ORIGINAL ARTICLE
Diagnostic Accuracy of Serum Procalcitonin to Diagnose Sepsis in Advanced Solid Tumor Patients with Fever Erni Juwita Nelwan1,2.
Reza Nugraha Yulisar3.
Randy Adiwinata4.
Ikhwan Rinaldi5.
Cleopas Martin Rumende6.
Robert Sinto1* Division of Tropical and Infectious Disease.
Department of Internal Medicine.
Faculty of Medicine Universitas Indonesia Ae Dr.
Cipto Mangunkusumo Hospital.
Jakarta.
Indonesia.
Faculty of Medicine Universitas Indonesia.
Jakarta.
Indonesia.
Department of Internal Medicine.
Faculty of Medicine Universitas Indonesia Ae Dr.
Cipto Mangunkusumo Hospital.
Jakarta.
Indonesia.
Department of Internal Medicine.
Faculty of Medicine Sam Ratulangi University.
Manado.
Indonesia.
Division of Hematology-Oncology.
Department of Internal Medicine.
Faculty of Medicine Universitas Indonesia Ae Dr.
Cipto Mangunkusumo Hospital.
Jakarta.
Indonesia.
Division of Respirology and Critical Care.
Department of Internal Medicine.
Faculty of Medicine Universitas Indonesia Ae Dr.
Cipto Mangunkusumo Hospital.
Jakarta.
Indonesia.
*Corresponding Author:
Robert Sinto.
MD.
Division of Tropical and Infectious Disease.
Department of Internal Medicine.
Faculty of Medicine Universitas Indonesia Ae Dr.
Cipto Mangunkusumo Hospital.
Jl.
Diponegoro No.
Jakarta 10430.
Indonesia.
Email: robert.
sinto@ndm.
ABSTRACT
Background: Diagnosis of infection in advanced solid tumor patients can be challenging since signs and symptoms might be overlapping due to paraneoplastic condition.
Delay diagnosis of existing infection can lead to more severe conditions and increased mortality.
Procalcitonin (PCT) has been used to support the diagnosis of bacterial infection and sepsis.
Unfortunately.
PCT also increases in malignancy even without an infection.
We investigated the diagnostic accuracy of PCT in advanced solid tumor patients with fever to diagnose sepsis.
Methods: A cross-sectional study was conducted in solid advanced tumor patients with fever patients who were admitted to Cipto Mangunkusumo Hospitals.
Indonesia between June 2016 and April 2018.
Sepsis was defined using 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference criteria.
The diagnostic accuracy of PCT was determined using the receiver operating characteristic (ROC) curve.
Results: A total of 194 subjects were enrolled in this study.
3% were female with a mean age of 49.
47A12.
87 years old.
7%) with advanced solid tumors.
Among this latter group, 39 patients .
%) were sepsis.
The ROC curve showed that the levels of PCT for sepsis in advanced solid tumor patients with fever were in the area under the curve (AUC) 0.
%CI 0.
785 Ae 0.
The Cut-off of PCT in advanced solid tumor patients with fever to classify as sepsis was 2.
87 ng/mL, with a sensitivity of 79.
5%, and a specificity of 79.
Conclusion:
PCT has good diagnosis accuracy in advanced solid tumor patients with fever to classify as sepsis, however a higher cut-off compared to non-cancerous patients should be used.
Keywords: Procalcitonin.
Solid tumor.
Advance Stage Cancer.
Sepsis.
Cut-off.
Acta Med Indones - Indones J Intern Med A Vol 56 A Number 2 A April 2024
Erni Juwita Nelwan
INTRODUCTION
Cancer patients have a higher risk of acquiring infection, which may be caused by impaired immunity due to cancer treatment-related adverse events, underlying immune dysregulation, and associated comorbidities.
Infections in cancer patients may lead to serious outcomes.
1 Study showed cancer patients with fatal infections had almost three times higher mortality rates compared to general populations.
2 Another study showed infection may be the cause of death in 60% of cancer patients.
3 Sepsis, which is a life-threatening condition due to organ dysfunction caused by a dysregulated host response to infection, was more commonly found among cancer patients.
4 Lower survival rate was found in cancer patients group with sepsis compared to non-cancer patients, therefore early diagnosis and aggressive treatment are important in managing this high-risk group.
Diagnosing infection in patients with cancer was challenging.
Fever, which is commonly caused by infections, may also occur in cancer patients and is not related to infectious causes.
Several noninfectious causes of fever in cancer patients may be caused due to chemotherapyinduced mucositis, neoplastic fever, druginduced fever, and others.
7 Inappropriate use of antibiotics in cancer patients with fever may lead to antimicrobial resistance.
8 Therefore, several biomarkers were evaluated to differentiate between infectious and noninfectious causes of fever in cancer patients.
Leukocytosis, which is usually an indicator of underlying inflammation or infection, was reportedly found in 4.
6% of patients with solid tumors.
9 Procalcitonin (PCT) has been commonly used as a specific marker for bacterial infection and sepsis, however, studies showed that PCT level may be influenced by solid tumor presence.
Therefore, some authors proposed a higher cut-off serum PCT level for diagnosing sepsis in cancer patients.
The stage of cancer also proposed may influence the PCT cut-off level.
Many variations of cut-off levels were reported between studies, establishing a challenge for PCT level interpretation, especially in advanced-stage tumor patients.
10,11 We aimed to find out the cut-off point of PCT for diagnosing sepsis in advanced solid tumor patients with fever in the Indonesian population.
Acta Med Indones-Indones J Intern Med
METHODS
Study Design A cross-sectional study was conducted on solid tumor patients with fever who were admitted to Cipto Mangunkusumo Hospitals.
Jakarta.
Indonesia between June 2016 and April Subjects were chosen consecutively from surgical and non-surgical wards, emergency departments, and outpatients.
Study Participants Study participants were adult solid tumor patients who had a complete staging confirmed by histological, imaging examinations, and had acute fever during inclusion .
emperature > 3oC).
Patients with any conditions that can influence serum PCT were excluded .
edullary thyroid carcinoma, neuroendocrine lung cancers, previous antibiotics therapy within the last 72 hours, shock, recent surgical, multiple trauma, resuscitation, dialysis, cirrhosis, or received any colony-stimulating factor.
Informed consent forms were completed by each subject before enrolling in this study.
All subjects underwent history taking, physical examinations, chest x-rays, and laboratory examinations .
omplete blood count, blood glucose, blood urea nitrogen, creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), urine analysis, serum PCT, blood and site-specific cultur.
Patients with any conditions that can influence serum PCT were excluded.
Tests of liver ultrasound and hepatitis markers were done in patients with increased ALT.
AST, or any suspicion of cirrhosis.
Sepsis was defined according to 2001 SCCM/ESICM/ACCP/ATS/ SIS International Sepsis Definitions Conference .
ocumented infections and either of the general parameters: fever >38.
3oC, hypothermia <36oC, heart rate >90 bpm, tachypnea > 30 bpm, altered mental status, significant edema or positive fluid balance (>20 ml/kg over 24 hour.
, hyperglycemia plasma glucose >140 in the absence of diabetes, and bacteremi.
Tumor staging was reviewed by a certified oncologist according to the American Joint Committee on Cancer (AJCC) criteria.
All subjects were already examined and confirmed histopathologically by an experienced pathologist Vol 56 A Number 2 A April 2024 Diagnostic Accuracy of Serum Procalcitonin to Diagnose Sepsis from the Department of Pathology Cipto Mangunkusumo Hospital.
The types of tumors were grouped into head and neck, colorectal, musculoskeletal, breast, lung, genitourinary, gynecology, and pancreaticobiliary.
Tumor staging was grouped into early and advanced stages .
ocally advanced and metastasi.
Laboratory Examinations Blood was taken by a certified nurse and processed according to the hospitalAos standard protocol.
PCT levels were measured in the Department of Clinical Pathology Cipto Mangunkusumo Hospital laboratorium using the BRAHMS PCT KRYPTORA tool, which was calibrated as specified by the manufacturerAos This tool has a lower limit of quantification of 0.
02 ng/mL.
BACTEC bottles were used for blood culture media.
Standard media transport was used for site-specific culture .
rine, feces, sputum, et.
All examinations were run through the appropriate machines which were calibrated and generated automatically.
considered that the investigators of the laboratory were blinded, as the laboratory staff were not included in the investigation team and did not know about the subjects.
Statistical Analysis Analysis was done using the Statistical Package for the Social Sciences (SPSS), v.
(IBM-corp.
Armonk.
NY) software.
MannWhitney test was used to compare WBC and PCT values between groups.
The p-value <0.
05 was considered statistically significant.
The cut-off point of PCT level for sepsis in metastatic solid tumor subjects with fever was done by AUC analysis from the ROC curve.
RESULTS
194 subjects participated in this study, mean age of 49 years old and predominantly female.
Gynecology cancer was the most common type, followed by head and neck, colorectal, breast, genitourinary, and pancreaticobiliary cancer.
Subjects were divided into early and advanced We also divided subjects into sepsis and non-sepsis groups.
There were 143 patients included in the advanced stage according to AJCC criteria.
A total of 39 advanced solid tumor patients were diagnosed with sepsis, mostly caused by pneumonia.
Bacteremia was found in 16 patients, among them we found 4 patients with only blood showed positive culture.
Subject characteristics are shown in Table 1 and advanced solid tumor patients with sepsis are shown in Table 2.
Table 1.
Baseline characteristics of the subjects.
Characteristics Age, years, meanASD Sex, n (%) Male Tumor group, n (%) Gynecology Head and neck Colorectal Breast Genitourinary Pancreatobilliary Lung Musculoskeletal Stage Early Advanced Sepsis, n(%) Procalcitonin, ng/mL, median .
in - ma.
N=194 47A12.
04 Ae 923.
Ethical Consideration and Approval This study was performed under the Declaration of Helsinki, the World Health Organization, and the ICH guideline for good clinical practice.
The study protocol has been approved by the Ethics Committee of the Faculty of Medicine.
University of Indonesia .
/UN2.
F1/ETIK/2.
All study respondents were given study information, the study purpose, and the confidentiality of the result.
All patients provided written informed consent to participate before study inclusion.
Table 2.
Characteristics of solid tumor patients with sepsis.
Characteristics Stage Early Advanced Infection site, n (%) Pneumonia Urinary Tract Skin and soft tissue Intra-abdominal Blood Procalcitonin, ng/mL, median .
in-ma.
N= 49 10 .
24 Ae 923.
Erni Juwita Nelwan Acta Med Indones-Indones J Intern Med In the advanced stage solid tumor group .
PCT level was significantly higher among patients with sepsis .
compared to non-sepsis patients .
03 (IQR 57.
685 (IQR 1.
p<0.
PCT concentration was higher among advanced-stage solid tumor patients with sepsis compared to early-stage solid tumor sepsis patients .
<0.
Meanwhile.
WBC levels were not different in all groups.
(Table .
We found PCT has good diagnosis accuracy for sepsis diagnosis in advanced solid tumor patients with fever (AUC 0.
%CI 0.
785Ae .
The cut-off for diagnosing sepsis in advanced solid tumor patients with fever was 87 ng/mL, with a sensitivity of 79.
5% and specificity of 79.
8% (Figure .
DISCUSSION
Female patients had a higher proportion in this study.
This finding may be explained due to WHO GLOBOCAN report in 2020, that the most common cancer in Indonesia was breast .
6%) and cervix uteri cancer .
2%).
13 Most of our patients had advanced-stage solid tumors.
This finding may be related to a lack of detection, screening programs, and patient awareness and In this study, we found a higher level of PCT was observed in advanced-stage solid tumor patients with sepsis compared to early-stage solid tumor patients with sepsis.
Elevated PCT levels may be attributed to numerous factors in cancer patients, including the presence of metastasis or neuroendocrine function of malignant tissue.
Table 3.
Serum PCT and WBC in advanced vs.
early solid tumor group with sepsis.
Variable PCT, ng/ml, median .
in-ma.
WBC, median .
in-ma.
Advanced Early Sepsis (N=.
96 Ae 923.
17,660 .
440 Ae 72.
Sepsis (N=.
24 Ae 252.
21,940 .
770 Ae 26.
Figure 1.
Procalcitonin ROC curve for sepsis in advanced solid tumor patients with fever.
Vol 56 A Number 2 A April 2024 Diagnostic Accuracy of Serum Procalcitonin to Diagnose Sepsis This can be seen in the study by Matzaraki et al that found that PCT level was correlated with different tumor stages.
They found higher PCT levels in healthy solid tumor patients with generalized metastatic disease compared to the healthy control group or solid tumor without metastases group.
11 Chaftari et al also found higher PCT levels in stage IV cancer patients compared to stage I-i cancer non-febrile patients .
190 vs.
127 ng/ml, p<0.
However, they also stated that febrile cancer patients with sepsis had higher PCT levels compared to non-infectious febrile cancer patients .
49 vs.
31 ng/ml, p:0.
, implying the usefulness of PCT in predicting sepsis in cancer patients.
15 Procalcitonin secretion was induced through two mechanisms.
The first pathway was due to direct stimulation by lipopolysaccharides (LPS) or other toxins that produced by pathogens.
The second pathway was by indirect stimulation of inflammatory cytokines such as IL-6, and TNF-.
16 Solid tumors may produce inflammatory cytokines which may affect the tumor microenvironment and produce a chronic inflammatory state.
Michalaki et al found that significantly higher levels of IL-6 and TNF- in metastatic disease compared to localized disease .
3 A7.
8 vs.
A0.
8 pg/ml.
p<0.
001 and 6.
3A3.
6 vs.
A0.
pg/ml.
p<0.
18 This finding may explain why higher median level of PCT in patients with advanced-stage solid tumors although without Interpretation of PCT level to determine sepsis may be difficult, due to higher level PCT baseline level in tumor patients.
Therefore, the usual cut-off level of PCT in the general population may not apply to cancer patients, especially those in an advanced stage.
Advancedstage cancer may decrease the specificity of PCT in determining infection.
The reported cut-off level of PCT in cancer patients varied between 19 Our study found that a cut-off point of 87 ng/mL had an overall good performance in detecting sepsis among febrile advanced-stage tumor patients.
Azis et al previously reported PCT cut-off for determining sepsis in metastatic cancer patients was 1.
14 ng/ml .
ensitivity 86% and specificity 88%).
They also found higher PCT levels in metastasis cancer patients with sepsis compared to non-metastasis cancer patients without sepsis .
48 vs.
92 ng/m.
The different cut-off levels may be explained due to Azis et al only included patients with metastasis, while our study included all advanced-stage cancer patients.
10 Vincenzi et al showed a PCT cut-off of 1.
52 ng/mL had a sensitivity of 61.
and specificity 70.
1% to detect bacteremia in advanced stage solid tumor patients with fever patient.
However, the proposed cut-off by Vincenzi et al was determined based on hemoculture positive or negative, they did not evaluate whether the patientAos condition which already in a septic condition or not.
Similarly.
Blouin et al found that a cut-off value 7 ng/mL .
ensitivity 61% and specificity 74%) was able to detect bacteremia in cancer However, this study did not account for the possibility of receiving treatment before drawing PCT samples from the patients.
Vassallo et al found that a PCT cut-off of 0.
ng/ml .
ensitivity 75% and specificity 55%) was a sensitive marker to differentiate between infection and tumor-associated fever in solid tumor patients.
However, the determined cut-off did not differentiate between sepsis condition or localized infection.
19 Ding et al reported a lower cut-off value for PCT, namely 0.
105 ng/ mL .
7% and specificity 80.
4%).
Unfortunately, the cut-off of this study also did not differentiate between sepsis and localized The strength of our study was our study method which had tight inclusion criteria to minimize bias of PCT level.
We did not use retrospective data which was mainly utilized in other studies.
therefore, we can accurately determine the sepsis condition and relationship with the PCT level at admission.
However, our study had also several limitations.
First, we did not use the SEPSIS-3 criteria for diagnosing sepsis in our study, due to the timing of the SEPSIS-3 criteria guidance released and the starting date of our study.
23 Second, we did not determine the type of bacteria that caused sepsis in our studies.
Gram-negative bacteremia is generally thought to produce more LPS than gram-positive and, therefore may variably affect Erni Juwita Nelwan the PCT level.
We propose a prospective study to determine the accuracy of our cut-off PCT level using real-world data.
CONCLUSION
PCT has good diagnosis accuracy for sepsis diagnosis in advanced solid tumor patients with fever.
The cut-off for diagnosing sepsis in advanced solid tumor patients with fever was 87 ng/mL, with sensitivity and specificity of 5% and 79.
8%, respectively.
LIST OF ABBREVIATIONS
AJCC American Joint Committee on Cancer ALT Alanine Aminotransferase AST Aspartate Aminotransferase AUC Area Under Curve PCT Procalcitonin ROC Receiver Operating Characteristics ACKNOWLEDGMENTS We thank the Division of Tropical and Infectious Disease Department of Internal Medicine Universitas Indonesia.
Cipto Mangunkusumo Hospital for accommodating and encouraging this research.
COMPETING INTERESTS
The authors declare that they have no competing interests.
FUNDING
This study was funded by the Cipto Mangunkusumo Hospital Research Grant.
REFERENCES