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cgi

Critical Care Medicine


Issue: Volume 28(4), April 2000, pp 977-983
Copyright: 2000 Lippincott Williams & Wilkins, Inc.
Publication Type: [Clinical Investigations]
ISSN: 0090-3493
Accession: 00003246-200004000-00011
Keywords: calcitonin, infection, sepsis, inflammation, critical illness, acute disease, protein precursors, diagnosis, differential
diagnosis, biological markers, antibiotics

[Clinical Investigations]

Calcitonin precursors are reliable markers of sepsis in a medical


intensive care unit
Mller, Beat MD; Becker, Kenneth L. MD, PhD; Schchinger, Hartmut MD; Rickenbacher, Peter R. MD; Huber, Peter R.
PhD; Zimmerli, Werner MD; Ritz, Rudolf MD

Author Information
From the Divisions of Medical Intensive Care (Drs. Mller, Schchinger, Rickenbacker, and Ritz) and Infectious
Diseases (Dr. Zimmerli), and the Department of Internal Medicine, Hormone Laboratory, Department of Chemical
Pathology (Dr. Huber), University Hospitals, Basel, Switzerland, and the Division of Endocrinology, and the
Department of Medicine, the Veterans Affairs Medical Center and George Washington University, Washington,
DC (Dr. Becker).
Supported, in part, by funds from the Division of Medical Intensive Care, University Hospitals, Basel, Switzerland.
We are indebted to the Brahms Company, Berlin, Germany, for providing some of the kit material.
Address requests for reprints to: Beat Mller; MD, Division of Endocrinology, Diabetology, and Metabolism, Dept.
of Internal Medicine, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland. E-mail:
happymiller@bigfoot.com
Abstract

Objective: The diagnosis of infection in critically ill patients is challenging because traditional markers of
infection are often misleading. For example, serum concentrations of calcitonin pre-cursors are increased in
patients with infections. However, their predictive accuracy for the diagnosis of sepsis in unselected patients
in a medical intensive care unit (ICU) is unknown. Therefore, we compared the usefulness of serum
concentrations of calcitonin precursors, C-reactive protein, interleukin-6, and lactate for the diagnosis of
sepsis in consecutive patients suffering from a broad range of diseases with an anticipated stay of >= 24 hrs
in a medical ICU.

Design: Prospective cohort study.

Setting: Medical intensive care unit in a university medical center.

Patients: 101 consecutive critically ill patients.

Intervention: None.

Measurements and Main Results: Blood samples were collected at various time points during the course of
the disease. Systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock were

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diagnosed according to standardized criteria, and patients were reclassified daily without prior knowledge of
the serum concentrations of calcitonin precursors or interleukin-6. At admission, 99% of the patients had
systemic inflammatory response syndrome, 53% had sepsis, and 5% developed sepsis during their stay in
the ICU. Calcitonin precursors, C-reactive protein, interleukin-6, and lactate levels increased with the severity
of infection (p < .01, one-way analysis of variance). In a receiver operating characteristic curve analysis,
calcitonin precursors were found to be the most reliable laboratory variable for the diagnosis of sepsis as
compared with C-reactive protein, interleukin-6, and lactate (p < .01, for each comparison). Calcitonin
precursor concentrations of > 1 ng/mL had sensitivity of 89% and specificity of 94% for the diagnosis of
sepsis. High serum concentrations of calcitonin precursors were associated with poor prognosis (p = .01).

Conclusions: In a medical ICU, serum calcitonin precursor concentrations are more sensitive and are specific
markers of sepsis as compared with serum C-reactive protein, interleukin-6, and lactate levels.

Sepsis is a common cause of morbidity and mortality, particularly in elderly, immunocompromised, and critically
ill patients (1-3). Indeed, sepsis is the most common cause of death in medical intensive care units (ICU) (4-6).
Despite the use of new treatment modalities, the mortality rate of sepsis remains high, often because of delayed
diagnosis and treatment (7, 8). Importantly, when appropriate antibiotic therapy is administered early in the
course of the disease, the occurrence of septic shock is reduced by half (9, 10).

Critically ill patients often manifest a systemic inflammatory response syndrome (SIRS) independently of an
infection (11). The clinical signs of infection and routine laboratory tests are not specific and are sometimes
misleading. The lack of specific early markers of infection might be responsible in part for withholding, delaying,
or overutilizing antimicrobial treatment in critically ill patients (7). Moreover, the misuse of antimicrobial agents
has contributed to the emergence of multiresistant microorganisms (12, 13), and this has become a major
problem in ICUs (14). In view of this diagnostic and therapeutic dilemma, an unequivocal test for the differential
diagnosis of infection and sepsis would be useful.

Calcitonin, a 32-amino-acid amidated hormone, is initially biosynthesized as a precursor, named preprocalcitonin


(15). This protein is processed into several calcitonin precursors (Figure 1). In adults and children, infection and
sepsis have been found to be associated with increased serum levels of calcitonin precursors (16-23). These
concentrations were shown to be positively correlated with a subsequent mortality rate (20). However, the
reliability of calcitonin precursor concentrations as diagnostic markers of sepsis in an unselected population of
critically ill patients in a medical ICU is unknown.

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Figure 1. Schematic diagram of the human calcitonin precursors. Segments of the calcitonin precursors, detectable by the
assay used in this study, are striped. No evidence was found for the presence of preprocalcitonin in normal or septic
serum.

To validate the previously reported elevated calcitonin precursor levels in a well-defined cohort of patients, we
compared the usefulness of serum concentrations of calcitonin precursors, C-reactive protein, interleukin-6, and
lactate for the diagnosis of sepsis in a medical ICU in nonselected patients suffering from a broad range of
diseases.

MATERIALS AND METHODS


Study Subjects. We studied 101 consecutive patients with an anticipated stay of >= 24 hrs who had been
admitted for intensive treatment to the medical ICU of the University Hospitals, Basel, Switzerland, between
September 1996 and June 1997. Informed consent was obtained before enrollment from conscious patients. For
unconscious patients, the consent was obtained from patient next of kin. The study protocol was approved by
the local ethical committee of the University Hospitals.

Study Design. Systemic inflammatory response syndrome, sepsis, severe sepsis, or septic shock was
diagnosed according to standardized criteria (11). In the present study, we report the data collected at admission
(during the first 24 hrs), on day 2, and on the day of discharge from the ICU, or on the day of death. At those
time points, the patients were either very sick or had stabilized and were ready for discharge to a medical ward.
Thus, a very high percentage (at admission, 99%) of patients were fulfilling two or more criteria for SIRS.
Therefore, at the time points investigated, all patients found to have an infection were also fulfilling two or more
criteria of SIRS and were, therefore, classified as septic. A patient could be classified one day as septic, and,
after treatment, as having infection without SIRS. Because the clinical spectrum of SIRS to septic shock is a fluid
continuum that can progress very rapidly, the patients were classified at the time of blood collection. No patient
showed signs of infection at admission or on day 2 with fewer than two criteria of SIRS. However, this
constellation occurred in two patients with resolving pneumonia under antibiotic therapy on the day of discharge
to the medical ward. As expected, these patients showed declining, yet still elevated, calcitonin precursor levels
in the absence of SIRS (1.2 ng/mL and 3.4 ng/mL, respectively). Because the focus of this study was on sepsis,
we excluded these two time points from analysis because they did not fit in any of the defined categories.

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The clinical investigation and classification were carried out without knowledge of the test results for calcitonin
precursors or interleukin-6, which were analyzed as batch analyses after the end of the study. Additionally, all
remainders of daily routine morning blood samples were collected, and the results of these routine blood
analyses (complete blood count, serum chemistry, blood gas analyses, and C-reactive protein) were also
recorded.

Definitions. The following terms were used in the study. Systemic inflammatory response syndrome (SIRS) with
no signs of infection, is characterized by the presence of at least two of the following four clinical criteria: a) fever
or hypothermia (temperature > 100.4F [>38C] or <96.8F [<36C]); b) tachycardia (>90 beats/min); c)
tachypnea (>20 breaths/min or PaCO2 <4.3 kPa [32 mm Hg] or the need for mechanical ventilatory support);
and d) an altered white blood cell count of >12,000 cells/L, <4,000 cells/L, or the presence of >10% band
forms, respectively. Sepsis is defined as SIRS with an infection (11). Infection was diagnosed by textbook
standard criteria (24), or in case of uncertainty, by one of the authors who is an infectious disease specialist
(WZ). Severe sepsis is defined as the presence of sepsis and at least one of the following manifestations of
inadequate organ perfusion or function: a) hypoxemia (PaO2 of <10 kPa [<75 mm Hg]); b) metabolic acidosis
(pH of <7.30); c) oliguria (output of <30 mL/hr); d) lactic acidosis (serum lactate level of >2 mmol/L); or e) an
acute alteration in mental status without sedation (a reduction by >=3 points from baseline value in the Glasgow
coma score). Septic shock is defined as the presence of sepsis accompanied by a sustained decrease in
systolic blood pressure (<90 mm Hg, or a drop of 40 mm Hg from baseline systolic blood pressure) despite fluid
resuscitation and the need for vasoactive amines to maintain adequate blood pressure. Severity of disease was
estimated by the Acute Physiology and Chronic Health Evaluation II (25, 26), calculated by means of deviation
of 12 physiologic variables from normal plus correction for age and different chronic illnesses (27).

Laboratory Measurements. For rapidity of determination, in the present study we chose to use a commercially
available immunoluminometric assay to measure calcitonin precursors (LUMItest PCT; Brahms Diagnostica,
Berlin, Germany). Two monoclonal antibodies bind at sites within two peptides: calcitonin and the calcitonin
carboxypeptide I (Figure 1). Therefore, several calcitonin precursors are detected by this assay, procalcitonin,
the conjoined calcitonin:calcitonin carboxypeptide-I, and perhaps, other yet uncharacterized peptides (28, 29).
This immunoluminometric assay requires 20-50 L of plasma or serum and can be completed within 3 hrs.
Interassay and intra-assay variations at low and high concentrations were <8% and <7%, respectively. The
assay has the disadvantage of insensitivity, with a detection limit of ~0.3-0.5 ng/mL. A sensitive
radioimmunoassay for calcitonin precursors has been developed that detects aminoprocalcitonin and the intact
procalcitonin molecule (30-32). This assay, which was not available at the time the current study was
commenced, has the advantage of a sensitivity of 0.004 ng/mL and detects values in nearly all normal persons.
For elevated values, the calcitonin precursor levels obtained were similar with both assays (n = 275, r2 = .94, p <
.01 by Spearman's rank-correlation test). Recent literature (16-23) refers to measurement of procalcitonin.
However, this is incorrect, because none of the presently available assays measure the procalcitonin molecule
exclusively (Figure 1). The commercially available two-site assay that we used for this study measures both
procalcitonin and the conjoined calcitonin: calcitonin-carboxypeptide I. The more sensitive radioimmunoassay
we developed uses an antibody to the amino portion of the prohormone. It detects both the intact procalcitonin
and the free aminoprocalcitonin. We have shown (32) that in sepsis, several calcitonin precursors may be
increased (intact procalcitonin, free aminoprocalcitonin, calcitonin-carboxypeptide-I, and the conjoined
calcitonin:calcitonin-carboxypeptide I). Importantly, the extent to which any specific calcitonin precursor is
increased, relative to the other peptides in hypercalcitonemic patients, varies. We have shown (32) that in the
presence of sepsis, the levels of calcitonin-carboxypeptide I and aminoprocalcitonin may be even higher than
procalcitonin values. For exactness of terminology, we have, therefore, chosen the term calcitonin precursors to
indicate, globally, the immunoreactive material detected by these assays.

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C-reactive protein was measured by an enzyme immunoassay (EMIT C-reactive protein assay; E. Merck
Diagnostica, Zrich, Switzerland); a value of > 10 mg/L was considered to be abnormally elevated. Lactate
concentrations were measured enzymatically (Du Pont, Wilmington, DE) (reference range 1.1-2.0 mmol/L).
Serum IL-6 concentrations were measured with a commercially available quantitative sandwich enzyme
immunoassay (CLB; Pelikine Compact, Amsterdam, Netherlands) with a limit of detection at 0.6 pg/mL.

Statistical Analysis. Data in the text are shown as mean SD, and in the figures as SEM. Logarithmic
transformation was applied to reduce skewness and normalize the distribution of data, if indicated by Shapiro-
Wilk's W test. Two-group comparison (survivors vs. nonsurvivors) of normally distributed data were performed by
Student's t-test. For multigroup comparisons, one-way analysis of variance was applied, with least square
difference for post hoc comparison. For data not normally distributed, the Mann-Whitney U test was used if only
two groups were compared, and the Kruskal-Wallis one-way analysis of variance was used if more than two
groups were being compared. Predictive accuracy, the ability of a test to discriminate diseased patients from
normal patients, was assessed by measuring the 95% confidence interval of the area under a receiver-
operating-characteristic curve (33, 34). Levels that were nondetectable were assigned a value equal to the lower
limit of detection for the assay. All testing was two-tailed, and a p of <.05 was considered statistically significant
(35).

RESULTS
Descriptive Characteristics of Patients. The median age of the 101 patients (55 men and 46 women) included in
this study was 59 yrs (range, 23-86 yrs) and the mean Acute Physiology and Chronic Health Evaluation II score
at admission was 22 8 points. The median length of stay in the ICU was 4 days (range, 0.2-60 days) with a
mortality rate of 23%. The principal diagnoses of all patients are summarized in Table 1. In 70% of the 101
patients, antimicrobial therapy was administered during the ICU stay, whereas an infection was diagnosed in
58% of the patients (in 53 patients at admission; five additional patients developed sepsis during their stay in the
medical ICU). The principal site of infection was the lung (Table 2). In 38 (66%) of the 58 patients with sepsis,
the etiological microorganism was identified and 14 patients (24%) had bacteremia.

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Table 1. Clinical diagnoses of the patients

Table 2. Site of infection and microbiology

Patients fulfilling more than two SIRS criteria were as follows: 99% of 101 patients at admission, 96% of 74
patients on day 2, and 68% of 95 patients on the day of discharge or death. Patients who were discharged or
died on day 2 were classified into the latter group. The following percentages of patients were classified as
having sepsis, severe sepsis, or septic shock: 53% at admission, 60% on day 2, and 36% on the day of
discharge or death.

Laboratory Data. For the time points presented in this study, patients could be categorized into the following five
groups: patients with neither signs of infection nor SIRS were classified as having no infection and no SIRS;
patients fulfilling two or more criteria for SIRS without infection were classified as having SIRS; and patients with
infection were classified as having sepsis, severe sepsis, or septic shock as defined above. Figure 2 illustrates
the higher variability of serum interleukin-6 concentrations as compared with calcitonin precursor measurements
in critically ill patients with different severities of disease and infection during their stay at the medical ICU. In the
absence of infection, serum calcitonin precursor concentrations were not significantly elevated in patients with
SIRS as compared with patients with no SIRS. Serum calcitonin precursor concentrations were significantly
elevated only in patients with sepsis, severe sepsis, or septic shock, as compared with uninfected patients with
or without SIRS (p < .01 for each comparison). In patients with sepsis, severe sepsis, or septic shock, serum
concentrations of calcitonin precursors and C-reactive protein were higher in those with microbiologically
documented bacterial infection as compared with those with no bacterial growth (36.9 60.5 vs. 6.6 8.9 ng/mL
and 252 139 vs. 140 105 mg/L, respectively, p < .01), whereas Acute Physiology and Chronic Health
Evaluation II score, interleukin-6, and lactate concentrations were not significantly different between the groups
(23.3 10.6 vs. 21.0 10.7 points, 797 1804 vs. 483 1327 pg/mL and 3.6 6.1 vs. 3.4 4.8 mmol/L,
respectively).

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Figure 2. Serum interleukin-6 and calcitonin precursor concentrations in critically ill patients. Interleukin-6 and calcitonin
precursors measurements from the day of admission (n = 101) are represented by circles, from day 2 (n = 74) by
squares, and from the day of discharge or death (n = 97) by triangles. p values of the logarithmic data (p < .01) were
calculated by one-way analysis of variance. Logarithmic data describe the rise of serum concentrations of interleukin-6
and calcitonin precursors with increased severity of disease and infection. Statistical results were similar for data
analyzed by time point or were combined. Diamonds represent mean, boxes SEM, and whiskers 1.96 SEM of the
combined data (total n = 272). SIRS denotes systemic inflammatory response syndrome. Other terms used are defined in
the Materials and Methods section.

Serum calcitonin precursor concentrations were higher in septic patients who died than in those who survived
(33.5 55.1 vs. 17.4 41.4 ng/mL, p = .01). The diagnostic reliability of serum calcitonin precursors compared
with interleukin-6, C-reactive protein, and lactate concentrations was evaluated by using receiver operating
characteristic curve analysis (Figure 3). Calcitonin precursors were found to be the most reliable markers for the
diagnosis of sepsis at all time points investigated (p = .01).

Figure 3. Receiver-operating-curve analysis of serum calcitonin precursors (solid circles) vs. interleukin-6 (solid triangles),
C-reactive protein (open circles), and lactate (open trianlgles) concentrations. Values are shown for all time points (n =
272; 101 values at admission, 74 values on day 2, and 97 values on day of discharge or death) for the diagnoses of
sepsis, severe sepsis, or septic shock.

Table 3 summarizes the predictive accuracy of the laboratory variables for the specific diagnoses of sepsis,
severe sepsis, or septic shock. With a cutoff value of 1 ng/mL, serum concentrations of calcitonin precursors
were found to be the most discriminatory laboratory variable as compared with interleukin-6, C-reactive protein,
and lactate values.

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Table 3. Evaluation of laboratory parameters for the diagnosis of sepsis in a medical intensive care unit (%)

DISCUSSION
The recognition of sepsis in critically ill patients is difficult because no single variable of inflammation allows the
establishment of the diagnosis (36). In this study of unselected but well-defined patients in a medical ICU, serum
calcitonin precursor concentrations were shown to be the most reliable markers for the diagnosis of sepsis;
furthermore, higher serum concentrations were associated with poorer prognosis.

The population of the present study was representative of patients admitted to a medical ICU (3, 37). It included
a broad range of unselected medical patients with severe illnesses, unlike prior studies focusing on selected
subpopulations, and excluding patients without infection or sepsis. The relatively high rate of negative culture
results found in this study illustrates a common diagnostic dilemma for the clinician in a medical ICU, namely,
many patients have been treated before admission, thus making the identification of a pathogenic
microorganism often impossible (38). Hence, there is no gold standard to accurately diagnose sepsis, and all
definitions and classifications are limited (39). To accurately validate signs and symptoms of infection, we
applied standardized textbook definitions (24) and the expertise of a board-certified, infectious disease specialist
(WZ).

Serum calcitonin precursor and interleukin-6 concentrations were determined in a blinded fashion and, therefore,
did not influence the clinical evaluation of the patients. In contrast, the interpretation of C-reactive protein and
lactate might be biased because their serum concentrations were known at the time of clinical investigation and
classification. The reliability of interleukin-6, C-reactive protein, and lactate was mainly limited by the high
variability of the test results in the different subgroups, thus reducing their usefulness as diagnostic markers in
individual patients. These traditional markers reflect the nonspecific response of the organism to various stimuli,
all resulting in a relatively common systemic inflammatory response, present in most critically ill patients (40,
41). In addition, only approximately half of the patients with septic syndrome have shown elevated cytokine
levels (42, 43). Reported results of different cytokine-studies are contradictory. For example, very high
concentrations of cytokines were reported (44) in patients with a rapid onset of septic shock; however, this could
not be confirmed in another trial (45). The conflicting results in the literature, and the high variance found in the
present study, might be explained by a sudden, transient, rather than sustained, cytokine release attributable to
down-regulating mechanisms. Consequently, the levels of cytokines diminish despite ongoing infection and,
therefore, are not reliable markers for the course of an infection (46). Another disadvantage is the bioinstability
of some cytokines, such as tumor necrosis factor-[alpha], requiring immediate refrigeration and involving a
fastidious, time-consuming determination. In contrast, calcitonin precursors are stable in vitro (47), and their
analysis is rapid and easily performed.

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The origin, metabolic pathway, and mediators responsible for the marked increase of calcitonin precursors
during sepsis are enigmatic. These peptides are found in low concentrations in sera of normal persons, and
several of these are variably increased in systemic inflammation, infection, and sepsis (31). Whether or not
bacterial infection has been found, increased serum calcitonin precursor levels occur in pancreatitis (48, 49),
chemical pneumonitis (50), burns (51, 52), and heat stroke (53). In addition, some parasitic infections such as
malaria (54) or fungal infections (55), can substantially increase serum calcitonin precursor levels. Also, viral
infections occasionally manifest moderately elevated calcitonin precursor concentrations (56). Whatever the
initiating provocative insult may be, markedly severe systemic inflammation, per se, may manifest increased
serum levels of calcitonin precursors. Additional studies are required to determine whether the increased serum
calcitonin precursor levels of such apparently non-bacterial insults are a manifestation of translocation to the
blood stream of bacterial products from the gut (57). The calcitonin precursor assay we used is reliable for the
diagnosis of sepsis in a medical ICU. However, it does not detect the hypercalcitonemia of incipient and mild
degrees of systemic inflammation or infection. Toward this goal, an alternative assay has been developed (31,
52).

The administration of the calcitonin prohormone, procalcitonin, to septic hamsters with peritonitis markedly
decreases their survival. Furthermore, treatment with procalcitonin-reactive antiserum increased survival of
hamsters with experimental sepsis (58). These observations indicate that the procalcitonin molecule is a
potentially harmful mediator involved in the response to sepsis. Whether treatment with antiserum reactive with
this prohormone is able to improve the prognosis of sepsis in humans remains to be clarified in future studies.

In summary, this study suggests that the measurement of calcitonin precursors is a reliable and important
marker for the diagnosis of sepsis in a medical ICU. The early diagnosis of sepsis might facilitate rapid initiation
of antimicrobial and other appropriate treatment, thus potentially improving the unfavorable prognosis of sepsis
and septic shock.

ACKNOWLEDGMENT
We are indebted to the staff of the medical ICU and of the laboratory of pathologic chemistry, University
Hospitals, Basel, Switzerland. We thank M. A. Viollier, Th. Witschi, R. H. Snider, R. Landmann, J. Hoch, and M.
Fischer for their help.

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Key Words: calcitonin; infection; sepsis; inflammation; critical illness; acute disease; protein precursors;
diagnosis; differential diagnosis; biological markers; antibiotics

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Figure 1 Table 2
Table 1

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Table 3

Figure 3

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