PrognostiÄki znaÄaj serumskih inflamatornih biomarkera i kliniÄkih bodovnih sistema tokom febrilne neutropenije kod obolelih od akutne mijeloidne leukemije
Introduction: Acute myeloid leukemia (AML) is the most common acute leukemia in the adult population with a five-year survival of about 24%. Serious and life-threatening infections, ie febrile neutropenia (FN), remains the main cause of morbidity and mortality in the group of patients with acute myeloid leukemia treated with intensive chemotherapy. Febrile neutropenia is a medical emergency, the early identification of which with adequate care leads to improved survival and reduced mortality. Various biomarkers and clinical scoring systems can help in adequate risk stratification in patients during febrile neutropenia and in the early recognition of critically ill patients. Invasive fungal infections are also a significant cause of morbidity and mortality in patients with acute myeloid leukemia, which should always be considered when diagnosing patients with febrile neutropenia. The prognostic significance of growth and differentiation factor 15 (GDF-15) in numerous malignancies, hematological diseases and even sepsis has been proven. Aims: To examine the sensitivity, specificity and predictive value of inflammatory biomarkers: CRP, PCT, lactate, galactomannan, mannan and 1,3- β-D glucan in assessing the severity of infection and the risk of developing complications during febrile neutropenia in patients with acute myeloid leukemia; to determine the significance and predictive value of these scoring systems: MASCC, CISNE, APACHE II, SOFA, qSOFA, LODS and MEWS in the course of febrile neutropenia in patients with acute myeloid leukemia; to compare the significance and predictive value of the mentioned inflammatory biomarkers and scoring systems during febrile neutropenia in patients with acute myeloid leukemia; to investigate the significance of growth and differentiation factor 15 (GDF-15) as an inflammatory biomarker during febrile neutropenia in patients with acute myeloid leukemia. Material and methods: The research was conducted as a prospective study at the Hematology Clinic of the Clinical Center of Vojvodina in the period from 2018 to 2020. Laboratory analyses for research purposes were performed at the Center for Laboratory Medicine of the Clinical Center of Vojvodina, the Institute of Microbiology and Immunology of the Faculty of Medicine, University of Belgrade, and the Microbiological Diagnostics Service of the Institute for Pulmonary Diseases of Vojvodina. For the purposes of the research, three groups of subjects were formed: the research group (107 febrile episodes) and two control groups (the first control group contained 46 patients and the second 30 healthy subjects). The control groups were formed to examine the significance of GDF-15: in the study group as an inflammatory biomarker, in the first control group as an independent prognostic factor in the prediction of mortality in patients with acute myeloid leukemia, and in the second control group consisting of healthy subjects as a reference values with which the values obtained in the first two groups will be compared. The following analyses were performed in the examined group: ABG, BG, CBC, CRP, PCT, ALT, AST, total and direct bilirubin, urea, creatinine, sodium, potassium, chlorine, fibrinogen, PT, aPTT, galactomannan, mannan, 1.3 -β-D glucan and GDF 15. Only GDF 15 was analised in both control groups. Several statistical methods were applied in the research. Descriptive analysis and frequency analysis, binomial logistic regression, one-way analysis of variance (ANOVA), canonical discriminant analysis, chi-square test and log rank analysis. Hypotheses are accepted or rejected with a risk of p < 0.05, that is, with a probability of 95%. Statistical data processing was carried out in SPSS v.23. The results are presented in text, tables and graphs. Results: For the purposes of this research, we defined the severity of the infection through the outcome of the infection after 48 hours of the initial fever: resolution of the fever, the existence of persistent fever or the occurrence of a fatal outcome within 48 hours of the initial febrile onset, that is, the occurrence of a fatal outcome within 28 days of the initial febrile onset. When we compared the importance of CRP, PCT and lactate in assessing the severity of infection in AML patients during FN, only lactate showed a statistically significant predictive value in all three previously defined criteria, which means that patients with higher lactate values had a higher the probability of a worse clinical course of FN. CRP and PCT did not prove to be statistically significant predictors of infection severity. In our study, capillary filling time was shown to be one of the most important prognostic parameters in assessing the severity and outcome of infection during FN in patients with AML. Based on the results of binary logistic regression, we concluded that AML patients with a longer capillary refill time have a higher probability of a worse outcome during FN. Suspicion of invasive fungal infection (IFI) was present in 16.82% of febrile episodes, mannan was negative in all febrile episodes, while galactomannan and BDG proved to be significant diagnostic markers of IFI. Examining the prognostic value of various scoring systems, qSOFA, MASCC and MEWS score had a statistically significant predictive value in our research. In patients with AML, we evaluated the importance of GDF-15 as an independent predictor of overall survival and primary chemoresistance, and its importance as an inflammatory biomarker in the FN phase, and we only proved its value as an inflammatory biomarker during FN. Conclusions: Lactates represent a more sensitive and significant biomarker compared to CRP and PCT in assessing the severity and outcome of infection during FN in AML patients. Galactomannan and BDG are significant biomarkers for the diagnosis of IFI in AML patients during FN. qSOFA, MASCC and MEWS proved to be the most significant scoring systems when it comes to stratifying the risk of developing complications during FN in AML patients, and at the same time they had the highest prognostic value. Clinical scoring systems have greater prognostic significance for assessing the severity of infection during FN in AML patients compared to individual biomarkers. GDF-15 has been shown to be a significant prognostic biomarker for assessing the severity of infection during FN in AML patients. Higher GDF-15 values were associated with a worse prognosis, in terms of persistent febrility after 48 hours of FN onset and a higher mortality rate within 28 days of FN development.
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