Overview

Submitted 8.19.09 | Revision Received 10.7.09 | Accepted 10.12.09

Procalcitonin: Uses in the Clinical Laboratory

for the Diagnosis of Sepsis
Ming Jin, PhD, Adil I. Khan, PhD
(Department of Pathology and Laboratory Medicine, Temple University Hospital and the School of Medicine, Philadelphia, PA)
DOI: 10.1309/LMQ2GRR4QLFKHCH9

Abstract
Sepsis is the systemic response to infection by
microbial organisms. A differential diagnosis
of infection caused by either bacteria or other
microbial organisms is essential for effective
treatment and prognostic assessment. Current
clinical laboratory methods in the diagnosis of
bacterial infections are either non-specific or
require longer turnaround times. Procalcitonin
(PCT) is a biomarker that exhibits greater
specificity than other proinflammatory markers
(eg, cytokines) in identifying patients with
sepsis and can be used in the diagnosis of
bacterial infections. In this article, we review
the current knowledge of PCT and its use in
the clinical laboratory setting.

Identifying whether the cause of inflammation in patients
is of bacterial origin has been an important area of develop-
ment in the clinical laboratory. Several clinical laboratory tests
have been applied to the diagnosis of sepsis.1 The broth cul-
ture method is the gold standard for the diagnosis of bacterial
infection, but a definitive result can take 24 hours or more
before a conclusive diagnosis. A number of the inflamma-
tory markers, such as leukocyte cell count, C reactive protein
(CRP), and cytokines (TNF-α, IL-1β, or IL-6), have been
applied in the diagnosis of inflammation and infection, but
their lack of specificity has generated a continued interest to
develop more specific clinical laboratory tests.2 One promising
marker has been procalcitonin (PCT), whose concentration
has been found to be elevated in sepsis. Owing its specificity
to bacterial infections, PCT has been proposed as a pertinent
marker in the rapid diagnosis of bacterial infection, especially
for use in hospital emergency departments and intensive care
units. Since its identification and association with sepsis in the
1990s, a large number of studies involving PCT and its clini-
cal application have been conducted. A test to determine PCT
levels has been available in Europe for several years and re-
cently was approved by the FDA for use in the United States.3
Biochemistry of PCT
Procalcitonin is a 116 amino acid peptide that has an
approximate MW of 14.5 kDa and belongs to the calcitonin
(CT) superfamily of peptides. It can be divided into 3 sec-
tions including the amino terminus of the PCT region, im-
mature calcitonin, and calcitonin carboxyl-terminus peptide-1
(CCP-1, also called katacalcin) (Figure 1).4 Procalcitonin
is encoded by CALC-1 gene located on chromosome 11.
Cleavage in 1 site of the primary transcript of CALC-1 gene
produces pre-PCT, which further undergoes proteolytic
cleavage of its signal sequence to produce PCT.5,6 The other
members of the CT superfamily of peptides include calcitonin
gene-related peptide I, II (CGRP-I, CGRP-II), amylin, and
adrenomedullin. Calcitonin gene-related peptide I is also en-
coded by CALC-1 gene and is generated by alternative splic-
ing of the primary transcript of CALC-1 mRNA. Calcitonin
gene-related peptide II, amylin, and adrenomedullin are en-
coded by other genes (Table 1).
Procalcitonin expression occurs in a tissue-specific man-
ner. In the absence of infection, transcription of the CALC-1
gene for PCT in the non-neuroendocrine tissue is suppressed,
except in the C cells of the thyroid gland where its expression
produces PCT, the precursor of CT in healthy and non-
infected individuals.5 The synthesized PCT then undergoes
post-translational processing to produce small peptides and
mature CT, which is generated as a result of the removal of
the C-terminal glycine from the immature CT by peptidyl-
glycine a-amidating monooxygenase (PAM).7 Mature CT is
stored in secretary granules and is secreted into the blood to
regulate the calcium concentration. In the presence of mi-
crobial infection, non-neuroendocrine tissues also express the
CALC-1 gene to produce PCT. A microbial infection induces
a substantial increase of CALC-1 gene expression in all paren-
chymal tissue and differentiated cell types in the body produc-
ing PCT.8 Its levels increase significantly in severe systemic
infections, as compared to other parameters of microbial
infections.9 The function of PCT synthesized in the non-
neuroendocrine tissues under microbial infection is presently
unclear; however, its detection has helped in the differential
diagnosis of inflammatory processes.
Overview of Sepsis
Sepsis refers to the systemic response to infection by micro-
bial agents, such as bacteria, fungi, and yeast, where the patient
typically develops fever, tachycardia, tachypnea, and leukocyto-
sis. Microbiologic cultures from the blood or the infection site
are frequently, although not invariably, positive. Severe sepsis is

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 Overview

followed by genitourinary infec-

tions, and gastrointestinal infec-
tions.11 Recently there has been
an increasing number of reports
on bacterial infections of hospi-
talized patients due to increased
nosocomial infections from cathe-
terization and immunosuppressive
therapies, in addition to increased
causes of methicillin-resistant
Staphylococcus aureus (MRSA).11
Distinguishing inflammation
due to bacterial, other microbial
infection, or organ rejection is
important in the treatment of the
immune reaction in hospitalized
patients. A common problem in
the clinical practice is that the
signs and symptoms of bacterial
and viral infections are widely
overlapping, especially in respira-
tory tract infections. Occasionally
the diagnostic uncertainty still
remains, even after obtaining
a patient history, performing a
physical examination, chest x-ray
test, and laboratory tests. Thus, a
laboratory test with more specific-
ity would significantly improve
the clinical differential diagnosis
in these cases. In addition, the
differential diagnosis of infection
would help in deciding whether
treatment with antibiotics would
be beneficial. In this regard, ap-
proximately 75% of all antibiotic
doses are prescribed for acute
Figure 1_Schematic showing the relationship of procalcitonin, calcitonin, and calcitonin respiratory infections that have
carboxypeptide-1. a predominantly viral etiology.5
The excessive use of antibiotics is
the main cause for the spread of
antibiotic-resistant bacteria. Thus,
associated with the hypoperfusion or dysfunction of at least decreasing the use of antibiotics is essential in combating the
1 organ. When severe sepsis is accompanied by hypotension increase of antibiotic-resistant micro-organisms.
or multiple organ system failure, the condition is known as
septic shock. Epidemiological studies indicate an incidence
of approximately 750,000 sepsis cases per year in the United
States.10 The signs and symptoms of sepsis are highly variable Diagnostic Methods for Sepsis
and are influenced by many factors, including the virulence The traditional method of diagnosis for sepsis includes
and bioburden of the pathogen, the portal of entry, and the culturing blood, urine, cerebrospinal fluid (CSF), or bron-
host susceptibility. Primary sites are respiratory tract infections, chial fluid specimens and usually takes 24 to 48 hours. Un-
fortunately, clinical symptoms
frequently manifest themselves in
the absence of a positive culture.
Table 1_The Relationship Between the Calcitonin Superfamily of Peptides The traditional clinical signs of
infection and the routine labora-
Chromosome 11 11 11 12 11 tory tests for sepsis, such as CRP
Genes CALC-1 CALC-II CALC-III CALC-IV CALC-V
or leukocyte count, lack diagnos-
Peptides *PCT I CGRP-II Pseudogene (non-translated gene)31 Amylin Adrenomedullin tic accuracy and are sometimes
*PCT II    misleading. In severe infections,
CGRP-I most classical pro-inflammatory
*PCT II differs from PCT I by 8 amino acids at the C terminus. cytokines, such as TNF-α, IL-1β,
or IL-6, are increased only briefly

174
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 Overview

or intermittently, if at all. In view of the

above diagnostic and therapeutic dilemmas,
a more unequivocal test for the differential
diagnosis of infection and sepsis is of para-
mount importance.

PCT Measurement in the Diagnosis

of Bacterial Infection
Since the mid 1990s, there has been an
increasing use of PCT measurements in identi-
fying systemic bacterial infections.3 The short
half-life (25–30 hours in plasma) of PCT,
coupled with its virtual absence in health and
specificity for bacterial infections, gives it a
clear advantage over the other markers of bac-
terial infection.3,4 Studies have also shown that
an increase in PCT levels is minimal in viral
infections while levels increase rapidly after a
single injection with endotoxin.12,13 Further-
more, elevations in PCT are not associated with
specific bacterial strains, although in a study
by Rowther and colleagues, strains from septic
patients with serum PCT levels >2 ng/mL were
identified and listed.14 Recently, Jacquot and
colleagues demonstrated that rapid measure-
ment of PCT could help rule out nosocomial Figure 2_Schematic showing the principles of TRACE technology.
infection in newborns hospitalized in intensive
care units.15
In another study, de Jager and colleagues
investigated the value of measuring PCT levels in the blood of while the acceptor molecule upon excitation emits a short-lived
patients infected with community-acquired pneumonia (CAP) signal in the nano-second range at 665 nm. When both mole-
caused by Legionella pneumophila in comparison to other cules are brought into close proximity by binding to PCT, the
conventional parameters such as CRP and WBC counts.16 resultant signal is amplified at 665 nm and prolonged to last
They found that initial high levels of PCT were indicative of a for a few micro-seconds. This prolongation ensures the signal
more severe disease, and this was reflected in a longer patient can be measured after the background fluorescence (common
stay in the intensive care unit (ICU) and/or in-hospital death. in biological samples) has decayed. In the BRAHMS’ assay,
Furthermore, persistently increased levels of PCT were always the donor molecule is an Europium Cryptate labeled poly-
indicative of an unfavorable outcome. Thus, determination of clonal sheep antibody recognizing epitopes in the immature
PCT levels provided valuable information on patient progno- CT region, while the acceptor molecule is an XL665 labeled
sis that could not be determined from conventional inflamma- monoclonal antibody raised against the CCP-1 region of
tory parameters such as CRP and WBC counts. Furthermore, PCT.18,19
the use of PCT measurements to efficiently treat patients with Samples suitable for the assay can be serum or plasma
antibiotics has been shown to decrease patient hospital stay. using either EDTA or heparin as the anticoagulants but not
Kristoffersen and colleagues reported that in those patients citrate since this has been shown to underestimate PCT levels.18
with chronic obstructive pulmonary disease, a single serum
PCT determination at the time of admission reduced the
mean length of stay from 7.1 days to 4.8 days.17
PCT Measurements in Other Diseases
Usefulness of PCT as a diagnostic marker in other in-
flammatory states has also been evaluated and reviewed by
Measurement of PCT Becker and co-workers.20 In malaria, PCT levels are elevated
Procalcitonin can be measured using a quantitative ho- in both severe and uncomplicated Plasmodium falciparum
mogenous assay (BRAHMS, Hennigsdorf, Germany). The malaria but could not be used to differentiate between the
assay is based on Time Resolved Amplified Cryptate Emission 2 types and was thus of limited use in its diagnosis.21,22 The
(TRACE) technology (Figure 2). A nitrogen laser at 337 nm value of PCT in the diagnosis of pulmonary tuberculosis
is directed at a sample containing PCT and 2 fluorescently (PTB) has also been investigated and shown to have little
labeled antibodies recognizing different epitopes of the PCT value.19 Baylan and co-workers found that serum PCT levels
peptide. The principal of the assay is based on the transfer of were slightly high on admission in patients with active PTB
non-radiative energy between “donor” and “acceptor” mol- in comparison with controls and patients on anti-tuberculous
ecules. The donor molecule, upon excitation, emits a long- chemotherapy. Although this difference was statistically
lived fluorescent signal in the milli-second range at 620 nm, significant, the PCT levels of most cases with PTB (58.7%)

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 Overview
were below the usual cut-off level (0.5 ng/mL).23 Hence,
PCT was not a reliable indicator in the diagnosis of active
PTB and could not be substituted for microbiological, epide-
miological, clinical, and radiological data.23 Nyamande and
Lalloo, however, found that PCT levels could be useful in
distinguishing community-acquired pneumonia (CAP) due
to common bacteria, such as Mycobacterium tuberculosis (TB)
and Pneumocystis jirovecii (PJP) in a high HIV prevalence
setting where atypical presentations often confounded the
empirical clinical diagnosis.24 Their study showed that PCT
levels differ significantly in patients with CAP due to TB,
PJP, and bacteria.
Procalcitonin determinations have been found consider-
able value in identifying whether inflammation following an
organ transplant is due to bacterial infection or organ rejec-
tion. Mendonca and colleagues demonstrated that in liver
transplant recipients, plasma PCT levels were significantly
increased in infected patients in comparison to those that had
acute liver rejection in whom the levels were similar to those
of non-complicated patients.25 Madershahian and co-workers
showed PCT levels following heart transplantation could serve
as a useful marker of prognosis.26 Procalcitonin levels were
found to be consistently low (<10 ng/mL) in patients with an
uneventful course following transplant but more frequently
increased in patients with postoperative complications and
even associated with an increased mortality early postopera-
tively when values exceed 80 ng/mL. Thus, PCT levels in the
first few days following cardiac transplantation could help
identify patients at risk for complications, when concentra-
tions exceeded the “normal” post-transplant range.26
Pitfalls in PCT Measurement
There are also reports in the literature where elevations
in PCT levels were not connected with bacterial infections.
Addisonian crisis caused by adrenal failure has been associated
with elevated PCT levels.27 Increased PCT levels, comparable
to what is observed in severe sepsis, were also seen in trans-
plant patients receiving pan T-cell antibody therapy.28 More
recently, Brodska and colleagues reported marked elevations
in PCT and CRP levels in patients scheduled for hematopoi-
etic stem cell transplantation and receiving anti-thymocyte
globulin during conditioning.29
Summary
Over the past 15 years, the use of PCT in identifying the
bacterial or non-bacterial origin of systemic inflammation has
been gaining widespread support, and it is likely this trend
will continue. Although PCT has proved to be an interesting
marker of sepsis, its physiological role still remains uncertain.
There is evidence suggesting the use of PCT in monitoring
patients with sepsis leads to reduced morbidity and mortality
of these patients. Administration of PCT to septic hamsters
increased their death rate, while anti-PCT antibody adminis-
tration increased their survival rate.30 The almost lack of PCT
expression in the healthy state and its expression in virtually
every organ during sepsis fuels the notion it is intrinsically
associated with the characteristic “organ shutdown” of severe
sepsis. Further research designed at elucidating the role of
PCT in sepsis would help in understanding the pathogenesis
176
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of sepsis with the aim to develop better and more efficacious
therapeutic regimens. LM
Acknowledgements: The authors would like to thank
Chris Ciotti, Stephen Barnes, and Jim Bromley (BRAHMS
USA) for helpful discussions on technical and clinical aspects
of the PCT assay.
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