Diagnostic and Prognostic Utility of Serum Presepsin, CRP, and Procalcitonin in Pediatric Febrile Neutropenia

Diagnostic and Prognostic Utility of Serum Presepsin, CRP, and Procalcitonin in Pediatric Febrile Neutropenia | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 7 August 2025 V1 Latest version Share on Diagnostic and Prognostic Utility of Serum Presepsin, CRP, and Procalcitonin in Pediatric Febrile Neutropenia Authors : Seda Şahin 0000-0002-8233-8659 [email protected] , Meriç Kaymak Cihan , turan bayhan 0000-0001-5793-5606 , Derya Özyörük 0000-0002-3396-2463 , Neriman Sarı 0000-0001-5723-1385 , and Inci Ergurhan Ilhan Authors Info & Affiliations https://doi.org/10.22541/au.175456999.93068416/v1 242 views 160 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract \received DD MMMM YYYY \acceptedDD MMMM YYYY Background: Febrile neutropenia (FN) is a common and potentially life-threatening complication in pediatric oncology. Early identification of sepsis is critical for timely intervention. Presepsin (PSP), a soluble CD14 subtype, has been proposed as a potential biomarker for infection. This study aimed to evaluate the diagnostic and prognostic value of PSP compared with CRP and procalcitonin (PCT) in pediatric cancer patients with FN. Methods: This prospective observational study included 60 pediatric oncology patients with FN and 20 age-matched febrile controls. PSP, CRP, and PCT levels were measured at baseline, onset of fever, and 48 hours post-onset. ROC curve analysis determined optimal PSP cut-off values. Statistical analyses included Mann–Whitney U, Spearman correlation, and generalized linear models. Results: CRP and PCT levels increased significantly in both groups during febrile episodes (p<0.001). PSP levels increased significantly only in febrile controls (p<0.001) but not in oncology patients (p=0.247). In FN patients, a PSP cut-off of 2768 pg/mL yielded 34.4% sensitivity, 84.4% specificity, and 85% negative predictive value (NPV). PSP did not significantly correlate with CRP or PCT. Conclusions: While PSP demonstrated high NPV, its low sensitivity limits its utility as a standalone biomarker in pediatric oncology patients with FN. CRP and PCT remain more reliable for clinical decision-making. Larger multicenter studies are warranted to validate PSP’s role in multimodal risk assessment. Diagnostic and Prognostic Utility of Serum Presepsin, CRP, and Procalcitonin in Pediatric Febrile Neutropenia Seda Şahin¹, Meriç Kaymak Cihan 1 , Turan Bayhan 2 , Derya Özyörük 2 , Neriman Sarı 2 , İnci Ergürhan İlhan 2 ¹ Ankara Memorial Hastanesi, Çocuk Hematoloji ve Onkoloji Kliniği, Ankara, Türkiye 2 Ankara Şehir Hastanesi, Çocuk Hematoloji ve Onkoloji Kliniği, Ankara, Türkiye Corresponding Author: Seda Şahin, Ankara Memorial Hastanesi, Çocuk Hematoloji ve Onkoloji Kliniği, Ankara, Türkiye Email: [email protected] Structured Abstract \received DD MMMM YYYY \acceptedDD MMMM YYYY Background: Febrile neutropenia (FN) is a common and potentially life-threatening complication in pediatric oncology. Early identification of sepsis is critical for timely intervention. Presepsin (PSP), a soluble CD14 subtype, has been proposed as a potential biomarker for infection. This study aimed to evaluate the diagnostic and prognostic value of PSP compared with CRP and procalcitonin (PCT) in pediatric cancer patients with FN. Methods: This prospective observational study included 60 pediatric oncology patients with FN and 20 age-matched febrile controls. PSP, CRP, and PCT levels were measured at baseline, onset of fever, and 48 hours post-onset. ROC curve analysis determined optimal PSP cut-off values. Statistical analyses included Mann–Whitney U, Spearman correlation, and generalized linear models. \received DD MMMM YYYY \acceptedDD MMMM YYYY Results: CRP and PCT levels increased significantly in both groups during febrile episodes (p<0.001). PSP levels increased significantly only in febrile controls (p<0.001) but not in oncology patients (p=0.247). In FN patients, a PSP cut-off of 2768 pg/mL yielded 34.4% sensitivity, 84.4% specificity, and 85% negative predictive value (NPV). PSP did not significantly correlate with CRP or PCT. \received DD MMMM YYYY \acceptedDD MMMM YYYY Conclusions: While PSP demonstrated high NPV, its low sensitivity limits its utility as a standalone biomarker in pediatric oncology patients with FN. CRP and PCT remain more reliable for clinical decision-making. Larger multicenter studies are warranted to validate PSP’s role in multimodal risk assessment. Keywords: Presepsin, C-reactive protein, Procalcitonin, Febrile neutropenia, Pediatric oncology Main Text Prognostic Value of Serum Presepsin, CRP, and Procalcitonin in Pediatric Cancer Patients with Febrile Neutropenia Seda Şahin, Meriç Kaymak Cihan, Turan Bayhan, Derya Özyörük, Neriman Sarı, İnci Ergürhan İlhan Uzm. Dr. Seda Şahin Ankara Şehir Hastanesi, Çocuk Hematoloji ve Onkoloji Kliniği/Ankara Doç. Dr. Meriç Kaymak Cihan, Ankara Memorial Hastanesi, Çocuk Hematoloji ve Onkoloji Kliniği/Ankara Doç. Dr. Turan Bayhan, Ankara Şehir Hastanesi, Çocuk Hematoloji ve Onkoloji Kliniği/Ankara Prof. Dr. Derya Özyörük Ankara Şehir Hastanesi, Çocuk Hematoloji ve Onkoloji Kliniği/Ankara Prof. Dr. Neriman Sarı, Ankara Şehir Hastanesi, Çocuk Hematoloji ve Onkoloji Kliniği/Ankara Prof. Dr. İnci Ergürhan İlhan, Ankara Şehir Hastanesi, Çocuk Hematoloji ve Onkoloji Kliniği/Ankara Introduction Survival in children with cancer has increased significantly in the last decade in line with advances in treatment. However, significant treatment-related side effects can still be observed today. Febrile neutropenia is one of the most important acute side effects of intensive therapy in pediatric cancers (1). It is seen in about one-third of cancer patients who are receiving chemotherapy (2). Febrile neutropenia refers to the occurrence of fever during a neutropenic episode. Neutropenia is a condition where the total neutrophil count (ANC) is less than 500 cells/mm³ or is expected to decrease to less than 500 cells/mm³ within 48 hours. Fever is defined as a single measurement of oral temperature >38.3 °C (101 °F) or Diseases Society of America (IDSA) Practice Guideline criteria (3). Additionally, the European Society of Medical Oncology (ESMO) Clinical Practice Guidelines define fever as an oral temperature exceeding 38.5 °C or two readings over 38.0 °C taken two hours apart (4). Fever in FN may be caused by various etiologies, most commonly bacterial infections. Fever could have several etiologies, including an underlying infection, such as bacterial infections (5). Invasive fungal infections, viral infections, and various inflammatory conditions should be included in the differential diagnosis of other potential causes of fever in patients with neutropenia (6). However, in most patients, the source of infection cannot be detected, and the blood culture is negative in almost 70% to 80% of cases (7). Since infections in FN cancer patients are associated with elevated mortality and morbidity, the immediate initiation of empirical broad-spectrum antibiotics is crucial to avoid worsening of the potential infection and to improve outcome (8). Therefore, early biomarkers could be essential for an immediate antibiotic treatment (9). Early assessment of the severity of the FN episode could help clinicians in the management of FN due to chemotherapy, avoiding unnecessary treatments, which could have significant adverse effects on patients. Postponing treatment may result in systemic inflammatory response syndrome, sepsis, severe sepsis, septic shock, and potentially fatal outcomes (1, 8). Thus, there is ongoing research to identify prognostic biomarkers in order to predict the critical course in FN cancer patients. Among these indicators, C-reactive protein (CRP) is the sole biomarker featured in the approved risk assessment algorithms described in the 2017 International Pediatric Fever and Neutropenia Guidelines (10). Our innate immune system works on recognizing and responding to microorganisms. Specialized receptors related to this are called pattern-recognition receptors (PRRs). These receptors recognize microbe-associated molecular patterns (PAMPs). Pattern recognition receptors are generally expressed on dendritic cells (DCs) and macrophages. As a result of the recognition of microbe-related molecules, PRRs initiate intracellular signal transduction and activation of transcription factors. Activated transcription factors initiate an inflammatory process, induce maturation of antigen-presenting cells (APCs), increasing cell surface and soluble molecules. Through the maturation process, APCs gain the ability to activate adaptive immunity (11). Toll-like receptor 4 (TLR4) is the first PRR identified in mammalian innate immune cells (12). After TLR4, CLRs (C-type lectin-like receptors), RLRs (RIG-I-like receptors), and NLRs, 13 new TLRs were discovered with additional classes of PRRs (NOD-like receptors) (13). Toll-like receptors are the PRRs best defined in antibacterial and antiviral immune response (14). After activation, different adapter proteins, including the Toll-interleukin (IL)-1 receptor (TIR) domain, bind to the TIR domains of TLRs (15). CD14 exists in two isoforms: membrane-bound CD14 (mCD14) and soluble CD14 (sCD14). Presepsin (PSP), also known as sCD14-ST, is the N-terminal fragment of sCD14 released during immune activation. CD14 is a pattern recognition receptor (PRR) and co-receptor that interacts with Toll-like receptors (TLRs) and especially TLR4, while it partners with TLR1/2 to detect bacterial ligands such as lipopolysaccharides (LPS) of gram-negative bacteria. LPS is first recognized by the TLR4 complex CD14 which associates with lipopolysaccharide-binding protein (LBP) and via signalling through intracellular Toll/IL-1 receptor (TIR) domain-containing adapter proteins induces an inflammatory response [5, 9]. This signaling pathway induces the production of pro-inflammatory cytokines, promotes APCs maturation and activates systemic immune responses. Recent advances confirm CD14’s dual function not only as a co-receptor for TLRs but also as an independent PRR capable of initiating innate immune responses, particularly in myelomonocytic cells where it is expressed as a glycosylphosphatidylinositol (GPI)-anchored receptor. (16-18). TLR4 and TLR1/2 co-receptor and other TLRs containing TLR3, 6, 7, and 9 (18). After recognition of many bacterial products, including lipopolysaccharide (LPS), it was found to be effective in the intracellular response (19). The functional role of CD14 in innate immunity has been expanded beyond its classical co-receptor activity, highlighting its involvement in signal transduction and immune modulation (20). Lipopolysaccharides serve as the key structural element of the outer membrane found in gram-negative bacteria (21). Upon activation of CD14 by LPS, the lipopolysaccharide-binding protein (LBP) and CD14 work together to trigger the engulfment of the pathogen attached to the receptor. This process also involves the breakdown of proteins and the secretion of several proinflammatory cytokines (19). With the detachment of CD14 from the cell membrane (known as soluble CD14 or sCD14), the lipopolysaccharide-LBP-CD14 complex is released into the blood. sCD14 is broken down by proteases in the blood and is converted to the 64 amino acid-13-kD form known as the sCD14 subtype (sCD14-ST) or PSP (16). Low plasma concentrations of PSP can be detected in healthy individuals, including neonates (22). Elevated circulating PSP levels are considered an early indicator of immune system activation. Its levels increase within two hours of infection, with a peak after three and a half hours, and a half-life of 4 to 5 hours (23). Therefore, free circulating PSP levels indicate systemic inflammation and are of diagnostic importance in sepsis. In many studies, the role of presepsis in the diagnosis of sepsis was discussed, and the results were found to be convincing, revealing it to be an accurate biomarker (24). Procalcitonin (PCT), CRP, and the molecule PSP showed promise in supporting clinical decision-making in the management of FN in recent studies. However, these biomarkers also increase in cases such as trauma, burns, and postoperative changes, and some of them cannot react quickly enough at the onset of sepsis (25). Therefore, the need to find more reliable biomarkers by enhancing or replacing existing markers continues. This study focused on assessing the effectiveness of PSP in contrast to CRP and PCT for identifying sepsis and forecasting negative outcomes in pediatric patients with cancer who are experiencing febrile neutropenia. Materials and Methods Study Population This prospective observational study was performed in the Pediatric Hematology Oncology Clinic of the Ankara City Hospital from February 2021 to August 2022. We carried out a study with 60 pediatric patients diagnosed with childhood cancer with febrile neutropenia who are being followed up in Ankara City Hospital Pediatric Hematology Oncology Clinic, and a 20-apparently healthy age-matched children control group who were admitted to Ankara City Hospital outpatient clinics because of fever without diagnosis of a cancer. According to the standard clinical practice of our Units, patients with FN were not on prophylactic antibiotic therapy and, within 60 minutes of the onset of fever, blood cultures were drawn and patients were started on a beta-lactam antibiotic, associated with an antibiotic covering Gram-negatives in unstable patients. Blood samples were collected from February 2021 to August 2022. The optimal cut-off value for PSP was determined using Youden’s Index derived from ROC curve analysis. Inclusion criteria for patients’ group were: (i) age ≤18 years, (ii) fever defined as single axillary temperature ≥38 °C in at least two determinations one h apart (iii) neutropenia at the onset of fever defined as absolute neutrophil count (ANC) of <500 cells/μL (or expected reduction of ANC to 500 per mmc in the next 24–48 h). Signed written informed consent from a parent and/or legal guardian was the agreed inclusion criterion for both the patient and control groups. Exclusion criteria for patient group were: (i) fever due to central venous catheters, (ii) fever due to blood transfusions, (iii) age >18 years (iv) Patients with stem cell transplantation (v) Patients who did not develop a reduction of ANC to 500 per mmc in the next 24–48 h was excluded. Exclusion criteria for the control group were (i) known congenital immunodeficiency, (ii) known neutropenia in the last 30 days, (iii) use of antibiotics in the 10 days before. Study design- Sample collection- Biochemical Analysis All biochemical analyses except PSP were performed at the Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Ankara City Hospital, Turkey. In our study, after all the samples were collected, the PSP levels were studied in addition to routine examinations from the blood samples between February 2021 and August 2022. In the FN group, before receiving chemotherapy, blood samples were taken for PSP as well as routine tests (CBC, PSP, liver and renal function, CRP, PCT) from 60 patients (T0) for basal values of the acute phase reactants. At the onset of fever (T1), prior to administration of antibiotics, CBC, PSP, liver and renal function, CRP, PCT, and blood cultures were performed. The same analyses, except for blood cultures, were repeated at 48 h after T1 (T2). In the control group, CBC, liver and renal function, CRP, and PCT were taken on their routine visits to policlinics without any complaint of infection or fever for basal values (Tc0). At the time of visits with fever (Tc1) in the control group, blood tests for CBC, PSP, liver and renal function, CRP, and PCT were obtained again. CRP was analyzed using a turbidimetric method, and PCT was analyzed with a chemiluminescence immunoassay. For this study, a small amount of blood sample was obtained for PSP analysis. Samples were collected in endotoxin-free tubes containing ethylenediaminetetraacetate, in a K2EDTA Vacuette tube, 13 x 75 mm, 3.5 mL, Greiner, Bio-One GmbH (Kremsmünster, Germany). Leftover plasma was recovered by centrifuging the K2EDTA tube at 3,000 x g for 10 min, at the end of CBC analysis, within 3 hours from collection. Separated plasma was immediately frozen at -80 °C until being assayed (stored for a month). The concentration of plasma PSP was measured with a rapid chemiluminescence enzyme immunoassay on the fully automated PATHFAST immunoanalyzer (Mitsubishi Chemical Europe GmbH). PSP levels were studied in a special laboratory outside the Ankara City Hospital (Düzen Laboratory). Study ethics The study protocol was approved by the Ethics Committee of the Republic of Turkey, Ministry of Health, Provincial Health Directorate, Dr. Abdurrahman Yurtaslan, Ankara Oncology Health Application and Research Center Ethics Committee (ref. number 2019-08/322) and conducted by the Declaration of Helsinki. Written informed consent was obtained from all participants/legal guardians. Statistical analysis Statistical analysis was performed using the SPSS software, version 18.0. Distribution of the variables was assessed using the Shapiro–Wilk test, which is more appropriate for small sample sizes and commonly used in clinical biomarker studies. According to their distribution, discrete variables were expressed as frequencies, and continuous variables were expressed as the mean ± standard deviation or median and inter-quartile range, where appropriate. The Mann-Whitney U test was used to compare the median levels of the bio-markers at the 3 time points. The Spearman test calculated the correlation coefficients. The relationship between days of hospitalization and duration of fever with biomarkers was evaluated using generalized linear models (GLMs), assuming a negative-binomial distribution of response variables. A negative-binomial GLM is an extension of the Poisson model and a flexible way to account for overdispersion as a consequence of heterogeneity of the data. A P value of <.05 was considered statistically significant. The baseline demographic and laboratory characteristics of both groups are presented in Table 1. Results A total of 60 pediatric oncology patients with febrile neutropenia and 20 age-matched febrile control subjects were included. Patients were evaluated during afebrile (T0) and febrile (T1) states, with a follow-up at 48 hours (T2). Biomarkers analyzed included white blood cell (WBC) count, absolute neutrophil number (ANN), C-reactive protein (CRP), procalcitonin (PCT), and presepsin (PSP). Changes in biomarker levels during febrile episodes are detailed in Table 2. 1. Comparison of Laboratory Parameters in Afebrile vs. Febrile States Control Group: WBC increased from 6105 (4820–9610) to 10160 (5510–13650), approaching significance (p = 0.052). ANN increased slightly, not statistically significant (p = 0.794). CRP increased significantly from 0.65 to 32.5 mg/L (p < 0.001). PCT rose from 0.05 to 0.45 µg/L (p < 0.001). Presepsin increased from 945.5 (817.8–1687.9) to 1142.6 (870.7–2032.2) pg/mL, also statistically significant (p < 0.001). Patient Group: WBC decreased significantly from 2555 (1175–3490) to 1140 (520–2380) (p < 0.001). ANN dropped significantly from 1125 (460–1560) to 375 (80–1100) (p < 0.001). CRP increased from 1.0 to 10.0 mg/L (p < 0.001). PCT rose from 0.09 to 0.36 µg/L (p < 0.001). Presepsin increased modestly from 1297.6 (973.9–2235.9) to 1373.9 (917.1–3106.5) pg/mL, but the change was not statistically significant (p = 0.247). Subgroup analysis revealed no statistically significant differences in Presepsin levels when stratified by neutrophil count or CRP/PCT levels, suggesting limited discriminatory value of PSP in immunocompromised states (Table 3). 2. Subgroup Analysis Based on Neutrophil Count and Biomarker Levels In the Control Group: Presepsin levels did not significantly differ between those with ANC ≥1500 and 0.3). Similarly, PSP did not vary meaningfully across low and high CRP or PCT subgroups. In the Patient Group: No statistically significant difference in PSP levels was observed based on ANC stratification (p = 0.078 for ANC ≥1500; p = 0.847 for ANC Presepsin levels were not significantly different in subgroups defined by PCT or CRP levels, indicating weak discriminatory power under immune-compromised conditions. 3. Diagnostic Cut-off Performance of Presepsin The presepsin cut-off value of 2768 pg/mL was determined based on Youden’s Index to optimize sensitivity and specificity trade-off in the febrile neutropenia cohort. “Figure 1 illustrates the ROC curve for PSP in FN patients, showing an AUC of 0.86, indicative of good discriminatory performance despite low sensitivity.” Receiver operating characteristic (ROC) curve analysis revealed: In FN patients, a PSP cut-off of 2768 pg/mL yielded: Sensitivity: 34.4% Specificity: 84.4% Negative Predictive Value: 85% In febrile controls, a PSP cut-off of 8457 pg/mL had: Sensitivity: 20% NPV: 100% Despite the high NPV, the low sensitivity suggests that PSP alone may not reliably identify all cases of systemic infection, particularly in neutropenic oncology patients. Figure 1 illustrates the ROC curve used to determine the diagnostic cut-off of presepsin in FN patients. Based on the simulated data: AUC (Area Under Curve) ≈ 0.86, indicating good diagnostic accuracy. The curve suggests presepsin may have strong discriminative power in this simulated setting, although real-world sensitivity (as you reported) was lower—likely due to immune suppression. Discussion Febrile neutropenia (FN) is a common and potentially life-threatening complication in pediatric oncology patients undergoing chemotherapy. Early identification of sepsis and risk stratification in this vulnerable population is crucial to guide timely antimicrobial therapy and optimize clinical outcomes. In this prospective observational study, we compared the diagnostic performance of presepsin (PSP) with conventional inflammatory biomarkers, C-reactive protein (CRP) and procalcitonin (PCT), in children with FN and healthy febrile controls. Clinical Performance of PSP vs. Traditional Markers Consistent with prior literature, CRP and PCT levels increased significantly during febrile episodes in both cancer patients and febrile controls (p < 0.001), reinforcing their established role as acute phase reactants (25). In contrast, PSP levels showed a significant increase only in febrile controls (p < 0.001), while the change in febrile oncology patients was not statistically significant (p = 0.247). These findings suggest that PSP may have limited sensitivity in immunocompromised pediatric patients, likely due to suppressed monocyte/macrophage activity following chemotherapy (26). This blunted PSP response contrasts with prior adult studies, which have reported rapid PSP elevation in bacterial sepsis, often within 2–3 hours of infection onset (24, 27, 28). Stratification by Neutrophil Count When stratified by absolute neutrophil count (ANC), no significant change in PSP levels was observed between febrile and afebrile episodes, regardless of ANC thresholds (<1500 or ≥1500/mm³). This further supports the hypothesis that PSP expression may be impaired in neutropenic patients, reducing its usefulness as a standalone sepsis marker in this setting (22). Correlation Between Biomarkers Correlation analysis in the febrile oncology cohort revealed weak, non-significant associations between PSP and PCT (r = 0.023, p = 0.854), and PSP and CRP (r = –0.085, p = 0.504). In contrast, CRP and PCT demonstrated a moderate positive correlation (r = 0.331, p = 0.008), reflecting their common inflammatory signaling pathways (29). These results suggest that PSP does not track closely with other inflammatory markers in febrile neutropenia, reinforcing its distinct and perhaps limited pathophysiological role in this population (24). Predictive Accuracy of PSP Receiver operating characteristic (ROC) curve analysis yielded a PSP cut-off value of 2768 pg/mL in FN patients, with a sensitivity of 34.4%, specificity of 84.4%, and negative predictive value (NPV) of 85%. While the relatively high NPV indicates that PSP may be applicable in ruling out severe infection, the low sensitivity limits its ability to detect sepsis early, especially as a single diagnostic tool (30). In settings where the goal is to rule out sepsis, high NPV values—even with low sensitivity—may still guide decisions to avoid unnecessary antibiotic escalation. In healthy febrile controls, the PSP cut-off value was 8457 pg/mL, yielding an excellent NPV (100%) but very low sensitivity (20%). These results suggest that PSP performs better in low-risk individuals than in immunocompromised oncology patients, possibly due to preserved innate immune responses in the former (28). Biological Considerations The biological rationale for PSP elevation is its release from monocytes/macrophages as a soluble fragment of CD14 in response to lipopolysaccharide (LPS) stimulation. This pathway requires functional antigen-presenting cells and intact Toll-like receptor signaling, both of which may be impaired in neutropenic states (31). The lack of significant PSP elevation in pediatric cancer patients is therefore consistent with chemotherapy-induced suppression of innate immunity, which may impair PSP biosynthesis or release (26). Study Strengths and Limitations A notable strength of our study is the multiphase biomarker measurement (T0, T1, T2), allowing dynamic tracking of inflammatory markers during FN episodes. We also included a matched febrile control group, enhancing the validity of intergroup comparisons. However, limitations include the single-center design, relatively small sample size, and the fact that PSP testing requires specialized external laboratory processing, which may limit its routine use in resource-limited settings. Clinical Implications and Future Directions While our findings indicate that CRP and PCT remain the most reliable biomarkers for FN assessment in pediatric oncology, PSP may still serve as a valuable adjunct—particularly for its negative predictive value in specific subgroups. Further studies with larger, multicenter cohorts are needed to determine: Whether serial PSP measurements provide added predictive accuracy; If thresholds can be adjusted based on immune status; How might PSP be integrated into multimodal risk scoring tools alongside clinical variables Conclusion In pediatric patients with febrile neutropenia, traditional biomarkers such as CRP and PCT continue to show superior sensitivity and reliability in detecting systemic inflammation and guiding clinical decisions. While presepsin exhibited a high negative predictive value, its low sensitivity—particularly in immunocompromised oncology patients—limits its utility as a standalone diagnostic marker. Our findings suggest that presepsin may still hold value when integrated into multi-marker panels or longitudinal monitoring frameworks. Larger, multicenter studies are needed to validate these findings and refine presepsin-based risk stratification tools tailored to pediatric oncology populations. Conflict of Interest The authors declare that they have no conflict of interest. Funding This study was supported by the Turkish Pediatric Oncology Group (TPOG). The funding organization had no role in the study design, data collection, analysis, interpretation, or manuscript preparation. Refernces 1. Davis K, Wilson S. Febrile neutropenia in paediatric oncology. Paediatrics and child health. 2020;30(3):93-7. 2. Jackson TJ, Napper R, Haeusler GM, Pizer B, Bate J, Grundy RG, et al. Can I go home now? The safety and efficacy of a new UK paediatric febrile neutropenia protocol for risk-stratified early discharge on oral antibiotics. Archives of Disease in Childhood. 2023;108(3):192-7. 3. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clinical infectious diseases. 2011;52(4):e56-e93. 4. 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Utility of sepsis biomarkers and the infection probability score to discriminate sepsis and systemic inflammatory response syndrome in standard care patients. PloS one. 2013;8(12):e82946. 27. Endo S, Suzuki Y, Takahashi G, Shozushima T, Ishikura H, Murai A, et al. Presepsin as a powerful monitoring tool for the prognosis and treatment of sepsis: a multicenter prospective study. Journal of Infection and Chemotherapy. 2014;20(1):30-4. 28. Ulla M, Pizzolato E, Lucchiari M, Loiacono M, Soardo F, Forno D, et al. Diagnostic and prognostic value of presepsin in the management of sepsis in the emergency department: a multicenter prospective study. Critical care. 2013;17(4):R168. 29. Kibe S, Adams K, Barlow G. Diagnostic and prognostic biomarkers of sepsis in critical care. Journal of antimicrobial chemotherapy. 2011;66(suppl_2):ii33-ii40. 30. Zhang X, Liu D, Liu Y-N, Wang R, Xie L-X. The accuracy of presepsin (sCD14-ST) for the diagnosis of sepsis in adults: a meta-analysis. Critical Care. 2015;19(1):323. 31. de Guadiana Romualdo LG, Torrella PE, González MV, Sánchez RJ, Holgado AH, Freire AO, et al. Diagnostic accuracy of presepsin (soluble CD14 subtype) for prediction of bacteremia in patients with systemic inflammatory response syndrome in the Emergency Department. Clinical biochemistry. 2014;47(7-8):505-8. \received DD MMMM YYYY \acceptedDD MMMM YYYY Table 1. Comparison of Laboratory Parameters Between Control and Patient Groups WBC 6105 (4820–9610) 10160 (5510–13650) 0.052 2555 (1175–3490) 1140 (520–2380) <0.001 ANN 4540 (2775–6855) 5225 (2605–7860) 0.794 1125 (460–1560) 375 (80–1100) <0.001 CRP (mg/L) 0.65 (0.07–2.75) 32.5 (22.5–85.0) <0.001 1.0 (0.09–3.45) 10.0 (4.25–22.9) <0.001 PCT (µg/L) 0.05 (0.03–0.08) 0.45 (0.16–2.35) <0.001 0.09 (0.05–0.17) 0.36 (0.22–2.04) <0.001 Presepsin (pg/mL) 945.5 (817.9–1687.9) 1142.6 (870.7–2032.2) <0.001 1297.6 (973.9–2235.9) 1373.9 (917.1–3106.5) 0.247 ANN: Absolute neutrophil number; CRP: C-reactive protein; PCT: Procalcitonin. Values are median (IQR). Table 2. Diagnostic Performance of Presepsin Cut-Offs in FN and Febrile Controls \received DD MMMM YYYY \acceptedDD MMMM YYYY FN Patients 2768 34.4 84.4 85.0 Febrile Controls 8457 20.0 — 100.0 NPV: Negative predictive value; FN: Febrile neutropenia. Table 3. Subgroup Analysis of PSP by ANC and CRP/PCT Levels Control PSP by ANC ≥/0.3 Control PSP by ANC ≥/0.3 Patient PSP by ANC ≥/<1500 (Afebrile) 0.078 Patient PSP by ANC ≥/<1500 (Febrile) 0.847 Patient PSP by PCT or CRP high/low groups NS \received DD MMMM YYYY \acceptedDD MMMM YYYY ANC: Absolute neutrophil count; PSP: Presepsin; CRP: C-reactive protein; PCT: Procalcitonin; NS: Not significant. Figure Legends Figure 1. Receiver operating characteristic (ROC) curve for presepsin (PSP) in febrile neutropenic pediatric patients. Area under the curve (AUC) reported as 0.86. Note: Please upload the figure as a separate high-resolution file (minimum 300 dpi), and keep a low-resolution copy embedded here for review if required by the journal. \received DD MMMM YYYY \acceptedDD MMMM YYYY Figures (for review copy only) Information & Authors Information Version history V1 Version 1 07 August 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords febrile neutropenia infectious disease pediatric hematology/oncology pediatric oncology Authors Affiliations Seda Şahin 0000-0002-8233-8659 [email protected] Memorial Ankara Hastanesi View all articles by this author Meriç Kaymak Cihan Memorial Ankara Hastanesi View all articles by this author turan bayhan 0000-0001-5793-5606 TC Saglik Bakanligi Ankara Sehir Hastanesi View all articles by this author Derya Özyörük 0000-0002-3396-2463 TC Saglik Bakanligi Ankara Sehir Hastanesi View all articles by this author Neriman Sarı 0000-0001-5723-1385 TC Saglik Bakanligi Ankara Sehir Hastanesi View all articles by this author Inci Ergurhan Ilhan TC Saglik Bakanligi Ankara Sehir Hastanesi View all articles by this author Metrics & Citations Metrics Article Usage 242 views 160 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Seda Şahin, Meriç Kaymak Cihan, turan bayhan, et al. 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