Intensive Care Med (2006) 32:1577–1583

DOI 10.1007/s00134-006-0306-3 ORIGINAL

Pierre Emmanuel Charles

Frédéric Dalle
Serum procalcitonin measurement
Serge Aho contribution to the early diagnosis
Jean-Pierre Quenot
Jean-Marc Doise of candidemia in critically ill patients
Hervé Aube
Nils-Olivier Olsson
Bernard Blettery

Received: 6 January 2006
Accepted: 30 June 2006
Published online: 8 August 2006
© Springer-Verlag 2006
P. E. Charles (u) · J.-P. Quenot ·
J.-M. Doise · H. Aube · B. Blettery
Hôpital Le Bocage, Service de Réanimation
Médicale,
C.H.U. de Dijon, France
e-mail:
pierre-emmanuel.charles@chu-dijon.fr
Tel.: +33-3-80293751
Fax: +33-3-80293807
F. Dalle
Hôpital Le Bocage, Laboratoire de
Parasitologie-Mycologie,
C.H.U. de Dijon, France
S. Aho
Hôpital Le Bocage, Service
d’Epidémiologie et d’Hygiène Hospitalière,
C.H.U. de Dijon, France
N.-O. Olsson
Hôpital Le Bocage, Laboratoire
d’Immunologie,
C.H.U. de Dijon, France
Abstract Background: Candidemia
is a life-threatening infection in
the ICU whose prognosis is highly
dependent on the stage at which it
is recognized. Procalcitonin (PCT)
levels have been shown to accurately
distinguish between bacteremia and
noninfectious inflammatory states
in critically ill patients with clinical
signs of sepsis. Little is known about
the accuracy of PCT for the diag-
nosis of candidemia in this setting.
Setting: A medical intensive care
unit in a teaching hospital. Patients
and methods: Review of the medical
records of every non-neutropenic
patient with either bacteremia or
candidemia and clinical sepsis in
whom PCT dosage at the onset of
infection was available between
May 2004 and December 2005.
Results: Fifty episodes of either
bacteremia (n = 35) or candidemia
(n = 15) were included. PCT levels
were found to be markedly higher
in patients with bacteremia than in
those with candidemia. Moreover,
a low PCT value was found to be an
independent predictor of candidemia
in the study population. According
to the calculation of the area under
the receiver operating characteristic
curve, PCT was found to be accurate
in distinguishing between candidemia
and bacteremia (0.96 [0.03]). A PCT
level of higher than 5.5 ng/ml yields
a 100% negative predictive value
and a 65.2% positive predictive
value for candidemia-related sepsis.
Conclusion: A high PCT value in
a critically ill non-neutropenic patient
with clinical sepsis is unlikely in the
setting of candidemia.

Introduction
The incidence of candidemia in critically ill patients has
constantly increased over the past two decades [1]. The
development of new efficient and well-tolerated antifungal
drugs has led to significant advances in the management of
these life-threatening infections. However, high mortality
rates are invariably reported, especially in the critically
ill medical patients [2]. Early recognition of candidemia
could improve the outcome, but diagnosis is still challeng-
ing given the lack of reliability of the available diagnostic
tools [3, 4, 5]. It is especially worth noting that fungal
blood cultures take a long time to grow and suffer from
low sensitivity. Polymerase chain reaction is a promising
but not yet routinely available tool [6]. It is therefore
difficult to achieve a reliable and prompt diagnosis of
candidemia. Serum procalcitonin (PCT) is a quickly
done and routinely available laboratory test that has been
reported to differentiate accurately between systemic
bacterial infection and non-infectious acute inflammatory
states in the ICU setting, whereas white blood cell count
(WBC) and serum C-reactive protein (CRP) failed to do
so [7, 8]. Only sparse and conflicting results regarding
the value of PCT in systemic fungal infections have been
1578

provided up to now [9, 10, 11]. Moreover, these studies had presented two distinct BSI episodes, he was included
included large proportions of patients with hematological twice in the same group or once in each group, according
malignancies and leukopenia, which might have led to to the species isolated (i.e., Candida spp. or bacteria).
PCT level underestimation [12]. We address therefore the The following information was extracted from the
question of the PCT value in non-neutropenic critically ill medical file of each patient: (1) main clinical and epi-
patients with sepsis related to Candida spp. bloodstream demiological data at ICU admission, such as age, gender,
infections (BSIs). type of admission (admission was considered as surgical
in the patients who had undergone surgery within the
30 days preceding the onset of BSI, and medical other-
Patients and methods wise), and severity of illness on admission, expressed
by the Simplified Acute Physiology Score II (SAPS II);
Definitions (2) patient characteristics at the onset of BSI, including
WBC (cells/mm3 ), CRP value (mg/l), the septic condition
One episode of candidemia was defined as the recovery of (i.e., sepsis, severe sepsis or septic shock), and the organ
Candida sp. in one or more blood cultures. One episode dysfunction expressed by the Sepsis-related Organ Failure
of bacteremia was defined as the recovery of any bacterial Assessment (SOFA) score; (3) infection source if known.
species in one or more blood cultures. Blood samples
were obtained by blood punctures before being processed
using the BACTEC system based both on mycosis and
standard aerobic and anaerobic media coupled with the Measurements of PCT level
9240 automate (Becton Dickinson Diagnostic Instrument
System, Paramus, NJ, USA). Yeast identification was Plasma PCT assessment is usually performed in our
based on a combination of microscopic examination and ICU in ®patients with clinically suspected sepsis. The
biochemical pattern study using the API 32C System Kryptor immunoassay is used according to the manu-
(Biomérieux, Lyon, France), while bacteria identification facturer instructions (Brahms, Hennigsdorf, Germany).
was based on standard methods. The onset of either The sensitivity of the assay is 0.06 ng/ml. The patients in
candidemia or bacteremia was defined as the day when whom the PCT measurement was either unavailable or not
the first positive blood culture was obtained. Two distinct performed within the 12 h following the blood sampling
episodes of BSI were considered to have occurred in one were excluded from further analysis because of the risk of
patient if at least 6 days had elapsed between the two sets false-negative result.
of positive blood cultures, provided appropriate therapy
was implemented and significant clinical improvement
was obtained between the two episodes. This time-interval Statistical analysis
was chosen since previously published data indicate that
blood culture negativity is obtained in a median time near Values are expressed as mean ± SD unless otherwise
to 2 days in patients with either bacteremia or candidemia stated. Continuous variables were compared using the
receiving appropriate antimicrobial treatment. Mann – Whitney U-test. Categorical variables were com-
pared using the chi-square test. We then examined the
independent contribution of factors that had been pre-
Study population dictive of candidemia in the univariate analysis. Because
of the small size of our sample and the non-parametric
We reviewed the medical files of all consecutive non- distribution of the variables of interest, a robust variance
neutropenic (defined as WBC > 1500/mm3) patients estimation was performed prior to logistical regres-
admitted to our 11-bed medical ICU with subsequent BSI sion [13]. Candidate variables were manually entered into
between 1 May 2004, and 31 December 2005. Only those a logistical regression model if the associated regression
with clinical sepsis (as defined by the American College coefficient had a p value less than 0.05. In addition,
of Chest Physicians/Society of Critical Care Medicine the diagnosis accuracy of serum PCT measurement at
Consensus Conference) at the onset of BSI were kept the onset of BSI was expressed as the area under the
for further analysis provided at least one PCT dosage corresponding receiver operating characteristic curve
obtained within a 24-h window surrounding the time (AUROCC). A p value < 0.05 was considered as statisti-
when the first positive blood culture was drawn. The BSI cally significance for all analyses. The Statview software
episodes were then divided into two groups according to was used (SAS Institute, Cary, NC, USA) except for the
the isolated pathogen, that is yeast (candidemia group) ROC curve plotting (Stata Statistical Package, College
or bacteria (bacteremia group). As a result, if one patient Station, TX, USA).
 1579

Results the first BSI episode has resolved when the second
occurred in all cases. The most frequently encountered
Study population characteristics bacterial species were Escherichia coli (n = 11), Staphy-
lococcus aureus (n = 9), Enterococcus species (n = 8) and
Over the 20-month study period, 77 BSI episodes in 70 pa- Pseudomonas aeruginosa (n = 4). Candida albicans was
tients admitted to our ICU were recorded. Seventy-eight responsible for 13 out of the 15 episodes of candidemia.
patients presented with septic shock without positive blood The median time elapsed between the onset of clinical
cultures during the same period. Among these episodes, sepsis was 1.5 days (range 0–12). The aforementioned
1 was excluded because of the absence of clinical sepsis,
6 because of concurrent neutropenia, 20 because of the
lack of available PCT measurement at the onset of BSI
(not done in time, n = 18; done in time but delayed anal-
ysis of the sample, n = 2). As a result, 50 BSI episodes in
44 patients were retained for final analysis.
The study population comprised 27 males (54.0%) and
23 females (46.0 %) (Table 1). The mean age was 64.8
(14.8) years. The mean SAPS II value at admission was
49.7 (18.4) points. The admission diagnosis was medical
in 35 patients (70.8%) and surgical in the remaining 15
(29.2%). At the onset of BSI, 27 patients (54.2%) pre-
sented with septic shock.
The excluded patients were not statistically different
from the others regarding gender, age, length of stay and
mortality rate (data not shown). However, the SAPS II
score was significantly higher in the excluded patients
than in the study population (63.2 [23.7] and 49.7 [18.7],
respectively; p = 0.012).

BSI episodes description

Among the 50 BSI episodes, 15 in 11 patients were caused

by Candida spp. (candidemia group) and 35 in 33 patients
by bacteria species (bacteremia group). Three patients
presented one episodes of bacteremia and one episode of
candidemia, successively. Three other patients presented
2 distinct episodes of candidemia. As defined previously,

Table 1 Description of the BSI episodes

Bacteremia group Candidemia group

n = 35 n = 15
Time elapsed between 6.1 (13.0) 12.8 (7.3)*
ICU admission and first
positive blood culture
(no. of days)
SOFA score 6.1 (3.9) 7.0 (4.3)
Septic shock at time 19 (54.3) 8 (53.3)
of first positive
blood culture (%)
Severe sepsis shock at 12 (34.3) 7 (46.7) Fig. 1 a Serum PCT level, b CRP level, and c WBC count at the on-
time of first positive set of either bacteremia (n = 35) or candidemia (n = 15) in critically
blood culture (%) ill patients and clinical sepsis. Data are presented as box plots with
Secondary sepsis (%) 6 (17.6) 13 (93.3)* median lines, 25th and 75th percentile boxes, and 10th and 90th-
Second BSI episode (%) 1 (2.9%) 7 (46.7%)* percentile error bars. The circles represent the outliers. A log scale
is used for the y-axis in a. *p < 0.05 between bacteremia and can-
*p < 0.05 didemia
1580

excluded BSI episodes included 27 bacteremia but no
candidemia. The excluded bacteremia episodes were not
different from the analyzed ones regarding distribution
of gram-negative and gram-positive bacteria (data not
shown).
Candidemia was more likely to be a 2nd BSI episode
than bacteremia (46.7% vs 2.9%; p < 0.001), and occurred
significantly later during the ICU stay (12.8 [7.3] days
vs 6.1 [13.0] days; p < 0.001). Similarly, candidemia
was more frequently a secondary sepsis than bacteremia
(93.3% vs 17.6%; p < 0.001). However, there was no
difference between candidemia and bacteremia in terms
of severe sepsis or septic shock frequency at the onset of
BSI, and SOFA score values as well (Table 1). In addition,
the infection source was mainly the lung or the urinary
tract in the latter group, whereas it was more likely to be
abdominal or unknown in the patients with candidemia,
but no significant difference was found regarding this
point.
univariate analysis, the logistical regression model in-
cluded being a second BSI episode, being a secondary
sepsis, PCT values and CRP levels (Table 1). Despite
being demographic variables, sex and admission diagnosis
(medical/surgical) were also entered into the multivariate
analysis since obvious differences existed between bac-
teremia and candidemia groups regarding these points
(65.7% vs 26.7% males, respectively; 82.9% vs 40.0%
medical admissions, respectively). In addition, only 6 out
of 44 patients had repeated measures (e.g., had presented
two distinct BSI episodes).
Our model showed that the PCT value was inde-
pendently associated with the risk of candidemia (co-
eff. = 0.79, 95% confidence interval 0.30–1.27; p = 0.001)
(Table 2).

Serum PCT, CRP and WBC measurements

The PCT value at the time of the BSI was markedly

lower in the candidemia group than in the bacteremia
group (1.23 [1.52], median = 0.65 [range 0.08–5.46] and
40.18 [69.33], median = 9.75 [range 1.00–259.5] ng/ml,
respectively; p < 0.001) (Fig. 1). The CRP value was
also found to be significantly lower in the candidemia
group than in the bacteremia group (114.1 [67.9], me-
dian = 190.5 [range 21.2–440.7] and 206.0 [105.0],
median = 95.2 [range 6.7–236.9] mg/l, respectively;
p = 0.006). The WBC was higher in the bacteremia group,
but the difference did not reach significance (18,347
[14,147], median = 14,600 [range 4,000–29,100] and Fig. 2 ROCC of serum PCT for the diagnosis of candidemia in criti-
cally ill patients with clinical sepsis and positive blood cultures. Cir-
15,053 [5,355], median = 14,700 [range 8,100–29,500] cles indicate PCT values and the dashed line represents the corre-
respectively, p = 0.974). Given the results obtained by sponding ROCC assuming a normal distribution of the variable

Table 2 Multivariate analysis β coeff. Variable type 95% CI p

of the predictive factors for
candidemia in the study Sex (male) −5.03 Dichotomous −8.42 −1.63 0.004
population Admission diagnosis (medical) −4.52 Dichotomous −8.05 −1.01 0.012
Second BSI episode (yes) −1.98 Dichotomous −6.95 2.98 0.433
Secondary sepsis (yes) 3.92 Dichotomous 0.93 6.90 0.010
CRP elevation 0.03 Continuous 0.01 0.04 0.002
PCT elevation 0.79 Continuous 0.30 1.27 0.001

Table 3 Diagnostic accuracy of a low serum PCT for discrimination between candidemia and bacteremia in critically ill patients with
clinical sepsis and positive blood cultures

PCT cutoff value No. of cases of Sensitivity Specificity Positive predictive Negative predictive
(ng/ml) candidemia below (%) (%) value (%) value (%)
cutoff value
PCT < 1.0 9 60.0 100 100 85.4
PCT < 2.0 12 80.0 88.6 75.0 91.2
PCT < 5.5 15 100 77.1 65.2 100

The corresponding ROCC was constructed in order to
assess to which extent PCT could differentiate between
candidemia and bacteremia (Fig. 2). The AUROCC was
0.96 (0.03). A negative predictive value of 100% to ex-
clude candidemia in patients with clinical sepsis was ob-
tained for a PCT level of 5.5 ng/ml (Table 3).
Discussion
The main finding of this study is that serum PCT is not
necessarily markedly elevated at the onset of candidemia
in critically ill patients with clinical sepsis, whereas
high values are generally encountered in the context of
bacteremia. Moreover, this seems to occur independently
of the level of systemic inflammation as assessed through
CRP measurements, as well as of other possible confound-
ing variables such as a surgical admission diagnosis. In
addition, the AUROCC of serum PCT was 0.96 and the
5.5 ng/ml threshold differentiates between candidemia and
bacteremia with a 100% negative predictive value.
It has previously been shown that PCT can accurately
distinguish sepsis from non-infectious inflammatory
states [7, 8, 14]. Moreover, it has been shown that this is
especially true in septic patients with positive blood cul-
tures if compared to those without [15, 16]. This has been
confirmed in critically ill patients with shock, in whom
the 1.0 ng/ml cutoff value has been shown to differentiate
between septic shock and cardiogenic shock [17]. Our
findings suggest, however, that actual Candida-related
severe sepsis or septic shock do not necessarily elicit
a substantial increase in serum PCT. Accordingly, 12
out of 15 episodes of candidemia were associated with
a PCT within the “normal range” of a localized, if not
absent, infection (i.e., less than 2.0 ng/ml). Although
there is a growing body of evidence supporting the fact
that serum PCT release is quickly triggered by systemic
bacterial infections, data are sparse and conflicting when
candidemia is considered [18, 19]. Some authors have
reported that both serum PCT and CRP are lower during
fungal infections than in bacterial infections in both
hospitalized adult patients and preterm infants [20, 21].
Conversely, other authors considered PCT as a valuable
marker for the prognosis of invasive yeast infections [10].
In addition, broad ranges of PCT values (from 0.382
to 238 ng/ml) have been reported in patients with can-
didemia, which could preclude the PCT diagnostic value
in this setting [22]. In addition, conclusions of such
studies are generally based on the data obtained in patients
with either systemic candidiasis or invasive pulmonary
aspergillosis, even though it is thought that the release of
systemic inflammatory mediators is low during this latter
infection [11, 21]. Finally, the serum PCT elevation pat-
terns in patients with candidemia is difficult to extrapolate
from these studies since systemic candidiasis was not
necessarily proven.
1581
To our knowledge, there are only very few data about
the PCT value in critically ill patients with Candida spp.-
related sepsis. The largest ICU studies did not include any
patient with invasive fugal infection [7, 8, 14, 23]. Some
authors have shown that PCT elevation is comparable in
patients with septic shock whatever bacteria or yeast is iso-
lated from blood cultures, but only two patients with can-
didemia were reported [17].
Several explanations could be put forward. Endotoxin
and pro-inflammatory cytokines are associated with serum
PCT elevation [24, 25, 26]. Fungal infection may trigger
a different pattern and/or magnitude of cytokine response
from the one encountered during bacterial infections. An-
other possible explanation is an impairment of the host im-
mune response in the patients with candidemia compared
with those suffering from bacteremia. Accordingly, can-
didemia occurred significantly later during the ICU stay
than did bacteremia. Moreover, fungal infection was a sec-
ondary sepsis in most of these patients. One could, then,
consider that patients with fungal infections were more
likely to suffer from so-called immune paralysis (i.e., a de-
pressed response to pro-inflammatory stimuli because of
previous exposition to microbial products) [27]. In add-
ition, it is worth noting that a larger proportion of patients
had undergone surgery in the candidemia group than in the
bacteremia group. Some recent reports have emphasized
that serum PCT interpretation is a matter of concern in sur-
gical patients [28, 29]. Accordingly, some authors found
lower PCT values in surgical patients with overt sepsis than
in their medical counterparts. As a result, it may be sug-
gested that our findings would have been different if only
medical patients had been selected. However, it is worth
noting that PCT was below the 2.0 ng/ml threshold in all
but one of the medical patients with candidemia. In add-
ition, our statistical analysis showed that a low PCT value
was an independent predictor of candidemia.
Our study presents several limitations. First, the lack of
statistical power resulting from the small sample size may
have contributed to concealing some differences between
the two groups of patients, and potential confounding fac-
tors might have been missed. Second, some fungal infec-
tion risk factors (i.e., fungal colonization, parenteral nu-
trition, previous exposition to broad spectrum antibiotics)
were not evaluated. Although it is unlikely, one cannot ex-
clude the possibility that these factors influenced the PCT
level in the candidemia group. Third, because of the retro-
spective design of the study, several bacteremia episodes
could not be assessed in terms of PCT value. One can-
not exclude the possibility that lower values of PCT would
have been found in those patients, thereby attenuating the
difference we noted between bacteremia and candidemia.
However, the Gram coloration result was the only factor
we found to significantly influence PCT level in the bac-
teremia group. It is worth noting that there was no dif-
ference regarding this point between the excluded patients
and those we retained for final analysis.
1582
As a conclusion, our results emphasize to which extent
the serum PCT elevation is highly predictive of bacterial
infection in patients with clinical sepsis. In addition, our
findings send a word of caution to the physicians who
have to deal with critically ill patients with clinically
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