Evaluation of procalcitonin as a marker of infection in a... sample of febrile hospitalized patients

Diagnostic Microbiology and Infectious Disease
49 (2004) 237–241
www.elsevier.com/locate/diagmicrobio
Evaluation of procalcitonin as a marker of infection in a nonselected
sample of febrile hospitalized patients
Patricia Mun˜oz, Nuria Simarro, Marisa Rivera, Roberto Alonso*, Luis Alcala´, Emilio Bouza
Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario “Gregorio Maran˜o´n”, Madrid, Spain
Received 6 January 2004; accepted 5 April 2004
Abstract
The level of procalcitonin is undetectable in healthy individuals and slightly increased in viral infections and noninfectious inflammatory
responses. It has been described to be notably increased in bacterial, parasitic, or fungal infections. Procalcitonin has been reported to be
a reliable marker for severe bacterial infections, although it has mainly been studied in specific entities or in selected groups of patients.
We prospectively determined the procalcitonin level in 103 unselected febrile hospitalized patients. Most of them had a proven (39) or
probable bacterial infection (44). Procalcitonin was more frequently positive in bacteremic patients (p ⫽ 0.01), in patients with a proven
bacterial infection (p ⬍ 0.01), and in those with a high sepsis score (p ⬍ 0.005), however; when cases with proven bacterial infection were
considered as a reference, the sensitivity of the test was only 54% and the specificity 70%. Procalcitonin determination should not be
included systematically in the screening of febrile hospitalized patients. © 2004 Elsevier Inc. All rights reserved.
1. Introduction
Although fever is the most frequent sign of infection,
microbiologic data are always needed for a definitive diagnosis of bacteremia. Blood culture results take at least 24 to
48 hours; therefore, a rapid laboratory test that is able to
identify severe bacterial infections would be very useful in
the initial management of febrile patients and in a more
appropriate use of antibacterial agents. Physicians often
prescribe useless antibiotics or prolong hospital stays unnecessarily rather than assume the risk of fatal consequences. This practice, although understandable, leads to an
increase in antibiotic usage, bacterial resistance, and general
costs.
Procalcitonin is a 116-amino acid peptid produced by the
thyroid gland as a precursor of the hormone calcitonin. It
has been reported to be a reliable marker for severe bacterial
infections and sepsis (Assicot et al., 1993; al-Nawas and
Shah, 1996; Gendrel and Bohuon, 2000; Whang et al.,
2000). Procalcitonin levels are undetectable in healthy individuals and slightly increased in severe viral infections
and noninfectious inflammatory responses (Karzai et al.,
1997). However, levels have been reported to be high in
* Corresponding author. ⫹34-91-586-8793; fax: ⫹34-91-504-4906;
E-mail address: ralonso.hgugm@salud.madrid.org (R. Alonso).
0732-8893/04/$ – see front matter © 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.diagmicrobio.2004.04.002
bacterial, parasitic, or fungal infections (Bernard et al.,
1998; Blijlevens et al., 2000).
Procalcitonin has been used for the differential diagnosis
of fever in several groups, including transplant recipients,
and patients with HIV, neutropenia, and burns (Gerard et
al., 1997; von Heimburg et al., 1998; Hammer et al., 1999;
Jaresova et al., 1999; Boeken et al., 2000; GiamarellosBourboulis et al., 2001).
The value of procalcitonin in the initial evaluation of a
nonselected group of patients hospitalized with fever has
only been assessed, to the best of our knowledge, in one
other recent article that identifies subjects with a high risk of
mortality (van Langevelde et al., 2000). Our objective was
to determine the usefulness of single procalcitonin measurements in the initial workup of febrile hospitalized patients.
2. Materials and methods
2.1. Collection of data
A prospective, noninterventional study was conducted in
our institution, a 1,750-bed general teaching hospital, over a
5-month period. During the study period, we identified all
hospitalized patients with fever (2 or more axillary temperatures ⬎38°C) that were admitted to our hospital. The study
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P. Mun˜ oz et al. / Diagnostic Microbiology and Infectious Disease 49 (2004) 237–241
enrolled 103 patients. Mean age was 62 years (17–92) and
the male:female ratio was 67:36. Most patients (89) were in
a medical department, and 14 were in surgical units.
Clinical data were recorded in a preestablished protocol
that included demographic data, underlying disease, sepsis
score, final diagnosis, microbiology results, and outcome.
All patients were followed until hospital discharge and
classified into 3 groups on the basis of clinical and laboratory findings: group 1, proven bacterial infection, microbiologically documented; group 2, probable bacterial infection, clinically documented but with negative or
nonobtained cultures; group 3, absence of bacterial infection or no infection with another, well-established diagnosis. All cases were discussed blind (without knowing the
procalcitonin test result) by at least 2 of the authors before
final classification.
Within 24 hours of the febrile peak, a serum-sample was
obtained by venipuncture to determine the procalcitonin
level. This was determined by immunoluminometric assay
(LUMItest PCT; Brahms-Diagnostica GmbH, Berlin, Germany). Briefly, 2 antigen-specific monoclonal antibodies
that bind procalcitonin, one of which is labeled, are used to
react with procalcitonin in the sample to form “sandwich
complexes.” The intensity of the luminescence signal is
directly proportional to the amount of procalcitonin in the
sample. By the inclusion of calibrators, the unknown procalcitonin concentration in the patient’s sample can be
quantified by comparing test values with a master curve.
Procalcitonin was considered positive if a level greater than
0.1 ng/mL was detected, as recommended by the manufacturer. All measurements were performed in duplicate.
A sepsis score was calculated for all patients as previously published (Sibbald and Vincent, 1995). The definition
of sepsis was based on the presence of 1) fever or hypothermia (temperature ⬎ 38°C or ⬍ 36°C); 2) tachycardia
(heart rate ⬎ 90 beats/min); 3) tachypnea (respiratory rate
⬎ 20 breaths/min), and 4) leukocytosis or leukopenia (leukocyte counts ⬎ 12,000 cells/L or ⬍ 4,000 cells/L) or over
10% immature forms (American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee, 1992). The score ranged from 1 (only one
of the described signs, lowest probability of sepsis) to 4 (all
4 signs, highest probability of sepsis). McCabe and Charlson scores were also considered in order to establish the
severity of underlying diseases (Charlson et al., 1987;
Valle´ s et al., 1997; Fauci et al., 1998).
2.2. Statistical analysis
Data were entered and categorized using Access (Microsoft, Redmond, WA). Measures of significance were
assessed by univariate and stratified analysis. Continuous
variables were analyzed using the Mann-Whitney U test,
and discontinuous variables were measured with the Fisher
exact test or the 2% test. All statistical tests were two-tailed.
The independent values of predictor variables and adjusted
Fig. 1. Distribution of patients according to their infection status. Group 1:
proven bacterial infections. Group 2: probable bacterial infections. Group
3: nonbacterial infections.
risk ratios with 95% confidence intervals were assessed by
stepwise logistic-regression analysis using SPSS software
(SPSS Inc., Chicago, IL). A p value of ⬍ 0.05 was established as the level of significance for all tests. Sensitivity,
specificity, and predictive values were determined for procalcitonin as an infection marker, taking both the presence
of bacteremia or proven bacterial infections as a reference.
3. Results
The distribution of the patients according to final diagnosis is shown in Figure 1. Most patients had a proven
bacterial infection (39 patients, group 1) or a probable
bacterial infection (44 patients, group 2). In 20 patients, the
cause of the fever was diagnosed as noninfectious (group 3).
The main epidemiologic and clinical characteristics of
these patients are shown in Table 1. The most common
infection sites were lower respiratory tract (31), urinary tract
(23), and intraabdominal infection (14). Microbiologically
documented infections corresponded to Gram-positive bacteria (17), Gram-negative bacteria (12), mixed bacterial
infections (6), fungi (4), mycobacteria (4), and virus (2).
Procalcitonin was positive in 40 of the 103 study patients
(38.8%), of whom 21 (53.8%) belonged to group 1, 13
(29,5%) to group 2, and 6 (30%) to group 3 (Table 1).
Procalcitonin was more frequently positive in patients with
a high sepsis score (Table 2) (83% vs 16%; p ⫽ 0.003) or
with bacteremia (Table 3) (65% vs 31%; p ⫽ 0.01), and
levels were not related to the site of infection, to the type of
microorganism isolated, or to the evolution of the patient.
When the presence of microbiologically proven bacteremia was used as the standard for comparison, procalcitonin
determination yielded the following values: sensitivity,
65%; specificity, 69%; positive predictive value, 38%; and
negative predictive value, 87%. If proven bacterial infection
was used as the standard for comparison, the corresponding
values were: sensitivity, 54%; specificity, 70%; positive
predictive value, 52%; and negative predictive value, 69%.
P. Mun˜ oz et al. / Diagnostic Microbiology and Infectious Disease 49 (2004) 237–241
239
Table 1
Clinical characteristics of 103 unselected patients who were admitted to the hospital because of fever
Group
Group 1 (n ⫽ 39)
Group 2 (n ⫽ 44)
Group 3 (n ⫽ 20)
Age
Male
Underlying disease
Organic
HIV infection
Neoplasia
None
McCabe
II
III
Charlson score (Mean)
0
1
2–4
ⱖ5
Sepsis score
1
2
3
4
Bacteremia
Antimicrobial therapy
Positive Procalcitonin (%)*
Deaths
59 ⫾ 20
12 (30.7%)
57 ⫾ 20
14 (31.8%)
58 ⫾ 20
10 (50%)
24 (61.5%)
2 (5%)
7 (18%)
6 (15%)
28 (63.5%)
0
10 (22.7%)
6 (13.6%)
9 (45%)
2 (10%)
6 (30%)
3 (15%)
13 (33.3%)
26 (66.6%)
2.2
6 (15.4%)
10 (25.6%)
19 (48.7%)
4 (10.2%)
12 (27.2%)
32 (72.7%)
2.3
9 (20.4%)
9 (20.4%)
18 (40.9%)
8 (18.2%)
8 (40%)
12 (60%)
2.5
3 (15%)
4 (20%)
9 (45%)
4 (20%)
1 (2.5%)
16 (41%)
18 (46.1%)
4 (10.2%)
23 (59%)
38 (97.4%)
21 (53.8%)
3 (7.6%)
1 (2.2%)
27 (61.3%)
14 (31.8%)
2 (4.5%)
0
42 (95.4%)
13 (29.5%)
1 (2.2%)
0
12 (60%)
8 (40%)
0
0
17 (85%)
6 (30%)
0
* p ⫽ 0.05; Group 1: proven bacterial infections; Group 2: probable bacterial infections; Group 3: non-bacterial infections.
4. Discussion
Procalcitonin serum level is claimed to be a diagnostic
and prognostic marker of bacterial sepsis, but most studies
deal with specific entities (e.g., bacteremia, rejection, and
pneumonia) or specific groups of patients (e.g., transplant
recipients, and burn, hematologic, and HIV-positive patients).
Our experience in the determination of the procalcitonin
levels in the initial workup of all patients admitted to the
hospital with fever shows that this analytical parameter is
high, especially in patients with a high sepsis score and in
those with positive blood cultures. Nevertheless, its low
sensitivity and specificity (it was negative in 16.6% of
patients with a sepsis score of 4 and in 34.7% of patients
with bacteremia, and positive in 30% of patients with a
noninfectious cause of fever) do not place it before clinical
judgment for the correct discrimination of patients with
sepsis. Therefore, its use in this case is not justified.
Table 2
Distribution of patients (N ⫽ 109) according to sepsis score
Sepsis score
1
2
3
4
(N
(N
(N
(N
⫽
⫽
⫽
⫽
2)
55)
40)
6)
p ⫽ 0.003.
Procalcitonin (⫹)
Procalcitonin (⫺)
0 (0%)
14 (25.4%)
21 (52.5%)
5 (83.3%)
2 (100%)
41 (74.6%)
19 (47.5%)
1 (16.6%)
We are aware that both sexes were not equally represented, two thirds of the patients enrolled in the study were
men. Nevertheless, we could not find any evidence to suggest that using procalcitonin as a marker of infection differed between a male or female population.
Many published reports have described the usefulness of
procalcitonin measurements as a marker of bacteremia or
sepsis (Liaudat et al., 2001; Carrol et al., 2002; GiamarellosBourboulis et al., 2002; Luzzani et al., 2003). Recently
Chirouze et al. (2002) defended a good correlation between
procalcitonin serum levels and bacteremia, although a positive predictive value of only 25% was reported for the
analytical parameter and a wide range of procalcitonin levels (0.05 to 87 ng/mL with a cutoff of 4 ng/mL) was
reported for the nonbacteremic subjects.
Table 3
Distribution of patients according to procalcitonin result and presence of
bacteremia or presence of proven bacterial infection
Bacteremia*
Yes (N ⫽ 23)
No (N ⫽ 2380)
Proven bacterial infection
Yes (N ⫽ 39)
No† (N ⫽ 64)
Procalcitonin (⫹)
Procalcitonin (⫺)
15 (65.2%)
25 (31.2%)
8 (34.7%)
55 (68.7%)
21 (53.8%)
19 (29.6%)
18 (46%)
45 (70.3%)
* p ⫽ 0.01.
a
Including probable bacterial infection, nonbacterial infection and noninfectious causes of fever.
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Other authors have described findings similar to ours. In
2000, van Langevelde et al. reported a negative procalcitonin value in 18% of patients with bacteremia (van Langevelde et al., 2000). High procalcitonin levels in the serum of
patients without bacterial or fungal infections have also
been reported (lack of specificity), (Hensel et al., 1998;
Monneret et al., 1998; Kettelhack et al., 2000; Sabat et al.,
2001; van Dissel, 2003). An illustrative example is a recent
description of increased procalcitonin levels during an attack of acute gouty arthritis. This increase was not due to the
presence of any microbiologically proven bacteremic infection, but to the inflammatory process caused by the interaction of urate crystals with polymorphonuclear leucocytes
in the synovial fluid (Debard et al., 2003).
We did not have any evidence that the use of procalcitonin as a marker was better or worse depending on the
infection site (e.g., lower respiratory tract, urinary tract, or
intraabdominal infection), although the number or cases
may be too small for this kind of analysis.
In our study, a positive procalcitonin result was not
associated with a higher risk of death either, although that
may be because our overall mortality was low (3.8%). In
other studies, procalcitonin was not a predictor of death in
patients with or without shock on admission (van Langevelde et al., 2000).
Of interest is that we selected a lower positive cut-off
than other authors (0.1 ng/mL instead of 0.5 ng/mL). This
cut-off was recommended by the manufacturer of the assay
we used. In our series, 50% of the positive procalcitonin
determinations had levels equal to or higher than 0.5 ng/mL,
although the separate analysis of these patients showed
similar results to the overall population (data not shown).
Some other authors have also decided to lower their positive
cut-off in order to increase the negative predictive value
(Chirouze et al., 2002).
In summary, procalcitonin testing could not identify all
patients with proven bacterial infection, even when a low
cut-off was used. In our opinion, procalcitonin determination should not be included in the systematic workup of
febrile patients admitted to the hospital.
Acknowledgment
We thank Thomas O’Boyle for help with the correction
of the English version of the manuscript.
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