Evaluation of C-reactive protein and procalcitonin as a mortality indicator in febrile neutropenic patients

Yıl 2025, Cilt: 18 Sayı: 2, 384 - 395, 01.04.2025

Hasan Öksüzoğlu , Duygu Mert , Gülşen İskender , Nagihan Ulu Demirci Mustafa Ertek

https://doi.org/10.31362/patd.1552581

Öz

Purpose: Febrile neutropenia (FN) is a common side effect of chemotherapy in cancer patients, leading to complications, increased healthcare costs, and mortality. Microbiological agents can be identified in 30-50% of FN cases. Therefore, there is a need for specific, highly effective, and rapid markers to indicate infection. Various biomarkers are currently under investigation and in clinical use. This study aims to evaluate their effectiveness in the early detection of infection and mortality by comparing quantitative C-reactive protein (CRP) and procalcitonin levels at the onset of FN and during treatment.
Material and methods: This study is a retrospective case-control study. It included 572 patients with febrile neutropenia (FN) who were followed up in the Hematology Clinic, Bone Marrow Transplantation Unit, and Medical Oncology Clinic between September 3, 2018, and May 25, 2022. A total of 748 FN episodes were recorded in these patients. Data were retrieved from the hospital information management system and documented using a pre-prepared form. Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) 26.0 software.
Results: Of the febrile neutropenia (FN) patients included in the study, 118 experienced mortality, whereas 630 survived. The mean age was 51.6 years in the mortality group and 50.5 years in the non-mortality group. Females constituted 47.9% of the cohort, while males accounted for 52.1%. Hematological malignancies were present in 67.2% of all patients. Bacteremia was identified in 36.5% of FN episodes. Although E. coli was the most frequently isolated microorganism, P. aeruginosa and A. baumannii were more commonly detected in patients who succumbed to the illness. Elevated C-reactive protein (CRP) and procalcitonin levels within the first five days of treatment were significantly associated with both mortality and the presence of bacteremia. Neither leukocyte count nor absolute neutrophil count at the time of diagnosis showed a significant association with mortality. However, prolonged duration of neutropenia, bloodstream infections, catheter-related bloodstream infections, and the presence of pneumonia emerged as significant risk factors for mortality.
Conclusion: CRP and procalcitonin levels were observed to have both prognostic and diagnostic value. Additionally, resistant Gram-negative bacterial growth was more frequently detected in the blood cultures of patients who did not survive. Further studies are needed to develop new treatment algorithms.

Anahtar Kelimeler

Febrile neutropenia, C-reactive protein, procalcitonin, mortality

Febril nötropenik hastalarda C-reaktif protein ve prokalsitoninin mortalite göstergesi olarak değerlendirilmesi

Öz

Giriş: FN, kemoterapötiklerin komplikasyonlara, maliyet artışı ve mortaliteye yol açabilen yan etkisidir. Enfeksiyon hastalıklarının sadece %30-50’sinde ateşin kaynağı ve mikrobiyolojik etkenler saptanabilmektedir. Bu nedenle enfeksiyonu gösterebilecek, spesifik, yüksek etkinlikli ve hızlı belirteçlere ihtiyaç duyulmaktadır. Bu nedenle çeşitli biyomarkerlar araştırılmakta ve günümüzde halen kullanılmaktadır. Çalışmamızda da nötropenik ateşte CRP ve prokalsitoninin tanısal, prognostik kullanılabileceği ve FN ataklarının klinik, laboratuvar özelliklerinin, kültürde üreyen mikroorganizmaların araştırılması amaçlanmıştır.
Gereç ve yöntem: Retrospektif, vaka – kontrol çalışması olarak yürütülen bu çalışma 3 Eylül 2018-25 Mayıs 2022 tarihleri arasında hematoloji, kemik iliği transplantasyon ve tıbbi onkoloji kliniğinde FN sebebiyle tedavi gören 18 yaş ve üstü hastalarda gelişen 748 FN atağı irdelendi. Hastane bilgi yönetim sistemi taranarak uygun olan hastalar veri formuna kaydedilerek The Package for Social Sciences 26.0 (SPSS 26.0) aracılığıyla analiz edildi.
Bulgular: Çalışmaya dahil edilen FN hastalarından 118 tanesinde mortalite gelişmişken, 630 tanesinde mortalite gelişmemiştir. Mortalite grubunda yaş ortalaması 51,6, mortalite olmayan grupta ise 50,5 bulunmuştur. Hastaların %47,9’unu kadın, %52,1’ini erkek hastalar oluşturmaktadır. Hastaların %67,2’sinin hematolojik malignitesi mevcuttu. FN ataklarında bakteriyemi oranı %36,5 bulundu ve en sık saptanan mikroorganizma E. coli olmasına rağmen P. aeruginosa ve A. baumannii üremesi olanlar mortalitesi olanlarda daha yüksek saptanmıştır. Tedavinin ilk beş gününde bakılan CRP ve prokalsitonin değeri mortalite ve bakteriyemisi olan hastalarda yüksek bulunmuştur. Tanı anında lökosit ve nötrofil sayısının mortaliteye etkisi olmadığı saptandı. Nötropeni süresi uzaması, kandolaşım enfeksiyonu, kateter ilişkili kandolaşım enfeksiyonu ve pnömoni varlığı mortalite açısından risk faktörü olarak saptanmıştır.
Sonuç: CRP ve prokalsitonin değerlerinin mortalite göstergesi olarak değerlendirildiği çalışmamızda hem prognostik hem de tanısal olarak kullanılabileceği öngörülmüştür. Mortalitesi olan hastalarda dirençli gram-negatif mikroorganizmaların daha hakim olduğu saptanmış olup yeni tedavi algoritmalarının geliştirilmesi için daha çok çalışmaya gereksinim duyulmaktadır.

Anahtar Kelimeler

Febril nötropeni, C-reaktif protein, prokalsitonin, mortalite

Kaynakça

• Südhoff T, Giagounidis A, Karthaus M. Evaluation of neutropenic fever: value of serum and plasma parameters in clinical practice. Chemotherapy. 2000;46(2):77-85. doi:10.1159/000007259
• Feld R. Multinational cooperation in trials and guidelines dealing with febrile neutropenia. Int J Antimicrob Agents. 2000;16(2):185-187. doi:10.1016/s0924-8579(00)00240-5
• Fleischhack G, Kambeck I, Cipic D, Hasan C, Bode U. Procalcitonin in paediatric cancer patients: its diagnostic relevance is superior to that of C-reactive protein, interleukin 6, interleukin 8, soluble interleukin 2 receptor and soluble tumour necrosis factor receptor II. Br J Haematol. 2000;111(4):1093-1102. doi:10.1046/j.1365-2141.2000.02458.x
• Massaro KS, Costa SF, Leone C, Chamone DA. Procalcitonin (PCT) and C-reactive protein (CRP) as severe systemic infection markers in febrile neutropenic adults. BMC Infect Dis. 2007;7:137. Published 2007 Nov 22. doi:10.1186/1471-2334-7-137
• Schuttrumpf S, Binder L, Hagemann T, Berkovic D, Trumper L, Binder C. Utility of procalcitonin concentration in the evaluation of patients with malignant diseases and elevated C-reactive protein plasma concentrations. Clin Infect Dis. 2006;43(4):468-473. doi:10.1086/505394
• Ruokonen E, Nousiainen T, Pulkki K, Takala J. Procalcitonin concentrations in patients with neutropenic fever. Eur J Clin Microbiol Infect Dis. 1999;18(4):283-285. doi:10.1007/s100960050277
• Kuderer NM, Dale DC, Crawford J, Cosler LE, Lyman GH. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer. 2006;106(10):2258-2266. doi:10.1002/cncr.21847
• Ghosh S, Chakraborty M, Samanta S, et al. Analysis of blood stream infections, antibiograms and clinical outcomes in haematological patients with febrile neutropenia: data from a tertiary care haematology institute in India. Ann Hematol. 2021;100(2):395-403. doi:10.1007/s00277-020-04324-8
• Du X, Min J, Shah CP, Bishnoi R, Hogan WR, Lemas DJ. Predicting in-hospital mortality of patients with febrile neutropenia using machine learning models. Int J Med Inform. 2020;139:104140. doi:10.1016/j.ijmedinf.2020.104140
• Hatamabadi H, Arhami Dolatabadi A, Akhavan A, Safari S. Clinical Characteristics and Associated Factors of Mortality in Febrile Neutropenia Patients; a Cross Sectional Study. Arch Acad Emerg Med. 2019;7(1):39. Published 2019 Jul 27.
• Lyman GH, Michels SL, Reynolds MW, Barron R, Tomic KS, Yu J. Risk of mortality in patients with cancer who experience febrile neutropenia. Cancer. 2010;116(23):5555-5563. doi:10.1002/cncr.25332
• Hosmer W, Malin J, Wong M. Development and validation of a prediction model for the risk of developing febrile neutropenia in the first cycle of chemotherapy among elderly patients with breast, lung, colorectal, and prostate cancer. Support Care Cancer. 2011;19(3):333-341. doi:10.1007/s00520-010-0821-1
• Reyes Mondragón AL, Cantú Rodríguez OG, Garza Acosta AC, et al. Performance of serum procalcitonin as a biochemical predictor of death in hematology patients with febrile neutropenia. Blood Cells Mol Dis. 2021;90:102586. doi:10.1016/j.bcmd.2021.102586
• Şahin S, Gencer S, Dogan M, Demirhan G, Özer S. Febril Nötropenik Olgularımızda C-Reaktif Proteinin İnfeksiyon ve Mortalite Göstergesi Olarak İncelenmesi. Flora. 2009;14(2):72-80.
• Halder R, Seth T, Chaturvedi PK, et al. Comparison of CRP and procalcitonin for etiological diagnosis of fever during febrile neutropenia in hematology patients- an experience from a tertiary care center in Northern India. Blood Cells Mol Dis. 2020;84:102445. doi:10.1016/j.bcmd.2020.102445
• Coyne CJ, Castillo EM, Shatsky RA, Chan TC. Procalcitonin as a Predictive Tool for Death and ICU Admission among Febrile Neutropenic Patients Visiting the Emergency Department. Medicina (Kaunas). 2022;58(8):985. Published 2022 Jul 23. doi:10.3390/medicina58080985
• Mert D, Ceken S, Iskender G, et al. Epidemiology and mortality in bacterial bloodstream infections in patients with hematologic malignancies. J Infect Dev Ctries. 2019;13(8):727-735. Published 2019 Aug 31. doi:10.3855/jidc.11457
• Demirel A, Tabak F, Ar MC, et al. Secondary Infections in Febrile Neutropenia in Hematological Malignancies: More Than Another Febrile Neutropenic Episode. Turk J Haematol. 2015;32(3):243-250. doi:10.4274/tjh.2013.0422
• Özden M, Denk A, Demirdağ K, Elkıran T. Febril nötropenik olgular ve risk faktörlerinin değerlendirilmesi. Mediterr J Infect Microb Antimicrob. 2013;2:3.
• Wang L, Wang Y, Fan X, Tang W, Hu J. Prevalence of Resistant Gram-Negative Bacilli in Bloodstream Infection in Febrile Neutropenia Patients Undergoing Hematopoietic Stem Cell Transplantation: A Single Center Retrospective Cohort Study. Medicine (Baltimore). 2015;94(45):e1931. doi:10.1097/MD.0000000000001931
• Kanafani ZA, Dakdouki GK, El Chammas KI, Eid S, Araj GF, Kanj SS. Bloodstream infections in febrile neutropenic patients at a tertiary care center in Lebanon: a view of the past decade. Int J Infect Dis. 2007;11(5):450-453. doi:10.1016/j.ijid.2006.12.008
• Horasan ES, Ersoz G, Tombak A, Tiftik N, Kaya A. Bloodstream infections and mortality-related factors in febrile neutropenic cancer patients. Med Sci Monit. 2011;17(5):CR304-CR309. doi:10.12659/msm.881773
• Feld R. Bloodstream infections in cancer patients with febrile neutropenia. Int J Antimicrob Agents. 2008;32(Suppl1):S30-S33. doi:10.1016/j.ijantimicag.2008.06.017
• Prat C, Sancho JM, Dominguez J, et al. Evaluation of procalcitonin, neopterin, C-reactive protein, IL-6 and IL-8 as a diagnostic marker of infection in patients with febrile neutropenia. Leuk Lymphoma. 2008;49(9):1752-1761. doi:10.1080/10428190802258956
• García de Guadiana Romualdo L, Español Morales I, Cerezuela Fuentes P, et al. Value of lipopolysaccharide binding protein as diagnostic marker of infection in adult cancer patients with febrile neutropenia: comparison with C-reactive protein, procalcitonin, and interleukin 6. Support Care Cancer. 2015;23(7):2175-2182. doi:10.1007/s00520-014-2589-1
• Lakshmaiah KC, Malabagi AS, Govindbabu, Shetty R, Sinha M, Jayashree RS. Febrile Neutropenia in Hematological Malignancies: Clinical and Microbiological Profile and Outcome in High Risk Patients. J Lab Physicians. 2015;7(2):116-120. doi:10.4103/0974-2727.163126
• Kara Ali R, Surme S, Balkan II, et al. An eleven-year cohort of bloodstream infections in 552 febrile neutropenic patients: resistance profiles of Gram-negative bacteria as a predictor of mortality. Ann Hematol. 2020;99(8):1925-1932. doi:10.1007/s00277-020-04144-w
• Aleissa MM, Gonzalez Bocco IH, Zekery Saad S, et al. The Relationship Between Antibiotic Agent and Mortality in Patients With Febrile Neutropenia due to Staphylococcal Bloodstream Infection: A Multicenter Cohort Study. Open Forum Infect Dis. 2022;9(8):ofac306. Published 2022 Jun 20. doi:10.1093/ofid/ofac306
• Garcia-Vidal C, Cardozo-Espinola C, Puerta-Alcalde P, et al. Risk factors for mortality in patients with acute leukemia and bloodstream infections in the era of multiresistance. PLoS One. 2018;13(6):e0199531. Published 2018 Jun 28. doi:10.1371/journal.pone.0199531