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Procalcitonin Levels Predict Bacteremia in
Procalcitonin Levels Predict Bacteremia in
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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
1
Department of Internal Medicine, Division of Endocrinology, Diabetes and Clinical
*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.
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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.
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3
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Introduction
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
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
and accurate predictors for blood culture positivity in patients with CAP.
clinical and laboratory parameters in a large and well defined derivation and
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trial and evaluated data from 925 patients confirmed with radiological CAP who were
Switzerland, between 12/06 and 03/08. A detailed description of the ProHOSP study
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
therapy. The primary endpoint was the combined medical failure rate of patients. A
for X-ray confirmation of CAP and for sampling two sets of pre-treatment blood
Full ethical approval for this trial has been obtained from all local ethical committees
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
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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-
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
samples were gram stained and subcultured. The correct identification of the
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
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.
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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
amplified cryptate emission (TRACE) technology assay (Kryptor® PCT, Brahms AG,
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
Statistical Analysis
This report adheres to the STROBE guidelines for reporting observational studies 32.
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
univariate and multivariate regression analysis adjusted for all significant parameters
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distribution for skewed variables (i.e. PCT concentrations) and outcomes were either
(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.
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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%
n=59, Escherichia coli n=3, Haemophilus influenzae n=2, Enterobacter cloacae n=2,
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
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
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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
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
analysis using all significant parameters from univariate analysis showed that only
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
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,
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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
Financial implications
assumed costs of 145 US Dollars (USD) for two sets of blood culture per patient
total costs for the whole CAP study cohort (925 patients times 145 USD) were
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
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Discussion
In this large prospective multicenter study including CAP patients from the
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
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
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
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.
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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
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
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.
CAP patients who received antibiotic treatment within 4-8 hours, the time to first
perspective 24. Within the ProHOSP trial, PCT was measured using a rapid sensitive
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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
PCT can be used for the evaluation of the patients without putting him at risk
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
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
single cut-off of any surrogate marker. Different microbes might induce distinct
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
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blood culture positivity. Thus, used in the proper context of CAP it may result in a
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Competing Interest
No commercial sponsor had any involvement in design and conduct of this study,
PS, MCC and BM received support from BRAHMS to attend meetings and fulfilled
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
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
“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
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Schoenenberger, MD, Christoph Henzen, MD, Claus Hoess, MD, Heiner C. Bucher,
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,
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References
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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;
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Table 2 Predictors for positive blood cultures (n=73) in univariate logistic regression
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Table 3
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No PCT measurement, PCT cut off PCT cut off PCT cut off PCT cut off PCT cut off
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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%
Copyright © 2010 American College of Chest Physicians
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
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
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Appendix I Area under the curve (AUC) of receiver operating curve (ROC) characteristic plot analysis and Diagnostic Accuracy.
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Figure Legends:
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)
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Figure 3. All CAP patients (n=925) with positive (dark grey) and negative (light grey)
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Flow chart
ROC curves
Figure 3. All CAP patients (n=925) with positive (dark grey) and negative (light grey) blood cultures
within different risk categories.
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