| BackgroundInvasive fungal infection(IFI)is a major complication of hematological diseases,particularly in patients with hematological malignancies,severe aplastic anemia or recipients of stem cell transplantation(SCT),and it constitutes a major threat to patient survival.With optimization of treatment principles,advances of SCT and improvement of antifungal prophylaxis strategies,the epidemiological senario of IFI is in frequent changes.Incidence of IFI manifests a trend of increase in accordance to widespread use of SCT and dose-intensified chemotherapy.On the other hand,with the application of galactomanan(GM)test,early diagnosis and therapy of IFI become possible in considerable proportion of high risk patients.At the same time,due to the use of newly generated antifungal agents, prognosis of IFI is improving.Institute of Hematology,Chinese Academy of Medical Sciences is a tertiary medical center for hematological diseases,and SCT center focuses on chemotherapy and SCT of leukemia and other hematological diseases.Our early investigation revealed a high incidence of IFI,with 1-year cumulative incidence of 18.7% in recipients of allogeneic SCT.Objects1. Investigating the incidence of IFI in SCT center,and revealing the risk factors and prognosis.2. Investigating the incidence,risk factors and prognosis of IFI in recipients of allogeneic SCT.3. Evaluating the efficacy of secondary antifungal prophylaxis and analyzing the risk factors of prophylaxis failureMethods1. Patient selection:Medical records of all patients with hospital stay over 2 weeks from January 2007 to December 2008 were carefully reviewed. Treatment and infections after January 1 2007were recorded. Patients received SCT in 2006 and discharged in 2007 were exluded from the study.2. The diagnosis of IFI was documented according to the revised the EORTC/MSG criteria (2008). The grading of curative effect was in accordance to RECIST.3. Statistical considerations:For categorical variables, the chi-square statistic or Fisher exact test were used to establish differences in their distribution between subgroups. Uivariate and multivariate logistical regression were used in analysis of risk factors of IFI, and recursive partitioning was used to reveal high risk patients. Incidence of IFI, IFI related mortality and TRM were estimated by the method of cumulative incidence function, and comparison of cumulative incidence curves was estimated by the method of competing risk regression. Probability of overall survival rates (OS) was estimated by the method of Kaplan-Meier product limit and comparison of survival curves was done by the log-rank test. Post-transplant events, such as GVHD, use of steroid and et al were treated as time-dependent covariates. Two sided p value of 0.05 was regarded as significant. The statistics was performed by the software R 2.10.1Results1. Incidence and risk factors analysis of IFI according to treatment cycles:From January 2007 to December 2008,1048 treatment cycles (ie chemotherapy, transplantation or hospitalization) and 451 cases of patients were recored. The diagnosis of 93 cases of IFI were made, including 6 proven,52 probable and 35 possible cases respectively, with an overall incidence of 8.87 per 100 treament cycles. Multivariate logistic regression revealed the following risk factors of IFI: age (OR OR 1.024,95%CI 1.009-1.040, P=0.002), female gender (OR 1.589, 95%CI 1.018-2.488, P=0.04), duration of aneutrophil (OR 1.028,95%CI 1.014-1.042, P＜0.0001) and uncontrolled disease (OR 2.620,95%CI 1.608-4.268, P=0.0001). Recursive partitioning found two groups of high risk patients:(1) patients with uncontrolled disease and aneutrophil duration≥58 days (7/12, 58.3%), (2) patients with uncontrolled disease, aneutrophil duration<58 days and age≥33 years (40/208,19.2%), especially female patients (27.1%).2. Cumulative incidence of IFI:At the end of follow up,111 cases of IFI were recoreded in the 451 patients, with 7 proven,64 probable and 40 possible cases respectively, with 1-year cumulative incidence of 27.1%. In all,107 cases of patients dide, of which 19 cases were IFI related, corresponding to 1-year cumulative incidence of 24.0% and 5.4% respectively.3. Prognosis of established IFI cases:After median follow-up of 168 (2-1048) days post the diagnosis of IFI,19 cases of IFI related mortality were observed, and 12 of them died within 42 days. The patients cohort showed 6-week and 12-week overall survival rate of 85.6% and 83.4% respectively,6-week and 12-week IFI related mortality rate of 12.4% and 13.5% respectively. Higher rate of IFI-realted mortality was observed in patients with proven and probable IFI in comparision to possible cases (16.6% vs 5.1%, p=0.006).4. Incidence of IFI in allo-SCT recipients:Of the study cohort,94 cases of allo-SCT cases free from a history of IFI were recorded. After a median follow-up of 510 (26-1100) days after conditioning,18 cases of IFI were recoreded, including 2 proven,11 probable and 5 possible cases, with 1-year cumulative incidence of 18.3%. Thirty-one cases died, and 8 of them were attributed to IFI related causes, corresponding to 1-year cumulative incidence of 30.6% and 8.7% respectively. In risk factors analysis, patients complicating grade 2-4 acute graft versus host disease had tendency of higher incidence (6/17 vs 12/77, p=0.051).6. Evaluation of efficacy of secondary antifungal prophylaxis:Fifty-seven cases of IFI cases recived 149 cycle of further therapy, including 13 cycles of allo-SCT,11 cycles of auto-SCT and 125 cycles of chemotherapy. They all received antifungal prophylaxis, including itraconazole (n=21) and voriconazole (n=33). After a median follow-up of 12 (12-1080) days,11 cases (7.4 per 100 cycles) expeienced failure of senconday prophylaxis, with 5 cases during allo-SCT and 6 cases during chemotherapy, leading to 1-year cumulative incidence of 24.5%. Multivariate logistic regression revealed two risk factors of failure for secondary prophylaxis: high dose corticosteroid (OR 13.5,95%CI 3.09-58.6, p=0.0005) and duration of aneutrophil> 14 days (OR 7.47,95%CI 1.69-32.9, p=0.008). Recursive portioning found the following group of patients in high risk:patients with high dose corticosteroid and aneutrophil duration≥14 days.Conclusion1. The IFI showed an oveall incidence of 8.87 per 100 treatment cycles, and 1-year cumulative incidence of 27.1%; age, female gender, duration of aneutrophil and uncontrolled diseases were risk factors of IFI; patients with uncontrolled disease and duration of aneutrophil≥58 days and patients with uncontrolled disease, duration of aneutrophil< 58 days and age≥33 years were at high risk of IFI.2. Allo-SCT recipients showed a 1-year cumulative incidence of 18.3%, with most cases late after SCT. Antimold agents may protect allo-SCT patients from IFI and IFI related mortality.3. Patients with established IFI showed 12-week survival rate and IFI related mortality rate of 83.4% and 13.5% respectively. Proven and probable cases had higher IFI-related mortality in comparison to possible cases.4. Secondary antifungal prophylaxis showed high efficacy, and can protect further chemotherapy and SCT, with 1-year cumulative incidence of prophylaxis failure at 24.5%; Use of high dose corticosteroid and duration of aneutrophil≥14 days were risk factors of prophylaxis failure, patients with the two risk factors concurrently were at the highest risk.
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