American Journal of Emergency Medicine 32 (2014) 448–451
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Brief Report
Procalcitonin and interleukin 6 for predicting blood culture positivity in sepsis☆ Mohammad Naffaa, MD a, b, Badira F. Makhoul, MD a, b, Amjad Tobia, MD a, b, Marielle Kaplan, PhD b, c, Doron Aronson, MD b, d, e, Zaher S. Azzam, MD a, b, e, Walid Saliba, MD MPH b, f,⁎ a
Department of Internal Medicine B, Rambam Health Care Campus, Haifa, Israel Ruth & Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel The Laboratory of Clinical Biochemistry, Rambam Health Care Campus, Haifa, Israel d Heart Institute, Rambam Health Care Campus, Haifa, Israel e The Rappaport Family Institute for Research in the Medical Sciences, Technion, Israel Institute of Technology, Haifa, Israel f Internal Medicine C, Ha'emek Medical Center, Afula, Israel b c
a r t i c l e
i n f o
Article history: Received 20 November 2013 Received in revised form 29 December 2013 Accepted 30 December 2013
a b s t r a c t Background: Procalcitonin and interleukin 6 (IL-6) are well-known predictors of blood culture positivity in patients with sepsis. However, the association of procalcitonin and IL-6 with blood culture positivity was assessed separately in previous studies. This study aims to examine and compare the performance of procalcitonin and IL-6, measured concomitantly, in predicting blood culture positivity in patients with sepsis. Methods: Forty adult patients with sepsis were enrolled in the study. Blood cultures were drawn before the institution of antibiotic therapy. The area under the curve (AUC) of the receiver operating characteristic curve was estimated to assess the performance of procalcitonin and IL-6 in predicting blood culture positivity. Results: Positive blood cultures were detected in 10 patients (25%). The AUC of procalcitonin and IL-6 was 0.85 and 0.61, respectively. The combined performance of procalcitonin and IL-6 was similar to that of procalcitonin alone, AUC of 0.85. On univariate analysis, only procalcitonin and IL-6 were associated with blood culture positivity. Multivariate logistic regression analysis showed that only procalcitonin was associated with blood culture positivity (odds ratio, 12.15 [1.29-114.0] for levels above the median compared with levels below the median). Using procalcitonin cut points of 1.35 and 2.14 (nanogram per milliliter) enabled 100% and 90% identification of positive blood cultures and reduced the need of blood cultures by 47.5% and 57.5%, respectively. Conclusions: Compared with IL-6, procalcitonin better predicts blood culture positivity in patients with sepsis. Using a predefined procalcitonin cut points will predict most positive blood cultures and reduce the need of blood cultures in almost half of patients with sepsis. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Sepsis is the most common cause of death in the setting of intensive care [1,2], and early diagnosis followed by immediate administration of antibiotics can be lifesaving [3,4]. Differentiating sepsis from other noninfectious systemic inflammatory response syndromes (SIRS) can be challenging [5], especially in the absence of clear site of infection. In such cases, positive blood culture might be the only means to confirm the diagnosis of sepsis. However, it usually takes 24 to 48 hours to attain culture result with subsequent delay in the diagnosis and treatment of sepsis. One reasonable approach may
☆ This work was supported in part by The Rappaport Family Institute for Research in the Medical Sciences, Technion, Israel Institute of Technology, Haifa, Israel. ⁎ Corresponding author. Department of Internal Medicine C, Ha'emek Medical Center Afula 18101, Israel. Tel.: +972 4 6495132; fax: +972 4 6495134. E-mail address: [email protected] (W. Saliba). 0735-6757/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajem.2013.12.058
suggest drawing blood cultures and instituting wide-spectrum antibiotic therapy while awaiting the results of blood culture. Nevertheless, this approach might be expensive and not without risks, as unnecessary antibiotics may favor and promote the emergence of highly resistant microorganisms. Procalcitonin has been suggested as a predictor of blood culture positivity in patients with different causes of sepsis, namely, community-acquired pneumonia [6], urosepsis [7], and line sepsis [8], and in patients with SIRS [9]. Interleukin 6 (IL-6) is a marker of inflammation that has also been found to be associated with blood culture positivity in patients with sepsis [10-15]. However, the performance of procalcitonin and IL-6 for the prediction of blood culture positivity was assessed separately in previous study. In this study, we aimed to examine and compare the performance of procalcitonin and IL-6 in predicting blood culture positivity in a cohort of patients with sepsis and to evaluate whether the combination of IL-6 and procalcitonin would improve the predictive performance for blood culture positivity.
M. Naffaa et al. / American Journal of Emergency Medicine 32 (2014) 448–451
2. Materials and methods 2.1. Study population The study was performed at Rambam Health Care Campus, Haifa, Israel, and included patients who were admitted to the department of internal medicine with the primary diagnosis of sepsis of any cause between March 29, 2009, and June 5, 2010. After the initiation of the study, owing to logistic problems, recruitment of patients in the study was withhold and continued several months later. The study was conducted in accordance with the principles of the Declaration of Helsinki and approved by The Rambam Hospital Institutional Review Board. The diagnosis of sepsis was made according to the published consensus as SIRS with suspected or proven infection [16]. Patients were excluded if they had any of the following: younger than 18 years, pregnancy, active cancer, and antibiotic treatment initiated before obtaining blood cultures. Data that were collected includes (1) demographic characteristics, (2) comorbidities, and (3) laboratory variables; hemoglobin levels, mean corpuscular volume, and red blood cell distribution width (RDW) were measured using the Advia 120 Hematology Analyzer (Siemens Healthcare Diagnostics, Munich, Germany). Glucose, blood urea nitrogen, and creatinine levels were measured using the “Dimension” (Siemens Healthcare Diagnostics). Interleukin 6 levels were determined using the “Quantikine human Interleukin 6 Elisa assay” (R&D Systems, Minneapolis, MN). Procalcitonin levels were analyzed using an automated microparticle immunoassay (Liaison Brahms PCT; Brahms Diagnostics, Berlin, Germany). 2.2. Study end point The end point of the study was blood culture positivity. Blood cultures were drawn from all participants in the study before the initiation of antibiotic treatment. 2.3. Statistical analysis Continuous variable are summarized with medians and interquartile range (IQR), and categorical variables are summarized with numbers and proportions. The Mann-Whitney U test was used to compare continuous variables between 2 groups, and the comparisons of categorical variables between groups were performed with χ 2 test or the Fisher exact test as appropriate. Logistic models were used to assess the univariate association between baseline parameters and blood culture positivity. Variables that were found to be significant in
449
univariate analysis were included in the multivariate analysis to assess the association between procalcitonin, IL-6, and blood culture positivity. For this purpose, procalcitonin and IL-6 were classified each into 2 groups according to their medians cut points. The strength of the association was estimated with odds ratio (OR) and 95% confidence interval (CI) using procalcitonin and interleukin levels below the median as reference groups. The predictive performance of procalcitonin and IL-6 for blood culture positivity was assessed by calculating the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. For all analyses, P b .05 for the 2-tailed tests was considered statistically significant. All statistical analyses were performed using SPSS 18.0 (SPSS, Inc, Chicago, IL). 3. Results Overall, 40 patients with sepsis were recruited in the study of 117 patients with sepsis who were admitted during the study period. The demographic, clinical, and laboratory characteristics of the study subjects are presented in Table 1. Positive blood cultures were detected in 10 patients (25%): 7 Escherichia coli (70%), 2 Klebsiella pneumoniae (20%), and 1 Enterobacter (10%). On univariate analysis, procalcitonin and IL-6 were the only variables that were significantly associated with blood culture positivity: OR of 15.54 (95% CI, 1.73-139.65), P = .014, and OR of 6.0 (95% CI, 1.08-33.27), P = .040, respectively, for levels above the medians compared with levels below the medians (Table 2). A multivariate logistic regression analysis using significant variables from univariate analysis (procalcitonin and IL-6) showed that procalcitonin was the only independent predictor of blood culture positivity (OR, 12.15 [95% CI, 1.29-114.0]; P = .029). The ROC curves showed that procalcitonin had a higher predictive accuracy for blood culture positivity compared with IL-6 (AUC, 0.85 [P = .001] and 0.61 [P = .288], respectively). The combined performance of both procalcitonin and IL-6 in predicating blood culture positivity was assessed using the calculated probabilities from a logistic regression model that included both procalcitonin and IL-6. The combined performance was similar to the performance of procalcitonin alone (AUC, 0.85 [P = .001]). The median cut point of procalcitonin (1.49 ng/mL) had a sensitivity of 90% for predicting blood culture positivity. Sensitivity remained unchanged with procalcitonin cut point of 2.14 ng/mL while it enabled reducing the need for obtaining blood cultures by 57.7%. Using a cut point of 1.35 ng/mL identified 100% of positive blood cultures and reduced the need for obtaining blood cultures by 47.5% (Table 3).
Table 1 Demographic, clinical, and laboratory characteristics of patients with sepsis according to blood culture results (n = 40) Variable
Age (y), median (IQR) Sex Female Male Smoking Duration of admission, median (IQR) Diabetes mellitus Hypertension Ischemic heart disease Creatinine (mg/dL), median (IQR) BUN (mg/dL), median (IQR) Sodium (mmol/L), median (IQR) Hemoglobin (g/dL), median (IQR) RDW, median (IQR) IL-6 (pg/mL), median (IQR) Procalcitonin (ng/mL), median (IQR)
All
Blood culture results for bacteremia
79.0 (68.2-84.0) 15 25 14 6.0 17 32 16 1.60 31.5 135 11.7 14.5 62.15 1.49
(37.5%) (62.5%) (35.0%) (3.0-11.0) (42.5%) (80.0%) (40.0%) (1.10-2.20) (21.0-40.2) (133-138) (11.0-12.8) (13.8-16.4) (40.54-132.80) (0.29-10.35)
P
Positive (n = 10)
Negative (n = 30)
79.5 (72.0-84.7)
76.0 (66.5-84.0)
5 (50.0%) 5 (50.0%) 2 (20.0%) 5.5 (3.7-11.0) 6 (60%) 10 (100%) 3 (30.0%) 1.33 (1.07-2.40) 30.5 (18.5-48.5) 134 (133-135) 11.8 (11.1-12.5) 14.3 (13.4-14.5) 98.16 (55.85-136.41) 10.65 (3.52-28.88)
10 (33.3%) 20 (66.7%) 12 (40.0%) 6.0 (3.0-12.0) 11 (36.7%) 22 (73.3%) 13 (43.3%) 1.60 (1.17-2.28) 32.0 (21.7-38.7) 136 (133-140) 11.7 (10.9-12.9) 14.5 (14.0-16.5) 54.17 (40.11-131.31) 0.49 (0.14-3.80)
.469 .283
.226 .939 .178 .076 .360 .450 .474 .131 .963 .196 .301 .001
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M. Naffaa et al. / American Journal of Emergency Medicine 32 (2014) 448–451
Table 2 Univariate analysis: ORs for bacteremia in patients with sepsis Variable
OR (95% CI)
P
Age (for 10-y increase) Sex Female Male Smoking Yes No Diabetes mellitus Yes No Hypertension Ischemic heart disease Yes No Hyperlipidemia Yes No Creatininea Above the median Below the median BUNa Above the median Below the median Sodiuma Above the median Below the median Hemoglobin levela Above the median Below the median RDWa Above the median Below the median IL-6a Above the median Below the median Procalcitonina Above the median Below the median
1.4 (0.71-2.94)
.307 .350
2.0 (0.47-8.56) Reference .262 0.37 (0.07-2.08) Reference .203 2.59 (0.60-11.23) Reference NC
.459
0.56 (0.12-2.60) Reference .278 2.33 (0.51-10.78) Reference .450 0.56 (0.12-2.60) Reference .468 0.58 (0.14-2.50) Reference .081 0.22 (0.04-1.21) Reference .885 1.14 (0.27-4.78) Reference .132 0.27 (0.05-1.48) Reference .040 6.0 (1.08-33.27) Reference .014 15.54 (1.73-139.65) Reference
Abbreviations: NC, OR not calculable because 1 cell had zero observations; BUN, blood urea nitrogen. a The corresponding median cut points: creatinine, 1.6 mg/dL; blood urea nitrogen, 31.5 mg/dL; sodium, 135 mmol/L; hemoglobin level, 11.7 g/dL; RDW, 14.5; IL-6, 62.15 pg/mL; procalcitonin, 1.49 ng/mL.
4. Discussion In concordance with previous studies [6-8,17,18], we have shown that procalcitonin is a strong and reliable predictor of blood culture positivity, with higher levels indicating increased probability for positive blood culture. The predictive accuracy for blood culture positivity of procalcitonin as estimated by the AUC of the ROC curve was 0.85 and is in line with previous studies [6-8,17]. We have also
Table 3 Prediction accuracy of procalcitonin at different cut point Procalcitonin cut points
Negative Potential reduction Sensitivity Specificity Positive likelihood likelihood in the need for ratio ratio blood cultures using procalcitonin below the cut point
1.35 (ng/mL) 1.49a (ng/mL) 2.14 (ng/mL) 3.77 (ng/mL)
47.5% 52.5% 57.5% 62.5%
a
100% 90% 90% 80%
63% 63% 73% 77%
2.70 2.43 3.33 3.48
This cut point represents the median of procalcitonin level.
0.01 0.16 0.14 0.26
shown that procalcitonin may be used to direct the need of obtaining blood cultures in patients with sepsis. This approach may be time and resources saving by precluding the need for obtaining blood cultures from almost half of the patients with sepsis while still enabling the detection all positive blood cultures. Procalcitonin, a product of the CALC-I gene [19], is a 116-amino acid peptide produced by C-cells in the thyroid, and its concentration in the serum of healthy people is very low [20]. Physiologically, the extrathyroid transcription of the CALC-I gene is blocked. Microbial infections increase the gene expression, leading to the release of procalcitonin from all parenchymal tissues and differentiated cell types throughout the body, including liver and peripheral blood mononuclear cells [21]. The inflammatory release of procalcitonin may be induced by 2 ways: (1) endotoxins and/or (2) proinflammatory cytokines released in a cell-mediated host response, including interleukin 1b, IL-6, and tumor necrosis factor α [21]. Our findings suggest that procalcitonin gene expression and procalcitonin levels are determined by the levels of bacterial mediators that are likely to be higher when the bacterial pathogens invade the blood stream as compared with lower levels in localized bacterial infection without bloodstream infection. In our study, IL-6 showed a modest but not significant value for predicting blood culture positivity (AUC, 0.61; P = .288). When assessed separately, IL-6 was associated with blood culture positivity (P = .04). This finding is in line with previous studies showing significant association between IL-6 and blood culture positivity [10-15]. However, our study showed that the association with IL-6 did not reach statistical significance when controlling for procalcitonin (P = .134). Furthermore, the combined performance of procalcitonin and IL-6 in predicting blood culture positivity was similar to the performance of procalcitonin alone. However, it should be emphasized that early in the course of the sepsis, serum IL-6 levels may not be highly increased as major proportion of serum IL-6 will bind to the soluble IL-6 receptor, and only later in the course, when all soluble receptors are occupied, serum IL-6 levels will be high enough to reflect the severity of sepsis and its related outcome [22]. In line with our findings, a previous study showed that the performance of procalcitonin in predicting blood culture positivity in patients with sepsis did not improve when combined with IL-6 or other markers such as C-reactive protein [23]. Our study has several limitations. The first and the most important is the small number of included subjects with sepsis. Secondly, we did not record the site of infection. Actually, this might be an advantage as we showed that procalcitonin is useful in predicting blood culture positivity in patients with sepsis, regardless of the specific cause or type. As sepsis continues to be among the leading causes of death, exerts heavy economic burdens, and indirectly promotes the emergence of highly resistant microorganisms [1,2,24], there is an increasing need for a biomarker that can rapidly and reliably rule out sepsis and direct the need for attaining blood cultures. Procalcitonin proves a good candidate for this purpose. The current evidence suggests that procalcitonin is useful for differentiating between bacterial and nonbacterial infection and in predicting blood culture positivity in patient with sepsis, whereas the prognosis of such patients may be better assessed by IL-6 [25]. Jekarl et al [26] in a recent article suggested procalcitonin as a diagnostic marker and IL-6 as a prognostic marker for sepsis. In conclusion, procalcitonin, but not IL-6, predicts blood culture positivity and results in approximately 50% reduction in the need for obtaining unnecessary blood cultures. Our study may serve as a basis for large scale studies in the future aiming to validate our results.
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Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Brief Report
Procalcitonin and interleukin 6 for predicting blood culture positivity in sepsis☆ Mohammad Naffaa, MD a, b, Badira F. Makhoul, MD a, b, Amjad Tobia, MD a, b, Marielle Kaplan, PhD b, c, Doron Aronson, MD b, d, e, Zaher S. Azzam, MD a, b, e, Walid Saliba, MD MPH b, f,⁎ a
Department of Internal Medicine B, Rambam Health Care Campus, Haifa, Israel Ruth & Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel The Laboratory of Clinical Biochemistry, Rambam Health Care Campus, Haifa, Israel d Heart Institute, Rambam Health Care Campus, Haifa, Israel e The Rappaport Family Institute for Research in the Medical Sciences, Technion, Israel Institute of Technology, Haifa, Israel f Internal Medicine C, Ha'emek Medical Center, Afula, Israel b c
a r t i c l e
i n f o
Article history: Received 20 November 2013 Received in revised form 29 December 2013 Accepted 30 December 2013
a b s t r a c t Background: Procalcitonin and interleukin 6 (IL-6) are well-known predictors of blood culture positivity in patients with sepsis. However, the association of procalcitonin and IL-6 with blood culture positivity was assessed separately in previous studies. This study aims to examine and compare the performance of procalcitonin and IL-6, measured concomitantly, in predicting blood culture positivity in patients with sepsis. Methods: Forty adult patients with sepsis were enrolled in the study. Blood cultures were drawn before the institution of antibiotic therapy. The area under the curve (AUC) of the receiver operating characteristic curve was estimated to assess the performance of procalcitonin and IL-6 in predicting blood culture positivity. Results: Positive blood cultures were detected in 10 patients (25%). The AUC of procalcitonin and IL-6 was 0.85 and 0.61, respectively. The combined performance of procalcitonin and IL-6 was similar to that of procalcitonin alone, AUC of 0.85. On univariate analysis, only procalcitonin and IL-6 were associated with blood culture positivity. Multivariate logistic regression analysis showed that only procalcitonin was associated with blood culture positivity (odds ratio, 12.15 [1.29-114.0] for levels above the median compared with levels below the median). Using procalcitonin cut points of 1.35 and 2.14 (nanogram per milliliter) enabled 100% and 90% identification of positive blood cultures and reduced the need of blood cultures by 47.5% and 57.5%, respectively. Conclusions: Compared with IL-6, procalcitonin better predicts blood culture positivity in patients with sepsis. Using a predefined procalcitonin cut points will predict most positive blood cultures and reduce the need of blood cultures in almost half of patients with sepsis. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Sepsis is the most common cause of death in the setting of intensive care [1,2], and early diagnosis followed by immediate administration of antibiotics can be lifesaving [3,4]. Differentiating sepsis from other noninfectious systemic inflammatory response syndromes (SIRS) can be challenging [5], especially in the absence of clear site of infection. In such cases, positive blood culture might be the only means to confirm the diagnosis of sepsis. However, it usually takes 24 to 48 hours to attain culture result with subsequent delay in the diagnosis and treatment of sepsis. One reasonable approach may
☆ This work was supported in part by The Rappaport Family Institute for Research in the Medical Sciences, Technion, Israel Institute of Technology, Haifa, Israel. ⁎ Corresponding author. Department of Internal Medicine C, Ha'emek Medical Center Afula 18101, Israel. Tel.: +972 4 6495132; fax: +972 4 6495134. E-mail address: [email protected] (W. Saliba). 0735-6757/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajem.2013.12.058
suggest drawing blood cultures and instituting wide-spectrum antibiotic therapy while awaiting the results of blood culture. Nevertheless, this approach might be expensive and not without risks, as unnecessary antibiotics may favor and promote the emergence of highly resistant microorganisms. Procalcitonin has been suggested as a predictor of blood culture positivity in patients with different causes of sepsis, namely, community-acquired pneumonia [6], urosepsis [7], and line sepsis [8], and in patients with SIRS [9]. Interleukin 6 (IL-6) is a marker of inflammation that has also been found to be associated with blood culture positivity in patients with sepsis [10-15]. However, the performance of procalcitonin and IL-6 for the prediction of blood culture positivity was assessed separately in previous study. In this study, we aimed to examine and compare the performance of procalcitonin and IL-6 in predicting blood culture positivity in a cohort of patients with sepsis and to evaluate whether the combination of IL-6 and procalcitonin would improve the predictive performance for blood culture positivity.
M. Naffaa et al. / American Journal of Emergency Medicine 32 (2014) 448–451
2. Materials and methods 2.1. Study population The study was performed at Rambam Health Care Campus, Haifa, Israel, and included patients who were admitted to the department of internal medicine with the primary diagnosis of sepsis of any cause between March 29, 2009, and June 5, 2010. After the initiation of the study, owing to logistic problems, recruitment of patients in the study was withhold and continued several months later. The study was conducted in accordance with the principles of the Declaration of Helsinki and approved by The Rambam Hospital Institutional Review Board. The diagnosis of sepsis was made according to the published consensus as SIRS with suspected or proven infection [16]. Patients were excluded if they had any of the following: younger than 18 years, pregnancy, active cancer, and antibiotic treatment initiated before obtaining blood cultures. Data that were collected includes (1) demographic characteristics, (2) comorbidities, and (3) laboratory variables; hemoglobin levels, mean corpuscular volume, and red blood cell distribution width (RDW) were measured using the Advia 120 Hematology Analyzer (Siemens Healthcare Diagnostics, Munich, Germany). Glucose, blood urea nitrogen, and creatinine levels were measured using the “Dimension” (Siemens Healthcare Diagnostics). Interleukin 6 levels were determined using the “Quantikine human Interleukin 6 Elisa assay” (R&D Systems, Minneapolis, MN). Procalcitonin levels were analyzed using an automated microparticle immunoassay (Liaison Brahms PCT; Brahms Diagnostics, Berlin, Germany). 2.2. Study end point The end point of the study was blood culture positivity. Blood cultures were drawn from all participants in the study before the initiation of antibiotic treatment. 2.3. Statistical analysis Continuous variable are summarized with medians and interquartile range (IQR), and categorical variables are summarized with numbers and proportions. The Mann-Whitney U test was used to compare continuous variables between 2 groups, and the comparisons of categorical variables between groups were performed with χ 2 test or the Fisher exact test as appropriate. Logistic models were used to assess the univariate association between baseline parameters and blood culture positivity. Variables that were found to be significant in
449
univariate analysis were included in the multivariate analysis to assess the association between procalcitonin, IL-6, and blood culture positivity. For this purpose, procalcitonin and IL-6 were classified each into 2 groups according to their medians cut points. The strength of the association was estimated with odds ratio (OR) and 95% confidence interval (CI) using procalcitonin and interleukin levels below the median as reference groups. The predictive performance of procalcitonin and IL-6 for blood culture positivity was assessed by calculating the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. For all analyses, P b .05 for the 2-tailed tests was considered statistically significant. All statistical analyses were performed using SPSS 18.0 (SPSS, Inc, Chicago, IL). 3. Results Overall, 40 patients with sepsis were recruited in the study of 117 patients with sepsis who were admitted during the study period. The demographic, clinical, and laboratory characteristics of the study subjects are presented in Table 1. Positive blood cultures were detected in 10 patients (25%): 7 Escherichia coli (70%), 2 Klebsiella pneumoniae (20%), and 1 Enterobacter (10%). On univariate analysis, procalcitonin and IL-6 were the only variables that were significantly associated with blood culture positivity: OR of 15.54 (95% CI, 1.73-139.65), P = .014, and OR of 6.0 (95% CI, 1.08-33.27), P = .040, respectively, for levels above the medians compared with levels below the medians (Table 2). A multivariate logistic regression analysis using significant variables from univariate analysis (procalcitonin and IL-6) showed that procalcitonin was the only independent predictor of blood culture positivity (OR, 12.15 [95% CI, 1.29-114.0]; P = .029). The ROC curves showed that procalcitonin had a higher predictive accuracy for blood culture positivity compared with IL-6 (AUC, 0.85 [P = .001] and 0.61 [P = .288], respectively). The combined performance of both procalcitonin and IL-6 in predicating blood culture positivity was assessed using the calculated probabilities from a logistic regression model that included both procalcitonin and IL-6. The combined performance was similar to the performance of procalcitonin alone (AUC, 0.85 [P = .001]). The median cut point of procalcitonin (1.49 ng/mL) had a sensitivity of 90% for predicting blood culture positivity. Sensitivity remained unchanged with procalcitonin cut point of 2.14 ng/mL while it enabled reducing the need for obtaining blood cultures by 57.7%. Using a cut point of 1.35 ng/mL identified 100% of positive blood cultures and reduced the need for obtaining blood cultures by 47.5% (Table 3).
Table 1 Demographic, clinical, and laboratory characteristics of patients with sepsis according to blood culture results (n = 40) Variable
Age (y), median (IQR) Sex Female Male Smoking Duration of admission, median (IQR) Diabetes mellitus Hypertension Ischemic heart disease Creatinine (mg/dL), median (IQR) BUN (mg/dL), median (IQR) Sodium (mmol/L), median (IQR) Hemoglobin (g/dL), median (IQR) RDW, median (IQR) IL-6 (pg/mL), median (IQR) Procalcitonin (ng/mL), median (IQR)
All
Blood culture results for bacteremia
79.0 (68.2-84.0) 15 25 14 6.0 17 32 16 1.60 31.5 135 11.7 14.5 62.15 1.49
(37.5%) (62.5%) (35.0%) (3.0-11.0) (42.5%) (80.0%) (40.0%) (1.10-2.20) (21.0-40.2) (133-138) (11.0-12.8) (13.8-16.4) (40.54-132.80) (0.29-10.35)
P
Positive (n = 10)
Negative (n = 30)
79.5 (72.0-84.7)
76.0 (66.5-84.0)
5 (50.0%) 5 (50.0%) 2 (20.0%) 5.5 (3.7-11.0) 6 (60%) 10 (100%) 3 (30.0%) 1.33 (1.07-2.40) 30.5 (18.5-48.5) 134 (133-135) 11.8 (11.1-12.5) 14.3 (13.4-14.5) 98.16 (55.85-136.41) 10.65 (3.52-28.88)
10 (33.3%) 20 (66.7%) 12 (40.0%) 6.0 (3.0-12.0) 11 (36.7%) 22 (73.3%) 13 (43.3%) 1.60 (1.17-2.28) 32.0 (21.7-38.7) 136 (133-140) 11.7 (10.9-12.9) 14.5 (14.0-16.5) 54.17 (40.11-131.31) 0.49 (0.14-3.80)
.469 .283
.226 .939 .178 .076 .360 .450 .474 .131 .963 .196 .301 .001
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Table 2 Univariate analysis: ORs for bacteremia in patients with sepsis Variable
OR (95% CI)
P
Age (for 10-y increase) Sex Female Male Smoking Yes No Diabetes mellitus Yes No Hypertension Ischemic heart disease Yes No Hyperlipidemia Yes No Creatininea Above the median Below the median BUNa Above the median Below the median Sodiuma Above the median Below the median Hemoglobin levela Above the median Below the median RDWa Above the median Below the median IL-6a Above the median Below the median Procalcitonina Above the median Below the median
1.4 (0.71-2.94)
.307 .350
2.0 (0.47-8.56) Reference .262 0.37 (0.07-2.08) Reference .203 2.59 (0.60-11.23) Reference NC
.459
0.56 (0.12-2.60) Reference .278 2.33 (0.51-10.78) Reference .450 0.56 (0.12-2.60) Reference .468 0.58 (0.14-2.50) Reference .081 0.22 (0.04-1.21) Reference .885 1.14 (0.27-4.78) Reference .132 0.27 (0.05-1.48) Reference .040 6.0 (1.08-33.27) Reference .014 15.54 (1.73-139.65) Reference
Abbreviations: NC, OR not calculable because 1 cell had zero observations; BUN, blood urea nitrogen. a The corresponding median cut points: creatinine, 1.6 mg/dL; blood urea nitrogen, 31.5 mg/dL; sodium, 135 mmol/L; hemoglobin level, 11.7 g/dL; RDW, 14.5; IL-6, 62.15 pg/mL; procalcitonin, 1.49 ng/mL.
4. Discussion In concordance with previous studies [6-8,17,18], we have shown that procalcitonin is a strong and reliable predictor of blood culture positivity, with higher levels indicating increased probability for positive blood culture. The predictive accuracy for blood culture positivity of procalcitonin as estimated by the AUC of the ROC curve was 0.85 and is in line with previous studies [6-8,17]. We have also
Table 3 Prediction accuracy of procalcitonin at different cut point Procalcitonin cut points
Negative Potential reduction Sensitivity Specificity Positive likelihood likelihood in the need for ratio ratio blood cultures using procalcitonin below the cut point
1.35 (ng/mL) 1.49a (ng/mL) 2.14 (ng/mL) 3.77 (ng/mL)
47.5% 52.5% 57.5% 62.5%
a
100% 90% 90% 80%
63% 63% 73% 77%
2.70 2.43 3.33 3.48
This cut point represents the median of procalcitonin level.
0.01 0.16 0.14 0.26
shown that procalcitonin may be used to direct the need of obtaining blood cultures in patients with sepsis. This approach may be time and resources saving by precluding the need for obtaining blood cultures from almost half of the patients with sepsis while still enabling the detection all positive blood cultures. Procalcitonin, a product of the CALC-I gene [19], is a 116-amino acid peptide produced by C-cells in the thyroid, and its concentration in the serum of healthy people is very low [20]. Physiologically, the extrathyroid transcription of the CALC-I gene is blocked. Microbial infections increase the gene expression, leading to the release of procalcitonin from all parenchymal tissues and differentiated cell types throughout the body, including liver and peripheral blood mononuclear cells [21]. The inflammatory release of procalcitonin may be induced by 2 ways: (1) endotoxins and/or (2) proinflammatory cytokines released in a cell-mediated host response, including interleukin 1b, IL-6, and tumor necrosis factor α [21]. Our findings suggest that procalcitonin gene expression and procalcitonin levels are determined by the levels of bacterial mediators that are likely to be higher when the bacterial pathogens invade the blood stream as compared with lower levels in localized bacterial infection without bloodstream infection. In our study, IL-6 showed a modest but not significant value for predicting blood culture positivity (AUC, 0.61; P = .288). When assessed separately, IL-6 was associated with blood culture positivity (P = .04). This finding is in line with previous studies showing significant association between IL-6 and blood culture positivity [10-15]. However, our study showed that the association with IL-6 did not reach statistical significance when controlling for procalcitonin (P = .134). Furthermore, the combined performance of procalcitonin and IL-6 in predicting blood culture positivity was similar to the performance of procalcitonin alone. However, it should be emphasized that early in the course of the sepsis, serum IL-6 levels may not be highly increased as major proportion of serum IL-6 will bind to the soluble IL-6 receptor, and only later in the course, when all soluble receptors are occupied, serum IL-6 levels will be high enough to reflect the severity of sepsis and its related outcome [22]. In line with our findings, a previous study showed that the performance of procalcitonin in predicting blood culture positivity in patients with sepsis did not improve when combined with IL-6 or other markers such as C-reactive protein [23]. Our study has several limitations. The first and the most important is the small number of included subjects with sepsis. Secondly, we did not record the site of infection. Actually, this might be an advantage as we showed that procalcitonin is useful in predicting blood culture positivity in patients with sepsis, regardless of the specific cause or type. As sepsis continues to be among the leading causes of death, exerts heavy economic burdens, and indirectly promotes the emergence of highly resistant microorganisms [1,2,24], there is an increasing need for a biomarker that can rapidly and reliably rule out sepsis and direct the need for attaining blood cultures. Procalcitonin proves a good candidate for this purpose. The current evidence suggests that procalcitonin is useful for differentiating between bacterial and nonbacterial infection and in predicting blood culture positivity in patient with sepsis, whereas the prognosis of such patients may be better assessed by IL-6 [25]. Jekarl et al [26] in a recent article suggested procalcitonin as a diagnostic marker and IL-6 as a prognostic marker for sepsis. In conclusion, procalcitonin, but not IL-6, predicts blood culture positivity and results in approximately 50% reduction in the need for obtaining unnecessary blood cultures. Our study may serve as a basis for large scale studies in the future aiming to validate our results.
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