Evaluation of procalcitonin as a marker of infection in a nonselected sample of febrile hospitalized patients

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1 Diagnostic Microbiology and Infectious Disease 49 (2004) Evaluation of procalcitonin as a marker of infection in a nonselected sample of febrile hospitalized patients Patricia Muñoz, Nuria Simarro, Marisa Rivera, Roberto Alonso*, Luis Alcalá, Emilio Bouza Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain Received 6 January 2004; accepted 5 April 2004 Abstract The level of procalcitonin is undetectable in healthy individuals and slightly increased in viral infections and noninfectious inflammatory responses. It has been described to be notably increased in bacterial, parasitic, or fungal infections. Procalcitonin has been reported to be a reliable marker for severe bacterial infections, although it has mainly been studied in specific entities or in selected groups of patients. We prospectively determined the procalcitonin level in 103 unselected febrile hospitalized patients. Most of them had a proven (39) or probable bacterial infection (44). Procalcitonin was more frequently positive in bacteremic patients (p 0.01), in patients with a proven bacterial infection (p 0.01), and in those with a high sepsis score (p 0.005), however; when cases with proven bacterial infection were considered as a reference, the sensitivity of the test was only 54% and the specificity 70%. Procalcitonin determination should not be included systematically in the screening of febrile hospitalized patients Elsevier Inc. All rights reserved. 1. Introduction Although fever is the most frequent sign of infection, microbiologic data are always needed for a definitive diagnosis of bacteremia. Blood culture results take at least 24 to 48 hours; therefore, a rapid laboratory test that is able to identify severe bacterial infections would be very useful in the initial management of febrile patients and in a more appropriate use of antibacterial agents. Physicians often prescribe useless antibiotics or prolong hospital stays unnecessarily rather than assume the risk of fatal consequences. This practice, although understandable, leads to an increase in antibiotic usage, bacterial resistance, and general costs. Procalcitonin is a 116-amino acid peptid produced by the thyroid gland as a precursor of the hormone calcitonin. It has been reported to be a reliable marker for severe bacterial infections and sepsis (Assicot et al., 1993; al-nawas and Shah, 1996; Gendrel and Bohuon, 2000; Whang et al., 2000). Procalcitonin levels are undetectable in healthy individuals and slightly increased in severe viral infections and noninfectious inflammatory responses (Karzai et al., 1997). However, levels have been reported to be high in * Corresponding author ; fax: ; address: ralonso.hgugm@salud.madrid.org (R. Alonso). bacterial, parasitic, or fungal infections (Bernard et al., 1998; Blijlevens et al., 2000). Procalcitonin has been used for the differential diagnosis of fever in several groups, including transplant recipients, and patients with HIV, neutropenia, and burns (Gerard et al., 1997; von Heimburg et al., 1998; Hammer et al., 1999; Jaresova et al., 1999; Boeken et al., 2000; Giamarellos- Bourboulis et al., 2001). The value of procalcitonin in the initial evaluation of a nonselected group of patients hospitalized with fever has only been assessed, to the best of our knowledge, in one other recent article that identifies subjects with a high risk of mortality (van Langevelde et al., 2000). Our objective was to determine the usefulness of single procalcitonin measurements in the initial workup of febrile hospitalized patients. 2. Materials and methods 2.1. Collection of data A prospective, noninterventional study was conducted in our institution, a 1,750-bed general teaching hospital, over a 5-month period. During the study period, we identified all hospitalized patients with fever (2 or more axillary temperatures 38 C) that were admitted to our hospital. The study /04/$ see front matter 2004 Elsevier Inc. All rights reserved. doi: /j.diagmicrobio

2 238 P. Muñoz et al. / Diagnostic Microbiology and Infectious Disease 49 (2004) enrolled 103 patients. Mean age was 62 years (17 92) and the male:female ratio was 67:36. Most patients (89) were in a medical department, and 14 were in surgical units. Clinical data were recorded in a preestablished protocol that included demographic data, underlying disease, sepsis score, final diagnosis, microbiology results, and outcome. All patients were followed until hospital discharge and classified into 3 groups on the basis of clinical and laboratory findings: group 1, proven bacterial infection, microbiologically documented; group 2, probable bacterial infection, clinically documented but with negative or nonobtained cultures; group 3, absence of bacterial infection or no infection with another, well-established diagnosis. All cases were discussed blind (without knowing the procalcitonin test result) by at least 2 of the authors before final classification. Within 24 hours of the febrile peak, a serum-sample was obtained by venipuncture to determine the procalcitonin level. This was determined by immunoluminometric assay (LUMItest PCT; Brahms-Diagnostica GmbH, Berlin, Germany). Briefly, 2 antigen-specific monoclonal antibodies that bind procalcitonin, one of which is labeled, are used to react with procalcitonin in the sample to form sandwich complexes. The intensity of the luminescence signal is directly proportional to the amount of procalcitonin in the sample. By the inclusion of calibrators, the unknown procalcitonin concentration in the patient s sample can be quantified by comparing test values with a master curve. Procalcitonin was considered positive if a level greater than 0.1 ng/ml was detected, as recommended by the manufacturer. All measurements were performed in duplicate. A sepsis score was calculated for all patients as previously published (Sibbald and Vincent, 1995). The definition of sepsis was based on the presence of 1) fever or hypothermia (temperature 38 C or 36 C); 2) tachycardia (heart rate 90 beats/min); 3) tachypnea (respiratory rate 20 breaths/min), and 4) leukocytosis or leukopenia (leukocyte counts 12,000 cells/l or 4,000 cells/l) or over 10% immature forms (American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee, 1992). The score ranged from 1 (only one of the described signs, lowest probability of sepsis) to 4 (all 4 signs, highest probability of sepsis). McCabe and Charlson scores were also considered in order to establish the severity of underlying diseases (Charlson et al., 1987; Vallés et al., 1997; Fauci et al., 1998) Statistical analysis Data were entered and categorized using Access (Microsoft, Redmond, WA). Measures of significance were assessed by univariate and stratified analysis. Continuous variables were analyzed using the Mann-Whitney U test, and discontinuous variables were measured with the Fisher exact test or the 2% test. All statistical tests were two-tailed. The independent values of predictor variables and adjusted Fig. 1. Distribution of patients according to their infection status. Group 1: proven bacterial infections. Group 2: probable bacterial infections. Group 3: nonbacterial infections. risk ratios with 95% confidence intervals were assessed by stepwise logistic-regression analysis using SPSS software (SPSS Inc., Chicago, IL). A p value of 0.05 was established as the level of significance for all tests. Sensitivity, specificity, and predictive values were determined for procalcitonin as an infection marker, taking both the presence of bacteremia or proven bacterial infections as a reference. 3. Results The distribution of the patients according to final diagnosis is shown in Figure 1. Most patients had a proven bacterial infection (39 patients, group 1) or a probable bacterial infection (44 patients, group 2). In 20 patients, the cause of the fever was diagnosed as noninfectious (group 3). The main epidemiologic and clinical characteristics of these patients are shown in Table 1. The most common infection sites were lower respiratory tract (31), urinary tract (23), and intraabdominal infection (14). Microbiologically documented infections corresponded to Gram-positive bacteria (17), Gram-negative bacteria (12), mixed bacterial infections (6), fungi (4), mycobacteria (4), and virus (2). Procalcitonin was positive in 40 of the 103 study patients (38.8%), of whom 21 (53.8%) belonged to group 1, 13 (29,5%) to group 2, and 6 (30%) to group 3 (Table 1). Procalcitonin was more frequently positive in patients with a high sepsis score (Table 2) (83% vs 16%; p 0.003) or with bacteremia (Table 3) (65% vs 31%; p 0.01), and levels were not related to the site of infection, to the type of microorganism isolated, or to the evolution of the patient. When the presence of microbiologically proven bacteremia was used as the standard for comparison, procalcitonin determination yielded the following values: sensitivity, 65%; specificity, 69%; positive predictive value, 38%; and negative predictive value, 87%. If proven bacterial infection was used as the standard for comparison, the corresponding values were: sensitivity, 54%; specificity, 70%; positive predictive value, 52%; and negative predictive value, 69%.

3 P. Muñoz et al. / Diagnostic Microbiology and Infectious Disease 49 (2004) Table 1 Clinical characteristics of 103 unselected patients who were admitted to the hospital because of fever Group Group 1 (n 39) Group 2 (n 44) Group 3 (n 20) Age Male 12 (30.7%) 14 (31.8%) 10 (50%) Underlying disease Organic 24 (61.5%) 28 (63.5%) 9 (45%) HIV infection 2 (5%) 0 2 (10%) Neoplasia 7 (18%) 10 (22.7%) 6 (30%) None 6 (15%) 6 (13.6%) 3 (15%) McCabe II 13 (33.3%) 12 (27.2%) 8 (40%) III 26 (66.6%) 32 (72.7%) 12 (60%) Charlson score (Mean) (15.4%) 9 (20.4%) 3 (15%) 1 10 (25.6%) 9 (20.4%) 4 (20%) (48.7%) 18 (40.9%) 9 (45%) 5 4 (10.2%) 8 (18.2%) 4 (20%) Sepsis score 1 1 (2.5%) 1 (2.2%) (41%) 27 (61.3%) 12 (60%) 3 18 (46.1%) 14 (31.8%) 8 (40%) 4 4 (10.2%) 2 (4.5%) 0 Bacteremia 23 (59%) 0 0 Antimicrobial therapy 38 (97.4%) 42 (95.4%) 17 (85%) Positive Procalcitonin (%)* 21 (53.8%) 13 (29.5%) 6 (30%) Deaths 3 (7.6%) 1 (2.2%) 0 * p 0.05; Group 1: proven bacterial infections; Group 2: probable bacterial infections; Group 3: non-bacterial infections. 4. Discussion Procalcitonin serum level is claimed to be a diagnostic and prognostic marker of bacterial sepsis, but most studies deal with specific entities (e.g., bacteremia, rejection, and pneumonia) or specific groups of patients (e.g., transplant recipients, and burn, hematologic, and HIV-positive patients). Our experience in the determination of the procalcitonin levels in the initial workup of all patients admitted to the hospital with fever shows that this analytical parameter is high, especially in patients with a high sepsis score and in those with positive blood cultures. Nevertheless, its low sensitivity and specificity (it was negative in 16.6% of patients with a sepsis score of 4 and in 34.7% of patients with bacteremia, and positive in 30% of patients with a noninfectious cause of fever) do not place it before clinical judgment for the correct discrimination of patients with sepsis. Therefore, its use in this case is not justified. Table 2 Distribution of patients (N 109) according to sepsis score Sepsis score Procalcitonin ( ) Procalcitonin ( ) 1(N 2) 0 (0%) 2 (100%) 2(N 55) 14 (25.4%) 41 (74.6%) 3(N 40) 21 (52.5%) 19 (47.5%) 4(N 6) 5 (83.3%) 1 (16.6%) p We are aware that both sexes were not equally represented, two thirds of the patients enrolled in the study were men. Nevertheless, we could not find any evidence to suggest that using procalcitonin as a marker of infection differed between a male or female population. Many published reports have described the usefulness of procalcitonin measurements as a marker of bacteremia or sepsis (Liaudat et al., 2001; Carrol et al., 2002; Giamarellos- Bourboulis et al., 2002; Luzzani et al., 2003). Recently Chirouze et al. (2002) defended a good correlation between procalcitonin serum levels and bacteremia, although a positive predictive value of only 25% was reported for the analytical parameter and a wide range of procalcitonin levels (0.05 to 87 ng/ml with a cutoff of 4 ng/ml) was reported for the nonbacteremic subjects. Table 3 Distribution of patients according to procalcitonin result and presence of bacteremia or presence of proven bacterial infection Procalcitonin ( ) Procalcitonin ( ) Bacteremia* Yes (N 23) 15 (65.2%) 8 (34.7%) No (N 2380) 25 (31.2%) 55 (68.7%) Proven bacterial infection Yes (N 39) 21 (53.8%) 18 (46%) No (N 64) 19 (29.6%) 45 (70.3%) * p a Including probable bacterial infection, nonbacterial infection and noninfectious causes of fever.

4 240 P. Muñoz et al. / Diagnostic Microbiology and Infectious Disease 49 (2004) Other authors have described findings similar to ours. In 2000, van Langevelde et al. reported a negative procalcitonin value in 18% of patients with bacteremia (van Langevelde et al., 2000). High procalcitonin levels in the serum of patients without bacterial or fungal infections have also been reported (lack of specificity), (Hensel et al., 1998; Monneret et al., 1998; Kettelhack et al., 2000; Sabat et al., 2001; van Dissel, 2003). An illustrative example is a recent description of increased procalcitonin levels during an attack of acute gouty arthritis. This increase was not due to the presence of any microbiologically proven bacteremic infection, but to the inflammatory process caused by the interaction of urate crystals with polymorphonuclear leucocytes in the synovial fluid (Debard et al., 2003). We did not have any evidence that the use of procalcitonin as a marker was better or worse depending on the infection site (e.g., lower respiratory tract, urinary tract, or intraabdominal infection), although the number or cases may be too small for this kind of analysis. In our study, a positive procalcitonin result was not associated with a higher risk of death either, although that may be because our overall mortality was low (3.8%). In other studies, procalcitonin was not a predictor of death in patients with or without shock on admission (van Langevelde et al., 2000). Of interest is that we selected a lower positive cut-off than other authors (0.1 ng/ml instead of 0.5 ng/ml). This cut-off was recommended by the manufacturer of the assay we used. In our series, 50% of the positive procalcitonin determinations had levels equal to or higher than 0.5 ng/ml, although the separate analysis of these patients showed similar results to the overall population (data not shown). Some other authors have also decided to lower their positive cut-off in order to increase the negative predictive value (Chirouze et al., 2002). In summary, procalcitonin testing could not identify all patients with proven bacterial infection, even when a low cut-off was used. In our opinion, procalcitonin determination should not be included in the systematic workup of febrile patients admitted to the hospital. Acknowledgment We thank Thomas O Boyle for help with the correction of the English version of the manuscript. References American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee (1992). Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20, al-nawas B, Shah PM (1996). Procalcitonin in patients with and without immunosuppression and sepsis. Infection 24, Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C (1993). 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