Results
Patient Characteristics
Three hundred ninety-eight transplants were performed at UPMC during the study period. Sixteen transplants were excluded (seven multivisceral transplants, three co-transplants with lung or heart, five deaths on day of transplant and one IFI at time of transplant), leaving 382 transplants in 367 unique patients available for analysis (15 patients were retransplanted in the study period). For purposes of our review, each transplant was considered to represent a patient at-risk for IFI. Two hundred thirty-seven and 145 transplants were performed in the universal and targeted prophylaxis time periods, respectively. Among the universal prophylaxis group, 99.6% (236/237) of patients received VORI prophylaxis. Among the targeted prophylaxis group, 38% (55/145) of patients received no antifungal prophylaxis, and 54% (78/145), 8% (11/145) and <1% (1/145) of patients received VORI, FLU and itraconazole (ITR), respectively; the patient who received ITR had a remote history of pulmonary histoplasmosis. Patient demographics, baseline characteristics, and risk factors for IFIs are noted in Table 1. Patients in the targeted prophylaxis group were more likely to receive a kidney–liver dual transplant (p = 0.003), undergo an operation exceeding 11 h (without need for substantial transfused blood products) (p = 0.02) or have a bile leak posttransplant (p = 0.04).
Invasive Fungal Infections
Twenty transplant recipients developed 22 IFIs (two patients had two infections), for an overall rate of 5.2% (20/382). Twenty-three pathogens were recovered from the 20 patients. Ten patients in both the targeted and universal prophylaxis groups were diagnosed with an IFI (6.9% [10/145] vs. 4.2% [10/237], respectively; p = 0.34). Details of IFIs are presented in Table 2. All patients developed their first episode of IFI within 30 days of transplant. Forty percent (8/20) of patients had breakthrough IFIs while receiving universal or targeted prophylaxis (n = 4 each). Thirty-five percent (7/20) of patients developed IFI after prophylaxis had been discontinued (median of 17 days after the antifungal prophylaxis was stopped) and 25% (5/20) developed IFI in the absence of prophylaxis. Seventy-eight percent (18/23) of pathogens were Candida spp.; the predominant spp. were C. glabrata (39%, 9/23) and C. albicans (22%, 5/23). There were two infections due to Cryptococcus neoformans, and one infection each due to Saccharomyces cerevisiae, Aspergillus fumigatus and Rhizomucor. Eight-five percent (17/20) of patients developed peritonitis or another intra-abdominal infection. In each instance, intra-abdominal infection was caused by a Candida spp. or S. cerevisiae; 19% (3/16) of patients with intra-abdominal candidiasis had candidemia due to the same spp. C. neoformans and A. fumigatus caused pulmonary infections. Rhizomucor caused disseminated infection in a human immunodeficiency virus/hepatitis C virus (HIV/HCV) co-infected patient. All patients with IFI were given algorithm-compliant prophylaxis, but prophylaxis was discontinued early in two patients. The reasons for discontinuation were VORI toxicity and an inability to continue VORI due to a lack of insurance coverage. Fifty percent (5/10) of patients with IFI in the targeted group did not receive antifungal prophylaxis, in keeping with the recommendations of the algorithm.
Risk factors for IFIs are presented in Table 3. Prophylaxis group (targeted vs. universal) designation was not associated with IFI on univariate analysis, nor was Model for End-Stage Liver Disease (MELD) score (p = 0.78). Of the 46 patients in the targeted prophylaxis group with a MELD > 30, 59% (27/46) received prophylaxis and 41% (19/46) did not; the only patient who developed an IFI (IFI rate of 2%, 1/46) did not receive prophylaxis prior to the IFI. From the entire cohort, 12% (47/382) of patients developed acute cellular rejection (ACR) requiring pulsed corticosteroid therapy. There was no association between IFI and ACR; 8% (4/47) and 5% (16/335) of patients with ACR and no ACR developed IFI, respectively; p = 0.29. Development of a bile leak within 30 days of transplant and living donor transplant were the only risk factors for IFI by univariate analysis (p = 0.0004 and 0.008, respectively), and the only independent predictors of IFI by multivariate analysis (p = 0.001 and 0.04, respectively; odds ratios = 7.13 and 2.96, respectively). Overall, 27% (6/22) of patients with posttransplant bile leak and 14% (7/49) of liver donor transplant recipients developed an IFI. Fifty-seven percent (4/7) of living donor recipients who developed IFIs had a bile leak.
The IFI rate in high-risk patients (defined as possessing a risk factor in Figure 1, living donor or bile leak) who received prophylaxis was 6% (12/202) compared to 4% (2/46) in low-risk patients (defined as the absence of risk factors) not receiving prophylaxis (p = 1.0).
Mortality
The overall mortality at 100 days and 1 year was 8% (32/382) and 16% (62/382), respectively. The 100-day mortality rate was 10% (15/145) in the targeted prophylaxis group and 7% (17/237) in the universal prophylaxis group (p = 0.26, log-rank test; Figure 2A). The 100-day mortality rate among patients with IFI was 15% (3/20) compared to 8% (29/362) among patients without IFIs (p = 0.25, log-rank test; Figure 2B). The attributable mortality rate for IFIs was 10% (2/20). The HIV/HCV co-infected patient who died due to disseminated Rhizomucor infection was in the universal prophylaxis group; the diagnosis was established at autopsy. A patient in the targeted prophylaxis group died due to persistent C. glabrata intra-abdominal infection.
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Figure 2.
Survival among liver transplant recipients, stratified by type of antifungal prophylaxis (A) and presence or absence of invasive fungal infections (IFIs) (B).
Compliance With Prophylaxis Algorithms
Overall compliance with the recommendations for antifungal prophylaxis was 97% (341/353). In the universal prophylaxis group, the median duration of prophylaxis in patients who would have been defined as high-risk was 9 days, with a 5% (5/107) IFI rate; corresponding data for low-risk patients were 4 days and 4% (5/130), respectively. After excluding the 20 patients with IFI, the duration of prophylaxis among patients who received an antifungal in the targeted group was significantly longer than in the universal group (median: 11 vs.6 days, interquartile range 5–25 and 3–10, respectively; p < 0.0001). No IFIs occurred during the 3-month roll-out period or in patients receiving noncompliant prophylaxis.
Toxicity
Antifungal prophylaxis was discontinued early due to concerns of toxicity in 2% (7/327) of patients; all received VORI prophylaxis. The reasons for early discontinuation were hepatotoxicity (three patients), mental status changes (two patients), diarrhea (one patient) and supratherapeutic tacrolimus levels due to a VORI interaction (one patient). Only the supratherapeutic tacrolimus level was definitively ascribed to VORI.