Diagnostic Value of Procalcitonin Levels as an

Early Indicator of Sepsis

HAKAN GUVEN, MD,* LEVENT ALTINTOP, MD,* AHMET BAYDIN, MD,*
SABAN ESEN, MD, DURSUN AYGUN, MD,* MURAT HOKELEK, MD, PHD,
ZAHIDE DOGANAY, MD,* AND YUKSEL BEK, PHD
Researchers and clinicians have been investigating and implementing
various methods of early diagnosis for sepsis before documentation of
infection. The aim of this study was to outline the efciency of procalci-
tonin (PCT), C-reactive protein (CRP), and white blood cell count (WBC)
in determining the early diagnosis of sepsis in the emergency depart-
ment. Between January 1999 and September 2000, 34 patients with signs
of systemic inammatory response syndrome (SIRS) were enrolled in the
study. The patients were divided into 2 groups according to nonsus-
pected sepsis and suspected sepsis clinically. Admission PCT was sig-
nicantly higher in suspected sepsis group (median 68.7 g/L; lower
[L] 15.24 g/L, upper [U] 120.54 g/L) compared with the unsus-
pected sepsis group (.23 g/L; L .10 g/L, U .44 g/L). PCT values
were compared with WBC and CRP levels. Predictive accuracy for sepsis
expressed as area under the receiver operating characteristic (ROC)
curve was .88 for PCT, .44 for WBC, and .34 for CRP. PCT can probably
be used as a predictive marker in bacterial infections in emergency
departments. (Am J Emerg Med 2002;20:202-206. Copyright 2002,
Elsevier Science (USA). All rights reserved.)
The number of patients presenting with sepsis or septic
shock is gradually increasing. Parallel with this, emergency
medicine physicians should expect to see a greater number
of patients with this problem in their daily practice.
1
For
emergency medicine physicians, the focus will most likely
be on differential diagnosis and investigating the strong
clues of sepsis. Prompt and effective decision making is
critical, early diagnosis for sepsis not only decreases the
mortality rate, but it is also necessary for emergency med-
icine physicians to perform further therapy steps (ie, uid
therapy, appropriate antibiotic use) simultaneously.
Sepsis has been dened as the systemic response of the
body to infection.
2
The documentation of infection can be
performed with positive culture, which is not an immedi-
ately available laboratory investigation in emergency de-
partment (ED) studies. Diagnostic uncertainty must be bal-
anced with some biologic parameters. In the literature, there
have been many described biologic parameters that facili-
tate a rapid diagnosis of sepsis, besides the classic bacterial
examinations.
3-5
One of these parameters is procalcitonin
(PCT), which was discovered recently as a marker of bac-
terial infection.
6
PCT, which consists of 116 amino acids, is
the prohormone of calcitonin. In the healthy individual, it is
secreted from C cells of the thyroid, and plasma concentra-
tions are very low in the picogram range.
7
Several animal
and human studies of sepsis have shown a sustained in-
crease in the concentration of plasma PCT that was ulti-
mately identied by a highly specic marker itself.
8-10
We conducted the present prospective study to determine
the accuracy of PCT, C-reactive protein (CRP), and white
blood cell count (WBC) among the patients who have at
least 2 criteria of systemic inammatory response syndrome
(SIRS) and clinically suspected and nonsuspected sepsis,
and who were admitted to the ED.
PATIENTS AND METHODS
Ondokuz Mayis University Hospital is a secondary refer-
ral hospital in the middle Black Sea region of Turkey. Most
patients are sent to the hospital by either a specialist or an
emergency medicine clinician for further investigation.
Many of them have risk factors for sepsis such as hospital-
ization, intravascular catheters, and urinary catheters.
Therefore, complex cases and other life-threatening dis-
eases are admitted to our ED from that area.
With approval from the local research ethical committee,
34 patients with signs of SIRS were enrolled in the study
between January 1999 and September 2000. There were 20
men and 14 women, with a mean age of 56.27 12.6 years
(range, 21-74 yrs). Patients were included on the basis of
clinical and laboratory ndings, described by the American
College of Chest Physicians/Society of Critical Care Med-
icine Consensus Conference.
11
They met at least 2 of the
criteria for SIRS: fever or hypothermia, tachycardia, tachy-
pnea, or abnormal WBC count.
The patients were divided into 2 groups according to
nonsuspected sepsis and suspected sepsis clinically. Cate-
gorization of patients was made without knowledge of PCT
and CRP levels. The term nonsuspected sepsis was used for
patients who had minor infections such as an upper respi-
ratory tract infection, otitis media, gastroenteritis with only
signs of SIRS. The nonsuspected sepsis group included 15
patients. This group was also designed as a control group.
The second group, called the suspected sepsis group, was
used for patients who had a higher risk for sepsis with
concomitant diseases, previous hospitalization, and a strong
suspicion of sepsis clinically but not documented bacteri-
ally.
From the Departments of *Emergency Medicine, Clinical Infec-
tious Disease, Microbiology, and Biostatistics, Ondokuz Mayis
University, School of Medicine, Samsun, Turkey.
Supported by Ondokuz Mayis University Department of Research
fund, grant no. T-257.
Manuscript received August 29, 2001, accepted December 10,
2001.
Address reprint requests to Hakan Guven, MD, Assistant Profes-
sor, Department of Emergency, Ondokuz Mays University School of
Medicine, 55139 Samsun, Turkey.
Key Words: Emergency departments, procalcitonin, C-reactive
protein, sepsis.
Copyright 2002, Elsevier Science (USA). All rights reserved.
0735-6757/02/2003-0012$35.00/0
doi:10.1053/ajem.2002.33005
202
Blood samples for PCT, CRP, and hemoculture were
collected before treatment. Samples for PCT and CRP were
centrifuged to separate the serum, which was frozen at
70C for further analysis. Blood samples were obtained
from 3 different sites of venous puncture for hemoculture.
We considered hemocultures as positive when the same
microorganism was isolated from 2 different hemocultures
of the patient.
PCT was measured by an immunoluminometric assay
(LUMItest PCT; Brahms Diagnostica, Berlin, Germany)
whose detection limit was 0.01 g/L. CRP was measured by
automatic laser nephelometry (BN II analyzer; Boehring
Dade, Marburg, Germany), normal range was 0 to 5 mg/L.
WBC (leukocyte) counts were determined by using an
automatic counter. The reference values were between
4,000 and 12,000 cells/mm
3
.
Comparison between groups was made by the nonpara-
metric Mann-Whitney test. Data were analyzed by diagnos-
tic efciency derived from the receiver-operating character-
istic (ROC) curve and area under the ROC curve. Statistical
analysis was performed by using SPSS (Chicago, IL),
WinEpiscope 2.0 statistical packet programs. Probability
values less than .05 were considered signicant.
RESULTS
The demographics (ie, age, sex) were similar between the
2 groups except for underlying medical illness. The sus-
pected sepsis group included 19 patients with a history of
previous cerebrovascular disease, chronic obstructive pul-
monary disease, and diabetes mellitus. A summary of these
cases is provided in Table 1. All of the suspected sepsis
group (n 19) were hospitalized and 6 of the patients died.
The nonsuspected sepsis group (n 15) was observed
mostly for less than 24 hours in the ED and discharged from
the hospital.
The mean and condence limits of the PCT level in the
suspected sepsis group was 67.89 g/L (L 15.24 g/L,
U 120.54 g/L). The nonsuspected sepsis group did not
have high levels of PCT in their serum, mean PCT level was
0.23 g/L (L .10 g/L, U .44 g/L). The PCT values
were signicantly higher in the suspected sepsis group than
in the nonsuspected sepsis group (P .001).
In the nonsuspected sepsis group, all blood cultures were
negative and we did not isolate any pathogen microorgan-
ism. Of the 19 patients in the suspected sepsis group, 13
patients had positive blood cultures together with high PCT
serum levels. Of the 6 patients that had negative blood
cultures, 4 patients PCT levels were higher than normal
levels, but in 2 of these patients the PCT levels were just
above the normal values. The other 2 patients had very high
values. These extreme levels, reaching 500 g/L, were
observed in patients with acute pancreatitis. In the last 2 of
these patients, PCT serum levels remained in the normal
range whereas bacteria were not isolated in blood cultures.
Each of the 19 patients belonging to the suspected sepsis
group showed an increase in CRP serum levels (165 51
mg/L). In contrast to PCT levels, CRP levels (108 64
mg/L) showed higher values than the normal range in the
nonsuspected sepsis group. There was no signicance in
CRP serum levels between groups (P .05).
The mean WBC was 16,947 (2,400-44,900 cells/mm
3
)
and 14,503 (3,200-21,000 cells/mm
3
) in the suspected and
nonsuspected sepsis groups, respectively. WBC level was
insignicant between groups (P .05).
Patients with documented bacteria and elevated PCT
levels (2 g/L), CRP levels (5 mg/L), and WBC level
less than 4,000 and greater than 12,000 cells/mm
3
were
considered to have a true-positive nding, and those pa-
tients with negative culture without elevated PCT and CRP
levels, and WBC between 4,000 and 12,000 cells/mm
3
were
considered to have a true-negative nding. The sensitivity,
TABLE 1. Serial PCT and CRP Determinations in the Suspected Sepsis Group With Blood Culture Results and Concomitant Diseases
Case No. Blood Isolate Age Concomitant Disease
PCT Level
(g/L)
CRP Level
(mg/L)
WBC
(cells/mm
3
) Outcome
1 CoNS 71 CVDCOPD 2.86 139 22,300 Died
2 CoNS 74 DMCVD 38.01 28.4 44,900 Survived
3 CoNS 21 Postpartum 91.9 176 16,100 Survived
4 CoNS 65 DMCVD 8.96 80 20,500 Survived
5 CoNS 45 COPD 153.2 200 2,460 Died
6 CoNS 60 COPD 21.3 191 8,900 Survived
7 Staphylococcus aureus() 58 Previous trauma 54.68 200 7,940 Died
8 Staphylococcus aureus() 68 COPD 18.24 200 11,200 Survived
9 Escherichia coli 64 Acute cholangitis 56.2 191 19,500 Survived
10 Escherichia coli 74 Diare 38 28 6,800 Survived
11 Enterococcus 45 Acute cholangitis 16.82 200 9,700 Survived
12 Enterococcus 61 Previous surgery 180.4 200 14,700 Survived
13 Proteus 47 Kidney stone 3.54 98 17,300 Died
14 50 Sheehans syndrome 2.32 200 15,900 Survived
15 66 COPDCVD 0.5 96 18,600 Died
16 65 COPD 0.83 200 41,800 Died
17 37 Acute pancreatitis 500 157 2,400 Survived
18 70 DM 2.72 200 30,200 Survived
19 47 Acute pancreatitis 318 200 10,800 Survived
Abbreviations: CoNS: Coagulase negative staphylococci; CVD, cerebrovascular disease; COPD, chronic obstructive pulmonary disease; DM,
diabetes mellitus.
203 GUVEN ET AL I DIAGNOSTIC VALUE OF PROCALCITONIN
specicity, and positive and negative predictive values of
PCT, CPR, and WBC derived from diagnostic evaluation
tests are presented in Table 2. The PCT concentration higher
than 2 g/L had 78.9% diagnostic efciency and 78.9%
negative and 100% positive predictive values for bacterial
sepsis. The CRP concentration higher than 5 mg/L had
68.4% diagnostic efciency and 46.2% positive and 0%
negative predictive values for sepsis. The WBC level less
than 4,000 and greater than 12,000 cells/mm
3
had 47.4%
diagnostic efciency and 52.9% positive and 41.7% nega-
tive predictive values. The ROC curves can be used to
evaluate the performance of classication schemes in which
there is 1 variable with 2 categories by which subjects are
classied. If the estimated area under the ROC curve is
more, the classication with that method is better. Figures 1,
2, and 3 contain ROC curves showing the sensitivity and
specicity of PCT, CRP, and WBC levels for sepsis. The
area under the ROC curve was 0.88, 0.44, 0.34, for PCT,
WBC, and CRP, respectively.
DISCUSSION
The goals of emergency medicine physicians should be
2-fold: to distinguish sepsis from other causes of SIRS and
start early therapy including an antibiotic regimen. The
critical point in patients with sepsis is the absence of doc-
umented infection at admission to the ED. The use of
cultures for identifying the presence of bacteria requires
time, which makes it inaccessible for clinical use in the ED,
TABLE 2. Specicity, Sensitivity, and Positive (PPV) and
Negative (NPV) Predictive Values of PCT, CRP, and WBC With
Diagnostic Evaluation Test
Sensitivity(%) Specicity(%) PPV(%) NPV(%)
PCT 78.9 100 100 78.9
CRP 68.42 0 46.42 0
WBC 47.4 46.7 52.9 41.2
FIGURE 1. The area under the curve was .88 for PCT in the
clinically suspected sepsis group.
FIGURE 2. The ROC of CPR for prediction of bacterial sepsis.
The area under the curve was .34 for CRP in the clinically
suspected sepsis group. Diagonal segments are produced by ties.
FIGURE 3. The ROC of WBC for prediction of bacterial sepsis.
The area under the curve was 0.44 for WBC in the clinically
suspected sepsis group.
204 AMERICAN JOURNAL OF EMERGENCY MEDICINE I Volume 20, Number 3 I May 2002
and negative cultures do not exclude the sepsis. Some
investigators have suggested that clinical sepsis has been
observed in the absence of documented infection in more
than 50% of patients with multiorgan dysfunction syn-
drome.
12
Therefore, the need to identify sepsis has led to the
development of a variety of biochemical parameters based
on the pathophysiology of sepsis. These biochemical pa-
rameters should be designed to assess the severity of illness
and possibly assist in differentiating the infection. Numer-
ous investigators have reported on the use of PCT in early
and differential diagnosis of bacterial sepsis. The sensitivity
(60%-100%) and specicity (79%-100%) reported in vari-
ous series were quite encouraging.
9,10,13
CRP levels, eryth-
rocyte sedimentation rate, and WBC values are also avail-
able parameters for the diagnosis of inammation, but their
sensitivity and specicity is lower than PCT in differenti-
ating acute bacterial infection from other types of inam-
mation.
13
We found that PCT has more specicity than CPR
for diagnosis of bacterial sepsis, and PTC showed better
diagnostic efciency and the area under the ROC curve than
CRP.
PCT is the prohormone of calcitonin. It is not found in
serum of healthy people, but high concentrations of PCT
have been reported in patients with bacterial infections and
septic inammation.
14
This study has evaluated the useful-
ness of PCT only for diagnosis of bacterial sepsis manage-
ment of critically ill patients in the ED. Recently designed
clinical studies for evaluating the efciency of PCT serum
concentrations have mostly been organized in adult and
neonate intensive care units. They tested either the diagnos-
tic or prognostic value of PCT and compared the results
with other inammation parameters.
15-17
Our results showed
that PCT values in suspected sepsis groups were signi-
cantly higher than nonsuspected sepsis groups (P .001). It
could be a useful tool in the emergency room for differential
diagnosis among patients with signs of SIRS.
Alterations in hematological parameters (eg, leukocytosis
or leukopenia, thrombocytopenia) and elevation of serum
acute-phase proteins (eg, CRP) may provide a clue of sep-
sis, but they were not consistent with our results, CRP
values and WBC were not signicantly different between
groups (P .05). This result may contrast with some
publications which mention that CRP is an available diag-
nostic test for infection.
18,19
This controversial result was
probably caused by high concentrations of CRP in the
nonsuspected sepsis group. It is well known that CRP is a
very sensitive marker and may be increased with minor or
viral infections and other insults such as trauma. These
insults can activate the cytokine cascade, which has pro-
found inuences on the generation of acute-phase proteins
from liver. Except for this common pathway, the specic
induction of bacterial inammation that activated cytokines
might also stimulate the synthesis of PCT from different
sources. The cellular origin of PCT is not known exactly but
possibly it originated from leukocytes and neuroendocrine
cells of the lung or intestine.
20-22
The patients suffered only
from SIRS elevated CRP but not PCT, whereas patients
with sepsis showed increases in both PCT and CPR values.
A similar clinical result was nd by Clyne and Olshaker,
23
who concluded that CRP had a limited use in the ED and
has no role in diagnosing some bacteria-related clinical
entities. These observations suggested that systemic inam-
mation induced by infectious stimuli may alert both liver
and other cells, which takes place in immunologic response.
In the present study, the highest values of PCT were
determined to be in 2 cases of acute pancreatitis and not
isolated bacteria in blood cultures. Recent studies showed
that PCT is not only a marker of bacteremia but it can also
be determined in high levels in diseases related to inam-
mation. According to the study by Brunkhorst et al,
24
pa-
tients with billiary pancreatitis presented with high PCT
serum levels.
If therapy is delayed, the patient will almost assuredly die
before the diagnosis is established.
1
The emergency medi-
cine physician must start empiric or presumptive therapy
rapidly before conrmation of the diagnosis. WBC, CRP,
and PCT levels may provide a clue of sepsis. But, we were
able to show an excellent sensitivity and specicity of PCT
as shown by the ROC curves. We also found high negative
predictive value (78.9%) of PCT. This is very important
because it may prevent inappropriate antibiotic usage. The
cost effectiveness, toxicity, and resistance problem against
antibiotics can be minimized.
25,26
These results may allow
us to determine that empiric regimens of broad-spectrum
antimicrobials should be initiated according to sustained
PCT serum values.
In conclusion, PCT serum levels might be a useful diag-
nostic tool in ED management of sepsis before documenta-
tion of bacteria. Early empiric antibiotic therapy might be
started before documentation of bacteria in the ED. The use
of PCT measurement to guide antibiotic therapy should be
a practical approach in critically ill patients with suspected
sepsis.
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