Clin Chem Lab Med 2014; 52(10): 1465–1472

Laura Magrini*, Giulia Gagliano, Francesco Travaglino, Francesco Vetrone, Rossella Marino,
Patrizia Cardelli, Gerardo Salerno and Salvatore Di Somma

Comparison between white blood cell count,

procalcitonin and C reactive protein as diagnostic
and prognostic biomarkers of infection or sepsis in
patients presenting to the emergency department
Abstract Conclusions: Our data demonstrate that WBC, but more
CRP and PCT are reliable diagnostic and prognostic bio-
Background: Procalcitonin (PCT) is currently the most
markers, when considered in combination and with sever-
studied infection biomarker and its blood levels seem to
ity clinical score. PCT confirms its stronger usefulness as
mirror the severity of illness and outcome. PCT is widely used
a diagnostic marker of sepsis. A multi-diagnostic tools
together with other biomarkers, such as white blood cells
approach is fundamental to perform a correct and rapid
(WBC) count and C reactive protein (CRP), in order to guide
diagnosis of infection and sepsis in ED.
antibiotic therapy. This study aimed to verify the diagnostic
and prognostic power of WBC, CRP and PCT in patients with
Keywords: C reactive protein; diagnosis; emergency
suspected infection in emergency department (ED).
department; infection; procalcitonin; prognosis; white
Methods: A total of 513 patients presenting to the ED
blood cells.
with signs/symptoms of local infections or sepsis were
enrolled. APACHEII score and in-hospital death were
recorded. Patients were subdivided into quartiles by age, DOI 10.1515/cclm-2014-0210
and the biomarkers were measured at baseline. Receiver Received February 26, 2014; accepted April 8, 2014; previously pub-
lished online May 6, 2014
operating characteristics (ROC) curves for evaluating
diagnostic and prognostic role of PCT, CRP and WBC were
calculated for each variable alone and combined.
Results: When compared each other for PCT, CRP, and
Background
WBC there was no significant difference between the four
Despite progress over the past half century in treating
subgroups. A direct correlation between PCT and WBC
patients with sepsis, the incidence of infections, sepsis,
was found in the II, III, and IV quartiles (the highest cor-
and septic shock is still increasing [1]. Several factors
relation, r = 0.34, p < 0.0003). PCT alone or when combined
could explain the increased incidence of sepsis, including
with WBC showed the best diagnostic and prognostic
the aging population, the increasing survival of patients
power at ROC analysis.
who have cancer or are immune-depressed, the increasing
numbers of invasive medical interventions, and the rising
of multidrug-resistant bacteria [2, 3]. For patients with
*Corresponding author: Dr. Laura Magrini, MD, Emergency Medicine, sepsis in-hospital mortality ranges from 28.3% to 41.1%
Medical-Surgery Sciences and Translational Medicine, Sapienza in North America and Europe [4]. As a consequence, an
University of Rome, Sant’Andrea Hospital, Via di Grottarossa
early diagnosis is crucial to its successful treatment [5, 6].
1035-1039, 00189 Rome, Italy, Phone: +39 0633775754,
Fax: +39 0633775018/5890, E-mail: magrinilau@libero.it Biomarkers have a pivotal role in this process because
Giulia Gagliano, Francesco Travaglino, Francesco Vetrone, Rossella they can indicate the presence of the severity of infections
Marino and Salvatore Di Somma: Department of Medical-Surgery or sepsis [7–9], can differentiate bacterial from viral and
Sciences and Translational Medicine, Sant’Andrea Hospital, fungal infection, and distinguish systemic sepsis from
Sapienza University of Rome, School of Medicine and Psychology,
local infection. Other potential uses of biomarkers include
Emergency Medicine, Rome, Italy
Patrizia Cardelli and Gerardo Salerno: Department of Molecular
the decision making to start antibiotic treatment and its
and Clinical Medicine, Sant’Andrea Hospital, Sapienza University of response [10]. Today a multitude of biomarkers has been
Rome, School of Medicine and Psychology, Rome, Italy proposed in the field of sepsis, but the most validated

Brought to you by | University of California - San Francisco

Authenticated
Download Date | 12/8/14 12:08 PM
1466      Magrini et al.: WBC, PCT, CRP and infections

remains procalcitonin (PCT) that has become part of
the International Guidelines for Management of Severe
Sepsis and Septic Shock 2012 [11]. Nevertheless, in every-
day clinical practice, worldwide, white blood cells (WBC)
count and C reactive protein (CRP) still represent the cor-
nerstones on which is based the diagnosis and prognosis
of infected patients together with other signs and symp-
toms like fever, tachycardia, and tachypnea, when a docu-
mented or suspected infection is detected [11, 12].
In emergency department (ED) diagnosis of sepsis can
be delayed by the overcrowding [13] and by the complexity of
patients, often elderly and with multiple comorbidities. All
these variables can alter signs and symptoms [14]. However,
these are also the most relevant risk factors for developing
sepsis [1]. Moreover, in early stages of the process, the source
of infection may be unclear and the related systemic response
indistinguishable from non-infectious diseases [15].
The aim of the present prospective study was to
clarify the reliability of WBC count, CRP and PCT alone or
coupled together as diagnostic and prognostic biomark-
ers of infection and sepsis in patients referred to the emer-
gency setting in different age groups.
Materials and methods
This was a retrospective, observational study conducted in a univer-
sity 400-bed hospital, S. Andrea Hospital of Rome. We studied 513
patients (Table 1) (263 males and 250 females; mean age 71.7 ± 15.9
years) referred to our ED with symptoms of infection, and in which
a diagnosis of infection or sepsis was formulated. The diagnosis was
performed in agreement with the International Guidelines for Man-
agement of Severe Sepsis and Septic Shock 2012 criteria. Infection
was documented, as appropriate, by chest X-ray, ultrasound exams,
computed tomography, and also by laboratory tests, urine culture,
blood culture, and cultural examination of buffer. We collected blood
samples to measure PCT, CRP, and blood cell count at baseline. Arte-
rial blood gas analysis was performed. Prognostic risk stratification
was performed using the Acute Physiology and Chronic Health Eval-
uation (APACHE) II score. Charlson index was also calculated (score
ranging from 0 to   ≥  3). In order to standardize data collection, the
worst physiologic and laboratory values from the last 24  h before
study inclusion while patients were still in the ED were used to cal-
culate the APACHE II scores. Clinical data of patients were recorded,
as well as in-hospital death. Entire population was subdivided into
quartiles by age (I: 19–69 years, II: 70–77 years, III: 78–83 years, IV:
84–102 years). This retrospective clinical trial was designed following
the criteria of the Declaration of Helsinki and approved by the ethical
committee of the hospital.
PCT assay
PCT was performed at the arrival in the ED (T0). Venous blood with-
drawal was performed for each patient with lithium heparinized
tubes. After clotting time, each sample was analyzed without stor-
age and performed on the mini-Vidas (Bio-Merieux, Marcy L’Etoile,
Craponne, France), using the ELFA technique (Vidas, Brahms PCT).
The lowest concentration measured by the assay is 0.05 ng/mL (95%
percentile). This is considered the cut-off for healthy individuals on
the basis of manufacturer’s instructions. Following manufacturer’s
instructions the repeatability (inter-assay precision) and inter-
assay reproducibility (inter-assay precision) were calculated using a

Table 1 Patients’ characteristics in total population, septic group, and in non-septic group.

  Total population  Septic patients  Non-septic patients  p-Valuea

n = 513 n = 221 n = 292

Age, yearsb   71.78 ± 15.90  73.88 ± 15.47  70 ± 16.08  ns

Gender M/F, n   263/250  105/116  142/140 
HR, bpmb   95.58 ± 19.48  102.25 ± 18.54  88.79 ± 17.62   < 0.001
RR, breaths/minb   21.54 ± 5.55  26.6 ± 5.16  19.25 ± 4.99   < 0.001
T, °Cb   37.31 ± 1.14  37.58 ± 1.19  36.83 ± 0.9   < 0.001
WBC, 103/μLb   13,229.38 ± 7083.80  15,969 ± 8323.87  11,155.29 ± 5102.55   < 0.001
PCT, ng/mLb   8.57 ± 31.61  17.16 ± 46.88  2.37 ± 6.79   < 0.001
CRP, mg/dLb   15.75 ± 13.73  20.19 ± 14.87  12.34 ± 11.81   < 0.001
Charlson Index score   1.86 ± 1.56  2.08 ± 1.74  1.69 ± 1.39   < 0.005
Past historyc
 DM   23.8%  11.3%  22.6%  ns
 CD   59.1%  31.2%  53%   < 0.002
 Neoplasms   5.8%  4%  2.4%  ns
 COPD   25.1%  16.6%  28.7%  ns
 CKD   12.9%  8.1%  10.7%  ns
a
p-Value is between septic vs. non-septic groups; bvalues expressed as mean ± SD; cvalues expressed as percentage. bpm, beats per minute;
CD, cardiovascular disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CRP, C reactive protein; DM, dia-
betes mellitus; HR, heart rate; ns, not significant; PCT, procalcitonin; RR, respiratory rate; SD, standard deviation; T °C, body temperature in
Celsius; WBC, white blood cells.

Brought to you by | University of California - San Francisco

Authenticated
Download Date | 12/8/14 12:08 PM
 Magrini et al.: WBC, PCT, CRP and infections      1467

protocol based on the recommendations of CLSIEP5-A2 document23.

Intra-assay coefficients of variation as determined in our laboratory
(15 human serum samples in duplicates in 5 parallel determina-
tions) were, depending on the sample concentration, between 2.0%
and 3.2%. Assay sensitivity (95th percentile on 200 normal subjects)
is  < 0.05 ng/mL.
WBC assay
WBC was performed at arrival in ED (T0). Each sample was analyzed
in central hospital laboratory by a Sysmex XE-2100 used to determine
full blood counts and WBC counts (WBC linearity: 0–440.00 × 103/μL;
body fluid linearity: WBC-BF:  > 0.050 × 103/μL).
CRP assay
CRP was assessed at baseline (T0). Each sample was ­analyzed in
­central hospital laboratory. CRP was measured on VITROS® ­Chemistry
Systems (Ortho-Clinical Diagnostics) using a “MicroSlide” method.
The reference range for CRP measurements was 0.01–1.50 mg/dL.
Statistical analysis
Data were normally distributed and they are expressed as
mean ± standard deviation (SD) or percentage (%). Comparison of
two means was performed using the Student’s t-test, and between
dichotomous variables it was assessed by χ2-test. Spearman’s rank
test has been used for coefficients of correlation. To determine the
prognostic value of biomarkers for death in total population, and
for diagnosis of sepsis, the receiver operating characteristics (ROC)
curve and area under the curve (AUC) were constructed and the
p-value was obtained. ROC curves were calculated for each vari-
able alone, and for PCT, CRP and WBC combined each other. Multi-
ple regression analysis was performed with PCT, WBC, gender and
age in quartiles as prognostic independent factors. A p-value  < 0.05
was considered to be statistically significant in all tests. Statistical
analysis was performed using MedCalc Statistical Software version
13.0.4 (MedCalc Software bvba, Ostend, Belgium; http://www.med-
calc.org; 2014).
Results
Table 1 describes the characteristics of patients. Patients
studied were mainly older than 65 years of age; there was
no difference for gender. When the studied population was
subdivided into septic and non-septic groups, there was a
statistical significant difference for heart rate, respiratory
rate, body temperature, WBC, PCT, and CRP between the
two groups. On the basis of past history most patients were
affected by cardiovascular diseases and chronic obstruc-
tive pulmonary disease (COPD). On the basis of Charlson
index score, patients’ groups results were expressed as
follows: 0 = 15.8%; 1 = 29.4%; 2 = 2 8.6%;   ≥  3 = 25.5%. Mean
score value was significantly higher in septic patients
than in non-septic patients (p < 0.005) (Table 1).
There was no statistical difference between the four
quartiles groups when the mean values were compared
with each other, either for PCT, CRP, and for WBC (Table 2).
For APACHE score there was a statistical significant dif-
ference between the quartiles I vs. III (p < 0.01), and vs.
IV (p < 0.0001); II vs. IV (p < 0.0007); II vs. IV (p < 0.006)
(Table 2).
A direct significant correlation between PCT and WBC
mean values was not found in patients with age lower than
70 years but in the last three quartiles of age (the highest
correlation, r = 0.34, p < 0.0003), while for PCT and CRP was
never found any correlation (Table 3). ROC curve analy-
sis showed a significant diagnostic and prognostic role of
PCT, and diagnostic for CRP when considered separately
(for diagnosis of sepsis: PCT AUC 0.79, p < 0.0001–WBC
AUC 0.53, p = 0.78–CRP AUC 0.72, p < 0.001 (Figure 1A);
for prognosis: PCT AUC 0.72, p < 0.0001–WBC AUC 0.63,
p = 0.18–CRP AUC 0.53, p = 0.23) (Figure 1B), and for diag-
nosis of sepsis in combination (for diagnosis of sepsis:
PCT+WBC AUC 0.79, p < 0.0001–CRP+WBC AUC 0.71,
p < 0.001–PCT+CRP+WBC AUC 0.80, p < 0.0001 (Figure 2A);
for prognosis: PCT+WBC AUC 0.65, p = 0.06–CRP+WBC

Table 2 Laboratory values (mean ± SD) of white blood cells, procalcitonin, C reactive protein, and APACHE score in each quartile of age.

  PCT, ng/mL  WBC, 103/μL  CRP, mg/dL  APACHE score, %

I quartile   6.83 ± 16.67  12,891.13 ± 7833.10  16.07 ± 14.03  16.37 ± 18.33

19–69 years        
II quartile   6.34 ± 18.45  12,690.36 ± 6277.90  14.68 ± 12.50  22.42 ± 12.57
70–77 years        
III quartile   6.67 ± 18.63  12,767.27 ± 6601.29  16.32 ± 15.58  25.20 ± 15.10
78–83 years        
IV quartile   14.72 ± 57.73  13,899.90 ± 7239.41  15.74 ± 11.74  39.41 ± 25.63
84–102 years        

APACHE, Acute Physiology and Chronic Health Evaluation; CRP, C reactive protein; PCT, procalcitonin; WBC, white blood cells; SD, standard
deviation.

Brought to you by | University of California - San Francisco

Authenticated
Download Date | 12/8/14 12:08 PM
1468      Magrini et al.: WBC, PCT, CRP and infections

Table 3 Correlation between procalcitonin and white blood cells, biomarkers of infection and sepsis in patients in an emer-
and between procalcitonin and C reactive protein in each quartile gency setting has been investigated. From our results it
of age.
seems that there is no difference between the three bio-
markers levels as for gender and age, while the presence
  r (95% CI)  p-Value
of comorbidities, such as, mainly cardiovascular and pul-
PCT and WBC monary diseases, could impact the severity of sepsis as
 I quartile   0.140 (–0.0121–0.285)  0.071
shown in Table 1.
 19–69 years    
 II quartile   0.295 (0.133–0.442)   < 0.0005 Even though a large volume of information has been
 70–77 years     collected about managing and treating septic patient [16–
 III quartile   0.265 (0.103–0.413)   < 0.0016 19], the lack of knowledge about the diagnostic criteria for
 78–83 years     sepsis by emergency teams is one of the greatest factors
 IV quartile   0.340 (0.161–0.498)   < 0.0003
limiting its adequate treatment. Many efforts have been
 84–102 years    
PCT and CRP
made in recent years to give a standardized definition
 I quartile   –0.16 (–0.331–0.0024)  0.053 to this syndrome and consequently make the diagnosis
 19–69 years     easier.
 II quartile   0.067 (–0.121–0.250)  0.48 Joint and combined efforts culminated in the Ameri-
 70–77 years     can College of Chest Physicians/Society of Critical Care
 III quartile   0.075 (–0.104–0.251)  0.40
Medicine Consensus Conference [2, 20] that paved the way
 78–83 years    
 IV quartile   0.035 (–0.174–0.242)  0.74 to the most recent International Guidelines for Manage-
 84–102 years     ment of Severe Sepsis and Septic Shock published in 2012.
To increase survival, diagnosis must be promptly
CRP, C reactive protein; PCT, procalcitonin; WBC, white blood cells.
made in ED and an appropriate treatment should be
immediately started.
AUC 0.64, p = 0.64–PCT+CRP+WBC AUC 0.65, p = 0.65)
Furthermore, ED setting is not comparable to regular
(Figure 2B). In multiple regression analysis, including as
ward or an Intensive Care Unit (ICU), since the length of
predictors both WBC and PCT, age and gender, for diagno-
visit time performed by the emergency physician is limited
sis PCT (p < 0.0001), WBC (p < 0.0001), and age (p = 0.004)
by the presence of overcrowding [13, 21], while patients
are all independently significantly associated to the risk
boarding to ED is not selected, and subjects with acute
of sepsis, while the most important significant predictor
diseases are, in many cases, elderly and with multiple
for hospital death appeared to be the age, and also WBC.
comorbidities that could mask infections.
PCT did not reach predictive significance for the risk to
As a consequence, in ED more than in other settings,
develop adverse outcomes (Table 4).
reliable, simple and rapid markers capable to detect infec-
tions and sepsis are needed.
Currently, the universally accepted criteria for the
Discussion diagnosis of sepsis include either patient’s general varia-
bles (fever, hypothermia, tachycardia, tachypnea, altered
In our study the reliability of WBC count, CRP and PCT mental status, hyperglycemia), either inflammatory vari-
used alone or in combination as diagnostic and prognostic ables (leukocytosis or leukopenia or normal WBC count

A 100 B 100

80 80
T0_WBC
Sensitivity
Sensitivity

60 T0_WBC
60 T0_PCT
T0_CRP T0_PCT
40 T0_CRP
40

20 20
0 0
0 40 80 0 40 80
100-Specificity 100-Specificity

Figure 1 ROC curve for (A) diagnosis of sepsis and (B) prognosis of in-hospital death.
In (A) ROC curve for diagnosis of sepsis: WBC AUC 0.533, p = 0.780; PCT AUC 0.798, p < 0.0001; CRP AUC 0.720, p = 0.001. In (B) ROC curve for
outcome (in-hospital death) in total population: WBC AUC 0.635, p = 0.180; PCT AUC 0.723, p < 0.0001; CRP AUC 0.538, p = 0.239. T0, time of
arrival in ED; WBC, white blood cells; PCT, procalcitonin; CRP, C reactive protein.

Brought to you by | University of California - San Francisco

Authenticated
Download Date | 12/8/14 12:08 PM
 Magrini et al.: WBC, PCT, CRP and infections      1469

A B 100
100
80

Sensitivity
80
Sensitivity

WBC_PCT_CRP_Diag 60 WBC PCT out

60
WBC CRP Diag 40 WBC CRP PCT out
40
WBC_PCT_Diag 20 WBC CRP PCT out
20
0 0
0 60 0 40 80
100-Specificity 100-Specificity

Figure 2 ROC curve for (A) diagnosis of sepsis and (B) prognosis of in-hospital death for combination of biomarkers.
In (A) ROC curve for diagnosis of sepsis: WBC+PCT AUC 0.799, p < 0.0001; WBC+CRP AUC 0.718, p = 0.001; WBC+PCT+CRP AUC 0.800,
p < 0.0001. In (B) ROC curve for outcome (in-hospital death) in total population: WBC+PCT AUC 0.656, p = 0.065; WBC+CRP AUC 0.643,
p = 0.097; WBC+PCT+CRP AUC 0.658, p = 0.095. WBC, white blood cells; PCT, procalcitonin; CRP, C reactive protein; Diag, diagnosis; Out,
outcome.

Table 4 Multiple regression analysis for (A) diagnosis of sepsis, and (B) risk for in-hospital death.

  Coefficient  Standard error  r partial  t  p-Value

(A) Independent variables

 (Constant)   –0.03967       
 Quartiles age   0.05345  0.01854  0.1296  2.884  0.0041
 WBC   0.00002224  0.000002846  0.3337  7.813   < 0.0001
 PCT   0.003180  0.0006417  0.2191  4.955   < 0.0001
 Gender   –0.01676  0.04064  –0.01896  –0.413  0.6801
(B) Independent variables
 (Constant)   –0.09295       
 Quartiles age   0.03341  0.01250  0.1228  2.673  0.0078
 WBC   0.000006101  0.000001883  0.1483  3.240  0.0013
 PCT   0.0007645  0.0004212  0.08370  1.815  0.0702
 Gender   0.04118  0.02722  0.06983  1.513  0.1310

CRP, C reactive protein; PCT, procalcitonin; WBC, white blood cells.

with greater than 10% immature forms, CRP, PCT) both
potentially altered especially in elderly patients [11, 20].
Although modification in inflammatory response and
WBC are well described and recognized in elderly due
to the immune senescence and to the progressive aging
of the bone marrow, little is known about PCT modifica-
tion in this type of subjects. While the correlation between
CRP and WBC is easily comprehensible during sepsis, and
also their plasma level variations in immuno-depressed
and elderly patients, the relationship between PCT and
inflammation, even the role played during infections, still
remains uncertain. Immune senescence is generally char-
acterized by chronic, low-grade, systemic inflammation
and impaired responses to immune challenge.
Thymic involution is well known, and there are sub-
stantial data in literature on the functional decline of
T cells with age. The decreased proliferation is corre-
lated to a decreased release of interleukin-2 and soluble
IL-2 receptor. However, soluble IL-2 receptor expression
on the cell surface is normal. Interferon-γ as the main
T-helper-1 cytokine is produced less by lymphocytes
of the elderly, whereas the T-helper-2 cytokines inter-
leukin-4 and interleukin-10 are produced in higher
amounts as compared to stimulated lymphocytes of
young donors. Monocyte function seems to be increased
in the elderly. Leukocytes of elderly produce higher
amounts of interleukins 1, 6, and 8 and tumor necrosis
factor-α after induction with lipopolysaccharide than
leukocytes from young donors [22, 23]. The production of
PCT is induced by pro-inflammatory cytokines, such as
interleukin-1, interleukin-6 and tumor necrosis factor-α,
and expressed by nearly all kinds of parenchymal cells
[24]. It is unknown how the increased inflammation
and declined functional reserve of parenchymal cells
in elderly would affect the response of PCT, but on the
basis of current knowledge, it could be postulated that,
unlike CRP and WBC, PCT remains a reliable expres-
sion of infection even in the more elderly population.
Moreover, it must be taken into account that inflamma-
tion (present also in infectious conditions), which takes
place on a cellular level, is triggered by a wide variety
of factors, such as oxidative stress, ingestion of toxins,

Brought to you by | University of California - San Francisco

Authenticated
Download Date | 12/8/14 12:08 PM
1470      Magrini et al.: WBC, PCT, CRP and infections
excess exposure to ultraviolet radiation, hormonal
changes, that are typical of the aging process.
For this reason we evaluated PCT and CRP values and
WBC count as positive predictive power in detecting sepsis
when used alone and combined together in a wide range of
age populations, including the elderly. We did not find rel-
evant differences between age expressed in quartiles and
the studied biomarkers (Table 2). From our results in the
group of elderly patients there was a significant increase of
PCT, but not in CRP. This indicates the different behavior of
these two biomarkers in case of infection or sepsis, prob-
ably due to the different kinetics, and also to the different
metabolism and biochemical origin of the two biomarkers.
In a very recent study, Loonen et  al. demonstrated that
PCT was able to significantly discriminate patients with
positive blood cultures from those with negative blood cul-
tures, while CRP levels remained similar in both groups.
ROC curve analysis showed that PCT was higher than
CRP in differentiating patients with blood culture proven
bloodstream infection from those without [25]. Also Arai
et  al. showed that in a group of adult infected patients
(aged more than 50 years) blood culture results were not
affected by WBC and CRP, but they were affected by PCT
(and platelets), and they suggested that these results
might help in explaining the mechanisms of sepsis [26].
For APACHE score there was a statistical difference in each
quartile evaluated with a progressive increase of the score
for the higher quartiles, probably because this score repre-
sents the severity of organ conditions. It could also be dif-
ferent due to the age of patients, i.e., comorbidities mostly
affect the score in the elderly. In a recent paper by Inno-
centi et al. it was shown that APACHE score, together with
other prognostic scores, was significantly higher in septic
patients with a bad prognosis, and could be considered an
accurate tool for risk stratification of sepsis in ED [27].
To our knowledge there are no data available in lit-
erature regarding the subdivision of quartiles of age and
on the evaluation of PCT or CRP and WBC in infectious or
sepsis conditions in ED.
When the correlation between PCT and WBC or
between PCT and CRP was evaluated, we found that a
direct significant correlation between PCT and WBC mean
values was found in the II, III and IV quartiles (the highest
correlation, r = 0.34, p < 0.0003), but not in the first (Table
3), while no significant correlation was shown between
PCT and CRP. The correlation between PCT and WBC was
not really strong but there was a rapid response of PCT
and WBC to the therapy which could be explained by
their similar kinetics. The kinetics of CRP is slower and its
response more non-specific to antibiotic therapy. Litera-
ture data agree with our findings, PCT has been shown to
Brought to you by | University of California - San Francisco
Authenticated
Download Date | 12/8/14 12:08 PM
detect infections and sepsis more rapidly than CRP, also in
an ED setting [28–30].
When ROC analysis was performed PCT was shown
to remain the best significant predictor for diagnosis of
sepsis (AUC 0.79, p < 0.0001) and for prognosis (AUC 0.72,
p < 0.0001), together with CRP for diagnosis of sepsis (AUC
0.72, p < 0.001) but not for prognosis, while WBC did not
show significant results (Figure 1). These data confirm
our previous studies on the diagnostic role of PCT and
CRP in patients affected with local infections and sepsis
in ED [30]. The explanation of the different behavior of
these three biomarkers in the diagnosis of sepsis could
be found in their different kinetics, and in the influence
of age and sex on WBC, but also for their daily biologi-
cal fluctuations as recently demonstrated by Tang et  al.
[31]. It is well known that in elderly people the WBC are
not always increased, even in severe sepsis, because of
the progressive aging of the bone marrow that results in
a decrease of WBC population. In fact, one of the four
SIRS findings is to have WBC  > 12,000/mm3 or  < 4000/
mm3 [11, 32, 33]. When we combined the three biomark-
ers together for diagnosis of sepsis, there was an increase
in the predictive diagnostic value (AUC 0.80, p < 0.0001),
even greater than the combination of PCT+WBC (AUC 0.79,
p < 0.0001), and of PCT+CRP (AUC 0.71, p < 0.001) (Figure
2). Jaimes et al. demonstrated in a large study population
that the repeated measurements of PCT, D-Dimer, and CRP
were not able to clearly discriminate septic from non-sep-
tic patients, but PCT was the only biomarker to identify
a subgroup of severely ill patients in ED. The diagnostic
accuracy of the three biomarkers, according to latent class
analysis (LCA) gold standard for diagnosis of sepsis, was
demonstrated by high ROC curves (CRP 0.71; PCT 0.95;
D-Dimer 0.73). They did not use a combination of the
three biomarkers, but one was considered singularly [15].
Instead, the innovative and adjunctive information of our
study is that a combination of the three studied biomark-
ers could improve diagnostic accuracy, even greater than
a combination of only two of them.
For the prognosis, in our population, a combination of
the three parameters appears to be less useful in compari-
son to the biomarkers when evaluated singularly, in fact
while AUC were slightly high (WBC+PCT 0.65–WBC+CRP
0.64–WBC+CRP+PCT 0.65) (Figure 2), they did not reach sta-
tistical significance. We can speculate that biomarkers used
singularly could be more useful in predicting outcomes.
This is probably because the wide inter-individual variabil-
ity of values for WBC or for the other two biomarkers causes
an extreme dispersion of significant values. The results of
a multiple regression analysis to identify variables associ-
ated with sepsis or mortality in total population show that

PCT, WBC and age subdivided in quartiles were strongly
independently associated with the presence of sepsis
(p < 0.0001, p < 0.0001 and p = 0.004, respectively) (Table 4),
while for prognosis the only two independent factors were
WBC and quartiles of age, PCT was not significant (Table 4).
In a recent published paper PCT measured at admission and
after 24  h did not show any significant difference accord-
ing to outcome, while clinical prognostic scores did [27].
However, this study was performed only on septic patients.
Moreover, Prkno et al. showed in a meta-analysis that PCT-
guided therapy did not affect mortality in septic patients but
it was helpful in guiding antibiotic therapy and in shorten-
ing the duration of therapy [34]. These data, together with
our results, show that PCT could be considered a useful
diagnostic tool, but a less accurate prognostic one.
This study has several limitations. First of all it is a
retrospective observational study with a limited studied
population number, and this could have affected prog-
nostic results. Furthermore, it is a single center study, and
we assessed only in-hospital death and not out of hospi-
tal events. Finally, we measured and correlated PCT, WBC
and CRP only at admission but not serially, during hospi-
talization, at, or after discharge.
Conclusions
This study confirms the reliability of WBC count, CRP and
PCT as diagnostic and prognostic biomarkers of infection
and sepsis in a wide range of ages, but particularly in aged
patients who are the most frequent infected/septic patients
hospitalized, and for this reason these biomarkers could be
particularly useful and suitable in ED. In a recent published
paper, by the GREAT network group, the potential usefulness
of biomarkers in ED for the management of septic patients
in an emergency setting has already been highlighted, but
also for risk stratification, and in guiding therapy [35]. Our
study reaffirms these findings, namely, the choice of the mul-
timarker approach (in combination) could help emergency
physicians to improve diagnosis and treatment of infections,
especially sepsis. Adding the WBC to PCT per se seems to be
of non-incremental value for an accurate, and fast diagnosis
of sepsis in patients with suspected infection in ED, in com-
parison to the combination of the three biomarkers.
Conflict of interest statement
Authors’ conflict of interest disclosure: The authors
stated that there are no conflicts of interest regarding the
publication of this article.
Brought to you by | University of California - San Francisco
Authenticated
Download Date | 12/8/14 12:08 PM
Magrini et al.: WBC, PCT, CRP and infections      1471
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
References
1. Martin GS. Sepsis, severe sepsis and septic shock: changes in
incidence, pathogens and outcomes. Expert Rev Anti Infect Ther
2012;10:701–6.
2. Knaus WA, Sun X, Nystrom O, Wagner DP. Evaluation of defini-
tions for sepsis. Chest 1992;101:1656–62.
3. Maseda E, Mensa J, Valía JC, Gomez-Herreras JI, Ramasco F,
Samso E, et al. Bugs, hosts and ICU environment: countering
pan-resistance in nosocomial microbiota and treating bacte-
rial infections in the critical care setting. Rev Esp Quimioter
2013;26:312–31.
4. Rohde JM, Odden AJ, Bonham C, Kuhn L, Malani PN, Chen LM,
et al. The epidemiology of acute organ system dysfunction from
severe sepsis outside of the intensive care unit. J Hosp Med
2013;8:243–7.
5. Balk RA, Bone RC. The septic syndrome: definition and clinical
implications. Crit Care Clin 1989;5:1–8.
6. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S,
et al. Duration of hypotension before initiation of effective
antimicrobial therapy is the critical determinant of survival in
human septic shock. Crit Care Med 2006;34:1589–96.
7. Biomarkers Definitions Working Group. Biomarkers and surro-
gate endpoints: preferred definitions and conceptual frame-
work. Clin Pharmacol Ther 2001;69:89–95.
8. Marshall JC, Reinhart K. Biomarkers of sepsis. Crit Care Med
2009;37:2290–8.
9. Faix JD. Biomarkers of sepsis. Crit Rev Clin Lab Sci 2013;50:
23–36.
10. Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit Care
2010;14:R15.
11. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal
SM, et al. Surviving sepsis campaign guidelines committee
including the pediatric subgroup. Surviving sepsis campaign:
International guidelines for management of severe sepsis and
septic shock: 2012. Intens Care Med 2013;39:165–228.
12. Kibe S, Adams K, Barlow G. Diagnostic and prognostic bio-
markers of sepsis in critical care. J Antimicrob Chemother
2011;66(Suppl 2):ii33–40.
13. Derlet RW, Richards JR. Overcrowding in the nation’s emergency
departments: complex causes and disturbing effects. Ann
Emerg Med 2000;35:63–8.
14. Bloos F, Reinhart K. Rapid diagnosis of sepsis. Virulence
2014;5:219–25.
15. Jaimes FA, De La Rosa GD, Valencia ML, Arango CM, Gomez CI,
Garcia A, et al. A latent class approach for sepsis diagnosis sup-
ports use of procalcitonin in the emergency room for diagnosis
of severe sepsis. BMC Anesthesiol 2013;13:23.
16. Park M, Azevedo LC, Maciel AT, Pizzo VR, Noritomi DT, Cruz
Neto LM. Evolutive standard base excess and serum lactate
level in severe sepsis and septic shock patients resuscitated
with early goal-directed therapy: still outcome markers? Clinics
2006;61:47–52.
1472      Magrini et al.: WBC, PCT, CRP and infections
17. Angele MK, Frantz MC, Chaudry IH. Gender and sex hormones
influence the response to trauma and sepsis – potential thera-
peutic approaches. Clinics 2006;61:479–88.
18. Vincent JL, Abraham E, Annane D, Bernard G, Rivers E, Van den
Berghe G. Reducing mortality in sepsis: new directions. Crit
Care 2002;6(Suppl 3):S1–18.
19. Crea F, Biasucci LM. Innate immune inflammatory response to
danger: when, how, and why does a friend become a foe? Eur
Heart J 2012;33:1434–7.
20. American College of Chest Physicians/Society of Critical Care
Medicine Consensus Conference. Definitions for sepsis and
organ failure and guidelines for the use of innovative therapies
in sepsis. Crit Care Med 1992;20:864–74.
21. Horwitz LI, Green J, Bradley EH. US Emergency department
performance on wait time and length of visit. Ann Emerg Med
2010;55:133–41.
22. Rink L, Cakman I, Kirchner H. Altered cytokine production in the
elderly. Mech Ageing Dev 1998;102:199–209.
23. Krabbe KS, Pedersen M, Bruunsgaard H. Inflammatory media-
tors in the elderly. Exp Gerontol 2004;39:687–99.
24. Lee SH, Chan RC, Wu JY, Chen HW, Chang SS, Lee CC. Diag-
nostic value of procalcitonin for bacterial infection in elderly
patients, a systemic review and meta-analysis. Int J Clin Pract
2013;67:1350–7.
25. Loonen AJ, de Jager CP, Tosserams J, Kusters R, Hilbink M, Wever
PC, et al. Biomarkers and molecular analysis to improve blood-
stream infection diagnostics in an emergency care unit. PLoS
One 2014;9:e87315.
26. Arai T, Kumasaka K, Nagata K, Okita T, Oomura T, Hoshiai A,
et al. Prediction of blood cultures results by measuring procal-
citonin levels and other inflammatory biomarkers. Am J Emerg
Med 2014;32:330–3.
27. Innocenti F, Bianchi S, Guerrini E, Vicidomini S, Conti A,
Zanobetti M, et al. Prognostic score for early stratification of
Brought to you by | University of California - San Francisco
Authenticated
Download Date | 12/8/14 12:08 PM
septic patients admitted to an emergency department-high
dependency unit. Eur J Emerg Med 2013 Aug 21. [Epub ahead of
print].
28. Castelli GP, Pognani C, Meisner M, Stuani A, Bellomi D, Sgarbi L.
Procalcitonin and C-reactive protein during systemic inflam-
matory response syndrome, sepsis and organ dysfunction. Crit
Care 2004;8:234–42.
29. Meidani M, Khorvash F, Abolghasemi H, Jamali B. Procalcitonin
and quantitative C-reactive protein role in the early diagnosis of
sepsis in patients with febrile neutropenia. South Asian J Cancer
2013;2:216–9.
30. Magrini L, Travaglino F, Marino R, Ferri E, De Berardinis B, Card-
elli P, et al. Procalcitonin variations after Emergency Department
admission are highly predictive of hospital mortality in patients
with acute infectious diseases. Eur Rev Med Pharmacol Sci
2013;17(Suppl 1):133–42.
31. Tang H, Jing J, Bo D, Xu D. Biological variations of leuko-
cyte numerical and morphologic parameters determined by
UniCelDxH 800 hematology analyzer. Arch Pathol Lab Med
2012;136:1392–6.
32. Caruso C, Buffa S, Candore G, Colonna-Romano G, Dunn-Walters
D, Kipling D, et al. Mechanisms of immunosenescence. Immun
Ageing 2009;6:10.
33. Falci C, Gianesin K, Sergi G, Giunco S, De Ronch I, Valpione S.
Immune senescence and cancer in elderly patients: results from
an exploratory study. Exp Gerontol 2013;48:1436–42.
34. Prkno A, Wacker C, Brunhorst FM, Schlattman P. Procalcitonin-
guided therapy in intensive care unit patients with severe sep-
sis and septic shock – a systematic review and meta-analysis.
Crit Care 2013;17:R291.
35. Di Somma S, Magrini L, Travaglino F, Lalle I, Fiotti N, Cervellin G,
et al. Opinion paper on innovative approach of biomarkers for
infectious diseases and sepsis management in the emergency
department. Clin Chem Lab Med 2013;51:1167–75.