THE DIAGNOSTIC VALUE OF PROCALCITONIN FOR EARLY DETECTION OF UROSEPSIS

Objective: To study procalcitonin as an early and accurate marker for urosepsis. Material & Method: We performed a diagnostic study of procalcitonin, CRP and peripheral blood leucocyte in 21 patients. Patients included 12 urosepsis patients with urosepsis, and 9 trauma patients without urosepsis. This study was conducted from September 2010 to December 2010. Results: Mean and standard deviation of procalcitonin level in urosepsis patients was 27,9 ± 30,7 ng/ml, 3 CRP was 8,9 ± 7,9 mg/l and blood leucocyte was 15125,0 ± 8969,9 mm . Sensitivity of procalcitonin in diagnosis of urosepsis was 83,3%, specificity was 77,8%, positive predictive value was 83,3%, negative predictive value was 77,8%, positive odds ratio was 3,75 and negative odds ratio was 0,2. Diagnostic value of procalcitonin was better compared to CRP and blood leucocyte. In the receiver operating characteristics (ROC) plot, area under the curve (AUC) for procalcitonin, blood leucocyte, and CRP were 0,806 (95% CI = 0,607 – 1,004), 0,773 (95% CI = 0,568 – 0,979), and 0,602 (95% CI = 0,341 – 0,863), respectively. Conclusion: Procalcitonin is an early marker for urosepsis cases with better diagnostic value than CRP and blood leucocyte.


INTRODUCTION
Sepsis is an infection accompanied by systemic responses. And, sepsis caused by infection in urinary 1,2 tract and/or male genital organ is called urosepsis. Approximately, 20-30% of sepsis cases may be caused by urinary tract infection considered as a risk factor of urosepsis. Actually, urosepsis may be caused by urinary tract stones (43%), prostate adenoma (25%), urologic cancers (18%), and catheterization (14%), manipulation actions in 1 urology, and other urologic diseases.
Moreover, the enforcement of sepsis can actualy be done by blood and urine tests, such as microbiological examination of blood culture. In urosepsis cases, the examination of blood and urin 3 cultures even is necessary. However, blood cultures used as a reference gold standard for sepsis cases still remain a dilemma. The occurrence of the dilemma is caused by the limitations of current microbial techniques for diagnosing bacterial 4 infections. In a large population with clinical diagnosis of sepsis, there are 15% of negative blood 5 culture results. Other literatures even state that in more than 50% of severe sepsis cases negative blood 3 culture results are obtained.
Therefore, the ideal sepsis markers should not only have high sensitivity and specificity, but can also be used easily with affordable cost. The ideal sepsis markers, furthermore, should also be able to know both the stages of diseases and the prognosis of patients. With the ideal sepsis markers, early treatment then can be performed, as a result, they can not only prevent the occurrence of severe sepsis and septic shock, but can also reduce the rates of 6 mortality significantly.
Furthermore, in published studies, the diagnostic value of PCT showed higher values of sensitivity (85%), specificity (91%), positive expected value (89%), and negative expected value (95%) than those of CRP, TNF-, IL-2, IL-6, IL-8, which then can be used to distinguish patients with sepsis and patients with SIRS. For instance, in the research conducted on 33 patients of ICU (Intensive Care Unit) diagnosed with SIRS, sepsis, and septic 13 shock , Castelli et al (2004) reported that there were the differences of CRP and PCT images. In this research, moreover, it is known that CRP concentrations immediately increased during severe organ dysfunction and systemic inflammatory, but the value was not increased during the more severe stages of the organ dysfunction. It is also known that PCT levels were particularly elevated in patients with organ dysfunction, severe sepsis, and septic shock. This is because the presence of different kinetic work on these two parameters. Since the concentration of PCT has higher levels than one of CRP, the significant increasing of PCT during severe sepsis and septic shock can actually be considered as the major force of 14 PCT. Procalcitonin is also considered to be better than CRP in detecting the onset of sepsis in 53 patients 1 5 who experienced septic shock. Thus, the procalcitonin examination in urosepsis cases is expected to be ale to detect early the occurrence of sepsis in urological disorders which can not only prevent the occurrence of more severe sepsis, and septic shock, but can also prevent the occurrence of 15 death.

OBJECTIVE
This research is aimed to study procalcitonin focused on its diagnostic value in order to be used as an early detection in urosepsis cases.

MATERIAL & METHOD
This research is a diagnostic research conducted from September 2010 to December 2010 in order to analyze the diagnostic values of blood leucocytes, blood culture, CRP, and procalcitonin towards urosepsis. Cross-sectional design was then used in this research. And, measurements were also conducted covertly (blinding) in urosepsis patients as diagnostic gold standard.
The samples of this research were patients of Dr. Soetomo Hospital who met the criteria of SIRS with abnormalities in the urologic field accompanied by infections in the urinary tract. The total number of sample obtained was 21 patients. After conducting blood culture examination, the sample was then divided into two groups, namely urosepsis group (12 patients) and non-urosepsis group (9 patients) including trauma and burns.
By examining sensitivity value, specificity value, positive expected value, negative expected value, and positive and negative probability ratios of procalcitonin, cross sectional analysis was then conducted. Next, both 2 x 2 table analysis, ROC curve analysis (Receiving Operating Characteristic) with the output of area under the curve (AUC), and tiered analysis were also conducted.

RESULTS
The characteristics of the research sample (Table 1) show that the average age of patients in the urosepsis group was about 46,1 years, while that in the non-urosepsis group was about 30,2 years. Moreover, it is also known that the age range in the urosepsis group was 13-60 years, while that in the non-urosepsis group was 10-52 years old.
Furthermore, five cases of bilateral hydronephrosis and one case of hydronephrosis on one side of the kidneys were found in this research. And, hydronephrosis even was also found in the case of perirenal abscess. Actually, hydronephrosis is a case found mostly in the urosepsis group. But, this case also comes with other diagnoses, such as urinary tract stones (83,3%), either pyelum stones, proximal ureteric stones, or distal ureteric stones, as well as benign prostatic enlargement (16,7%).
The value of procalcitonin found in 10 cases of urosepsis was high (table 2). The value was even higher than that of CRP and blood leucocytes in the urosepsis cases. Meanwhile, in trauma cases, the value of CRP and procalcitonin was as high as that of blood leucocytes.  From table 3, there were four mortality cases in the urosepsis group and one mortality case in the nonurosepsis group (trauma). In those four mortality cases in the urosepsis group, the value of procalcitonin obtained was high with the highest value reached 100.
The sensitivity of blood leucocytes was about 50%; the specificity of blood leucocytes was about 77,8%; the positive expected value of blood leucocytes was about 75%; the negative expected value of blood leucocytes was about 53,8%; the positive probability ratio of blood leucocytes was about 2,3; and the negative probability ratio of blood leucocytes was about 0,6 (table 4). It is also known that the specificity value of blood leucocytes is higher than other diagnostic values. And, the sensitivity value of blood leucocytes was also considered to be the lowest value compared to other diagnostic values.
From table 5, the sensitivity of CRP was about 58,3%; the specificity of CRP was about 77,8%; the positive expected value of CRP was about 77,8%, the negative expected value of CRP was about 58,3%; the positive probability ratio of CRP was about 2,6; and the negative probability ratio of CRP was about 0,5. It is also known that the specificity value and the positive expected value are the highest diagnostic values compared with other diagnostic values. And, the sensitivity of CRP was also considered to be higher than that of blood leucocytes.      (table 6). It is also known that the specificity value and the positive expected value are the highest diagnostic values compared with other diagnostic values. And, the sensitivity and speci-ficity values of blood cultures were also considered to be higher than those of blood leucocytes and CRP. From table 7, the sensitivity of procalcitonin was about 83,3%; the specificity of procalcitonin was about 77,8%; the positive expected value of procalcitonin was about 83,3%; the negative expected value of procalcitonin was about 77,8%; the positive probability ratio of procalcitonin was about 3,75, and the negative probability ratio of procalcitonin was about 0,2. It is also known that the sensitivity value and the positive expected value are the highest diagnostic values compared with other diagnostic values. And, the sensitivity of procalcitonin was also considered to be higher than that of blood leucocytes, CRP, and blood cultures. But, the specificity of procalcitonin was lower than that of blood cultures. ROC Curve (see Figure 1), furthermore, shows that procalcitonin has the highest diagnostic values compared with blood leucocytes and CRP. Besides that, it is also known that blood leucocytes has the highest diagnostic values compared with CRP.
The test results of variable(s) show that blood leucocytes has at least one tie between the positive actual state group and the negative actual state group. Statistics may also be biased, a) Under the nonparametric assumption, b) Null hypothesis : true area = 0,5.
Hydronephrosis, moreover, is actually the largest urology cases found in this research. The occurrence of hydronephrosis in this research was usually associated with both urinary tract stone cases (83,3%), either pyelum stones, proximal ureteric stones, or distal stones, and benign prostatic enlargement (16,7%). In another research, the occurrence of hydronephrosis, on the other hand, was caused not only by urinary tract stone obstruction (52%) caused by either stones in proximal, middle, or distal ureter, but also by uretropelvic junction obstruction (UPJ) 17 (26%) and by a tumor pressing the ureter (12%).
Meanwhile, mortality urosepsis obtained in this research was only about 33,33%. The urosepsis  Based on another research, it is also known that Escherichia coli is the largest uropatogen. Escherichia coli became uropatogen for boys who are not circumcised. Among 79 patients studied, it was found that 66 young male patients (84%) all of whom had not been circumcised had Eschericia coli. Thus, the research result can be concluded that Escherichia coli is uropatogen which has high risk of urinary tract 21 infections. Escherichia coli is also considered to be germs mostly found in renal colic and urinary tract stone cases (68,7%), Proteus (18,7%), as well as 22 Enterococcus and Citrobacter (6,3% for each).
The diagnostic value of procalcitonin obtained in this research then is known to be the highest one, especially for its sensitivity compared to that of blood leucocytes, CRP, and blood cultures. The sensitivity value of procalcitonin obtained was about 83,3%, while its specificity one was about 77,8%. Moreover, its positive expected value was about of 83,3%, while its negative expected value was about 77,8%. And, its positive probability ratio was about 3,75, while its negative probability ratio was about 0,2%.
On the other hand, the sensitivity value of CRP obtained was about 58,3%, while its specificity was about 77,8%. Its positive expected value, furthermore, was about 77,8%, while its negative expected value was about 58.3%. And, its positive probability ratio was about 2,6 %, while its negative probability ratio was about 0,5%. In a research analyzing biomarkers, CRP in urinary diversion cases conducted urgently in patients with renal colic and urinary stones even was known to be about 75,8% for its sensitivity value, 88,9% for its specificity value, 87,2% for its positive expected value, and 78,6% for 22 its negative expected value.
In a research comparing procalcitonin and CRP in order to determine the estimation of severity degree of sepsis in community-acquired pneumonia (CAP), moreover, it is also known that the sensitivity value of procalcitonin obtained was about 46.3% in patients with SIRS, while its specificity value was about 85,3% in patients without SIRS. On the other hand, the sensitivity value of CRP was about 98,1% in patients with SIRS, while its specificity value was about 0% in patients without SIRS. The positive expected value of procalcitonin, furthermore, was about 83,3%, while its negative expected value was about 50%. On the other side, the positive expected value of CRP was about 60,9%, while its negative 23 expected value was about 0%.
In a research evaluating procalcitonin as a marker of infection in patients with fever in the hospital, Nasution: The diagnostic value of procalcitonin mortality occured in this research was usually associated with the discoveries of blood culture and urine culture. Blood leucocyte values obtained in this research were also not normal. The high values of CRP and procalcitonin in patients with urosepsis actually can cause mortality. In other literature, the furthermore, it is also known that the sensitivity value of procalcitonin with bacteremia was about 65%, while its specificity value was about 69%. Its positive expected value, moreover, was about 38%, while its negative expected value was about 87%. In addition, the sensitivity value of procalcitonin suspected of having bacterial infection was about 54%, while its specificity value was about 70%. Its positive expected value, moreover, was about 52%, while its negative expected value was about 69% (Munoz et al, 24 2004).
ROC curve value of CRP in this research, furthermore, is indicated to have a weak diagnostic value for AUC obtained from ROC method, about 60,2%. Meanwhile, blood leucocytes is indicated to have middle diagnostic value based on the ROC curve since AUC value obtained from ROC method was about 77,3%. This is in contrast with the results of another research analyzing biomarkers. CRP in urinary diversion cases conducted urgent in patients with renal colic and urinary stones, for instance, obtained a good diagnostic value for ROC curve value of CRP since AUC value obtained from ROC method was about 86,8%, but also obtained a weak diagnostic value for ROC curve value of leukocytes since AUC value obtained from ROC method was 22 about 68,8%.
ROC curve value of procalcitonin in this research, on the other hand, had good diagnostic value since AUC value obtained from ROC method was about 80,6%. This result is actually similar with that in the previous research which found that procalcitonin obtained was better than CRP in order to detect early the occurrence of renal parenchymal inflammation in cases of children who have urinary tract infection. Similarly, in that research, AUC value of procalcitonin obtained from ROC curve was about 98,8% also indicating a very good diagnostic value, as well as AUC value of CRP obtained was about 25 95,7% indicating a very good diagnostic value, too.
Besides providing diagnostic value in sepsis cases, procalcitonin actually can also serve as a monitor of antibiotic use in order to become more effective and efficient. It is because the excessive use of antibiotics can not only cause high cost, but can also increase bacterial resistance. Approximately, 110 patients who underwent surgery, but only 57 of whom use antibiotics monitored by procalcitonin every day. Meanwhile, another group, 53 patients, used standard antibiotic usage for about 8 days. And, it is then known that the use of antibiotics in those patients monitored with procalcitonin is shorter than that in patients monitored as the control group (5,9 ± 26 1,7 days vs. 7,9 ± 0,5 days, p < 0,001).
Researcher, moreover, have better diagnostic value of procalcitonin than that of CRP and blood leukocytes in the cases of urosepsis exemined in this research. Actually, it is not easy to get patients with early urosepsis cases, but by using inclusion and exclusion criteria the sample of this research finally could be collected. Procalcitonin with high diagnostic value (especially procalcitonin value > 25 ng / ml) obtained in this study can be considered as an early warning of impending mortality in those urosepsis patients. Therefore, it had better to conduct special treatments immediately and seriously for those patients with procalcitonin, > 25 ng / ml.
The finding obtained after the examination of blood leucocytes and CRP in this research is that procalcitonin can provide additional diagnostic value in early cases of urosepsis. Besides that, the finding also shows that the prognosis of urosepsis is associated with procalcitonin value. The higher the procalcitonin value is, the poorer the prognosis is.

CONCLUSION
Finally, it can be concluded that procalcitonin have good diagnostic value (better than CRP and blood leucocytes). As a result, it can be used as an early detection of urosepsis cases.