Procalcitonin levels to predict bacterial infection in Surgical Intensive Care Unit patients

Jin You Jhan; Yen Ta Huang; Cian Huei Shih; Jhen Da Yang; Yi Tsen Lin; Shin-Jie Lin; Hsiao Hui Yang; Lee Ying Soo; Guan Jin Ho

doi:10.4103/fjs.fjs_54_17

ORIGINAL ARTICLE

Year : 2017 | Volume : 50 | Issue : 4 | Page : 135-141

Procalcitonin levels to predict bacterial infection in Surgical Intensive Care Unit patients

Jin You Jhan¹, Yen Ta Huang², Cian Huei Shih³, Jhen Da Yang⁴, Yi Tsen Lin⁵, Shin-Jie Lin⁵, Hsiao Hui Yang⁶, Lee Ying Soo⁷, Guan Jin Ho⁸
¹ Department of Surgery, Buddhist Tzu Chi General Hospital; Division of Cardiothoracic Surgery, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
² Department of Surgery; Surgical Intensive Care Unit, Buddhist Tzu Chi General Hospital; Department of Pharmacology, Tzu Chi University, Hualien, Taiwan
³ Nurse Practitioner, Department of Nursing, Surgical Intensive Care Unit, Buddhist Tzu Chi General Hospital; Ph.D. Student, Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
⁴ Nurse Practitioner, Department of Nursing, Surgical Intensive Care Unit, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
⁵ Nurse Practitioner, Department of Nursing, Surgical Intensive Care Unit, Buddhist Tzu Chi General Hospital; M.S. Student, Institute of Nursing, Tzu Chi University, Hualien, Taiwan
⁶ Department of Surgery, Buddhist Tzu Chi General Hospital; School of Medicine, Tzu Chi University, Hualien, Taiwan
⁷ Department of Surgical Intensive Care Unit, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
⁸ Department of Surgical Intensive Care Unit, Buddhist Tzu Chi General Hospital; School of Medicine, Tzu Chi University, Hualien, Taiwan

Date of Submission	23-Nov-2016
Date of Decision	13-Jan-2017
Date of Acceptance	02-Mar-2017
Date of Web Publication	19-Jul-2017

Correspondence Address:
Guan Jin Ho
SICU of Tzu Chi General Hospital, 707, Section 3, Chung Yang Road, Hualien 970
Taiwan

Source of Support: None, Conflict of Interest: None

Read associated Erratum: Erratum: Procalcitonin levels to predict bacterial infection in surgical intensive care unit patients with this article

DOI: 10.4103/fjs.fjs_54_17

Abstract

Background: Infection-induced inflammatory response might be aggravated by surgery insults. The clinical presentation of Surgical Intensive Care Unit (SICU) patients might be different from medical critically ill patients.
Purpose: To evaluate the diagnostic and prognostic values of procalcitonin (PCT) to predict bacterial infection in SICU patients.
Methods: We retrospectively analyzed the 2-year (2013 and 2014) records of 342 adult SICU cases with suspected bacterial infection in SICU of Hualien Tzu Chi Hospital. The past histories, the first infection-related parameters when SICU admission, culture results, infection-related laboratory examinations, and outcomes were collected.
Results: Median of PCT level in patients with negative and any positive culture was 0.84 (interquartile range [IQR] 0.18–6.21) and 2.27 (IQR 0.54–9.93) ng/ml, respectively. Infection from blood, urine, and skin/soft tissue elicited significantly higher PCT levels. PCT in receiver operating characteristic (ROC) curve demonstrated the most accurate to predict bacterial infection (area under the ROC curve [AUC]: 0.61; 95% confidence interval [CI]: 0.54–0.63) and bacteremia (AUC: 0.73; 95% CI: 0.66–0.80) compared to white blood cell count, ratio of neutrophils, and neutrophil-to-lymphocyte count ratio (NLCR). Significantly higher PCT levels (4.12 ng/ml, 1.12–19.99; median, IQR) were observed in mortality cases. Higher PCT levels were significantly accompanied with higher NLCR, as well as higher incidence of leukopenia and bandemia. Using Kaplan–Meier analysis, significantly higher intrahospital mortality was observed in cases with above the cutoff PCT levels of 0.5 and 2 ng/ml cases, respectively.
Conclusion: PCT is a relatively more useful tool to predict bacterial and particularly bloodstream infection compared to other infection-related parameters in routinely clinical practice. Initial PCT levels may be a prognostic factor of SICU patients with bacterial infection.

Keywords: Bacterial infections, critical care, hospital surgery departments, procalcitonin

How to cite this article:
Jhan JY, Huang YT, Shih CH, Yang JD, Lin YT, Lin SJ, Yang HH, Soo LY, Ho GJ. Procalcitonin levels to predict bacterial infection in Surgical Intensive Care Unit patients. Formos J Surg 2017;50:135-41

How to cite this URL:
Jhan JY, Huang YT, Shih CH, Yang JD, Lin YT, Lin SJ, Yang HH, Soo LY, Ho GJ. Procalcitonin levels to predict bacterial infection in Surgical Intensive Care Unit patients. Formos J Surg [serial online] 2017 [cited 2021 May 7];50:135-41. Available from: https://www.e-fjs.org/text.asp?2017/50/4/135/211088

Introduction

Bacterial infections and followed sepsis are major threats to surgical patients' survival. Early intervention with an appropriate antimicrobial regimen(s) for infected patients is associated with a better outcome.^[1] However, some patients with bacterial infections have atypical symptoms or signs. In contrast, only parts of patients with systemic inflammatory response syndrome (SIRS) are resulted from bacterial infections. To find the most arcuate laboratory examination for early identification of bacterial infection in Intensive Care Unit (ICU) practice is very important.

Procalcitonin (PCT), near undetectable in plasma of healthy individuals, is an intracellular precursor of calcitonin produced by C-cells of the thyroid gland.^[2] PCT is induced by activated monocytes/macrophages and released into circulation in SIRS.^[3] In particular when bacterial infections occur, PCT secretion is stimulated by various cytokines, for example, tumor necrosis factor-α. In viral infections, the PCT production may be downgraded from increased production of interferon-gamma production.^[4] Using PCT to guide antibiotic decisions has been extensively studied in patients with bacterial infection.^[5] Although PCT is thought as a helpful biomarker for early diagnosis of sepsis in critically ill patients, the positive likelihood ratio in meta-analysis is not good enough.^[6] Furthermore, the diagnostic value of C-reactive protein, commonly used to predict bacterial infection in Taiwan, has been demonstrated worse than PCT.^[7] The aim of our study is to analyze the clinical significance of PCT in our Surgical ICU (SICU) cases to predict bacterial infections.

Methods

Patient population

This is a single-center, 2-year retrospective study, from January 1, 2013, to December 31, 2014. We enrolled all adult (≧18-year-old) cases admitted in SICU of Hualien Tzu Chi Hospital with PCT tests. In clinical practice, we subjectively arranged PCT test for any patient with any symptoms/signs of suspicious infection. In this 15-bed SICU, cases came from the department of general and hepato-biliary-pancreatic surgery, colorectal surgery, cardiovascular and thoracic surgery, plastic surgery, orthopedic surgery, otolaryngology, urology, as well as obstetrics and gynecology. The clinical data including past histories, infection-related laboratory examinations (PCT, white blood cell [WBC] count, ratios of segment plus band form leukocyte [segment + band], and neutrophil-to-lymphocyte count ratio [NLCR]), culture results, and outcomes were collected. We choose the first parameters of infection-related laboratory examinations when bacterial infection was suspected. The patients with insufficient or incomplete data were excluded from the study. We also excluded the patients with positive fungal culture. After chart review, a total of 342 patients were enrolled in this study. The primary outcome is survival rate during admission courses.

Data definition

According to PCT levels, we divided the data into four ranges (0.05–0.5 ng/ml, 0.5–2 ng/ml, 2–10 ng/ml, and >10 ng/ml) to differentiate the severity.^[8] We defined the patients with positive culture (sputum, urine, stool, blood, skin and soft tissue [SST], and drainage culture) as infectious status. The blood culture-positive group twice is bacteremia.

Statistical analysis

The diagnostic values of PCT and other parameters were assessed by the receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC). Results for categorical are presented as proportions (%) and compared by Chi-square tests. Results for normally and nonnormally distributed continuous variables are presented as mean (± standard deviation) and median (25%–75% interquartile range [IQR]), respectively. For normal distribution analysis, we used Kolmogorov–Smirnov test to examine any continuous variables. Normally and nonnormally distributed continuous variables were compared by Student t-tests and Mann–Whitney U-test, respectively. Variables were considered statistically significant if P < 0.05. Statistical tests of the data and figures were performed by SPSS 22 software (IBM Corporation, Armonk, NY, USA) and GraphPad Prism 6 (GraphPad Software, La Jolla, CA, USA).

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee of the institute. Informed written consent was obtained from all patients prior to their enrollment in this study.

Results

Population characteristics

In these 342 SICU patients with suspected infection, the median of age was 62 years old (IQR 53–76) and male gender accounted for 71.1%. About underlying diseases, ratios of diabetes mellitus, cirrhotic liver, and end-stage renal disease (ESRD) cases were 30.4%, 17.5%, and 9.1%, respectively. The positive culture results were 56.5% (65/115), 31.6% (56/177), 40% (50/125), 82.4% (89/108), 77.5% (124/160), and 45.8% (11/24) from blood, urine, drainage, wound, sputum, and stool, respectively. Median of ICU admission days was 6 (IQR 3–10) days. There was no correlation between the length of ICU admission days and PCT levels (P = 0.394 analyzed by Pearson's correlation coefficient). The intrahospital mortality was 22.5%. We compared the infection-related parameters between survivors and nonsurvivors during admission course; only PCT levels reached statistically significant difference [Figure 1]. Significantly higher PCT levels were observed in mortality case who were suspected bacterial infection in SICU.

Figure 1: Distribution of (a) white blood cell count, (b) ratios of segmented plus band form leukocytes, (c) neutrophil-to-lymphocyte count ratio, (d) procalcitonin levels in survivors and nonsurvivors. Red lines indicate median, while blue error bars indicate interquartile range. Each dot in the figures indicates individual value

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Diagnostic performance of procalcitonin and other infection-related parameters

The ROC curves and the detailed AUCs of WBC count, ratios of segmented plus band form WBC, NLCR, and PCT to predict the positive culture and bacteremia are shown in [Figure 2]a and [Figure 2]b, respectively. The difference of AUC between WBC count and 0.5, which means the test is no better than tossing a coin, did not reach statistical significance to predict bacterial infection in SICU patients. In contrast, only AUC of PCT was significantly higher than 0.5 to predict bacteremia in SICU patients. [Figure 2]c and [Figure 2]d demonstrates the comparison of any two parameters to predict bacterial infection and bacteremia. Compared to WBC count, AUCs of PCT and NLCR showed significantly higher to predict bacterial infection [Figure 2]c. AUC of PCT showed significantly higher than any other parameters to predict bacteremia [Figure 2]d.

Figure 2: Diagnostic value of procalcitonin levels and other parameters to predict bacterial infection and bacteremia. Receiver operating characteristic curves and the area under the receiver operating characteristic curve predict (a) bacterial infection and (b) bacteremia, respectively. Intragroup comparison of area under the receiver operating characteristic curve to predict (c) bacterial infection and (d) bacteremia, respectively. Error bar = standard error of mean

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Difference of procalcitonin levels from individual culture site

We also analyzed the PCT levels from individual culture site [Table 1]. In our study, median of PCT level was 0.84 (IQR: 0.18–6.21) ng/ml when patients without any positive culture. Patients with any positive culture had significantly higher PCT levels (2.27 ng/ml, 0.54–9.93; median, IQR). Among all culture site obtainment, patients with bacteremia had the highest PCT levels (9.05 ng/ml, 1.80–58.23; median, IQR). The difference of PCT levels between cases with positive and negative cultures from blood, urine, and skin reached statistical significance. Higher PCT levels were observed in SICU patients with bacteremia, urinary tract infection (UTI), and SST infection (SSTI).

Table 1: Difference of PCT levels from individual culture site

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Clinical data analysis divided by four intervals of procalcitonin levels

According to the previous report, PCT levels are divided into four groups: 0.05–0.5, 0.51–2, 2.01–10, and more than 10.01 ng/ml, which indicates the mimic condition of local infection, systemic infection, sepsis, and septic shock, respectively.^[8] The analysis is showed in [Table 2]. About underlying conditions, P values regarding the incidence of past history with ESRD among four groups was just 0.05. ESRD patients who were suspected bacterial infection seemed to have higher PCT levels. Compared to other laboratory examinations regarding bacterial infection, higher PCT levels were accompanied with higher NLCR, as well as higher incidence of leukopenia and bandemia with statistically significance difference. Pearson's correlation coefficient was significantly positive between PCT levels and NLCR (r = 0.20, P < 0.0001).

Table 2: Clinical data analysis divided by the severity according to PCT levels

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Survival curves using different cutoff levels of procalcitonin

We demonstrated the difference of intrahospital survival rate by Kaplan–Meier curves with different cutoff levels of PCT (0.5, 2, and 10 ng/ml, respectively) based on above description.^[8] Analyzed by log-rank test, intrahospital survival rates were significantly different with cutoff PCT levels of 0.5 and 2 ng/ml [Figure 3]a and [Figure 3]b. Intrahospital survival rate did not reach statistically significant difference between below and above 10 ng/ml of PCT levels [Figure 3]c.

Figure 3: Kaplan–Meier curves of intrahospital mortality using cutoff procalcitonin levels of (a) 0.5, (b) 2, (c) 10 ng/ml

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Discussion

In our study, PCT was better to predict bacterial infection and bacteremia in SICU patients. PCT levels were higher in mortality cases who admitted to SICU due to suspected or confirmed bacterial infection. Patients with bacteremia, UTI, and SSTI had higher PCT levels. Once PCT level >0.5 ng/ml, survival rate was deteriorated. We reviewed original articles from PubMed and found that only a few studies ^{[9],[10],[11],[12],[13]} investigating the diagnostic value of PCT from patients in Taiwan. Similarly, there were only two studies ^[14],[15] demonstrated PCT as a prognostic or severity marker in infected Taiwan patients.

The AUC values to predict bacterial infection in our investigation is lower than other studies focusing on standard care patients or patients with autoimmune disease.^[16],[17] Increased nonspecific inflammatory response in the early phase of surgical insults seems to trigger much higher inflammatory response after surgical infections, which results in false positive of PCT levels.^[18] One study reported the usefulness of PCT as a marker of systemic infection in emergency department patients with the cutoff value of 0.5 ng/ml.^[19] In our study, median of PCT level higher than 0.5 ng/ml in patients without any positive culture may explain the higher inflammatory response in SICU patients. Therefore, the lower diagnostic accuracy of PCT levels to predict bacterial infection in SICU patients than those in medical and noncritically ill populations seems reasonable. In contrast, the AUC values to predict bacteremia in our study are similar to other reports, and AUC values of bacteremia prediction in these reports (including our study) appear higher than other infection diseases.^[20],[21] The relationship between bloodstream infection and cytokine releases might be more directly. In our study, PCT levels in patients with bacteremia are higher than some studies.^{[21],[22],[23]} Again, it may explain the higher inflammatory response in SICU patients. Renal elimination is one of the major routes for the elimination of PCT, so it is reasonable that higher PCT level is found in ESRD cases in our study.^[24] Lower PCT levels were observed in cases with fungal infection,^[22] so we excluded patients with positive fungal culture in this study.

NLCR is an easily available biomarker, which can be calculated from a complete blood count. NLCR has previously been shown to predict outcomes in oncological patients and has subsequently been tested in a number of malignancies including lung, ovary, and breast.^[25] In acute inflammatory phase, neutrophilia and lymphopenia are presented on laboratory examination.^[26] NLCR is also considered as a biomarker of bacterial infections.^[27] In our study, although significant, the correlation between PCT levels and NLCR was poor. NLCR is the second powerful tool to predict bacterial and bloodstream infection in SICU patients in our study. More exaggerated inflammatory response in surgical patients may be one of the explanations.

This study has some limitations. First, we did not collect enough clinical data regarding patients' severity, for example, APACHE II score or SOFA score. Lack of pathogen analysis was a weakness in this investigation because the presentation of PCT levels is different from Gram-positive and negative pathogens.^[22],[23] PCT variations after antibiotic therapy may influence the outcome of patients with acute infectious diseases.^{[28],[29],[30]} There are no fixed intervals to check PCT in our clinical practice, so we were not able to determine the PCT variations.

Conclusion

Although not good enough for SICU patients, PCT is a relatively more useful diagnostic tool to predict bacterial and particularly bloodstream infection compared to other infection-related parameters in routinely clinical practice in our study. Initial PCT levels may be a prognostic factor of SICU patients with bacterial infection. A new diagnostic parameter for improving the predictive accuracy of bacterial infection in SICU patients should be explored in the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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