2000 - Calcitonin Precursors Are Reliable Markers of Sepsis in a Medical Intensive Care Unit (CritCare)

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Critical Care MedicineNúmero: Volume 28(4), April 2000, pp 977-983Copyright: © 2000 Lippincott Williams & Wilkins, Inc.Tipo de publicación: [Clinical Investigations]ISSN: 0090-3493Registro: 00003246-200004000-00011Palabras clave: calcitonin, infection, sepsis, inflammation, critical illness, acute disease, protein precursors, diagnosis, differential diagnosis, biological markers, antibiotics

Calcitonin precursors are reliable markers of sepsis in a medical intensive care unitMüller, Beat MD; Becker, Kenneth L. MD, PhD; Schächinger, Hartmut MD; Rickenbacher, Peter R. MD; Huber, Peter R. PhD; Zimmerli, Werner MD; Ritz, Rudolf MD

Información sobre el autorFrom the Divisions of Medical Intensive Care (Drs. Müller, Schächinger, 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 theDepartment 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 Müller; MD, Division of Endocrinology, Diabetology, and Metabolism, Dept. of Internal Medicine, University Hospital, Petersgraben 4,

CH-4031 Basel, Switzerland. E-mail: [email protected]

Abstract

Objective: The diagnosis of infection in critically ill patients is challenging because traditional markers ofinfection are often misleading. For example, serum concentrations of calcitonin pre-cursors are increased in patientswith infections. However, their predictive accuracy for the diagnosis of sepsis in unselected patients in a medicalintensive care unit (ICU) is unknown. Therefore, we compared the usefulness of serum concentrations of calcitoninprecursors, C-reactive protein, interleukin-6, and lactate for the diagnosis of sepsis in consecutive patients sufferingfrom 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 thedisease. Systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock were diagnosed accordingto standardized criteria, and patients were reclassified daily without prior knowledge of the serum concentrations ofcalcitonin precursors or interleukin-6. At admission, 99% of the patients had systemic inflammatory responsesyndrome, 53% had sepsis, and 5% developed sepsis during their stay in the ICU. Calcitonin precursors, C-reactiveprotein, 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 mostreliable 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 specificityof 94% for the diagnosis of sepsis. High serum concentrations of calcitonin precursors were associated with poorprognosis (p = .01).

Conclusions: In a medical ICU, serum calcitonin precursor concentrations are more sensitive and are specificmarkers 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 criticallyill 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 delayeddiagnosis and treatment (7, 8). Importantly, when appropriate antibiotic therapy is administered early in the courseof 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 aninfection (11). The clinical signs of infection and routine laboratory tests are not specific and are sometimesmisleading. The lack of specific early markers of infection might be responsible in part for withholding, delaying, or

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misleading. The lack of specific early markers of infection might be responsible in part for withholding, delaying, oroverutilizing antimicrobial treatment in critically ill patients (7). Moreover, the misuse of antimicrobial agents hascontributed to the emergence of multiresistant microorganisms (12, 13), and this has become a major problem inICUs (14). In view of this diagnostic and therapeutic dilemma, an unequivocal test for the differential diagnosis ofinfection 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 andsepsis have been found to be associated with increased serum levels of calcitonin precursors (16-23). Theseconcentrations were shown to be positively correlated with a subsequent mortality rate (20). However, the reliabilityof calcitonin precursor concentrations as diagnostic markers of sepsis in an unselected population of critically illpatients in a medical ICU is unknown.

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

To validate the previously reported elevated calcitonin precursor levels in a well-defined cohort of patients, wecompared the usefulness of serum concentrations of calcitonin precursors, C-reactive protein, interleukin-6, andlactate 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 beenadmitted for intensive treatment to the medical ICU of the University Hospitals, Basel, Switzerland, betweenSeptember 1996 and June 1997. Informed consent was obtained before enrollment from conscious patients. Forunconscious patients, the consent was obtained from patient next of kin. The study protocol was approved by thelocal ethical committee of the University Hospitals.

Study Design. Systemic inflammatory response syndrome, sepsis, severe sepsis, or septic shock was diagnosedaccording to standardized criteria (11). In the present study, we report the data collected at admission (during thefirst 24 hrs), on day 2, and on the day of discharge from the ICU, or on the day of death. At those time points, thepatients were either very sick or had stabilized and were ready for discharge to a medical ward. Thus, a very highpercentage (at admission, 99%) of patients were fulfilling two or more criteria for SIRS. Therefore, at the time pointsinvestigated, 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

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therefore, classified as septic. A patient could be classified one day as septic, and, after treatment, as havinginfection without SIRS. Because the clinical spectrum of SIRS to septic shock is a fluid continuum that can progressvery rapidly, the patients were classified at the time of blood collection. No patient showed signs of infection atadmission or on day 2 with fewer than two criteria of SIRS. However, this constellation occurred in two patients withresolving pneumonia under antibiotic therapy on the day of discharge to the medical ward. As expected, thesepatients showed declining, yet still elevated, calcitonin precursor levels in the absence of SIRS (1.2 ng/mL and 3.4ng/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.

The clinical investigation and classification were carried out without knowledge of the test results for calcitoninprecursors or interleukin-6, which were analyzed as batch analyses after the end of the study. Additionally, allremainders 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) withno signs of infection, is characterized by the presence of at least two of the following four clinical criteria: a) feveror hypothermia (temperature > 100.4°F [>38°C] or <96.8°F [<36°C]); 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/µL, <4,000 cells/µL, 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 ofuncertainty, by one of the authors who is an infectious disease specialist (WZ). Severe sepsis is defined as thepresence 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 (areduction by >=3 points from baseline value in the Glasgow coma score). Septic shock is defined as the presence ofsepsis accompanied by a sustained decrease in systolic blood pressure (<90 mm Hg, or a drop of 40 mm Hg frombaseline systolic blood pressure) despite fluid resuscitation and the need for vasoactive amines to maintain adequateblood 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 chronicillnesses (27).

Laboratory Measurements. For rapidity of determination, in the present study we chose to use a commerciallyavailable 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 carboxypeptideI (Figure 1). Therefore, several calcitonin precursors are detected by this assay, procalcitonin, the conjoinedcalcitonin:calcitonin carboxypeptide-I, and perhaps, other yet uncharacterized peptides (28, 29). Thisimmunoluminometric assay requires 20-50 µL of plasma or serum and can be completed within 3 hrs. Interassay andintra-assay variations at low and high concentrations were <8% and <7%, respectively. The assay has the disadvantageof insensitivity, with a detection limit of ~0.3-0.5 ng/mL. A sensitive radioimmunoassay for calcitonin precursors hasbeen developed that detects aminoprocalcitonin and the intact procalcitonin molecule (30-32). This assay, which wasnot available at the time the current study was commenced, has the advantage of a sensitivity of 0.004 ng/mL anddetects 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 tomeasurement of procalcitonin. However, this is incorrect, because none of the presently available assays measurethe procalcitonin molecule exclusively (Figure 1). The commercially available two-site assay that we used for thisstudy measures both procalcitonin and the conjoined calcitonin: calcitonin-carboxypeptide I. The more sensitiveradioimmunoassay we developed uses an antibody to the amino portion of the prohormone. It detects both the intactprocalcitonin and the free aminoprocalcitonin. We have shown (32) that in sepsis, several calcitonin precursors maybe increased (intact procalcitonin, free aminoprocalcitonin, calcitonin-carboxypeptide-I, and the conjoinedcalcitonin:calcitonin-carboxypeptide I). Importantly, the extent to which any specific calcitonin precursor isincreased, relative to the other peptides in hypercalcitonemic patients, varies. We have shown (32) that in thepresence of sepsis, the levels of calcitonin-carboxypeptide I and aminoprocalcitonin may be even higher thanprocalcitonin values. For exactness of terminology, we have, therefore, chosen the term calcitonin precursors toindicate, globally, the immunoreactive material detected by these assays.

C-reactive protein was measured by an enzyme immunoassay (EMIT C-reactive protein assay; E. MerckDiagnostica, Zürich, Switzerland); a value of > 10 mg/L was considered to be abnormally elevated. Lactateconcentrations 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. Logarithmictransformation was applied to reduce skewness and normalize the distribution of data, if indicated by Shapiro-Wilk'sW test. Two-group comparison (survivors vs. nonsurvivors) of normally distributed data were performed by Student'st-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 werecompared, and the Kruskal-Wallis one-way analysis of variance was used if more than two groups were being

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compared, and the Kruskal-Wallis one-way analysis of variance was used if more than two groups were beingcompared. Predictive accuracy, the ability of a test to discriminate diseased patients from normal patients, wasassessed 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. Alltesting 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 inthis study was 59 yrs (range, 23-86 yrs) and the mean Acute Physiology and Chronic Health Evaluation II score atadmission was 22 ± 8 points. The median length of stay in the ICU was 4 days (range, 0.2-60 days) with a mortalityrate 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 thepatients (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 etiologicalmicroorganism was identified and 14 patients (24%) had bacteremia.

Table 1. Clinical diagnoses of the patients

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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 74patients on day 2, and 68% of 95 patients on the day of discharge or death. Patients who were discharged or died onday 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 followingfive 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 withinfection were classified as having sepsis, severe sepsis, or septic shock as defined above. Figure 2 illustrates thehigher variability of serum interleukin-6 concentrations as compared with calcitonin precursor measurements incritically ill patients with different severities of disease and infection during their stay at the medical ICU. In theabsence of infection, serum calcitonin precursor concentrations were not significantly elevated in patients with SIRSas compared with patients with no SIRS. Serum calcitonin precursor concentrations were significantly elevated only inpatients 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 calcitoninprecursors and C-reactive protein were higher in those with microbiologically documented bacterial infection ascompared 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 lactateconcentrations 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 andcalcitonin 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 ofinterleukin-6 and calcitonin precursors with increased severity of disease and infection. Statistical results weresimilar 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 usedare 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 withinterleukin-6, C-reactive protein, and lactate concentrations was evaluated by using receiver operating characteristiccurve analysis (Figure 3). Calcitonin precursors were found to be the most reliable markers for the diagnosis of sepsisat all time points investigated (p = .01).

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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 alltime points (n = 272; 101 values at admission, 74 values on day 2, and 97 values on day of discharge or death) for thediagnoses 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 werefound to be the most discriminatory laboratory variable as compared with interleukin-6, C-reactive protein, andlactate values.

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 theestablishment of the diagnosis (36). In this study of unselected but well-defined patients in a medical ICU, serumcalcitonin 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 includeda broad range of unselected medical patients with severe illnesses, unlike prior studies focusing on selectedsubpopulations, and excluding patients without infection or sepsis. The relatively high rate of negative culture resultsfound in this study illustrates a common diagnostic dilemma for the clinician in a medical ICU, namely, many patientshave 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) andthe 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-reactiveprotein and lactate might be biased because their serum concentrations were known at the time of clinicalinvestigation and classification. The reliability of interleukin-6, C-reactive protein, and lactate was mainly limited bythe high variability of the test results in the different subgroups, thus reducing their usefulness as diagnostic markersin 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). Inaddition, 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 cytokineswere reported (44) in patients with a rapid onset of septic shock; however, this could not be confirmed in anothertrial (45). The conflicting results in the literature, and the high variance found in the present study, might beexplained by a sudden, transient, rather than sustained, cytokine release attributable to down-regulatingmechanisms. Consequently, the levels of cytokines diminish despite ongoing infection and, therefore, are not reliablemarkers for the course of an infection (46). Another disadvantage is the bioinstability of some cytokines, such astumor necrosis factor-[alpha], requiring immediate refrigeration and involving a fastidious, time-consumingdetermination. In contrast, calcitonin precursors are stable in vitro (47), and their analysis is rapid and easilyperformed.

The origin, metabolic pathway, and mediators responsible for the marked increase of calcitonin precursors

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The origin, metabolic pathway, and mediators responsible for the marked increase of calcitonin precursorsduring sepsis are enigmatic. These peptides are found in low concentrations in sera of normal persons, and several ofthese are variably increased in systemic inflammation, infection, and sepsis (31). Whether or not bacterial infectionhas 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 fungalinfections (55), can substantially increase serum calcitonin precursor levels. Also, viral infections occasionallymanifest moderately elevated calcitonin precursor concentrations (56). Whatever the initiating provocative insultmay be, markedly severe systemic inflammation, per se, may manifest increased serum levels of calcitoninprecursors. Additional studies are required to determine whether the increased serum calcitonin precursor levels ofsuch apparently non-bacterial insults are a manifestation of translocation to the blood stream of bacterial productsfrom 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 orinfection. Toward this goal, an alternative assay has been developed (31, 52).

The administration of the calcitonin prohormone, procalcitonin, to septic hamsters with peritonitis markedlydecreases their survival. Furthermore, treatment with procalcitonin-reactive antiserum increased survival ofhamsters with experimental sepsis (58). These observations indicate that the procalcitonin molecule is a potentiallyharmful mediator involved in the response to sepsis. Whether treatment with antiserum reactive with thisprohormone 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 markerfor the diagnosis of sepsis in a medical ICU. The early diagnosis of sepsis might facilitate rapid initiation ofantimicrobial and other appropriate treatment, thus potentially improving the unfavorable prognosis of sepsis andseptic shock.

ACKNOWLEDGMENT

We are indebted to the staff of the medical ICU and of the laboratory of pathologic chemistry, UniversityHospitals, 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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