Diagnostic Value of Procalcitonin, Interleukin-6,
and Interleukin-8 in Critically Ill Patients Admitted
with Suspected Sepsis
STEPHAN HARBARTH, KATARINA HOLECKOVA, CÉLINE FROIDEVAUX, DIDIER PITTET, BARA RICOU,
GEORGES E. GRAU, LASZLO VADAS, JÉRÔME PUGIN, and the Geneva Sepsis Network
Infection Control Program, Division of Infectious Diseases, Division of Medical Intensive Care, Division of Surgical Intensive Care, Department of
Pathology, and Laboratoire Central de Chimie Clinique, The University of Geneva Hospitals, Geneva, Switzerland
To assess the diagnostic value of procalcitonin (PCT), interleukin
(IL)-6, IL-8, and standard measurements in identifying critically ill
patients with sepsis, we performed prospective measurements in
78 consecutive patients admitted with acute systemic inflamma-
tory response syndrome (SIRS) and suspected infection. We esti-
mated the relevance of the different parameters by using multi-
variable regression modeling, likelihood-ratio tests, and area under
the receiver operating characteristic curves (AUC). The final diag-
nosis was SIRS in 18 patients, sepsis in 14, severe sepsis in 21, and
septic shock in 25. PCT yielded the highest discriminative value,
with an AUC of 0.92 (CI, 0.85 to 1.0), followed by IL-6 (0.75; CI,
0.63 to 0.87), and IL-8 (0.71; CI, 0.59 to 0.83; p  0.001). At a cut-
off of 1.1 ngml, PCT yielded a sensitivity of 97% and a specificity
of 78% to differentiate patients with SIRS from those with sepsis-
related conditions. Median PCT concentrations on admission (ng
ml, range) were 0.6 (0 to 5.3) for SIRS; 3.5 (0.4 to 6.7) for sepsis;
6.2 (2.2 to 85) for severe sepsis; and 21.3 (1.2 to 654) for septic
shock (p  0.001). The addition of PCT to a model based solely on
standard indicators improved the predictive power of detecting
sepsis (likelihood ratio test; p  0.001) and increased the AUC
value for the routine value-based model from 0.77 (CI, 0.64 to
0.89) to 0.94 (CI, 0.89 to 0.99; p  0.002). In contrast, no additive
effect was seen for IL-6 (p  0.56) or IL-8 (p  0.14). Elevated PCT
concentrations appear to be a promising indicator of sepsis in
newly admitted, critically ill patients capable of complementing
clinical signs and routine laboratory parameters suggestive of se-
vere infection.
Keywords: Critical care; biological markers, blood; calcitonin, blood;
protein precursors, blood; interleukin-6, blood; interleukin-8, blood;
sepsis, blood, diagnosis; sepsis syndrome, blood, diagnosis
Sepsis can be difficult to distinguish from other noninfectious
conditions in critically ill patients admitted with clinical signs
of acute inflammation (1, 2). This issue is of paramount impor-
tance given that therapies and outcomes greatly differ between
(Received in original form September 19, 2000 and in revised form March 30, 2001 )
Supported by grants from the Swiss National Foundation for Scientific Research
(Cooperation in Science and Research with CEECNIS, and Grant No1 32-50764
to J.P.)
Dr. Pugin is the recipient of a fellowship from the Prof. Dr. Max Cloetta Foundation.
Dr. Harbarth is the recipient of a Max Kade Fellowship Award.
Dr. Holeckova is the recipient of a grant from the University of Geneva.
Presented in part at the 38th Interscience Conference on Antimicrobial Agents
and Chemotherapy, San Diego, California, September 1998.
The hospital ethics committee approved the study protocol.
Correspondence and requests for reprints should be addressed to Jérôme Pugin,
M.D., Division of Medical Intensive Care, The University of Geneva Hospitals,
1211 Geneva 14, Switzerland. E-mail: jerome.pugin@medecine.unige.ch
This article has an online data supplement, which is accessible from this issue’s
table of contents online at www.atsjournals.org
Am J Respir Crit Care Med Vol 164. pp 396–402, 2001
Internet address: www.atsjournals.org
patients with and those without sepsis. Thus, there is an unmet
need for clinical or laboratory tools distinguishing between
the systemic inflammatory response syndrome (SIRS) and the
various forms of sepsis. To date, no single clinical or biological
indicator of sepsis has gained unanimous acceptance (3), al-
though several attempts have been made to correlate cytokine
levels with sepsis and patient prognosis (1, 4). Among the po-
tentially useful sepsis markers, interleukin (IL)-6, IL-8, and
procalcitonin (PCT) have been proposed to be the most prom-
ising candidates (1). The latter in particular has been postu-
lated to be superior to clinical variables or commonly used
laboratory tests, such as C-reactive protein or leukocyte count,
and to even correlate with the severity of microbial invasion
(5–9). However, several investigators have questioned the di-
agnostic and prognostic accuracy of routine PCT measure-
ments, retrieving inconsistent and variable results depending
on the severity of illness and infection in the studied patient
population (10–14).
In view of these conflicting findings and the paramount im-
portance of the timely diagnosis of sepsis at time of admission
to the intensive care unit (ICU), the present cohort study pro-
spectively investigated the diagnostic value of PCT, IL-6, and
IL-8 in a group of severely ill patients admitted with signs of
acute, severe inflammation. Specifically, we assessed whether
PCT, IL-6, IL-8, or standard parameters at time of admission
are helpful in distinguishing sepsis from severe systemic non-
infectious inflammation in newly admitted, critically ill pa-
tients with suspected infection.
METHODS
Study Setting and Population
Over a 7-mo period, all consecutive patients admitted with a sus-
pected diagnosis of infection and hospitalized in the medical and sur-
gical ICUs of the University of Geneva Hospitals were eligible, in-
cluding neutropenic and immunosuppressed patients. On average,
1,700 adult patients are admitted each year to the 18-bed medical ICU
for a mean length of stay of 4 d. The surgical ICU is a 20-bed unit with
1,600 admissions and a mean length of stay of 4 d.
At time of enrollment, all included patients had to be newly admit-
ted to one of the ICUs, had to have a clinically suspected infection,
and had to fulfill at least two criteria of SIRS (15). Clinically sus-
pected infection was defined as an explicit statement by the attending
physician indicating the suspicion of an ongoing infection, combined
with the initiation of a diagnostic work-up to rule out infection and
the prescription of antimicrobial therapy (16). Patients were not en-
rolled in case of early discharge or death, withholding of life-support,
or complete absence of antimicrobial treatment.
Every effort was made to identify patients with suspected sepsis as
early as possible after ICU admission. This was accomplished by dedi-
cated research fellows, who visited the ICUs twice daily, and by the
cooperation of the attending physicians, who indicated to the research
team each patient admitted with suspected sepsis. Patients originated
either from the emergency room, the general wards, or from the oper-
ating room.
Harbarth, Holeckova, Froidevaux, et al.: Procalcitonin, IL-6, and IL-8 for Sepsis Diagnosis 397

Data Collection
Variables recorded at baseline and several times daily during follow-
up included patient demographics, principal diagnosis, vital signs, res-
piratory parameters, routine blood tests and microbiologic culture re-
sults. Survival or death in the ICU was assessed during a follow-up of
as long as 28 d. Death was defined as sepsis-related or sepsis-unre-
lated (e.g., cerebral death or cardiogenic shock). The severity of the
patients’ condition was measured according to the simplified acute
physiology scoring (SAPS) II system (17). Microbiologic tests and an-
timicrobial therapy were prescribed by physicians on service accord-
ing to the usual practice in the participating ICUs, without interfer-
ence by the research team. The hospital ethics committee on human
research approved the study protocol.
Included patients were classified as having SIRS, sepsis, severe
sepsis, or septic shock at the time of admission, according to estab-
lished consensus definitions (15, 16). Importantly, this case ascertain-
ment was done retrospectively by two independent investigators with-
out the knowledge of plasma PCT, IL-6, and IL-8 values, on the basis
of the review of the complete patient charts, results of microbiologic
cultures, chest radiographs, and, when available, postmortem exami-
nation reports. Concordance among the two independent investiga-
tors was excellent and the interrater reliability was high (  0.9). Dis-
agreement was settled by consensus involving a third party.
nary outcome events, case subjects classified as confirmed sepsis, se-
vere sepsis, or septic shock ( sepsis syndrome) were compared with
control patients with SIRS and initial suspicion of infection.
We analyzed associations between different levels of each individ-
ual clinical and biological parameter and the risk of sepsis syndrome
at admission, after dividing the values for each marker into quartiles.
This was done because few continuous variables satisfied the linearity
assumption. To estimate the potential clinical relevance of the cyto-
kine measurements, we used likelihood-ratio tests to determine
whether logistic regression models that included measurements of cy-
tokines and routine clinical and laboratory variables provided a signif-
icantly better fit than did logistic regression models limited to stan-
dard laboratory and clinical measurements alone (20). In order to
determine the prognostic power of the candidate parameters regard-
ing patients’ survival, we used time-dependent Cox proportional haz-
ards modeling (21).
Statistical software programs (STATA, version 6.0, Stata Inc.;
Statview, version 4.1, Abacus Concepts, Berkeley, CA) were used for
data processing and analyses. All p values were two-sided, and statisti-
cal significance was set at an -value of 0.05.

Measurements of Procalcitonin, IL-6, and IL-8 Plasma Levels

Within 12 h after admission and study entry, whole heparinized blood
was drawn via an arterial line for cytokine measurements and daily
thereafter at 6:00 A.M. during the entire ICU stay until ICU discharge
or death. Blood was put on ice and plasma was collected by centrifu-
gation at 4 C, aliquoted, and stored at 70 C until the day of assay.
PCT, IL-6, and IL-8 plasma levels were determined batchwise using
commercial assays. Plasma PCT concentrations were measured in du-
plicates using an immunoassay with a sandwich technique and a
chemiluminescent detection system, according to the manufacturer’s
protocol (LumiTest; Brahms Diagnostica, Berlin, Germany). As re-
cently pointed out by Müller and colleagues (9), the LumiTest does
not measure exclusively the procalcitonin molecule, but also several
other calcitonin precursors that are “captured” by the sandwich ELISA.
The term “procalcitonin” as used here may therefore lack scientific
precision, but it was favored over “calcitonin precursors” because it is
widely used by critical care physicians and investigators.
PCT levels were found to be  0.2 ngml in plasma from 15 healthy
donors. The coefficient of variation (CV) of the test was 9% at a PCT
plasma concentration of 1.2 ngml, and 4.4% at 56 ngml.
IL-6 and IL-8 were measured using semiautomated, chemilumi-
nescent immunoassays (ImmuliteOne; DPC-Biermann, Bad Nauheim,
Germany). The median value (range) of plasma IL-6 and IL-8 levels
in 15 healthy blood donors was 2.6 ( 1 to 11.3) pgml and 5 (4 to 27)
pgml, respectively. The CVs were 4.3 and 8.8%, respectively. PCT,
IL-6, and IL-8 plasma measurements were performed by trained labo-
ratory technicians, blinded to the patients’ clinical course. In a ran-
domly selected subgroup of 35 patients, we also quantified plasma lev-
els of TNF- (Medgenix, Belgium), soluble TNF receptors (sTNFR) I
and II, IL-10, and IL-1ra, using ELISA tests (R&D Systems, Abing-
don, UK).

Statistical Analysis
Values were expressed as the mean SD or as the median and inter-
quartile range in case of a skewed distribution. Comparison of group
differences for continuous variables was done by one-way ANOVA
or nonparametric Kruskal-Wallis test, when appropriate. The signifi-
cance of difference in proportions was tested with use of the
2-statis-
tic. We also used univariate-correlation analyses to establish the rela-
tion between parameters.
Sensitivity, specificity, and positive and negative predictive values
of each cytokine parameter were calculated according to standard
methods (18). The diagnostic accuracy of the cytokine plasma levels
determined at study entry was expressed as the area under the receiver Figure 1. Plasma levels of PCT, IL-6, and IL-8 in patients with SIRS (n 
operating characteristic curve (AUC), which was derived from logistic 18), sepsis (n  14), severe sepsis (n  21), and septic shock (n = 25).
regression analysis (19). These values were calculated for the cutoff Data are presented as box plots with median lines, 25- and 75-percen-
that represented the best discrimination as derived from the AUCs. tile boxes, and 10- and 90-percentile error bars, using a log scale for the
For the purpose of the logistic regression analysis, which requires bi- Y-axis. The circles represent the outliers.
398 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 164 2001

RESULTS Several of those cytokines levels were highly correlated (Ta-

ble E2. See Online Data Supplement). For example, the corre-
Characteristics of the Study Population
lation coefficient for the relation between PCT and TNF-
We prospectively enrolled 78 adult ICU patients meeting the was 0.86; between PCT and sTNFR I, 0.78; and between IL-6
criteria for SIRS (n  18), sepsis (n  14), severe sepsis (n  and TNF-, 0.92 (all p  0.001). In contrast, correlation coeffi-
21), or septic shock (n  25). The main patient characteristics cients between routinely available clinical and laboratory indi-
are shown in Table E1 (see Online Data Supplement). As ex- cators of inflammation (e.g., leukocyte count, C-reactive pro-
pected, patients admitted with septic shock were more se- tein, temperature) and the additionally measured cytokines
verely ill at baseline than were those without. The former were small; less than 40% of the variance in any of the cyto-
were more likely to have a higher SAPS II score, heart rate, kine markers was explained by any of the standard measures.
and lactate and to have a lower core temperature, mean arterial
pressure, platelet count, arterial pH, and oxygenation status. Discriminative Power of Clinical and Biological
Infections were microbiologically proven in 44 of 60 infected Sepsis Indicators
patients (73%) with 53% Gram-negative, 38% Gram-positive In an additional attempt to assess the diagnostic value of the
bacteria, and 9% mixed infections. Leading sources of infec- sepsis indicators, we stratified the continuous values for each
tion were the respiratory tract (n  38) and the intra-abdominal indicator into quartiles, and then analyzed associations be-
space (n  10). Twenty-three infected patients had a docu- tween different levels of each individual clinical and biological
mented bloodstream infection. marker and the risk of sepsis syndrome at admission (Table
E3. See Online Data Supplement). No differences in clinical
Baseline Plasma Levels of PCT, IL-6, and IL-8
variables such as temperature or heart rate were observed be-
Baseline plasma levels of the inflammation markers IL-6, IL-8, tween septic patients and noninfected patients with SIRS, ex-
and PCT were higher among case subjects with severe sepsis cept for the mean arterial pressure (p  0.03). Conversely, six
or septic shock than among control subjects with SIRS only biological parameters predicted sepsis syndrome by bivariate
(Figure 1). PCT appeared to be most helpful in differentiating analysis (Table E3). In order of significance, these were PCT,
patients with sepsis from those with SIRS. Median PCT levels IL-6, IL-8, monocyte count, arterial pH, and C-reactive pro-
on admission (ngml, range) were 0.6 (0 to 5.3) for SIRS; 3.5 tein. PCT was the most powerful predictor of sepsis syndrome
(0.4 to 6.7) for sepsis, 6.2 (2.2 to 85) for severe sepsis; and 21.3 in this bivariate analysis (p  0.001).
(1.2 to 654) for septic shock (p  0.001). The accuracy of the
candidate parameters to distinguish patients with SIRS from
those with septic conditions varied (Table 1). As shown in Fig-
ure 2 (upper panel ), PCT yielded the highest discriminative
value with an AUC of 0.92 (95% confidence interval [CI], 0.85
to 1.0) followed by IL-6 (AUC, 0.75; CI, 0.63 to 0.87) and IL-8
(AUC, 0.71; CI, 0.59 to 0.83; p  0.001). At a cutoff point set
at 1.1 ngml, PCT yielded a sensitivity of 97% and a specificity
of 78% to differentiate patients with SIRS from those with
sepsis, severe sepsis, or septic shock.
Serum C-reactive protein concentrations increased from
119 89 mgl for SIRS to 159 51 mgL for sepsis, 254 181
mgl for severe sepsis, and 228 119 mgl for septic shock
(p  0.04 in Table E1) (See Online Data Supplement). C-reac-
tive protein yielded an AUC of 0.76 (CI, 0.58 to 0.93), a value
similar to IL-6. At a cutoff value of 150 mgl, the sensitivity
and specificity were 68 and 73%, respectively.
Correlation of the Study Parameters with Other
Sepsis Mediators
In a randomly selected subgroup of 35 patients, additional
proinflammatory and antiinflammatory cytokines (TNF-,
STNFR I and II, IL-10, and IL-1ra) were determined and cor-
related with the main study parameters PCT, IL-6, and IL-8.

TABLE 1. DIAGNOSTIC PERFORMANCE OF DIFFERENT

SEPSIS INDICATORS

Procalcitonin Interleukin-6 Interleukin-8

Cutoff value, ng/ml* 1.1 200 30

Sensitivity, % 97 67 63
Specificity, % 78 72 78
Positive predictive value, % 94 89 90
Negative predictive value, % 88 39 39
Area under the receiver operating 0.92 0.75 0.71 Figure 2. Receiver operating characteristics curves (ROC) of plasma
curve (95% confidence interval) (0.85–1.0) (0.63–0.87) (0.59–0.83) parameters (PCT; IL-6; and IL-8; upper panel), and of a clinical model
* Sensitivity, specificity, and predictive values were calculated for the cutoff, which with and without PCT (lower panel). Areas under the ROC were: upper
represented the best discrimination as derived from the receiver operating characteris- panel, PCT, 0.92; IL-6, 0.75; IL-8, 0.71; and lower panel, clinical model
tic curves. with PCT, 0.94, and clinical model without PCT, 0.77.
Harbarth, Holeckova, Froidevaux, et al.: Procalcitonin, IL-6, and IL-8 for Sepsis Diagnosis
Clinical Significance of the Diagnostic Indicators
To explore the diagnostic performance of the parameters from
a clinical perspective, we evaluated the accuracy of the cyto-
kine levels and clinical indicators of inflammation as predic-
tors of sepsis in a series of analyses. First, we determined the
independent predictive value of the different clinical and bio-
logical sepsis indicators by performing multivariable logistic
regression modeling. In the global stepwise analysis including
all variables described in Table E3, only PCT (adjusted odds
ratio [AOR] per 1-point increase, 2.3; CI, 1.4 to 3.7; p  0.001)
was found to be an independent predictor of sepsis syndrome.
In a similar model that was limited to the routinely available
parameters without PCT, IL-6, and IL-8, increasing levels of
C-reactive protein (AOR, 1.01; CI, 1.0 to 1.03; p  0.023) and
an elevated proportion of leukocyte band forms (AOR, 1.06;
CI, 1.0 to 1.14; p  0.067) tended to predict sepsis syndrome.
Second, likelihood-ratio tests were used to compare the fit
of predictive models that were based on measurement of rou-
tinely available sepsis markers in combination with the study
parameters to the fit of models based only on standard indica-
tors (core temperature, heart rate, blood pressure, white blood
cell count). In these models, the addition of PCT significantly
improved the power of detecting sepsis syndrome (p  0.001).
Figure 3. Daily variations of procalcitonin (PCT) levels during ICU hos-
pitalization. (Panel A) Patients admitted with severe sepsis and septic
shock who survived. (Panel B) Patients admitted with severe sepsis and
septic shock who died. (Panel C) Control patients admitted with SIRS
and initial suspicion of infection.
399
In contrast, no additive effect was seen for IL-6 (p  0.56) or
IL-8 (p  0.14).
Third, as a measure of clinical usefulness, we evaluated the
combined role of the cytokine levels and clinical markers as
predictors of sepsis using AUC analysis. As shown in Figure 2
(lower panel ), the inclusion of PCT increased the AUC value
for the routine value-based model from 0.77 (CI, 0.64 to 0.89)
to 0.94 (CI, 0.89 to 0.99; p  0.002). Again, no such effect was
observed with IL-6 or IL-8.
Severity of Sepsis and Final Outcome
We further evaluated the time course of PCT, IL-6, and IL-8
in relation to the prognosis and severity of sepsis. The evolu-
tion of serum PCT concentrations during follow-up of patients
with severe sepsis and septic shock are shown in Figure 3. A
slow decrease or no decrease in PCT levels 48 h after admis-
sion was consistently associated with a poor outcome (Figure
3, panel B). All patients who died of sepsis or related compli-
cations never had PCT levels below 1.1 ngmL, except for one
single time point in one patient. Conversely, PCT levels de-
creased under the cutoff of 1.1 ngml within 8 d in all survivors
except for one (Figure 3, panel A). In contrast, IL-6 and IL-8
did not demonstrate this uniform pattern in septic patients
(Figure E1. See Online Data Supplement). Within the 8-d pe-
riod after onset of severe sepsis or septic shock, six survivors
still had elevated IL-6 or IL-8 levels. Interestingly, we ob-
served that in four patients with prolonged ICU stay and com-
Figure 4. PCT, IL-6, and IL-8
baseline levels in patients with
sepsis, severe sepsis, and sep-
tic shock who survived (n 
38) or who died (n  18)
of sepsis-related death. Four
patients who died from causes
unrelated to sepsis were
omitted from the analysis.
Data are presented as box
plots with median lines, 25-
and 75-percentile boxes, and
10- and 90-percentile error
bars, using a log scale for
the Y-axis. The circles rep-
resent the outliers.
400 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
plicated courses of sepsis, peaks in plasma PCT levels coin-
cided with clinical episodes of septic shock (Figure 3, panel D)
(Figure E2. See Online Data Supplement).
Values of plasma PCT, IL-6, and IL-8 in infected patients
at the time of admission relative to sepsis-related death are
shown in Figure 4. The most discriminative parameter to pre-
dict sepsis-related death in infected patients at the time of ad-
mission was an IL-6 value above 1,000 ngml.
Finally, we assessed all follow-up values of the candidate
parameters as determinants of survival in the entire cohort of
infected and noninfected patients. During 832 d at risk, the
mean plasma levels of IL-6 (mean difference, 4,689.1 ngml;
p  0.0003), IL-8 (mean difference, 1021.9 ngml; p  0.0001)
and PCT (mean difference, 25.7 ngml; p  0.004) differed be-
tween those patients who survived and those who died. We
then included each cytokine measurement in a time-dependent
Cox proportional hazards model. In this longitudinal analysis
that also included noninfected patients, only increasing levels
of IL-8 predicted death (AOR per 1,000 ng increment, 1.05; CI,
1.00 to 1.10; p  0.046), whereas IL-6 (p  0.82) and PCT (p 
0.36) did not indicate an increased risk of death.
DISCUSSION
The principal findings of this study performed in newly admitted,
critically ill patients with suspected sepsis are: (1) the confirma-
tion of the previously described good diagnostic accuracy of PCT;
(2) the modest discriminative value of IL-6, IL-8, and other indi-
cators of inflammation; (3) the additive effect of PCT to improve
the predictive power of routinely available sepsis parameters; (4)
the excellent correlation of PCT with other biologic markers of
sepsis such as TNF-; and (5) the good concordance of PCT
plasma levels with the clinical evolution of septic patients.
Critical care physicians have at their disposal a variety of
data to serve as a guide in discriminating infectious from non-
infectious conditions in newly admitted patients. In a number
of cases, the diagnosis of sepsis becomes clear after complet-
ing the medical history and physical examination of a newly
admitted patient (22). In other circumstances of non-infec-
tious insults causing SIRS (e.g., trauma, burns, hemorrhages,
hypothermia, pancreatitis, and surgery), or in comatose pa-
tients, the diagnosis of sepsis remains difficult. In these cases,
several indicators have been proposed as new diagnostic tests
to assess the competing probabilities of various candidate ill-
nesses in the differential diagnosis of sepsis (23, 24). The present
results confirm and extend earlier findings demonstrating that
PCT is among the most promising sepsis markers in critically
ill patients, capable of complementing clinical signs and rou-
tine laboratory parameters suggestive of severe infection at
time of ICU admission. Recently, Müller and colleagues (9)
investigated 101 patients admitted to a medical ICU and sug-
gested that PCT is a more reliable marker of sepsis than is
C-reactive protein, IL-6, and lactate levels. Another group
from Germany (25) recently reported average PCT concentra-
tions of 0.4 3.4 ngml for SIRS, 0.5 2.9 ngml for sepsis,
6.9 3.9 ngml for severe sepsis and 12.9 4.4 ngml for septic
shock. On the basis of their findings, the investigators con-
cluded that PCT measurement appears to be useful to discrim-
inate between sepsis and severe sepsis, in contrast to C-reac-
tive protein, blood cell counts, or body temperature. Lastly,
Viallon and colleagues (26) investigated 61 patients with cir-
rhotic ascites or spontaneous bacterial peritonitis and found
PCT values similar to those in the present study: median PCT
serum levels and interquartile ranges were 3.2 (2.3 to 10.1),
13.8 (8.7 to 18.4), and 26.5 (24.0 to 52.0) ngml in patients with
sepsis, severe sepsis, and septic shock, respectively.
VOL 164 2001
Our study has several important implications for clinicians.
First, as a putative new test to diagnose sepsis on ICU admis-
sion, PCT offers a high level of certainty than other currently
available candidates do. In the current study, a cutoff point of
1.1 ngml detected virtually all septic patients. This accuracy,
although not perfect, may guide physicians in their clinical de-
cision-making and their stepwise approach to the complex
management of critically ill patients requiring several interven-
tions in a short period of time. Second, in the recovery phase of
severe sepsis or septic shock, a greatly decreased PCT level in-
dicates a favorable clinical evolution and may prompt physi-
cians to withdraw antimicrobial treatment. Third, measure-
ment of PCT is of practical value since it increases 2 to 4 h after
bacterial or endotoxin challenge (24). The test can be per-
formed within 3 to 4 h and may give valuable information long
before blood culture results are back. Thus, in contrast to many
other cytokine markers with purely theoretical utility (27),
measuring PCT with a commercially available assay is realistic,
inexpensive and may even be cost-effective by better directing
diagnostic and therapeutic interventions in critically ill patients
with SIRS of undetermined origin. This, of course, requires
further prospective testing. Finally, PCT is not only helpful in
the diagnosis of sepsis, but also indicative of its severity. As
previously suggested (9, 28), we demonstrated that constantly
elevated PCT levels in infected patients were associated with
poor prognosis. In contrast, the rapid decrease of PCT levels
during the first week after ICU admission had a good prognos-
tic value. The relation between these findings and the patho-
physiology of sepsis remains to be elucidated. It is, however,
tempting to hypothesize that persistently elevated PCT values
during the course of sepsis may identify subgroups of patients
who have difficulties in clearing their systemic infection.
One interesting finding was that PCT levels in infected pa-
tients correlated well with circulating cytokines such as TNF-,
thus representing a suitable surrogate marker for key cytokines
during septic shock. Taking into account that poor immuno-
logic characterization was one of the main reasons for failure in
trials with immunomodulating agents, the rapid measurement
of PCT may improve the results of future intervention trials to
detect and treat patients with severe sepsis and septic shock (8,
29). Thus, bedside documentation of elevated PCT levels may
become an additional entry criterion for sepsis trials (8).
Our study has several strengths. First, our study population
was a large, diverse group of critically ill adult patients admit-
ted to both medical and surgical ICUs in different phases of
infectious and noninfectious conditions. This allowed us to
make group comparisons not previously reported by other
studies, in order to increase the generalizability of the study
findings. In contrast, most of the previous studies that at-
tempted to draw conclusions about PCT were based on small
patient samples (30) or selected patient groups such as febrile
children, postsurgical patients, or patients with specific dis-
eases only (31–34). Second, following high methodologic stan-
dards (35), we used prospective surveillance and consecutive
patient enrollment, intensive clinical and laboratory data col-
lection and follow-up, and powerful statistical methods to ac-
curately describe and analyze the diagnostic performance of
the studied parameters. Third, outcomes were determined by
blinded investigators without knowledge of the plasma cyto-
kine levels, and vice versa. Fourth, we classified patients with
SIRS and suspected infection according to predetermined,
well-established outcome categories, after incorporation of all
available clinical, laboratory, and histologic evidence. Fifth, in
contrast to other studies (9, 30, 31), we did not include clini-
cally unrealistic control patients without suspected infection,
but only patients with a high pretest probability of sepsis, cov-
Harbarth, Holeckova, Froidevaux, et al.: Procalcitonin, IL-6, and IL-8 for Sepsis Diagnosis
ering the spectrum of patients that is likely to be encountered
in the future use of the tests (35). Finally, our study was de-
signed as a real-life study, to closely resemble clinical practice.
Therefore, we evaluated the combined role of the cytokines
and clinical indicators of inflammation as predictors of sepsis
in a series of analyses, in which we explored the diagnostic ac-
curacy of these different parameters from a clinical perspec-
tive. In summary, in contrast to many previous studies, our
study fulfills all important criteria for the optimal design of
studies assessing the accuracy of diagnostic tests (35).
IL-6 and IL-8 are potent inflammatory mediators and their
plasma concentrations have been tested as prognostic factors in
several studies (27, 36, 37). The results of the present study sug-
gest that measurement of these cytokines is not optimal for dis-
criminating patients with infectious from those with noninfec-
tious conditions. In particular, we confirm the observation by
other investigators that IL-8 is not a good indicator of systemic
infection, although elevated IL-8 levels are indicative of multi-
ple organ failure and an increased likelihood of death (38). Our
findings are also consistent with the results reported by De
Werra and colleagues (39), who observed increased IL-6 con-
centrations in patients with cardiogenic shock. Thus, persis-
tently high IL-6 and IL-8 levels are very sensitive markers of in-
flammation and are likely to be of prognostic value in critically
ill patients with multiorgan failure (27, 40). However, their diag-
nostic accuracy is limited in critically ill patients by the unspe-
cific elevation caused by the accompanying inflammation inde-
pendent of the infection. In contrast to IL-6 and IL-8, PCT does
respond rather to an infection than to the inflammation.
Several limitations of this study merit consideration. Using
clinical criteria and microbiologic evidence, it may have been
difficult to ascertain the exact etiology of SIRS in all patients.
This may have introduced some misclassification bias, but
since investigators blinded to the cytokine results performed
the case ascertainment, we do not believe that this lack of a
gold standard compromised our study conclusions. Our data
are also limited because we did not include enough patients
with underlying autoimmune disease or other diseases that
may increase PCT levels without infection. Major surgery such
as kidney transplantation or cardiopulmonary bypass surgery,
in particular, may distort PCT measurement (32, 41). More-
over, antibiotic therapy may have an important impact on
PCT values. Because antimicrobial treatment was a criterion
for study inclusion, all patients in our study already received at
least one dose of an antimicrobial agent at the time of first
blood collection. Thus, similar studies should be conducted in
order to elucidate the exact relation between adequate antibi-
otic treatment and the time course of daily PCT serum levels.
Finally, our results may not apply to patients with localized or
mild infections not requiring ICU treatment. In those patients,
PCT levels may fall below the proposed cutoff and other pa-
rameters may be more useful to diagnose or exclude infection.
In conclusion, in this prospective, blinded evaluation of
three different sepsis indicators in a consecutive series of pa-
tients, PCT proved to be the best indicator of infection in newly
admitted critically ill patients. Our results indicate that clinical
variables are of moderate diagnostic value for the diagnosis of
sepsis on ICU admission. Thus, our data raise the possibility
that the addition of PCT to the standard work-up of critically ill
patients with suspected sepsis could increase diagnostic cer-
tainty and generate an improved patient management.
References
1. Carlet J. Rapid diagnostic methods in the detection of sepsis. Infect Dis
Clin North Am 1999;13:483–494.
401
2. Ueda S, Nishio K, Minamino N, Kubo A, Akai Y, Kangawa K, Matsuo
H, Fujimura Y, Yoshioka A, Masui K, et al. Increased plasma levels of
adrenomedullin in patients with systemic inflammatory response syn-
drome. Am J Respir Crit Care Med 1999; 160:132–136.
3. Boucher BA, Hanes SD. Searching for simple outcome markers in sep-
sis: an effort in futility? Crit Care Med 1999;27:1390–1391.
4. Gogos CA, Drosou E, Bassaris HP, Skoutelis A. Pro- versus anti-inflam-
matory cytokine profile in patients with severe sepsis: a marker for
prognosis and future therapeutic options. J Infect Dis 2000;181:176–180.
5. Gendrel D, Raymond J, Coste J, Moulin F, Lorrot M, Guerin S, Ravilly
S, Lefevre H, Royer C, Lacombe C, et al. Comparison of procalcitonin
with C-reactive protein, interleukin 6 and interferon-alpha for differ-
entiation of bacterial vs. viral infections. Pediatr Infect Dis J 1999;
18:875–881.
6. Hatherill M, Tibby SM, Sykes K, Turner C, Murdoch IA. Diagnostic
markers of infection: comparison of procalcitonin with C reactive pro-
tein and leucocyte count. Arch Dis Child 1999;81:417–421.
7. Bossink AW, Groeneveld AB, Thijs LG. Prediction of microbial infec-
tion and mortality in medical patients with fever: plasma procalcito-
nin, neutrophilic elastase-alpha1-antitrypsin, and lactoferrin com-
pared with clinical variables. Clin Infect Dis 1999;29:398–407.
8. Oberhoffer M, Karzai W, Meier-Hellmann A, Bogel D, Fassbinder J,
Reinhart K. Sensitivity and specificity of various markers of inflam-
mation for the prediction of tumor necrosis factor-alpha and interleu-
kin-6 in patients with sepsis. Crit Care Med 1999;27:1814–1818.
9. Müller B, Becker KL, Schachinger H, Rickenbacher PR, Huber PR,
Zimmerli W, Ritz R. Calcitonin precursors are reliable markers of
sepsis in a medical intensive care unit. Crit Care Med 2000;28:977–983.
10. Mimoz O, Benoist JF, Edouard AR, Assicot M, Bohuon C, Samii K.
Procalcitonin and C-reactive protein during the early posttraumatic
systemic inflammatory response syndrome. Intensive Care Med 1998;
24:185–188.
11. Lapillonne A, Basson E, Monneret G, Bienvenu J, Salle BL. Lack of
specificity of procalcitonin for sepsis diagnosis in premature infants.
Lancet 1998;351:1211–1212.
12. Ugarte H, Silva E, Mercan D, De Mendonca A, Vincent JL. Procalcito-
nin used as a marker of infection in the intensive care unit. Crit Care
Med 1999;27:498–504.
13. Ruokonen E, Nousiainen T, Pulkki K, Takala J. Procalcitonin concen-
trations in patients with neutropenic fever. Eur J Clin Microbiol Infect
Dis 1999;18:283–285.
14. Vincent JL. Procalcitonin: THE marker of sepsis? Crit Care Med 2000;28:
1226–1228.
15. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA,
Schein RM, Sibbald W. Definitions for sepsis and organ failure and
guidelines for the use of innovative therapies in sepsis. Chest 1992;101:
1644–1655.
16. Rangel-Frausto SM, Pittet D, Costigan M, Hwang TS, Davis CS, Wenzel
RP. The natural history of the systemic inflammatory response syn-
drome (SIRS): a prospective study. JAMA 1995;273:117–123.
17. Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiol-
ogy Score (SAPS II) based on a European-North American multi-
center study. JAMA 1993;270:2957–2963.
18. Farr BM, Shapiro DE. Diagnostic tests: distinguishing good tests from
bad and even ugly ones. Infect Control Hosp Epidemiol 2000;21:278–284.
19. Hanley JA, McNeil BJ. The meaning and use of the area under a re-
ceiver operating characteristic (ROC) curve. Radiology 1982;143:29–36.
20. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and
other markers of inflammation in the prediction of cardiovascular dis-
ease in women. N Engl J Med 2000;342:836–843.
21. Christensen E. Multivariate survival analysis using Cox’s regression
model. Hepatology 1987;7:1346–1358.
22. Bates DW, Cook EF, Goldman L, Lee TH. Predicting bacteremia in
hospitalized patients: a prospectively validated model. Ann Intern
Med 1990;113:495–500.
23. Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C.
High serum procalcitonin concentrations in patients with sepsis and
infection. Lancet 1993;341:515–518.
24. Karzai W, Oberhoffer M, Meier-Hellmann A, Reinhart K. Procalcito-
nin: a new indicator of the systemic response to severe infections. In-
fection 1997;25:329–334.
25. Brunkhorst FM, Wegschneider K, Forycki ZF, Brunkhorst R. Procalci-
tonin for early diagnosis and differentiation of SIRS, sepsis, severe
sepsis, and septic shock. Intensive Care Med 2000;26:S148–S152.
26. Viallon A, Zeni F, Pouzet V, Lambert C, Quenet S, Aubert G, Guyo-
march S, Tardy B, Bertrand JC. Serum and ascitic procalcitonin levels
in cirrhotic patients with spontaneous bacterial peritonitis: diagnostic
402 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
value and relationship to pro-inflammatory cytokines. Intensive Care
Med 2000;26:1082–1088.
27. Casey LC, Balk RA, Bone RC. Plasma cytokine and endotoxin levels
correlate with survival in patients with the sepsis syndrome. Ann In-
tern Med 1993;119:771–778.
28. Schroder J, Staubach KH, Zabel P, Stuber F, Kremer B. Procalcitonin as
a marker of severity in septic shock. Langenbecks Arch Surg 1999;384:
33–38.
29. Abraham E, Matthay MA, Dinarello CA, Vincent JL, Cohen J, Opal
SM, Glauser M, Parsons P, Fisher Jr. CJ, Repine JE. Consensus con-
ference definitions for sepsis, septic shock, acute lung injury, and
acute respiratory distress syndrome: time for a reevaluation. Crit Care
Med 2000;28:232–235.
30. Selberg O, Hecker H, Martin M, Klos A, Bautsch W, Kohl J. Discrimi-
nation of sepsis and systemic inflammatory response syndrome by de-
termination of circulating plasma concentrations of procalcitonin,
protein complement 3a, and interleukin-6. Crit Care Med 2000;28:
2793–2798.
31. Chiesa C, Panero A, Rossi N, Stegagno M, De Giusti M, Osborn JF,
Pacifico L. Reliability of procalcitonin concentrations for the diagno-
sis of sepsis in critically ill neonates. Clin Infect Dis 1998;26:664–672.
32. Meisner M, Tschaikowsky K, Hutzler A, Schick C, Schuttler J. Postoper-
ative plasma concentrations of procalcitonin after different types of
surgery. Intensive Care Med 1998;24:680–684.
33. Muller CA, Uhl W, Printzen G, Gloor B, Bischofberger H, Tcholakov
O, Buchler MW. Role of procalcitonin and granulocyte colony stimu-
lating factor in the early prediction of infected necrosis in severe acute
pancreatitis. Gut 2000;46:233–238.
34. Kettelhack C, Hohenberger P, Schulze G, Kilpert B, Schlag PM. Induc-
tion of systemic serum procalcitonin and cardiocirculatory reactions
after isolated limb perfusion with recombinant human tumor necrosis
factor-alpha and melphalan. Crit Care Med 2000;28:1040–1046.
35. Lijmer JG, Mol BW, Heisterkamp S, Bonsel GJ, Prins MH, van der
VOL 164 2001
Meulen JH, Bossuyt PM. Empirical evidence of design-related bias in
studies of diagnostic tests. JAMA 1999;282:1061–1066.
36. Patel RT, Deen KI, Youngs D, Warwick J, Keighley MR. Interleukin 6
is a prognostic indicator of outcome in severe intra-abdominal sepsis.
Br J Surg 1994;81:1306–1308.
37. Gardlund B, Sjolin J, Nilsson A, Roll M, Wickerts CJ, Wretlind B.
Plasma levels of cytokines in primary septic shock in humans: correla-
tion with disease severity. J Infect Dis 1995;172:296–301.
38. Rau B, Steinbach G, Gansauge F, Mayer JM, Grunert A, Beger HG.
The potential role of procalcitonin and interleukin 8 in the prediction
of infected necrosis in acute pancreatitis. Gut 1997;41:832–840.
39. De Werra I, Jaccard C, Corradin SB, Chiolero R, Yersin B, Gallati H,
Assicot M, Bohuon C, Baumgartner JD, Glauser MP, et al. Cytokines,
nitritenitrate, soluble tumor necrosis factor receptors, and procalcito-
nin concentrations: comparisons in patients with septic shock, cardio-
genic shock, and bacterial pneumonia. Crit Care Med 1997;25:607–
613.
40. Damas P, Ledoux D, Nys M, Vrindts Y, De Groote D, Franchimont P,
Lamy M. Cytokine serum level during severe sepsis in human IL-6 as
a marker of severity. Ann Surg 1992;215:356–362.
41. Eberhard OK, Langefeld I, Kuse ER, Brunkhorst FM, Kliem V, Schlitt
HJ, Pichlmayr R, Koch KM, Brunkhorst R. Procalcitonin in the early
phase after renal transplantation: will it add to diagnostic accuracy?
Clin Transplant 1998;12:206–211.
Appendix
Members of the Geneva Sepsis Network involved in the
present study were: D. Pittet (chair), J.-C. Chevrolet, J.-M.
Dayer, P. Eggimann, J. Garbino, G. E. Grau, S. Harbarth, D.
Hochstrasser, A. Kocher, D. Lew, C. Pastor, J. Pugin, B. Ricou,
J. A. Romand, N. Sotirov, P. M. Suter.