Arab Journal of Gastroenterology 16 (2015) 10–13

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Original Article

Role of procalcitonin in diagnosis of bacterial infection in trans-arterial chemoembolisation treated hepatocellular carcinoma patients Hesham K. Dabbous, Fatma A. Ali-Eldin ⇑, Iman M.F. Montasser Department of Tropical Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt

a r t i c l e

i n f o

Article history: Received 27 August 2014 Accepted 15 March 2015

Keywords: Hepatocellular carcinoma Trans-arterial chemoembolisation Procalcitonin

a b s t r a c t Background and study aim: Trans-arterial chemoembolisation (TACE) became the treatment of choice for multinodular hepatocellular carcinoma. The use of prophylactic antibiotics following intervention is controversial. This study aimed to assess the role of serum procalcitonin level in early diagnosis of bacterial infection following TACE to optimise antibiotic intake in those patients. Patients and methods: This study was carried on HCC patients diagnosed according to AASLD who underwent TACE and developed post interventional fever within 48 h. Laboratory investigations including CBC, neutrophil count, C-reactive protein and ESR (pre and after intervention) were done. Cultures were done according to the suspected site of infection. Serum procalcitonin was done for all the included patients before and after TACE. Results: Forty two TACE treated patients were included with post interventional fever within 48 h. Their ages ranged between 45 and 65 (mean 53.83 ± 5.23). All patients received antibiotic prophylaxis started 24 h pre intervention and for 5 days after according to the local protocol. Five patients (11.9%) had positive blood cultures post intervention. The analysis of laboratory results showed statistical significant correlation between procalcitonin levels and positive cultures, post interventional CRP and TLC and pre interventional INR and bilirubin, while there was statistical significant correlation between CRP and post interventional temperature, total leucocytic count and site of focal lesion. Conclusion: Procalcitonin seems to be a promising marker for diagnosis of sepsis in TACE treated HCC patients to optimise the unnecessary use of antibiotics. Ó 2015 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.

Introduction During the past 20 years, the number of patients diagnosed with hepatocellular carcinoma (HCC) has increased worldwide [1]. In Egypt, annual proportion of HCC showed a significant rising trend from 4.0% in 1993 to 7.2% in 2002 [2]. Trans-arterial chemoembolisation (TACE) has become the treatment of choice for multinodular hepatocellular carcinoma [3]. Chemoembolisation has played an important role in the treatment of large HCCs in patients who are not surgical candidates [4,5]. Procalcitonin (PCT) is a protein consisting of 116 amino acids with a molecular weight of 13 kDa. It can act as a hormone and a cytokine. It is produced by several cell types in response to pro-inflammatory stimuli, particularly bacterial infection. It is released under the stimulation of sepsis [6]. PCT levels rise within 6–12 h of bacterial infection. In patients with sepsis, severe sepsis, and septic shock, PCT levels can reach 1000 ng/ml once the bacterial

⇑ Corresponding author.

infection is resolved; PCT levels rapidly decrease [7]. Several studies confirmed the value of procalcitonin in early prediction and diagnosis of sepsis [8,9]. Moreover; PCT can assist in identifying patients without serious bacterial infections and limit antimicrobial use [10]. This study aimed to assess the role of serum procalcitonin level in early diagnosis of bacterial infection following TACE to optimise antibiotic intake in those patients.

Patients and methods This prospective study was carried out in HCC Clinic, Tropical Medicine Department; Ain Shams University Hospitals. After approval of the Research and Ethics Committee of Ain Shams University, Cairo, Egypt, the trial was registered with the federal clearinghouse for randomised trials; www.clinicaltrials.gov (NCT01518829). The study was carried on HCC patients diagnosed according to AASLD who underwent TACE and developed post interventional

http://dx.doi.org/10.1016/j.ajg.2015.03.001 1687-1979/Ó 2015 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.

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fever within 48 h. Laboratory investigations including CBC, neutrophil count, C-reactive protein and ESR (pre and after intervention) were done. Cultures (blood, sputum, punctures site swab, etc, . . .) were done according to the suspected site of infection. Serum procalcitonin level was done for all the included patients before and after TACE. Inclusion criteria Hepatocellular carcinoma patients (diagnosed according to AASLD) [11] who underwent TACE who developed post interventional fever more than 38 °C for more than 24 h. Exclusion criteria Hepatocellular carcinoma patients who did not develop fever after intervention, proven infection elsewhere (i.e. urinary tract infection, respiratory tract infection, . . ., etc.), other tumours elsewhere. Patients who develop fever less than 38 °C or fever that resolved in the first 24 h following the procedure were excluded from the study. According to the unit protocol, all the included patients received intravenous 3rd generation cephalosporin 1 g/12 h and oral metronidazole three times daily starting before the procedure and for 5 days after the procedure. Antibiotics intake is extended in those patients who develop fever. TACE technique Catheterisation of the hepatic artery was done through right femoral puncture. Diagnostic hepatic angiography was used for detection of tumour blush, then selective catheterisation of tumour feeding artery with injection of Adriablastin (1–2 mg/kg max 100 mg) and lipidol emulsion and embolisation of tumour bed and feeding artery by gel foam. After that post-embolisation hepatic angiography was done to detect disappearance of tumour blush. Procalcitonin test principle The RayBio Human Procalcitonin ELISA (Enzyme-Linked Immunosorbent Assay) kit is an in vitro enzyme-linked immunosorbent assay for the quantitative measurement of human procalcitonin in serum, plasma, cell culture supernatants and urine. This assay employs an antibody specific for human Procalcitonin coated on a 96-well plate. Standards and samples are pipetted into the wells and procalcitonin present in a sample is bound to the wells by the immobilised antibody. The wells are washed and biotinylated anti-human procalcitonin antibody is added. After washing away unbound biotinylated antibody, HRPconjugated streptavidin is pipetted to the wells. The wells are again washed, a TMB substrate solution is added to the wells and colour develops in proportion to the amount of procalcitonin bound. The Stop Solution changes the colour from blue to yellow, and the intensity of the colour is measured at 450 nm (RayBio Human Procalcitonin ELISA Kit Protocol). Statistical analysis IBM SPSS statistics (V. 19.0, IBM Corp., USA, 2010) was used for data analysis. Data were expressed as mean ± SD for quantitative parametric measures in addition to Median, Percentiles for quantitative non-parametric measures and both number and percentage for categorised data. Student’s t-test, Wilcoxon Rank Sum

test, Ranked Spearman correlation test, and Chi square test were used. The probability of error 0.05 was considered significant. Results TACE was done in 196 patients according to BCLC guidelines for HCC management [12]. Forty two (21.4%) of TACE treated HCC patients developed post interventional fever within 48 h after the manoeuver and were included in the study. They were thirty three males and nine females. Their ages ranged between 45 and 65 (mean 53.83 ± 5.23). Prior to TACE, twenty three patients were Child A and nineteen patients were Child B; their mean MELD was 11.48 ± 3.52. Post intervention, eighteen patients (42.9%) had ascites compared to fourteen (33.3%) pre-intervention with statistical significant difference (p = 0.00). As regards MELD score it ranged between 6 and 20 (mean 12.55 ± 3.69). Seventeen patients (40.5%) were Child class A, twenty four patients (57.1%) were Child class B and one patient (2.4%) became Child class C and this mount statistical significant deference between the pre and post interventional Child classification and MELD of the studied patients (p = 0.00). The analysis of the laboratory results showed statistical significant increase in post interventional TLC, neutrophils%, HB, AST, ALT, Bilirubin, CRP and procalcitonin (p < 0.5) (Table 1). Although all patients received antibiotic prophylaxis 24 h pre intervention and for 5 days after according to our unit local protocol, five patients had positive blood cultures post intervention (Klebsiella pneumonia was the most common pathogen). Those 5 patients were 2 males and three females, their ages ranged between 49 and 62 years. Two of them were child A and 3 were Child B. Three of them had single focal lesion in the right lobe from 5 to 6 cm in diameter. The other 2 had 2 hepatic focal lesions 5–9 cm in diameter. Those 5 patients stayed in the hospital for 9–14 days after culture results antibiotics were shifted according to culture results and they showed a good clinical response and were discharged with complete resolution of infection. Post interventional procalcitonin levels were significantly higher in patients with positive blood culture (1.2 ± 0.31) than those with negative cultures (0.38 ± 0.23) (p = 0.00). While, there were non significant differences as regards total leucocytic count, neutrophil count, CRP, ESR, site or size of focal lesions between patients with positive and patients with negative blood cultures (p > 0.05). Correlation between serum procalcitonin level and CRP level with the studied parameters is summarised in Table 2. There was statistical significant correlation between procalcitonin levels and positive cultures, post interventional CRP levels and TLC, while there was statistical significant correlation between CRP levels and post interventional temperature, total leucocytic count and site of focal lesion.

Table 1 Comparison between pre and post interventional laboratory results. Variable

Pre intervention

Post intervention

t

p

TLC cell/cmm Neutrophils % HB g/dl PLT/cmm AST u/l ALT u/l BIL mg/dl ALB g/l INR ESR CRP mg/ml Procalcitonin ng/ml

5.22 ± 1.99 56.55 ± 8.98 12.54 ± 1.55 113.67 ± 76.34 53.60 ± 12.66 51.00 ± 10.67 1.43 ± 0.48 3.05 ± 0.39 1.27 ± 0.27 55.48 ± 36.72 11.69 ± 16.05 0.33 ± 0.19

7.96 ± 3.10 74.40 ± 9.75 11.80 ± 1.55 106.98 ± 75.70 72.62 ± 15.96 86.31 ± 20.26 2.22 ± 0.92 2.98 ± 0.48 1.34 ± 0.28 59.57 ± 37.47 28.76 ± 28.71 0.48 ± 0.36

7.92 9.46 3.27 0.91 5.07 9.86 4.42 0.82 1.08 0.82 3.93 2.95

0.00 0.00 0.00 0.37 0.00 0.00 0.00 0.42 0.29 0.42 0.00 0.01

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Table 2 Correlation between serum procalcitonin and CRP levels with the studied parameters. Variable

Procalcitonin r

Age Sex Temperature Positive culture Child classification INR Bilirubin Albumin AST ALT Site of focal lesion Number of focal lesions Size of focal lesion AFP CRP ESR TLC Neutrophil percent

CRP P

0.16 0.14 0.00 0.76 0.12 0.10 0.28 0.05 0.01 0.29 0.25 0.04 0.06 0.12 0.44 0.24 0.32 0.06

0.30 0.37 0.98 0.00 0.43 0.56 0.07 0.76 0.95 0.06 0.10 0.81 0.69 0.44 0.00 0.13 0.04 0.69

r

P 0.04 0.02 0.33 0.21 0.22 0.04 0.03 0.04 0.19 0.07 0.45 0.28 0.28 0.08

– 0.26 0.46 0.21

0.81 0.92 0.03 0.18 0.17 0.79 0.84 0.79 0.22 0.66 0.003 0.07 0.08 0.64 – 0.10 0.002 0.18

Fig. 1. Receiver Operating Characteristic (ROC) curve analysis showing the diagnostic performance of CRP.

Fig. 2. Receiver Operating Characteristic (ROC) curve analysis showing the diagnostic performance of procalcitonin in the studied patients.

On constructing Receiver Operating Characteristic (ROC) curve analysis for CRP, area under the curve was 0.64, cut off value was 17 mg/ml with sensitivity 60% and specificity 56.8% (Fig. 1), while the ROC curve for Procalcitonin showed area under the curve was 0.98 cut of value was 0.95 ng/ml with sensitivity 80% and specificity 97.3% (Fig. 2).

Discussion HCC is a major global health problem, the main difficulties regarding evaluation of tumour responses, assignment of severity of disease, and measurement of treatment outcomes in HCC relate to the fact that 80% of patients with HCC have 2 diseases, namely the cancer and the underlying cirrhosis [13]. Chemoembolisation (TACE) is the most widely used primary treatment for unresectable HCC [14] and the recommended first line-therapy for patients at intermediate stage of the disease [12]. The procedure is generally well tolerated, with major complications in only 4–7% of procedures and a 30-day mortality of approximately 1% [15]. However, the procedure has been associated with several complications such as acute hepatic failure (2.6% of cases), liver infarction (0.3%), hepatic biloma formation (0.8%), liver abscess (0–1.4%), or septicemia (2.6–11%) [16]. One of the most common complications of TACE is post embolisation syndrome which is a transient self limiting symptom or sign complex of low-grade fever and general malaise [17]. The duration depends on the volume of necrosis produced and the overall condition of the patient. If small areas are treated, the patient is unlikely to experience post-ablation syndrome at all. If very large areas of liver tumours are ablated, the syndrome may persist for 2–3 weeks. The majority of patients who have this syndrome will experience some malaise for 2–7 days depending on the volume of tumour and surrounding tissue ablated and the integrity of the patient’s immune system [18]. This study revealed that the percentage of males (78.6%) was higher than that of females (21.4%) with male to female ratio (3.7:1). An epidemiological study which was done in Lower Egypt on 1012 HCC cases reported that male to female ratio was (5:1) [19], while other study was carried out in Gharbiah PopulationBased Cancer Registry, Egypt, on 1186 HCC cases and revealed male to female ratio 4:1 [20]. In the current study, right hypochondrial pain was the most presenting complaint in the studied group, being present in 58.5% of patients. This finding is consistent with Abd el-Wahab et al. [19] reported that 78% of HCC patients presented with abdominal pain. HCCs were discovered accidentally in 29.4% of patients in this study. Abd el-Wahab et al. [21] reported that 144 of 385 (37.4%) HCC patients were presented with no symptoms and discovered accidentally and that was the main presentation in that series. In other series, 8.8% of the HCC patients were discovered accidentally and were being asymptomatic [19]. In this series, on comparing the post-interventional laboratory values to pre-interventional ones, we found that there was a significant increase in post treatment total leucocytic count, neutrophils, CRP and procalcitonin level. These findings were in accordance with other authors [22,23]. However, there was no significant difference between pre and post-treatment ESR values. As regards sensitivity and specificity of procalcitonin as a marker of bacterial infection; our results revealed sensitivity 80% and specificity 97.3% these go with other studies such as Hatherill et al. [24] where sensitivity was 94% and specificity was 47%; Lorrot et al. [25] where sensitivity was 89% and specificity was 88% and Schwarz et al. [26] where sensitivity was 100% and specificity was 74%. In order to evaluate the accuracy of determination of procalcitonin (PCT) and C-reactive protein (CRP) levels for the diagnosis of bacterial infection the current study revealed the diagnostic accuracy of PCT markers was higher than that of CRP markers among our patients as shown in the ROC curve (sensitivity of PCT was 80% vs. 60% for CRP) and (specificity of PCT was 97.3% vs. 56.8% for CRP). In this study, the area under the curve (AUC) of CRP was 0.64 (95% CI: 0.37–0.91). The cut off value was established at 17 ng/ml with sensitivity of 60% and specificity of 56.8%, NPV was 92% and PPV was 58%. While the area under the

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curve (AUC) of procalcitonin was 0.95 (95% CI:0.94–1.0), the cut off value was established at 0.95 ng/ml with sensitivity of 80% and specificity of 97.3% NPV of 97% and PPV of 96%. The difference between AUC of CRP and that of Procalcitonin was 0.31 which mounted statistical significance (p < 0.5). And thus there was statistical significant difference between both as markers of sepsis in TACE treated HCC patients. These results agree with a meta-analysis evaluating the accuracy of determination of procalcitonin (PCT) and C-reactive protein (CRP) levels for the diagnosis of bacterial infection. PCT level was more sensitive 88% (95% CI, 80–93%) vs. 75% (95% CI, 62–84%) and more specific 81% (95% CI, 67–90%) vs. 67% (95% CI, 56–77%) than CRP level for differentiating bacterial from non-infective causes of inflammation. On the basis of this analysis, the diagnostic accuracy of PCT markers was higher than that of CRP markers among patients hospitalised for suspected bacterial infections. Also, in patients with decompensated liver cirrhosis high PCT level was sensitive and specific tool for the initial diagnosis of bacterial infection. On the other hand Serum PCT was within normal ranges in patients with simple steatosis or steato-hepatitis and has no diagnostic value in NAFLD [27]. Elefsiniotis et al. [28] reported that serum procalcitonin levels remain below the threshold of 0.5 ng/ml in all patients with un-complicated cirrhosis, irrespective of the cause of the disease, while they are significantly elevated when bacterial infection complicates the course of the disease. On the other hand a significant proportion of patients with acute alcoholic hepatitis on a cirrhotic background as well as of patients with acute on top chronic viral hepatitis, without bacterial infection, exhibit serum procalcitonin levels above 0.5 ng/ml, suggesting that this cut-off value is probably not enough to discriminate between patients with or without bacterial infection within these subgroups of patients with liver disease as some authors reported that procalcitonin may arise also from hepatocytes. Although some centres all over the world does not recommend the use of prophylactic antibiotic in patients undergoing TACE; others recommend antibiotic regimen with cephalosporin and levofloxacin prophylaxis against post-procedural infectious complications [29–31]. In this study only five patients (11.9%) had positive blood cultures post intervention. There was statistical significant correlation between procalcitonin levels and positive cultures, post interventional CRP levels and TLC and pre interventional INR and bilirubin. Our study has limitations. All patients included were empirically treated with antibiotics 1 day before the intervention and for 5 days after according to our local protocol, however, this could alter the results of the inflammatory markers post intervention and culture results. Finally, we can conclude that procalcitonin measurement seems to be a promising marker in diagnosis of sepsis in TACE treated HCC patients to optimise the unnecessary use of antibiotics. Further studies of larger sample size are needed to obtain more convincing results. We also recommend studying the value of procalcitonin in diagnosis of bacterial infection after other modalities of HCC treatment. Conflict of interest There is no conflict of interest. References [1] Okuda K. Hepatocellular carcinoma. J Hepatol 2000;32:225–37. [2] El-Zayadi AR, Badran HM, Barakat EM, Mel-D Attia, Shawky S, Mohamed MK, et al. Hepatocellular carcinoma in Egypt: a single center study over a decade. World J Gastroenterol 2005;11(33):5193–8. [3] Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemo-embolization improves survival. Hepatology 2003;37:429–42.

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