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Objective: The use of procalcitonin (ProCT) as a marker of extrapolated inappropriately to clinical usage. Furthermore, at-
several clinical conditions, in particular, systemic inflammation, tempts at meta-analyses are greatly compromised by the diver-
infection, and sepsis, will be clarified, and its current limitations gent circumstances of reported studies and by the sparsity and
will be delineated. In particular, the need for a more sensitive different timing of the ProCT assays. Although a high ProCT
assay will be emphasized. For these purposes, the medical liter- commonly occurs in infection, it is also elevated in some nonin-
ature comprising clinical studies pertaining to the measurement fectious conditions. Thus, the test is not a specific indicator of
of serum ProCT in various clinical settings was examined. either infection or sepsis. Moreover, in any individual patient, the
Data Source and Selection: A PubMed search (1965 through precipitating cause of an illness, the clinical milieu, and compli-
November 2007) was conducted, including manual cross-refer- cating conditions may render tenuous any reliable estimations of
encing. Pertinent complete publications were obtained using the severity or prognosis. It also is apparent that even a febrile septic
MeSH terms procalcitonin, C-reactive protein, sepsis, and biolog-
patient with documented bacteremia may not necessarily have a
ical markers. Textbook chapters were also read and extracted.
serum ProCT that is elevated above the limit of functional sensi-
Data Extraction and Synthesis: Available clinical and other
tivity of the assay. In this regard, the most commonly applied
patient data from these sources were reviewed, including any
data relating to precipitating factors, clinical findings, associated assay (i.e., LUMItest) is insufficiently sensitive to detect poten-
illnesses, and patient outcome. Published data concerning sensi- tially important mild elevations or trends. Clinical studies with a
tivity, specificity, and reproducibility of ProCT assays were re- more sensitive ProCT assay that is capable of rapid and practi-
viewed. cable day-to-day monitoring are needed and shortly may be
Conclusions: Based on available data, the measurement of available. In addition, investigations showing that ProCT and its
serum ProCT has definite utility as a marker of severe systemic related peptides may have mediator relevance point to the need
inflammation, infection, and sepsis. However, publications con- for evaluating therapeutic countermeasures and studying the
cerning its diagnostic and prognostic utility are contradictory. In pathophysiologic effect of hyperprocalcitonemia in serious infec-
addition, patient characteristics and clinical settings vary mark- tion and sepsis. (Crit Care Med 2008; 36:941–952)
edly, and the data have been difficult to interpret and often KEY WORDS: procalcitonin; inflammation; infection; sepsis
I n the past decade, there have been to clinical usage. Moreover, some have tients harboring neuroendocrine tumors
a large number of publications reported disappointing results or unen- (8) (Table 1). This increase occurred in
concerning procalcitonin (ProCT) thusiastic conclusions (1–7). The objec- persons with cancer of the neuroendo-
as a serum marker of systemic in- tive of the authors is to review the mea- crine C-cells of the thyroid (i.e., medul-
flammation, infection, and sepsis. Results surement of serum ProCT in several lary thyroid cancer) (9), in those with
from these studies vary greatly according clinical settings, to discuss its clinical small cell cancer of the lung (10), and in
to the type of protocol, diverse character- utility and its limitations, and to elabo- those with a carcinoid tumor. Conse-
istics of the patients, clinical milieu, and rate on the need for a more sensitive and quently, CT was established as a serum
conclusions drawn from the data. Al- practicable test that would enable serial marker to assist in the diagnosis or fol-
though most reports were promising, determinations. Furthermore, although low-up of many of these patients and to
some were extrapolated inappropriately its use in infections and sepsis will be evaluate their response to therapy (9, 11).
discussed in detail, it will be emphasized Subsequently, it was demonstrated that
that elevations of serum ProCT are not not only the CT hormone but also its
specific for these conditions. larger molecular weight precursors, in
From Veterans Affairs Medical Center (KLB, RS,
ESN) and George Washington University (KLB, ESN), particular, the 116-aminoacid prohor-
Washington, DC. Hyperprocalcitonemia in mone, ProCT, are increased in these con-
The authors have not disclosed any potential con- ditions (12). Indeed, it now has been
flicts of interest.
Neuroendocrine Cell Disorders
shown that an assay for ProCT may be as
For information regarding this article, E-mail:
drkbecker@gmail.com Initially, it was determined that levels useful a marker for medullary thyroid
Copyright © 2008 by the Society of Critical Care of the mature 32-amino acid hormone, cancer as is the assay for CT (13).
Medicine and Lippincott Williams & Wilkins calcitonin (CT), and its related peptides Remarkably, in these neoplastic con-
DOI: 10.1097/CCM.0B013E318165BABB are increased in the serum of some pa- ditions, increased levels of serum CT and
LUMItest2 BRAHMS ILMA Commercial ProCT and 80 500 235 2 hrs 45 mins
CT:CCP1
ProCa-S BRAHMS ILMA Research ProCT and 5 20 31 3 hrs
CT:CCP1
PCT sensitive BRAHMS ILMA Research ProCT and 5 50 13 3 hrs
CT:CCP1
Kryptor BRAHMS TRACE Commercial ProCT and 20 60 53 50, 25–45 minsd
CT:CCP1
QPCT BRAHMS Solid-phase Commercial ProCT and (500) (500) (500) Bedside
CT:CCP1
NProCT Becker ELISA Research ProCT and 10 20 33e 16–18 hrs
NProCT
ILMA, immunoluminometric assay; ProCT, procalcitonin; CT:CCPI, the conjoined peptide consisting of calcitonin ⫹ calcitonincarboxypeptide 1 (see
Becker et al (8)); NProCT, aminoprocalcitonin; TRACE, time-resolved amplified cryptate emission; ELISA, enzyme-linked immunosorbent assay. As shown
above, no currently available commercial assay measures procalcitonin exclusively. All detect at least one other constituent of this prohormone. High-power
liquid chromatography studies of calcitonin gene peptides extracted from concentrated normal human serum reveal very low levels of ProCT (2.46 pg/mL)
along with its component peptides (NProCT, CT, and CCP1) (18). In hyperprocalcitonemic states, procalcitonin and its constituent peptides all may be
increased to varying extent from patient to patient. Unless the hyperprocalcitonemia is due to secretion from a neuroendocrine tumor, the amidated free
CT remains low. CT is not measured in any of the above assays. Because ProCT is always increased whenever NProCT and/or CT:CCP1 is increased, for
simplicity of expression, the assay is referred to by all investigators as a “procalcitonin” assay. aBased on the assay performance from the authors’ laboratory;
b
only the LUMItest is currently available in the US (data obtained from the manufacturer’s data sheet); cdiscrepancy between functional sensitivity and
healthy control values (LUMItest, PCT sensitive, Kryptor) imply great uncertainty in actual values; dfirst number is time until results are obtained for first
sample, and second range is time for second sample and dilution, if necessary; ethis level is 90% aminoprocalcitonin; based on chromatography studies,
the actual mean level of ProCT in healthy controls is ⬍4 pg/mL. ProCT ⫹ CT:CCP1 ⬍5 pg/mL.
Table 2. Principal causes of hyperprocalcitonemia that detects the 116 kDa ProCT peptide values less than this level (2, 22–28).
exclusively. Depending on the type of as- With this assay, values below this level
A. Neuroendocrine tumors
Medullary thyroid cancer
say, all tests detect various portions of are best referred to as indeterminate.
Small cell lung cancer several CT precursors (Table 2). More- Furthermore, because 0.5 ng/mL exceeds
Carcinoid syndrome over, the determination of minimally el- the average normal value by more than
B. Noninfectious systemic inflammation evated values of serum ProCT and the ten-fold, many mild increases in ProCT
Inhalational injury
Pulmonary aspiration
reproducible detection of small changes values are missed.
Pancreatitis from day to day require an assay that is Pathophysiology of Hyperprocalci-
Heat stroke very sensitive (15, 16). In 1995, the au- tonemia. Subsequent to the discovery of
Mesenteric infarction thors developed such an assay for the the secretion of ProCT by neuroendo-
C. Severe infection
aminoterminus of ProCT that also detects crine neoplasms, it was demonstrated
Bacterial
Viral the intact ProCT prohormone (17). This that the large molecular weight precur-
Parasitic research assay quantitates normal levels sors of CT, including ProCT, were also
D. Sepsis (0.033 ⫾ 0.003 ng/mL, 90% of which is markedly increased in the sera of patients
E. Trauma
aminoprocalcitonin) (18); its utility in with severe systemic inflammatory con-
Mechanical injury
Burns evaluating systemic inflammation and ditions, such as inhalational injury (29),
Surgery sepsis has been reported in several pub- pulmonary aspiration (30), severe burns
lications (18 –21). However, the assay uti- (31, 32), pancreatitis (33, 34), heat stroke
lized in the vast majority of studies (35), mesenteric infarction (36), multi-
throughout the world is the immunolu- trauma (37, 38), and extensive surgery
its precursors do not seem to be detri-
minometric PCT assay (i.e., LUMItest, (24, 39), and in infections such as pneu-
mental, nor are there any observable clin-
BRAHMS, Henningsdorf, Germany), monitis (30). In 1983, increased serum
ical effects. Thus, patients with medullary
which detects the ProCT prohormone ProCT was reported (albeit at that time
thyroid cancer, whose sera often contain
and the conjoined segment of CT and described as a high molecular weight
enormous levels of this family of pep-
tides, may live for many years without calcitonin-carboxyl-peptide I. Although form of CT) in the infectious illness as-
signs or symptoms other than the me- the sensitivity of this assay is purportedly sociated with toxic shock syndrome (40),
chanical effects of the primary or meta- 0.08 ng/mL (i.e., the low standard pro- and later also in sepsis (41) (as discussed
static lesions (14). vided), the functional sensitivity is ⵑ0.5 below). In contrast to the neuroendo-
ng/mL (Table 1) (21). Thus, any reference crine cell origin of medullary thyroid
in the literature for this assay that spec- cancer, small cell cancer of the lung, and
Current ProCT Assay
ifies a ProCT level of ⬍0.5 ng/mL is un- the carcinoid tumor, in marked systemic
Although it would be highly desirable, certain and subject to great error. Appro- inflammatory conditions such as infec-
there is no assay (research or otherwise) priately, some authors chose to disregard tion and sepsis, the principal source of
Fold Increase
able (18). The cause for this nearly ubiq-
uitous constitutive secretion may be due
to changes in the promotor for the ProCT 600