Examination of breakthrough invasive fungal infection risk factors in patients followed with hematological malignancy

Introduction and Objectives: Invasive fungal infection that develops under antifungal treatment or prophylaxis is defined as breakthrough fungal infection (b-IFI). It is an important cause of morbidity and mortality in patients with hematological malignancies and its frequency is increasing. The aim of this study is to evaluate the frequency of b-IFI development, the distribution of b-IFI agents and resistance, parameters showing host immunosuppression, fungal agent characteristics, mortality and survival rates. Material and Method: Between January 1, 2017 and December 31, 2022, patients with a diagnosis of invasive fungal infection followed in İnönü University Faculty of Medicine, Department of Internal Medicine, Department of Hematology and Bone Marrow Transplantation Unit were retrospectively screened, 170 patients were included in the study. Breakthrough invasive fungal infection (b-IFI) was defined as an invasive fungal infection that developed while taking antifungal agents for >7 days for treatment or prophylaxis, taking into account the EORTC-MSG and European Confederation of Medical Mycology (ECMM) definitions. Those with b-IFI were considered as the patient group, and those without b-IFI were considered as the control group. Hematological disease diagnosis type and treatment approaches, parameters showing host immunosuppression, fungal agent distribution and resistance status, antifungal treatment approaches, laboratory and radiological features, mortality/survival rates were compared between b-IFI and control groups. Analyzes were evaluated in 22 package programs of SPSS (Statistical Package for Social Sciences; SPSS Inc., Chicago, IL). Chi-square analysis (Pearson Chi-square) was used to compare categorical variables between groups. Mann Whitney U-test was used to compare paired groups. Univariate analysis in overall survival was evaluated by Kaplan-Meier. Log Rank (Mantel-Cox) analysis was performed to compare survival time among categorical variables. The statistical significance level in the analyzes was accepted as p<0.05. Results: 83 of 170 patients were evaluated as b-IFI. 51.8% of b-IFIs were invasive aspergillosis, 24.1% mucormycosis, 18.1% invasive candidiasis, 4.8% Saprochaete capitata fungemia, 1.2% Trichosporon asahii fungemia. In our study, AML and ALL were found to be significantly higher in the b-IFI group than in the non-b-IFI group. The rate of relapse/refractory hematological disease in the b-IFI group was found to be significantly higher than the group without b-IFI. The rate of development of b-IFI was found to be significantly higher in those who used FLAG-IDA as a chemotherapy regimen than in those who did not use it. The rate of development of b-IFI in allogeneic transplant type was found to be significantly higher than the rate of b-IFI development in autologous transplant type. In addition, the duration of engraftment was significantly higher in those who developed b-IFI than those who did not. The neutrophil counts and lymphocyte counts at the time of diagnosis of those who developed b-IFI were found to be significantly lower than those who did not develop b-IFI. The rate of development of b-IFI was found to be significantly higher in patients with deep neutropenia before diagnosis compared to those without deep neutropenia. Similarly, the duration of neutropenia was significantly longer in the b-IFI group than in the non-b-IFI group. C. parapsilosis, C. guilliermondii and C. tropicalis were observed most frequently in the breakthrough candidemia group. Fluconazole susceptibility was studied in 12 of 15 breakthrough candidemia episodes and 11 were found to be susceptible. Among the three common factors, the lowest survival rate was in the breakthrough mucormycosis group, and the highest survival rate was in the breakthrough aspergillosis group. The 100-day mortality was 81.5% in the b-IFI group and 71.6% in the non-b-IFI group, and there was no significant difference between the two groups. Conclusion: In our study, breakthrough invasive fungal infection agents, risk factors and mortality rates are shown. Antimicrobial susceptibility tests were studied in breakthrough yeast infections, and most of the agents were found to be fluconazole sensitive. In our study, parameters showing host immunosuppression were found to be associated with breakthrough invasive fungal infection. Additionally, it is the first study to show that the use of FLAG-IDA/ATG chemotherapies, long engraftment period after BIT, and lymphopenia are associated with b-IFI. Keywords: Breakthrough invasive fungal infection, resistance, risk factors, mortality