
> 100 mg/L 2.01 1.10 3.67 <0.05
> 200 mg/L 2.79 1.70 4.58 <0.001
Procalcitonin (µg/L) 4.39 3.13 6.16 <0.001
> 0.1 µg/L 11.36 1.56 82.56 0.02
> 0.25 µg/L 15.37 4.80 49.22 <0.001
> 0.5 µg/L 8.65 4.25 17.60 <0.001
> 1.0 µg/L 9.19 4.87 17.34 <0.001
21
Page 22 of 29
Table 3
Derivation set (n=463)

Parameters AUC 95%CI Sensitivity Specificity LR+ LR-
Procalcitonin 0.83 0.78-0.89
> 0.1 µg/L 98% 16% 1.16 0.15
> 0.25 µg/L 98% 42% 1.66 0.06
> 0.5 µg/L 95% 55% 2.14 0.08
> 1.0 µg/L 88% 66% 2.62 0.17
Validation set (n=462)
> 0.1 µg/L 100% 11% 1.12 0.01
> 0.25 µg/L 93% 38% 1.5 0.18
> 0.5 µg/L 80% 54% 1.74 0.37
> 1.0 µg/L 76% 63% 2.04 0.37
Overall cohort (n=925)
> 0.1 µg/L 99% 13% 1.14 0.1
> 0.25 µg/L 96% 40% 1.59 0.11
> 0.5 µg/L 88% 55% 1.94 0.23
> 1.0 µg/L 84% 64% 2.35 0.26
22
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Table 4 Estimation of costs according to different PCT cut off values
No PCT measurement, PCT cut off PCT cut off PCT cut off PCT cut off PCT cut off
Blood culture in all patients 0.1 µg/L 0.25 µg/L 0.5 µg/L 1.0 µg/L 1.5 µg/L
Reduction in blood culture collection (%) - 12.6% 36.9% 51.5% 60.5% 67.5%
Total costs for blood culture collection in USD 134’125 117’225 84’633 65’051 52’979 43’591
Total costs for initial PCT measurement in USD - 27`750 27`750 27`750 27`750 27`750
Total costs per patient in USD 145 157 121 100 87 77
Missed pathogens in blood cultures, n (%) - 1 (1.4%) 3 (4.1%) 9 (12.3%) 12 (16.4%) 14 (19.2%)
Number needed to screen to detect 1 pathogen 12.7 11.2 8.3 7.0 6.0 5.1
NOTE.- CAP community-acquired pneumonia, PCT procalcitonin, USD US-Dollars; for cost calculations, 145 USD per two blood
cultures and 30 USD per PCT measurement was assumed.
23
Page 24 of 29
Appendix I Area under the curve (AUC) of receiver operating curve (ROC) characteristic plot analysis and Diagnostic Accuracy.
Parameters AUC 95%CI p Sensitivity Specificity LR+ LR-

> 0.1 µg/L 99% 13% 1.14 0.10

> 0.25 µg/L 96% 40% 1.59 0.11
> 0.5 µg/L 88% 55% 1.94 0.23
> 1.0 µg/L 84% 64% 2.35 0.26
C-Reactive Protein 0.67 0.59-0.74 <0.0001

> 20 mg/L 96% 9% 1.05 0.46
> 50 mg/L 89% 18% 1.09 0.60
> 100 mg/L 81% 33% 1.20 0.59
> 200 mg/L 61% 64% 1.70 0.61
Blood urea nitrogen 0.64 0.57-0.71 <0.0001
> 11 mmol/l 32% 78% 1.44 0.87
White blood count 0.58 0.50-0.65 <0.0001
9 9
≤ 5 x10 /L or ≥ 20 x10 /L 22% 84% 1.34 0.93
Systolic blood pressure 0.61 0.54-0.68 <0.0001
< 90 mmHg 7% 97% 2.37 0.96
Pulse rate 0.60 0.53-0.67 <0.0001
> 125/min 17% 93% 2.46 0.89
Temperature 0.59 0.52-0.66 <0.0001
< 35 or > 40 ° C 10% 96% 2.37 0.94
Antibiotic pretreatment 0.59 0.57-0.63 <0.0001 7% 73% 0.25 1.28
Congestive heart failure 0.55 0.51-0.58 <0.0001 8% 82% 0.46 1.12
Renal dysfunction 0.58 0.52-0.64 <0.0001 37% 79% 1.76 0.80
NOTE.- Predictors at defined cut off points with corresponding sensitivity, specificity, and positive and negative likelihood ratio. P-
value refers to the comparison of procalcitonin with other parameters in ROC analysis. AUC area under the curve, LR+ positive
likelihood ratio, LR- negative likelihood ratio.
24
Page 25 of 29
Figure Legends:
Figure 1: Patient flow in the derivation and the validation cohort
CAP community-acquired pneumonia, LRTI lower respiratory tract infection, COPD
chronic obstructive pulmonary disease.
Figure 2: Receiver operating Curves analysis
A. Comparing Derivation and validation cohort
B. Comparing PCT and other laboratory and clinical parameters in the overall cohort
Figure 3: Percentage of patients with positive (dark grey) and negative (light grey)
blood cultures within different risk categories.
25
Page 26 of 29
Figure 1 Flow chart
Figure 2. Receiver operating curve (ROC) analysis
Figure 3. All CAP patients (n=925) with positive (dark grey) and negative (light grey)
blood cultures within different risk categories.
26
Page 27 of 29
Flow chart

Page 28 of 29
ROC curves

Page 29 of 29
Figure 3. All CAP patients (n=925) with positive (dark grey) and negative (light grey) blood cultures
within different risk categories.

Procalcitonin levels Predict Bacteremia in Patients with
community-acquired Pneumonia: A prospective cohort trial.
Fabian Müller, Mirjam Christ-Crain, Thomas Bregenzer, Martin Krause, Werner
Zimmerli, Beat Mueller, Philipp Schuetz and for the ProHOSP Study Group
Chest; Prepublished online March 18, 2010;
DOI 10.1378/chest.09-2920
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Procalcitonin levels Predict Bacteremia in

Patients with community-acquired Pneumonia:

Chest; Prepublished online March 18, 2010;

Chest is the official journal of the American College of Chest Physicians. It

CHEST Papers in Press are peer-reviewed, accepted articles that

Downloaded from chestjournal.chestpubs.org at Memorial University on January 4, 2011

Word count: abstract: 246 Main text: 2860

Procalcitonin levels Predict Bacteremia in Patients with community-acquired

Pneumonia: A prospective cohort trial.

for the ProHOSP Study Group*

Nutrition, University Hospital Basel, 2 Department of Internal Medicine, Kantonsspital

Aarau, 3 Department of Internal Medicine, Kantonsspital Münsterlingen 4 Department

of Internal Medicine, Kantonsspital Liestal, Switzerland

ClinicalTrials.gov identifier NCT00350987

Background: Guidelines recommend blood culture sampling from hospitalized

Community-acquired pneumonia (CAP) is a common and potentially life-threatening

disease which puts an enormous strain on health-care resources 1. In the diagnostic

work up of CAP patients, identification of the causative organism to target a more

routinely in all hospitalized patients with CAP{Mandell, 2007 #6340} 3. Nevertheless

the benefit and cost-effectiveness of routine drawing of blood cultures is

restricts a widespread adoption. Hence, there is an unmet need to identify simple

Procalcitonin (PCT) has emerged as a biomarker for bacterial infections because it

promising candidate biomarker for prediction of blood culture positivity. Herein, we

evaluated the prognostic accuracy of PCT as compared to other commonly used

validation cohort of CAP patients.

Material and Methods

Setting and population studied

The present study is a predefined sub-study of the previously published ProHOSP

admitted to the Emergency Department (ED) of the University Hospital Basel,

has been published elsewhere14,23. In brief, consecutive patients with lower

algorithm or an algorithm based on current guidelines for conducting antibiotic

study website provided information on the evidence-based management of all

cultures. A predefined secondary endpoint of this study was the evaluation of

prognostic parameters for outcomes and blood culture positivity.

and all patients gave written informed consent.

Participants and Definitions

for LRTI within 14 days, severe immunosuppression other than corticosteroids,

accompanying chronic infection or endocarditis and most severe medical co-

morbidity where death was imminent.

treatment. Diagnosis of CAP was made if additionally to the LRTI criteria an

underlying infiltrate on chest radiograph was present24.

therapy. Blood cultures were processed using an automated colorimetric detection

system (BacT/ALERT, bioMerieux, Durham, NC, USA) in three hospitals and an

equivalent blood culture system (BACTEC Becton-Dickinson, Cockeysville, Md.) in

pathogen was achieved according to routine laboratory procedures.

In accordance with a recently published study 6, a bacteremic episode was defined

coagulase-negative staphylococci were assumed to be contaminants. Growth of

Streptococcus spp. other than pneumococci (n=4) and Enterobacteriaeceae (n=3)

Clinical examination and Laboratory data

concentration and blood urea nitrogen. CRP concentrations were determined by an

enzyme immunoassay having a detection limit of < 5 mg/dl (EMIT, Merck

Diagnostica, Zurich, Switzerland). PCT was measured using a time-resolved

Hennigsdorf, Germany) with a functional assay sensitivity of 0.06 µg/L.

Derivation and Validation Sets

and served as an independent test of the derived rule.

Discrete variables are expressed as counts (percentage) and continuous variables

prognostic performance of different parameters to predict blood culture positivity,

were used. Thereby, logarithmic transformation was performed to obtain normal

positive blood cultures or negative blood cultures. Receiver-operating-characteristics

(Figure 1). The following pathogens were detected: Streptococcus pneumoniae

Enterobacter aerogenes n=1, Streptococcus pyogenes n=1, Streptococcus

acidominimus n=1, Streptococcus mitis n=1, Pseudomonas aeruginosa n=1,