Infectious Disease Department and Liver Transplant Group, Hospital Ramon y Cajal, Crtra Colmenar Km 9.1, Madrid 28034, Spain
Received 25 April 2003; returned 1 June 2003; revised 12 August 2003; accepted 17 August 2003
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Abstract |
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Patients and methods: From January 1998, patients who fulfilled four or more variables identified as risk factors for IFI received a cumulative dose of 11.5 g of lipid formulations of amphotericin B (L-AmpB; AmBisome or Abelcet). The development of IFI in these patients was compared with historical patients.
Results: Two hundred and eighty liver transplant recipients were analysed over a period of 8 years. In the historical group, IFI were observed in 22 of 131 patients (17%) and invasive aspergillosis in 13 of them (10%). After January 1998, IFI were observed in nine of 149 (6%) (P < 0.01) and invasive aspergillosis in six patients (4%) (P = 0.08). In patients with four or more risk factors (high risk) for IFI, the administration of L-AmpB reduced the risk from 36% to 14% (P = 0.07), and the risk of aspergillosis from 23% to 5% (P = 0.08). Notably, prophylaxis reduced the risk of aspergillosis from 32% to 0% in dialysed patients (P = 0.03). Variables independently associated with IFI in high-risk patients were dialysis [odds ratio (OR) 3.9; 95% confidence interval (CI) 116.7] and surgical reintervention (OR 5.4; 95% CI 1.224.6), while L-AmpB was a protective factor in this multivariate analysis (OR 0.1; 95% CI 0.020.8). The analysis in these high-risk patients was not able to demonstrate an association between the administration of L-AmpB and higher survival.
Conclusions: Selected risk factors are good predictors of IFI in liver transplant recipients. The administration of L-AmpB in high-risk patients is independently associated with a reduction of IFI.
Keywords: Abelcet, AmBisome, Aspergillus, liver transplantation
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Introduction |
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Although the most frequent fungal infections are caused by Candida spp., infections due to Aspergillus spp. have the worst prognosis.1,2 Invasive aspergillosis has been reported in 1.56.5% of liver transplant patients,35 although other authors have reported higher frequencies.6 A nationwide study carried out by the Spanish Study Group for Infections in the Transplant Patient documented the development of invasive aspergillosis in 2.8% of 1719 liver transplant recipients, with a case fatality rate of 86%.7
Early diagnosis of invasive aspergillosis is difficult. The identification of risk factors for invasive aspergillosis in transplant patients could allow the use of antifungal agents for prophylaxis, avoiding the development of an invasive mycosis with high morbidity and mortality.
In January 1998, we started a prophylactic approach to fungal infections based on the administration of a 11.5 g cumulative dose of lipid formulations of amphotericin B (L-AmpB) to liver transplant recipients at high risk of invasive fungal infection (IFI). The results were compared with the previous period, in which no prophylaxis was used.
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Patients and methods |
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Pre-emptive prophylaxis for IFI with L-AmpB was initiated in January 1998. Patients transplanted before January 1998 did not receive specific prophylaxis other than fluconazole, which was administered universally (see below). These patients were considered to be the historical group.
This study was approved by the Ethics Committee at our institution.
Prophylaxis criteria and dose
In the group of patients that received pre-emptive prophylaxis, a cumulative dose of 11.5 g of AmBisome (Gilead Sciences, Foster City, CA, USA) or Abelcet (Elan Pharmaceuticals, Dublin, Ireland) (100 mg a day, 1015 days) was administered to patients with four or more of the following risk factors for IFI: high number (>30 units) of packed red cells required during the transplantation procedure; renal failure (creatinine clearance <25 mg/mL or creatinine serum level >2.5 mg/dL); dialysis requirement (or haemofiltration); retransplantation; surgical reintervention (with a general anaesthesia); positive cytomegalovirus (CMV) antigenaemia (>10 cells/200 000) or CMV disease; acute rejection episode; fungal colonization (only applied to moulds); prolonged antibiotic therapy (>5 days); and intensive care unit stay before transplantation.
Diagnosis of IFI
Invasive candidiasis was defined by histopathological evidence of tissue invasion or isolation of Candida in normally sterile body fluids, including blood cultures.
Invasive aspergillosis was categorized as proven or probable.8 Proven aspergillosis was assigned when tissue histopathology showed septate, acute branching hyphae with or without a positive culture for Aspergillus spp. from the same site, or, in the absence of histopathology, a positive culture from tissue obtained by an invasive procedure. Probable aspergillosis applied only to patients with pulmonary disease with chest radiographic appearance of new nodules or cavities, and two sputum cultures or one bronchoalveolar lavage, washing or brushing cultures for Aspergillus spp. In the absence of pulmonary infiltrates, the isolation of Aspergillus spp. in sputum and not confirmed in bronchoalveolar lavage was considered colonization.
Prophylaxis and immunosuppression protocols
Bacterial prophylaxis included ampicillin and cefotaxime for 48 h after the transplant procedure and was prolonged to 5 days in patients with allograft dysfunction. From 1994 to 1996, oral ofloxacin was also given as selective bowel decontamination. Fungal prophylaxis consisted of the administration of oral fluconazole (100 mg once daily for 20 days) during the hospitalization period to all patients. Co-trimoxazole was given for Pneumocystis carinii prophylaxis during the first 6 months. Pre-emptive therapy guided by antigenaemia (pp65) was used for CMV-seropositive recipients. CMV prophylaxis (intravenous ganciclovir 5 mg/kg twice daily for 14 days, followed by oral aciclovir 800 mg four times a day for 3 months) was given to seronegative recipients of seropositive donors.
The immunosuppression regimen generally included ciclosporin or tacrolimus, a tapering course of corticosteroids, and azathioprine or mycophenolate. Rejection episodes were initially treated with corticosteroid boluses or increasing doses of tacrolimus if it was the immunosuppressor used. Corticosteroid-resistant acute rejection episodes were treated with OKT3.
Statistical analysis
Patient characteristics were compared using Students t-test for continuous data (separate estimates of variance were used when variances differed significantly) and the MantelHaenszel extended 2 test for categorical data. Fishers exact test was used when the expected number of cases per cell was below five. Odds ratios (ORs) and 95% confidence intervals (CIs) are given with
2 and P values to illustrate the amount of risk associated with some of the effects. Multiple logistic regression analysis was used to determine the independent risk factors associated with IFI and/or mortality.
All statistical associations were assessed with two-tailed tests. A P value 0.05 was considered to indicate statistical significance. Statistical analysis of the data was performed with the Epi-Info software package, version 6 (CDC, Atlanta, GA, USA) and SPSS 9.0 for Windows.
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Results |
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The other six patients (numbers 24, 25, 26, 27, 30 and 31), who developed an IFI after January 1998, had not received pre-emptive L-AmpB prophylaxis. Two of them (numbers 26 and 30) should have received pre-emptive L-AmpB prophylaxis based on the number of risk factors they had (four or more), but it was not administered. Both of them developed invasive aspergillosis (on day +30 and +7, respectively). Patients 24, 25, 27 and 31 did not have risk factors for fungal infection and they did not receive pre-emptive L-AmpB prophylaxis. However, they developed a fungal infection (three Aspergillus spp., one C. albicans), although in all cases these infections were observed after day +60 (late fungal infections).
In the historical group, IFI and aspergillosis developed in 22 (17%) and 13 (10%), respectively, of the 131 patients transplanted before January 1998 (Table 4). With the exception of CMV antigenaemia and rejection episodes, the analysis of the historical group demonstrated a high association between the considered risk factors and the development of an IFI. In these patients, retransplantation (OR 6.0; 95% CI 1.721.1) and surgical reintervention (OR 5.1; 95% CI 1.814.5) were independently associated with IFI in multivariate analysis. When analysis was focused to aspergillosis, dialysis was the only risk factor independently associated with this complication in the historical group (OR 5.5; 95% CI 1.519.6), although retransplantation and reintervention were associated in univariate analysis (Table 4).
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A significant decrease in the number of IFI was documented after January 1998. In addition, a significant reduction in mortality rate at 3 months and a trend at 12 months after transplantation was observed (Table 5).
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Although a higher overall survival was observed in patients transplanted after January 1998 in patients with more than four risk factors, an association between pre-emptive prophylaxis and a higher survival could not be demonstrated (Table 7). However, independent factors associated with a higher mortality in patients with more than four risk factors included: transplantation before 1998 (OR 4.7; 95% CI 1.119.9), dialysis requirements (OR 3.9; 95% CI 1.014.8) and the presence of IFI (OR 4.3; 95% CI 1.116.4).
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Discussion |
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Strategies for the prevention of fungal infection in transplant recipients have shown varying degrees of efficacy depending on the fungus to be prevented. The benefit of the use of fluconazole has been reported previously.9 A prospective, randomized, double-blind, placebo-controlled study performed in >200 liver transplant recipients has shown the efficacy of the administration of fluconazole, 400 mg daily, for 10 weeks, in the prevention of Candida spp. colonization (90% versus 28%), superficial infection (28% versus 4%) and deep infection (23% versus 6%); although overall mortality was similar in all the groups, mortality related with fungal infections was lower in those who received fluconazole.9 The use of universal antifungal prophylaxis with fluconazole could have influenced the low number of Candida spp. infections in our transplant population.
However, prevention of invasive aspergillosis in solid organ transplant recipients has not been successful, with the exception of aerosolized amphotericin B in lung transplantation.10,11 Different approaches to preventing aspergillosis in solid organ transplant recipients have been tested. A clinical trial performed with 71 liver transplant patients comparing an oral solution of itraconazole with placebo showed a significant decrease in superficial mycoses, but not a reduction in the risk of Aspergillus infection.12 Another study did not demonstrate benefit with the administration of low doses of amphotericin B desoxycholate (0.10.5 mg/kg) for Aspergillus prophylaxis in liver transplant recipients.4
More recently, similar to the approach to fungal prophylaxis in bone marrow transplantation,13 there have been some promising results with the use of lipid formulations of amphotericin B in liver transplant recipients. Preliminary studies with AmBisome showed efficacy in candidiasis prevention, but the number of patients included was too small to demonstrate a reduction in Aspergillus spp. infections.14 Recently, Singh et al.15 reported a decrease in the rate of aspergillosis and candidiasis with the prophylactic administration of Abelcet or AmBisome in liver transplant recipients who needed dialysis, compared with a historical group. In this study, the rate of invasive mycoses in the group of historical patients who needed dialysis during the post-transplant period was 36% (eight of 22 patients), a rate higher than the 7% (nine of 126) of invasive mycoses in patients that did not need dialysis. These differences were also observed for aspergillosis (14% versus 2%). This scenario forced them to use lipid formulations of amphotericin B in those patients who required dialysis, maintaining treatment until death, discharge or the end of dialysis. The adoption of this antifungal prophylaxis for patients who required dialysis represented a decrease in the rate of invasive mycoses (zero of 38 patients), that was significant when it was compared with 36% of invasive mycoses of the historical group (P = 0.03). In this study, fungal prophylaxis was the only protective factor in a multivariate analysis, including age, CMV infection and immunosuppression. However, as in our study, the mortality rate in the two groups was not modified. Our results confirm those obtained by Singh et al.,15 in a higher number of patients and in a population with risk factors other than dialysis.
Risk factors for the development of invasive aspergillosis have been assessed in several reports. In fact, we have recently demonstrated in a casecontrol study that dialysis requirement is an independent factor associated with the risk of aspergillosis in liver transplant recipients.16 In the same study, retransplantation and the presence of a positive Aspergillus antigenaemia in serum samples obtained during the post-transplant period were also independently associated with aspergillosis in the multivariate analysis.16 When we decided to use pre-emptive L-AmpB prophylaxis after January 1998 we had not identified these risk factors in our population. L-AmpB was administered to patients at risk of fungal infection according to risk factors reported previously by Briegel et al.17 We gave the same value to all the risk factors and considered as candidates for pre-emptive L-AmpB prophylaxis those patients who fulfilled four or more of these factors. The analysis of our historical group revealed that the weight of the risk factors used was unequal. In agreement with our previous casecontrol study,16 dialysis was the only risk factor independently associated with the development of aspergillosis in patients who did not receive pre-emptive L-AmpB prophylaxis. When we analysed, in the present study, the risk of global fungal infection (aspergillosis and candidiasis), the risk factors independently associated with fungal infection were retransplantation and surgical reintervention.
After the findings of our two studies, we have modified our criteria for administering pre-emptive L-AmpB prophylaxis in liver transplant recipients. Now, we administer pre-emptive L-AmpB prophylaxis to patients who have any of the following risk factors: dialysis, retransplantation, surgical reintervention or, based on our previous study, a positive Aspergillus antigenaemia.
Some studies have reported failure of AmBisome (1 mg/kg/day) to prevent aspergillosis in liver transplant recipients.18,19 Our study may have some limitations. The study is retrospective and the comparator group is historical, avoiding the analysis of some factors related with the moment of the study (surgical, epidemiological or ambient factors). The importance of environmental factors or those related to the immunosuppression protocol used during these years makes the analysis of the role of pre-emptive L-AmpB prophylaxis for decreasing the rate of mycoses observed in recent years more difficult. The real contribution of pre-emptive L-AmpB prophylaxis to the improvement in survival in this period, which includes other potential benefit factors not investigated in this study, is not known.
In conclusion, the decision to administer pre-emptive L-AmpB prophylaxis to liver transplant recipients should be based on the presence of specific risk factors. In our experience, dialysis, retransplantation, surgical reintervention and Aspergillus antigenaemia are good markers to guide this prophylaxis. The administration of a cumulative dose of 11.5 g of lipid formulations of amphotericin B in patients at risk could decrease the development of IFI, mainly aspergillosis. The effect on survival should be evaluated in larger, prospective studies.
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Footnotes |
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References |
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