Clinical Implications of Elevated Initial Procalcitonin Levels in Febrile Patients with Pancreatic Cancer

Corresponding author : Jaihwan Kim Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173 beongil, Bundang-gu, Seongnam 13620, Korea Tel. +82-31-787-7075 Fax. +82-31-787-4051 E-mail: drjaihwan@snu.ac.kr

^*Wootaek Seo and Hyeon-Gi Kim contributed equally to this work as the first authors.

Received April 23, 2025 Revised May 22, 2025 Accepted May 26, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

요약

배경/목적

췌장암 환자의 발열 시 세균 감염 여부를 빠르게 감별할 수 있는 지표가 필요하다. 본 연구는 프로칼시토닌의 감염 예측력과 임상적 유용성을 평가하고자 하였다.

방법

2021년 분당서울대학교병원에서 입원한 췌장암 환자 149명의 199건 발열 에피소드를 후향적으로 분석하였다. 백혈구 수치, C-반응단백, 프로칼시토닌의 감염 예측력을 민감도-특이도 곡선(receiver operating characteristic curve) 분석을 통해 비교하였다.

결과

프로칼시토닌이 높은 군에서 그람음성균 감염, 양성 혈액 배양률, 발열 이후 입원 기간이 유의하게 높았다. 세 지표의 곡선하면적(area under the curve)은 백혈구 수치 0.550, C-반응 단백 0.580, 프로칼시토닌 0.763으로 나타났다.

결론

프로칼시토닌은 췌장암 환자의 발열 시 세균 감염 예측에 유용한 보조 지표가 될 수 있다.

Keywords: 췌장신생물, 발열, 프로칼시토닌, C-반응단백, 백혈구수

Abstract

Background/Aim

Pyogenic infections are common in pancreatic cancer patients with fever. This study evaluated procalcitonin as a biomarker for bacterial infection in this population.

Methods

A retrospective study was conducted at Seoul National University Bundang Hospital on 149 pancreatic cancer patients who experienced 199 febrile episodes during hospitalization in 2021. The diagnostic performance of white blood cell (WBC) count, C-reactive protein (CRP), and procalcitonin was assessed using receiver operating characteristic curve analysis and area under the curve (AUC).

Results

Among 199 febrile episodes, 57.3% occurred in patients with metastatic disease. The most common cause of fever was cholangitis (22.6%), followed by pneumonia (10.1%). Positive blood cultures were more frequent in patients with elevated procalcitonin (51.7% vs. 14.9%, p<0.001). Gram-negative infections were more common in the high procalcitonin group, while culture-negative cases predominated in the low group. Procalcitonin showed stronger correlation with CRP (r=0.31) than with WBC (r=0.16). AUCs were 0.550 (WBC), 0.580 (CRP), and 0.763 (procalcitonin). Patients with procalcitonin ≥1.84 ng/mL had longer hospital stays (9.36 vs. 7.37 days; p=0.0266).

Conclusions

Procalcitonin showed the highest diagnostic accuracy for bacterial infection in febrile pancreatic cancer patients and may help guide antibiotic decisions.

Keywords: Pancreatic neoplasms, Fever, Procalcitonin, C-reactive protein, Leukocyte count

INTRODUCTION

Cancer can lead to various complications in patients [1]. Common issues include cachexia, infection, and pain [2,3]. Among these, biliary tract infection and pyogenic abscess are frequent causes of fever in patients with pancreatic cancer [4]. However, fever can also arise from non-infectious causes, such as neoplastic or drug-induced fever, including reactions to antibiotics. Non-infectious fever is relatively common in clinical practice [5,6]. Given the risk of sepsis or potential disruption of anti-cancer treatment, prompt and accurate identification of bacterial infections is essential [7,8].

Diagnosing non-septic fever can be challenging due to the complexity of medical conditions and the high incidence of pyogenic infections in patients with pancreatic cancer. Blood cultures are important for distinguishing between infectious and non-infectious causes of fever, but they have limitations in sensitivity, specificity, and turnaround time [9]. Therefore, there is a growing need for reliable biomarkers that can quickly and accurately predict bacterial infections.

Procalcitonin is a biomarker used to detect bacterial infections [10]. It is a protein produced by the thyroid gland and released into the bloodstream in response to bacterial infections [11]. Levels of procalcitonin can be measured through a simple blood test, and elevated levels may indicate the presence of a bacterial infection. While its effectiveness has been extensively studied across various patient populations [12], its reliability as a marker for bacterial infections in febrile patients with pancreatic cancer remains unclear.

This study aimed to evaluate the utility of procalcitonin as a biomarker in febrile patients with pancreatic cancer.

METHODS

1. Study population

This study was conducted at Seoul National University Bundang Hospital, a single tertiary medical center, between January and December 2021. Electronic medical records were retrospectively reviewed to identify patients who met the following criteria: 1) a pathological diagnosis of pancreatic ductal adenocarcinoma, 2) hospitalization due to fever, 3) a body temperature of 38°C (100.4°F) or higher, and 4) initial laboratory tests, including white blood cell (WBC) count, C-reactive protein (CRP), procalcitonin, as well as blood cultures performed within 24 hours of fever onset. Patients with a fever below 38°C or missing any of the four laboratory tests were excluded. Current anti-cancer treatment was defined as therapy administered within 1 month before fever onset.

This study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Seoul National University Bundang Hospital (B-2306-837-104). The authors had access only to de-identified data, and no personally identifiable information was available during or after data collection.

2. Definition

In this study, fever was defined as a body temperature of 38°C (100.4°F) or higher [13]. The resectability of pancreatic cancer was assessed according to the National Comprehensive Cancer Network pancreatic cancer guidelines, version 2.2024 [14]. A positive blood culture was defined as the presence of bacteria in one or more blood culture bottles. Chronic kidney disease (CKD) was classified as a glomerular filtration rate below 60 mL/min/1.73 m2 for at least 3 months, with or without renal damage [15].

3. Clinical outcomes

The primary outcome of this study was to compare the predictive value of three inflammatory biomarkers-WBC count, CRP, and procalcitonin-for bacterial infection. Secondary outcomes included comparisons of the causes of fever, isolated pathogens, and the hospital length of stay after fever onset based on procalcitonin level.

4. Statistics

Chi-square test and Fisher’s exact test were used to compare categorical data, with post-hoc residual analysis performed to identify significant group differences. Student’s t-test was used for continuous variables in SPSS Statistics version 23.0 (IBM Corp., Armonk, NY, USA). Receiver operating characteristic curves were generated for positive blood culture results and the area under the curve (AUC) was calculated. The AUC values of WBC, CRP, and procalcitonin were compared to assess their predictive value for bacterial infection using Youden’s index, which balances sensitivity and specificity to provide a comprehensive measure of test accuracy [16]. The correlation between WBC, CRP, and procalcitonin levels was analyzed using scatter plots. AUC comparison and correlation analysis were performed using MedCalc (MedCalc Software Ltd., Ostend, Belgium).

RESULTS

1. Comparison of biomarkers for predicting bacterial infection

A total of 149 pancreatic cancer patients experienced fever, leading to 199 individual febrile episodes. Twelve patients had recurrent febrile episodes, resulting in duplicate counting in the total event number. Five patients experienced three recurrences, three had four recurrences, and two patients had five and six recurrences, respectively.

The optimal threshold for WBC count was determined to be 11,450/µL, with a sensitivity of 50.0% and a specificity of 63.8% for detecting positive blood cultures. Similarly, the identified cutoff for CRP level was 12.36 mg/dL, with sensitivity and specificity values of 52.0% and 71.1%, respectively. The optimal threshold for procalcitonin level was determined to be 1.84 ng/mL, with a sensitivity of 60.0% and a specificity of 81.9%.

The AUC values for WBC count, CRP, and procalcitonin in predicting bacterial infection based on blood culture results were 0.550, 0.580, and 0.763, respectively (Fig. 1). Comparative analyses were conducted to assess differences in AUC values among these biomarkers. The AUC difference was 0.031 for WBC versus CRP (p=0.6128), 0.212 for WBC versus procalcitonin (p=0.0004), and 0.182 for CRP versus procalcitonin (p=0.001). Combining the three biomarkers did not improve infection prediction compared to using each biomarker individually (AUC values of combined biomarkers; CRP and WBC, 0.555; procalcitonin and CRP, 0.543; procalcitonin and WBC, 0.559).

2. Correlations between biomarkers

Scatter plots illustrating the correlations among various biomarkers are shown in Fig. 2. Notably, a significant correlation coefficient (r) of 0.31 (p<0.001) was observed between CRP and procalcitonin levels (Fig. 2A). Similarly, correlation coefficients of 0.26 (p<0.001) and 0.16 (p=0.021) were observed between WBC count and procalcitonin levels (Fig. 2B) and between WBC count and CRP levels (Fig. 2C), respectively.

3. Comparison of baseline characteristics based on procalcitonin cutoff levels

Patients were divided into two groups based on the procalcitonin cutoff value: ≥1.84 ng/mL (higher group) vs. <1.84 ng/mL (lower group) (Table 1). The mean age differed significantly between the two groups (67.5 years in higher group vs. 63.7 years in lower group; p=0.007). However, there were no significant differences in gender, past medical history, surgical resectability, current cancer therapy, and chemotherapy regimen.

A significant difference was also observed in bacterial culture results between the higher and lower procalcitonin groups. Gram-negative bacterial infections were significantly more frequent in the higher procalcitonin group and less common in the lower procalcitonin group, whereas negative blood culture results were more common in the lower group. In contrast, gram-positive infections showed no significant difference between the two groups.

The length of hospital stay after fever onset was significantly longer in the higher procalcitonin group (9.36 vs. 7.37 days; p=0.0266) (Fig. 3).

4. Causes of fever

Table 2 outlines the various clinical causes of fever. Cholangitis was the most common cause (45 cases; 22.6%), followed by pneumonia (20 cases; 10.1%). In 10 cases (5.0%), the cause of the fever remained undetermined. When stratified by procalcitonin levels, the distribution of fever causes showed no statistically significant differences between the two groups.

5. Identified bacterial pathogens

Bacterial pathogens were detected in 64 isolates, as presented in Table 3. The most commonly identified pathogen was the gram-negative Escherichia coli (19 isolates; 29.7%), followed by the gram-positive Enterococcus spp. (14 isolates; 21.9%). When stratified by procalcitonin levels, Escherichia coli was significantly more prevalent in the higher procalcitonin group (42.1% vs. 11.5%; p=0.009). Conversely, Pseudomonas aeruginosa was significantly more prevalent in the lower procalcitonin group (0.0% vs. 15.4; p=0.024). Other bacteria showed no significant differences between the groups.

The distribution of bacterial culture results according to procalcitonin levels is summarized in Table 4. Higher procalcitonin levels were significantly associated with gram-negative bacterial infections, whereas cultures with no bacterial growth were more prevalent in the lower procalcitonin group.

DISCUSSION

This study aimed to evaluate the utility of procalcitonin as a biomarker for predicting bacterial infections in febrile patients with pancreatic cancer. While previous studies have explored the clinical significance of procalcitonin in febrile patients with cancer [6,17], studies especially focused on pancreatic cancer remained limited. Our study addresses this gap by investigating procalcitonin not only as a diagnostic tool but also as a potential prognostic marker for clinical outcomes in this patient population.

Our findings indicate that procalcitonin demonstrated higher AUC values compared to CRP or WBC count. Additionally, it demonstrated superior discriminative ability in the early stages of febrile episodes. These results suggest that procalcitonin could serve as a more reliable biomarker for predicting bacterial infections in febrile patients with pancreatic cancer, facilitating early triage and potentially improving outcomes for this vulnerable group. Notably, we identified a subset of patients who exhibited elevated procalcitonin levels despite having normal or borderline WBC and CRP values, and were subsequently diagnosed with bacteremia. This suggests that procalcitonin may provide complementary diagnostic information independent of conventional inflammatory markers, particularly in diagnostically ambiguous situations.

Based on the upper reference level of procalcitonin at 0.5 ng/mL, previous research in patients with hematological cancers suggested an optimal cutoff level of 0.5 ng/mL [17]. However, a study focusing on patients with advanced solid tumors identified a higher optimal cutoff value of 1.52 ng/mL [6]. Our study further supports this trend, identifying 1.84 ng/mL as the optimal cutoff for procalcitonin, yielding the highest positive predictive value (sensitivity, 60.0%; specificity, 81.9%). This relatively elevated cutoff may be attributed to the clinical characteristics of our cohort, which included a substantial proportion of patients with metastatic pancreatic cancer, a high prevalence of biliary infections, and a considerable number receiving chemotherapy. These factors are likely to contribute to an enhanced systemic inflammatory response. Accordingly, procalcitonin thresholds may need to be interpreted with consideration of specific patient populations and clinical settings, as supported by recent evidence suggesting infection-specific variability in optimal cutoff values [18].

Building on these observations, the association between elevated procalcitonin levels and bacterial infections suggests its potential utility in clinical decision-making. Patients with procalcitonin levels of ≥1.84 ng/mL were not only more likely to have a bacterial infection but also experienced longer hospital stays, suggesting its possible role as a prognostic marker. In addition, a higher proportion of these patients received broad-spectrum antibiotics, indicating that procalcitonin levels may reflect not only infection severity but also the intensity of therapeutic interventions. Consistently, previous studies have shown that higher procalcitonin levels are associated with worse clinical outcomes, including extended hospitalization [19].

Moreover, the significant differences in bacterial culture results across procalcitonin groups reinforce its relevance in distinguishing infection types. The predominance of gram-negative infections in the high procalcitonin group supports the notion that procalcitonin may serve as an indicator of gram-negative bacterial infections rather than infections caused by other species. This is consistent with previous research showing significantly higher procalcitonin levels in gram-negative sepsis compared to gram-positive sepsis [20]. Conversely, the higher frequency of negative blood cultures in the low procalcitonin group suggests that alternative non-infectious causes of fever should be considered in these patients. These findings highlight the potential of procalcitonin to enhance current diagnostic approaches in febrile pancreatic cancer patients, enabling more targeted antibiotic strategies and reducing unnecessary antimicrobial exposure.

Scatter plots were used to visually assess the correlations among the three biomarkers. While the correlation coefficients between biomarker levels were relatively modest, the associated p-values indicated statistical significance. These findings suggest that each biomarker may be used interchangeably despite differences in their discriminative abilities in febrile patients with pancreatic cancer.

This study has several limitations. First, procalcitonin levels can be elevated in the absence of infection due to factors such as severe stress, trauma, surgery, or cardiogenic shock [21,22]. Additionally, severe liver dysfunction has been shown to influence procalcitonin levels [23]. While procalcitonin is typically not elevated in viral infections, it can be elevated in fungal infections [18,20]. In this study, a few non-bacterial infections were identified through microbiological tests, including polymerase chain reaction for viral pathogens and blood cultures for fungal organisms. Specifically, two cases of coronavirus disease 2019 and one fungal infection were included. Although potential confounding factors, their small number likely had minimal impact on the overall findings. Second, individuals with CKD exhibit elevated baseline levels of inflammatory biomarkers due to increased production of inflammatory cytokines [24,25]. However, the study included only five patients with CKD, potentially limiting the generalizability of the findings. Third, although our study demonstrated meaningful results for procalcitonin, the use of empirical antibiotics remains practically unavoidable in current clinical practice [26].

In conclusion, procalcitonin exhibited superior diagnostic accuracy in distinguishing positive bacterial blood cultures in febrile patients with pancreatic cancer, particularly in early fever stages. Its elevation reinforced its role as a bacterial infection marker and a prognostic indicator of infection severity. These findings support procalcitonin’s utility as both a diagnostic and prognostic biomarker for guiding clinical decision-making

Notes

Conflict of Interest

Jong-Chan Lee is currently serving as an Editor in Editorial Board of the Korean Journal of Pancreas and Biliary Tract; however, Jong-Chan Lee was not involved in the peer reviewer selection, evaluation, or decision process of this article. Wootaek Seo, Hyeon-Gi Kim, Hee-Eon Lim, Kwangrok Jung, Jin-Hyeok Hwang, and Jaihwan Kim have no potential conflicts of interest to declare.

ETHICAL APPROVAL

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Fig. 1.

The receiver operating characteristics curve analysis shows the diagnostic performance of WBC count and CRP and procalcitonin levels in predicting bacterial infection, with area under the curve values of 0.550, 0.580, and 0.763, respectively. WBC, white blood cell; CRP, C-reactive protein.

Fig. 2.

Scatter plots depict the correlation between biomarker levels. (A) The correlation coefficient between CRP and procalcitonin was 0.31 (p<0.001). (B) The correlation coefficient between WBC count and procalcitonin was 0.26 (p<0.001). (C) The correlation coefficient between WBC count and CRP was 0.16 (p=0.021). CRP, C-reactive protein; WBC, white blood cell.

Fig. 3.

Box plot comparing hospital stay duration after fever onset between the higher and lower procalcitonin groups. Patients with higher procalcitonin levels (≥1.84 ng/mL) had significantly longer hospital stay after fever onset compared to those with lower procalcitonin levels (<1.84 ng/mL) (mean, 9.36 vs. 7.37 days; p=0.0266).

Table 1.

Baseline characteristics of patients

	Higher procalcitonin (n=58)	Lower procalcitonin (n=141)	All patients (n=199)	p-value
Age (years)	67.5 (47-87)	63.7 (40-88)	65 (40-88)	0.007
Gender
Male	31 (53.4)	71 (50.3)	102 (51.3)	0.810
Past history
Diabetes mellitus	33 (56.9)	60 (42.6)	93 (46.7)	0.092
Hypertension	35 (60.3)	62 (44.0)	97 (48.7)	0.052
Resectability
Resectable	3 (5.2)	19 (13.5)	22 (11.1)	0.147
Borderline resectable	7 (12.1)	8 (5.7)	15 (7.5)	0.209
Locally advanced	14 (24.1)	34 (24.1)	48 (24.1)	0.999
Metastatic	34 (58.6)	80 (56.7)	114 (57.3)	0.931
Current cancer therapy
Chemotherapy	38 (65.5)	77 (54.6)	115 (57.8)	0.208
Radiation therapy	0 (0.0)	3 (2.1)	3 (1.5)	0.632
Operation	2 (3.4)	10 (7.1)	12 (6.0)	0.513
Chemotherapy regimen (n=115)
FOLFIRINOX	19 (50.0)	45 (58.4)	64 (55.7)	0.511
Gemcitabine (alone or combination)	16 (42.1)	26 (33.8)	42 (36.5)	0.504
Others	3 (7.9)	6 (7.8)	9 (7.8)	>0.999
Result of blood culture
Positive	30 (51.7)	21 (14.9)	51 (25.6)	<0.001

Values are presented as mean (range) or number (%). Higher procalcitonin, ≥1.84 ng/mL; lower procalcitonin, <1.84 ng/mL.

FOLFIRINOX, chemotherapy regimens including irinotecan, oxaliplatin, folinic acid, and fluorouracil.

Table 2.

Causes of fever

	Higher procalcitonin (n=58)	Lower procalcitonin (n=141)	All patients (n=199)	p-value
Cholangitis	18 (31.0)	27 (19.1)	45 (22.6)	0.069
Pneumonia	7 (12.1)	13 (9.2)	20 (10.1)	0.544
Neutropenic fever	4 (6.9)	15 (10.6)	19 (9.5)	0.414
Neoplastic fever	2 (3.4)	16 (11.3)	18 (9.0)	0.077
Liver abscess	6 (10.3)	11 (7.8)	17 (8.5)	0.761
Peritonitis	7 (12.1)	9 (6.4)	16 (8.0)	0.292
Enterocolitis	5 (8.6)	9 (6.4)	14 (7.0)	0.798
Postoperative fever	1 (1.7)	12 (8.5)	13 (6.5)	0.148
Urinary tract infection	0 (0.0)	7 (5.0)	7 (3.5)	0.192
Cholecystitis	4 (6.9)	2 (1.4)	6 (3.0)	0.110
Pancreatitis	1 (1.7)	5 (3.5)	6 (3.0)	0.820
Chemotherapy-induced fever	1 (1.7)	5 (3.5)	6 (3.0)	0.820
COVID-19	0 (0.0)	2 (1.4)	2 (1.0)	0.897
Others	2 (3.4)	8 (5.7)	10 (5.0)	0.767

Values are presented as number (%). Higher procalcitonin, ≥1.84 ng/mL; lower procalcitonin, <1.84 ng/mL.

COVID-19, coronavirus disease 2019.

Table 3.

Pathogens isolated from blood cultures

Pathogen	Higher procalcitonin	Lower procalcitonin	Number of isolates	p-value
Gram negative	28 (73.7)	18 (69.2)	46 (71.9)	0.697
Escherichia coli	16 (42.1)	3 (11.5)	19 (29.7)	0.009
Klebsiella spp.	7 (18.4)	5 (19.2)	12 (18.8)	>0.999
Pseudomonas aeruginosa	0 (0.0)	4 (15.4)	4 (6.3)	0.024
Citrobacter spp.	1 (2.6)	3 (11.5)	4 (6.3)	0.295
Aeromonas spp.	2 (5.3)	0 (0.0)	2 (3.1)	0.510
Enterobacter cloacae	1 (2.6)	1 (3.8)	2 (3.1)	>0.999
Stenotrophomonas maltophilia	0 (0.0)	1 (3.8)	1 (1.6)	0.406
Eikenella corrodens	1 (2.6)	0 (0.0)	1 (1.6)	>0.999
Bacteroides fragilis	0 (0.0)	1 (3.8)	1 (1.6)	0.406
Gram positive	10 (26.3)	8 (30.8)	18 (28.1)	0.697
Enterococcus spp.	8 (21.1)	6 (23.1)	14 (21.9)	0.908
Streptococcus spp.	1 (2.6)	1 (3.8)	2 (3.1)	>0.999
Staphylococcus aureus	0 (0.0)	1 (3.8)	1 (1.6)	0.406
Pediococcus acidilactici	1 (2.6)	0 (3.8)	1 (1.6)	> 0.999
Total	38 (100.0)	26 (100.0)	64 (100.0)

Values are presented as number (%). Higher procalcitonin, ≥1.84 ng/mL; lower procalcitonin, <1.84 ng/mL. The figures were rounded to the second decimal place.

Table 4.

Distribution of blood culture results

Blood culture result	Higher procalcitonin (n=66)	Lower procalcitonin (n=146)	Total (n=212)	p-value
Gram negative	28 (42.4)	18 (12.3)	46 (71.9)	<0.001
Gram positive	10 (15.2)	8 (5.5)	18 (28.1)	0.038
No growth	28 (42.4)	120 (82.2)	148 (100.0)	<0.001

Values are presented as number (%). Higher procalcitonin, ≥1.84 ng/mL; lower procalcitonin, <1.84 ng/mL.