procalcitonina

Diagnostic Value of Procalcitonin Levels as anEarly Indicator of Sepsis HAKAN GUVEN, MD,* LEVENT ALTINTOP, MD,* AHMET BAYDIN, MD,* SABAN ESEN, MD,† DURSUN AYGUN, MD,* MURAT HOKELEK, MD, PHD,‡ ZAHIDE DOGANAY, MD,* AND YUKSEL BEK, PHD§ Researchers and clinicians have been investigating and implementing various methods of early diagnosis for sepsis before documentation of infection. The aim of this study was to outline the efficiency of procalci- tonin (PCT), C-reactive protein (CRP), and white blood cell count (WBC) in determining the early diagnosis of sepsis in the emergency depart- ment. Between January 1999 and September 2000, 34 patients with signs of systemic inflammatory response syndrome (SIRS) were enrolled in the study. The patients were divided into 2 groups according to nonsus- pected sepsis and suspected sepsis clinically. Admission PCT was sig- nificantly higher in suspected sepsis group (median 68.7 ␮g/L; lower [L] ؍ 15.24 ␮g/L, upper [U] ؍ 120.54 ␮g/L) compared with the unsus- pected sepsis group (.23 ␮g/L; L ؍ .10 ␮g/L, U ؍ .44 ␮g/L). PCT values were compared with WBC and CRP levels. Predictive accuracy for sepsis expressed as area under the receiver operating characteristic (ROC) curve was .88 for PCT, .44 for WBC, and .34 for CRP. PCT can probably be used as a predictive marker in bacterial infections in emergency departments. (Am J Emerg Med 2002;20:202-206. Copyright 2002, Elsevier Science (USA). All rights reserved.) The number of patients presenting with sepsis or septic shock is gradually increasing. Parallel with this, emergency medicine physicians should expect to see a greater number of patients with this problem in their daily practice. 1 For emergency medicine physicians, the focus will most likely be on differential diagnosis and investigating the strong clues of sepsis. Prompt and effective decision making is critical, early diagnosis for sepsis not only decreases the mortality rate, but it is also necessary for emergency med- icine physicians to perform further therapy steps (ie, fluid therapy, appropriate antibiotic use) simultaneously. Sepsis has been defined as the systemic response of the body to infection. 2 The documentation of infection can be performed with positive culture, which is not an immedi- ately available laboratory investigation in emergency de- partment (ED) studies. Diagnostic uncertainty must be bal- anced with some biologic parameters. In the literature, there have been many described biologic parameters that facili- tate a rapid diagnosis of sepsis, besides the classic bacterial examinations. 3-5 One of these parameters is procalcitonin (PCT), which was discovered recently as a marker of bac- terial infection. 6 PCT, which consists of 116 amino acids, is the prohormone of calcitonin. In the healthy individual, it is secreted from C cells of the thyroid, and plasma concentra- tions are very low in the picogram range. 7 Several animal and human studies of sepsis have shown a sustained in- crease in the concentration of plasma PCT that was ulti- mately identified by a highly specific marker itself. 8-10 We conducted the present prospective study to determine the accuracy of PCT, C-reactive protein (CRP), and white blood cell count (WBC) among the patients who have at least 2 criteria of systemic inflammatory response syndrome (SIRS) and clinically suspected and nonsuspected sepsis, and who were admitted to the ED. PATIENTS AND METHODS Ondokuz Mayis University Hospital is a secondary refer- ral hospital in the middle Black Sea region of Turkey. Most patients are sent to the hospital by either a specialist or an emergency medicine clinician for further investigation. Many of them have risk factors for sepsis such as hospital- ization, intravascular catheters, and urinary catheters. Therefore, complex cases and other life-threatening dis- eases are admitted to our ED from that area. With approval from the local research ethical committee, 34 patients with signs of SIRS were enrolled in the study between January 1999 and September 2000. There were 20 men and 14 women, with a mean age of 56.27 Ϯ 12.6 years (range, 21-74 yrs). Patients were included on the basis of clinical and laboratory findings, described by the American College of Chest Physicians/Society of Critical Care Med- icine Consensus Conference. 11 They met at least 2 of the criteria for SIRS: fever or hypothermia, tachycardia, tachy- pnea, or abnormal WBC count. The patients were divided into 2 groups according to nonsuspected sepsis and suspected sepsis clinically. Cate- gorization of patients was made without knowledge of PCT and CRP levels. The term nonsuspected sepsis was used for patients who had minor infections such as an upper respi- ratory tract infection, otitis media, gastroenteritis with only signs of SIRS. The nonsuspected sepsis group included 15 patients. This group was also designed as a control group. The second group, called the suspected sepsis group, was used for patients who had a higher risk for sepsis with concomitant diseases, previous hospitalization, and a strong suspicion of sepsis clinically but not documented bacteri- ally. From the Departments of *Emergency Medicine, †Clinical Infec- tious Disease, ‡Microbiology, and §Biostatistics, Ondokuz Mayis University, School of Medicine, Samsun, Turkey. Supported by Ondokuz Mayis University Department of Research fund, grant no. T-257. Manuscript received August 29, 2001, accepted December 10, 2001. Address reprint requests to Hakan Guven, MD, Assistant Profes- sor, Department of Emergency, Ondokuz Mayıs University School of Medicine, 55139 Samsun, Turkey. Key Words: Emergency departments, procalcitonin, C-reactive protein, sepsis. Copyright 2002, Elsevier Science (USA). All rights reserved. 0735-6757/02/2003-0012$35.00/0 doi:10.1053/ajem.2002.33005 202 Blood samples for PCT, CRP, and hemoculture were collected before treatment. Samples for PCT and CRP were centrifuged to separate the serum, which was frozen at Ϫ70°C for further analysis. Blood samples were obtained from 3 different sites of venous puncture for hemoculture. We considered hemocultures as positive when the same microorganism was isolated from 2 different hemocultures of the patient. PCT was measured by an immunoluminometric assay (LUMItest PCT; Brahms Diagnostica, Berlin, Germany) whose detection limit was 0.01 ␮g/L. CRP was measured by automatic laser nephelometry (BN II analyzer; Boehring Dade, Marburg, Germany), normal range was 0 to 5 mg/L. WBC (leukocyte) counts were determined by using an automatic counter. The reference values were between 4,000 and 12,000 cells/mm 3 . Comparison between groups was made by the nonpara- metric Mann-Whitney test. Data were analyzed by diagnos- tic efficiency derived from the receiver-operating character- istic (ROC) curve and area under the ROC curve. Statistical analysis was performed by using SPSS (Chicago, IL), WinEpiscope 2.0 statistical packet programs. Probability values less than .05 were considered significant. RESULTS The demographics (ie, age, sex) were similar between the 2 groups except for underlying medical illness. The sus- pected sepsis group included 19 patients with a history of previous cerebrovascular disease, chronic obstructive pul- monary disease, and diabetes mellitus. A summary of these cases is provided in Table 1. All of the suspected sepsis group (n ϭ 19) were hospitalized and 6 of the patients died. The nonsuspected sepsis group (n ϭ 15) was observed mostly for less than 24 hours in the ED and discharged from the hospital. The mean and confidence limits of the PCT level in the suspected sepsis group was 67.89 ␮g/L (L ϭ 15.24 ␮g/L, U ϭ 120.54 ␮g/L). The nonsuspected sepsis group did not have high levels of PCT in their serum, mean PCT level was 0.23 ␮g/L (L ϭ .10 ␮g/L, U ϭ .44 ␮g/L). The PCT values were significantly higher in the suspected sepsis group than in the nonsuspected sepsis group (P Ͻ .001). In the nonsuspected sepsis group, all blood cultures were negative and we did not isolate any pathogen microorgan- ism. Of the 19 patients in the suspected sepsis group, 13 patients had positive blood cultures together with high PCT serum levels. Of the 6 patients that had negative blood cultures, 4 patients’ PCT levels were higher than normal levels, but in 2 of these patients the PCT levels were just above the normal values. The other 2 patients had very high values. These extreme levels, reaching 500 ␮g/L, were observed in patients with acute pancreatitis. In the last 2 of these patients, PCT serum levels remained in the normal range whereas bacteria were not isolated in blood cultures. Each of the 19 patients belonging to the suspected sepsis group showed an increase in CRP serum levels (165 Ϯ 51 mg/L). In contrast to PCT levels, CRP levels (108 Ϯ 64 mg/L) showed higher values than the normal range in the nonsuspected sepsis group. There was no significance in CRP serum levels between groups (P Ͼ .05). The mean WBC was 16,947 (2,400-44,900 cells/mm 3 ) and 14,503 (3,200-21,000 cells/mm 3 ) in the suspected and nonsuspected sepsis groups, respectively. WBC level was insignificant between groups (P Ͼ .05). Patients with documented bacteria and elevated PCT levels (Ͼ2 ␮g/L), CRP levels (Ͼ5 mg/L), and WBC level less than 4,000 and greater than 12,000 cells/mm 3 were considered to have a true-positive finding, and those pa- tients with negative culture without elevated PCT and CRP levels, and WBC between 4,000 and 12,000 cells/mm 3 were considered to have a true-negative finding. The sensitivity, TABLE 1. Serial PCT and CRP Determinations in the Suspected Sepsis Group With Blood Culture Results and Concomitant Diseases Case No. Blood Isolate Age Concomitant Disease PCT Level (␮g/L) CRP Level (mg/L) WBC (cells/mm 3 ) Outcome 1 CoNS 71 CVDϩCOPD 2.86 139 22,300 Died 2 CoNS 74 DMϩCVD 38.01 28.4 44,900 Survived 3 CoNS 21 Postpartum 91.9 176 16,100 Survived 4 CoNS 65 DMϩCVD 8.96 80 20,500 Survived 5 CoNS 45 COPD 153.2 200 2,460 Died 6 CoNS 60 COPD 21.3 191 8,900 Survived 7 Staphylococcus aureus(ϩ) 58 Previous trauma 54.68 200 7,940 Died 8 Staphylococcus aureus(ϩ) 68 COPD 18.24 200 11,200 Survived 9 Escherichia coli 64 Acute cholangitis 56.2 191 19,500 Survived 10 Escherichia coli 74 Diare 38 28 6,800 Survived 11 Enterococcus 45 Acute cholangitis 16.82 200 9,700 Survived 12 Enterococcus 61 Previous surgery 180.4 200 14,700 Survived 13 Proteus 47 Kidney stone 3.54 98 17,300 Died 14 — 50 Sheehan’s syndrome 2.32 200 15,900 Survived 15 — 66 COPDϩCVD 0.5 96 18,600 Died 16 — 65 COPD 0.83 200 41,800 Died 17 — 37 Acute pancreatitis 500 157 2,400 Survived 18 — 70 DM 2.72 200 30,200 Survived 19 — 47 Acute pancreatitis 318 200 10,800 Survived Abbreviations: CoNS: Coagulase negative staphylococci; CVD, cerebrovascular disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus. 203 GUVEN ET AL I DIAGNOSTIC VALUE OF PROCALCITONIN specificity, and positive and negative predictive values of PCT, CPR, and WBC derived from diagnostic evaluation tests are presented in Table 2. The PCT concentration higher than 2 ␮g/L had 78.9% diagnostic efficiency and 78.9% negative and 100% positive predictive values for bacterial sepsis. The CRP concentration higher than 5 mg/L had 68.4% diagnostic efficiency and 46.2% positive and 0% negative predictive values for sepsis. The WBC level less than 4,000 and greater than 12,000 cells/mm 3 had 47.4% diagnostic efficiency and 52.9% positive and 41.7% nega- tive predictive values. The ROC curves can be used to evaluate the performance of classification schemes in which there is 1 variable with 2 categories by which subjects are classified. If the estimated area under the ROC curve is more, the classification with that method is better. Figures 1, 2, and 3 contain ROC curves showing the sensitivity and specificity of PCT, CRP, and WBC levels for sepsis. The area under the ROC curve was 0.88, 0.44, 0.34, for PCT, WBC, and CRP, respectively. DISCUSSION The goals of emergency medicine physicians should be 2-fold: to distinguish sepsis from other causes of SIRS and start early therapy including an antibiotic regimen. The critical point in patients with sepsis is the absence of doc- umented infection at admission to the ED. The use of cultures for identifying the presence of bacteria requires time, which makes it inaccessible for clinical use in the ED, TABLE 2. Specificity, Sensitivity, and Positive (PPV) and Negative (NPV) Predictive Values of PCT, CRP, and WBC With Diagnostic Evaluation Test Sensitivity(%) Specificity(%) PPV(%) NPV(%) PCT 78.9 100 100 78.9 CRP 68.42 0 46.42 0 WBC 47.4 46.7 52.9 41.2 FIGURE 1. The area under the curve was .88 for PCT in the clinically suspected sepsis group. FIGURE 2. The ROC of CPR for prediction of bacterial sepsis. The area under the curve was .34 for CRP in the clinically suspected sepsis group. Diagonal segments are produced by ties. FIGURE 3. The ROC of WBC for prediction of bacterial sepsis. The area under the curve was 0.44 for WBC in the clinically suspected sepsis group. 204 AMERICAN JOURNAL OF EMERGENCY MEDICINE I Volume 20, Number 3 I May 2002 and negative cultures do not exclude the sepsis. Some investigators have suggested that clinical sepsis has been observed in the absence of documented infection in more than 50% of patients with multiorgan dysfunction syn- drome. 12 Therefore, the need to identify sepsis has led to the development of a variety of biochemical parameters based on the pathophysiology of sepsis. These biochemical pa- rameters should be designed to assess the severity of illness and possibly assist in differentiating the infection. Numer- ous investigators have reported on the use of PCT in early and differential diagnosis of bacterial sepsis. The sensitivity (60%-100%) and specificity (79%-100%) reported in vari- ous series were quite encouraging. 9,10,13 CRP levels, eryth- rocyte sedimentation rate, and WBC values are also avail- able parameters for the diagnosis of inflammation, but their sensitivity and specificity is lower than PCT in differenti- ating acute bacterial infection from other types of inflam- mation. 13 We found that PCT has more specificity than CPR for diagnosis of bacterial sepsis, and PTC showed better diagnostic efficiency and the area under the ROC curve than CRP. PCT is the prohormone of calcitonin. It is not found in serum of healthy people, but high concentrations of PCT have been reported in patients with bacterial infections and septic inflammation. 14 This study has evaluated the useful- ness of PCT only for diagnosis of bacterial sepsis manage- ment of critically ill patients in the ED. Recently designed clinical studies for evaluating the efficiency of PCT serum concentrations have mostly been organized in adult and neonate intensive care units. They tested either the diagnos- tic or prognostic value of PCT and compared the results with other inflammation parameters. 15-17 Our results showed that PCT values in suspected sepsis groups were signifi- cantly higher than nonsuspected sepsis groups (P Ͻ.001). It could be a useful tool in the emergency room for differential diagnosis among patients with signs of SIRS. Alterations in hematological parameters (eg, leukocytosis or leukopenia, thrombocytopenia) and elevation of serum acute-phase proteins (eg, CRP) may provide a clue of sep- sis, but they were not consistent with our results, CRP values and WBC were not significantly different between groups (P Ͼ .05). This result may contrast with some publications which mention that CRP is an available diag- nostic test for infection. 18,19 This controversial result was probably caused by high concentrations of CRP in the nonsuspected sepsis group. It is well known that CRP is a very sensitive marker and may be increased with minor or viral infections and other insults such as trauma. These insults can activate the cytokine cascade, which has pro- found influences on the generation of acute-phase proteins from liver. Except for this common pathway, the specific induction of bacterial inflammation that activated cytokines might also stimulate the synthesis of PCT from different sources. The cellular origin of PCT is not known exactly but possibly it originated from leukocytes and neuroendocrine cells of the lung or intestine. 20-22 The patients suffered only from SIRS elevated CRP but not PCT, whereas patients with sepsis showed increases in both PCT and CPR values. A similar clinical result was find by Clyne and Olshaker, 23 who concluded that CRP had a limited use in the ED and has no role in diagnosing some bacteria-related clinical entities. These observations suggested that systemic inflam- mation induced by infectious stimuli may alert both liver and other cells, which takes place in immunologic response. In the present study, the highest values of PCT were determined to be in 2 cases of acute pancreatitis and not isolated bacteria in blood cultures. Recent studies showed that PCT is not only a marker of bacteremia but it can also be determined in high levels in diseases related to inflam- mation. According to the study by Brunkhorst et al, 24 pa- tients with billiary pancreatitis presented with high PCT serum levels. If therapy is delayed, the patient will almost assuredly die before the diagnosis is established. 1 The emergency medi- cine physician must start empiric or presumptive therapy rapidly before confirmation of the diagnosis. WBC, CRP, and PCT levels may provide a clue of sepsis. But, we were able to show an excellent sensitivity and specificity of PCT as shown by the ROC curves. We also found high negative predictive value (78.9%) of PCT. This is very important because it may prevent inappropriate antibiotic usage. The cost effectiveness, toxicity, and resistance problem against antibiotics can be minimized. 25,26 These results may allow us to determine that empiric regimens of broad-spectrum antimicrobials should be initiated according to sustained PCT serum values. In conclusion, PCT serum levels might be a useful diag- nostic tool in ED management of sepsis before documenta- tion of bacteria. Early empiric antibiotic therapy might be started before documentation of bacteria in the ED. The use of PCT measurement to guide antibiotic therapy should be a practical approach in critically ill patients with suspected sepsis. REFERENCES 1. 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