Antifungal Prophylaxis for Solid Organ Transplant Recipients: Seeking Clarity Amidst Controversy

Organ transplant recipients comprise a growing and an increasingly important group of immunocompromised hosts. Between the period 1990–1993 and the period 1994–1997, the number of transplantation procedures performed in the United States alone increased 41% for liver, 81% for kidney-pancreas, 102% for pancreas, 120% for lung, and 136% for intestinal transplantations [1]. Invasive fungal infections remain one of the most significant infectious complications among organ transplant recipients. Although mycelial fungi (e.g., phaeohyphomycetes) have emerged as important pathogens within the last decade, most invasive fungal infections in these patients are due to Aspergillus and Candida [2–4]. Management of invasive mycoses, particularly aspergillus infections, has proven remarkably challenging. Antifungal prophylaxis for solid organ transplant recipients remains a complex and controversial issue. There is a striking paucity of randomized trials in the literature. Consequently, institutional practices involving antifungal prophylaxis vary widely. Nevertheless, knowledge accrued regarding epidemiology and risk factors and published data, albeit largely from cohort studies and case series, can contribute substantially toward devising rational antifungal prophylactic strategies. In this overview, I discuss the demographic characteristics and predisposing variables for fungal infections that are the pathophysiological basis for my recommendations and the approaches I outline, the disadvantages of antifungal prophylaxis, and, finally, briefly outline directions for future studies. Clinical events (e.g., augmented immunosuppression associated with high-dose corticosteroids and OKT3 monoclonal antibodies) tend to enhance the risk of invasive fungal infections, regardless of the type of solid organ transplant. However, there are risk factors sufficiently unique to account for the diversity among different types of organ transplant recipients in the incidence of fungal infections, and also in the predilection toward specific fungal pathogens, time of onset, and risk of dissemination. The frequency of invasive mycoses among organ transplant recipients and the predominant fungal pathogens are outlined in table 1. Although candidal infections are a significant complication in liver and pancreas transplant recipients, the impact of aspergillosis is greatest in the context of liver and lung transplantation. An estimated 9.3% of deaths in lung transplant recipients and 16.9% in liver recipients are due to invasive aspergillosis [3]. Liver transplant recipients. Invasive aspergillosis has been described in 1%–8% of liver transplant recipients [5, 27–30]. Aspergillus infections in liver transplant recipients are notable for their early occurrence. The median time to onset after transplantation was 17 days in one study [28] and 16 days in another [27]. In the study by Bonham et al. [31], 8 (31%) of 26 CNS lesions that occurred within 30 days of transplantation were infectious, and Aspergillus caused 6 (75%) of these lesions. In other studies, 81%–100% of the liver transplant recipients who developed invasive aspergillosis were still in the intensive care unit after transplant surgery [27–29]. Virtually all liver transplant recipients with invasive aspergillosis have had evidence of significant hepatic and/or renal dysfunction [3, 5, 29]. In a study comprising 26 proven cases of invasive aspergillosis, poor allograft function was documented in all cases; the median serum bilirubin level was 21.8 mg/dL [28]. Thrombocytopenia in liver transplant recipients is a marker of severity of hepatic dysfunction [32]. It has been proposed that platelets may play a critical role in the host defense against Aspergillus by augmenting polymorphonuclear leukocyte—mediated damage to the fungal hyphae. The nadir in posttransplantation thrombocytopenia correlated with a higher risk of invasive fungal infections in liver transplant recipients [32]. Fulminant hepatic failure, as an indication for transplantation, was associated with a higher risk of invasive fungal infections after liver transplantation [33]. Systemic fungal infections developed in 9 (21%) of 42 patients undergoing liver transplantation for acute liver failure; 5 of the fungal infections were due to Aspergillus [33]. Finally, approximately one-fourth of the cases of invasive aspergillosis have occurred after retransplantation [28]. Renal dysfunction, particularly that requiring dialysis, portends a significantly greater risk for the development of invasive aspergillosis after liver transplantation. Fifty-eight percent of the liver transplant recipients with invasive aspergillosis in one report [28] and 80% in another [27] were undergoing either hemodialysis or continuous venovenous hemofiltration prior to Aspergillus infection. Requirement of dialysis was an independently significant predictor of invasive fungal infections in a study of liver transplant recipients [34]. Therefore, although renal failure may merely be a marker of the critically-ill nature of these patients, it is also plausible that functional abnormalities of granulocytes and macrophages associated with renal dysfunction augment the risk of developing invasive aspergillosis. Regardless, institution of dialysis is a readily discernible clinical event that identifies liver transplant recipients at risk for Aspergillus infections. For liver transplant recipients studied between 1981 and 1990, use of OKT3 monoclonal antibody was shown to be an independent risk factor for invasive aspergillosis [5]; in that study, none of the patients with aspergillus infections had received OKT3 monoclonal antibodies. Use of OKT3 monoclonal antibody after liver transplantation has declined substantially in the current immunosuppressive era. At many institutions, including mine, OKT3 monoclonal antibodies are used only for 1% of the patients. In a multicenter study conducted between 1990 and 1996, only 8% of the patients with invasive aspergillosis had received OKT3 monoclonal antibodies [28]. Effective prophylactic strategies for cytomegalovirus infection have also led to a significant decline in the occurrence of this infection in liver transplant recipients, consequently reducing its role as a predictor of invasive fungal infections in more recent reports [28]. Liver transplant recipients appear to be uniquely predisposed to dissemination of Aspergillus beyond the lungs and for CNS involvement [35] (table 2). One report [35] described extrapulmonary spread of Aspergillus in 11 (92%) of 12 liver transplant recipients, 6 (38%) of 16 hematologic patients, and 9 (45%) of 20 non—liver transplant patients with invasive aspergillosis (P < .02). Overall, disseminated disease has been described in 50%–60% of liver transplant recipients with invasive aspergillosis [3, 31]. Liver transplant recipients are also recognized to be at high risk for invasive candidiasis; invasive candidiasis accounts for 62%–91% of all invasive fungal infections after liver transplantation [4, 38–40]. Risk factors for invasive candidiasis in liver transplant recipients largely reflect the technical difficulties of the surgical procedure and an overall greater severity of illness in the patient. Longer operation time, blood loss, repeated operation, retransplantation, antibiotic usage, and renal failure are among the most significant risk factors for invasive candidiasis [4, 38, 39]. Return to surgery prior to invasive candidiasis was an independently significant predictor of death in liver transplant recipients with candidemia [40]. It is noteworthy that whereas studies before 1990 described invasive candidiasis in 16%–30% of the patients, several reports in the 1990s have reported lower rates, ranging from 5% to 10% (even in the absence of systemic antifungal prophylaxis) [4, 7, 28, 39, 41]. Although unproven, this decrease probably reflects greater technical expertise and perhaps a lower requirement of corticosteroids in the modern immunosuppressive era. Lung transplant recipients. Aspergillus infections in lung transplant recipients demonstrate several unique features. Direct communication of the transplanted lung with the environment and impaired local host defenses, including mucociliary clearance, render airway colonization a common occurrence in these patients [42]. During surgery, the bronchial arteries are disrupted at the site of anastomosis [43]. Until collaterals from bronchial circulation develop, the anastomotic healing is dependent upon blood supply from pulmonary circulation of the transplanted lung. The anastomotic site with transient devascularization therefore remains susceptible to ischemic injury, necrosis, and potentially infection with Aspergillus. Following lung transplantation, Aspergillus can be detected in airway specimen cultures for 9%–68% (average, 29%) of the patients [2, 9–11, 44]. I personally reviewed the cases of 2001 lung transplant recipients described thus far and found the following: 219 (23%) of 969 patients had airway colonization with Aspergillus without disease, 23 (4%) of 615 had tracheobronchitis, and 85 (6%) of 1542 had invasive aspergillosis. Tracheobronchitis is an entity observed specifically in lung transplant recipients [45]. Characterized by endobronchial lesions ranging from mild bronchitis to ulcers and pseudomembranes, isolated tracheobronchitis is probably early or locally invasive disease with the potential to progress to disseminated infection. Lesions in the vicinity of or involving the anastomotic site can result in fatal bronchopleural fistulas [8]. In cases reported in the literature, 93% of the patients with isolated tracheobronchitis were treated with antifungal agents with or without debridement; progression to invasive aspergillosis or death occurred in 13%. Although airway colonization with Aspergillus is associated with a low positive predictive value for invasive aspergillosis, it portends a higher risk for subsequent invasive infection. Patients with airway specimen cultures positive for Aspergillus within 6 months of lung transplantation were 11-fold more likely to develop invasive aspergillosis [12]. In another report, isolation of Aspergillus from a respiratory specimen was associated with a 22-fold greater risk for subsequent invasive aspergillosis [6]. Notably, patients with cystic fibrosis who are colonized with Aspergillus before transplantation are not deemed to be at higher risk for invasive aspergillosis after transplantation [12, 46]. Other risk factors for invasive aspergillosis in lung transplant recipients include cytomegalovirus infection, obliterative bronchiolitis, rejection, and increased immunosuppression [6, 12, 47, 48]. Although Aspergillus species other than Aspergillus fumigatus are frequently isolated from airway specimen cultures, invasive disease in lung transplant recipients has almost exclusively been due to A. fumigatus [9]. In a report where surveillance respiratory cultures were performed, 56% of the Aspergillus species detected were non-fumigatus. However, invasive disease was described only in patients colonized with A. fumigatus [9]. The median time to onset of aspergillus infections in published reports was 120 days. Overall, 49% of the infections have occurred within 3 months, 68%, within 6 months, and 79%, within 9 months of lung transplantation. When patients with airway colonization are excluded, the mortality rate among lung transplant recipients with invasive aspergillosis is 68% (table 2). Pancreas transplant recipients. Although aspergillosis occurs infrequently, candidiasis is a major infection in pancreas transplant recipients. Intra-abdominal abscesses and deep wound- and surgical site—infections due to Candida occur in 7%–14% of pancreas transplant recipients and have been associated with significantly poorer allograft and patient survival [13, 14, 36, 49]. One-year survival was 70% for patients with intra-abdominal fungal infections, compared with 92% for those without infection (P = .0007) [14]. Significant risk factors that have been documented for candidal infections in these patients are as follows: donor age (vs. recipient age), enteric (vs. bladder) drainage, pancreas after kidney transplantation (vs. pancreas transplantation alone), preoperative peritoneal dialysis (vs. hemodialysis), and pancreas retransplantation [14, 36]. Heart transplant recipients. Heart transplant recipients are generally perceived to be at a lower risk for aspergillus infections than are lung or liver transplant recipients. The incidence of invasive aspergillosis among heart transplant recipients has been reported to vary widely (1%–15%), with an overall frequency of 5.2% (102 of 1948) in studies reported thus far [15–17, 50, 51]. It should be noted, however, that these reports have almost all included patients who underwent transplantation in the 1970s or 1980s, patients who contracted infections in an outbreak setting, or patients for whom antilymphocyte preparations, including OKT3 monoclonal antibodies, were used as part of induction immunosuppressive therapy [15–17, 50, 51]. These variables in aggregate may account for the high prevalence of aspergillosis among this patient population. Unique risk factors predisposing heart transplant recipients to invasive aspergillosis have not been identified. Other solid organ transplant recipients. In the absence of graft failure requiring reinstitution of hemodialysis or intense immunosuppressive therapy, invasive aspergillosis occurs infrequently in kidney transplant recipients (table 1). The frequency of candidal infections among kidney transplant patients is also low (table 1). Invasive fungal infections have been described in 40%–59% of small bowel transplant recipients. Most of these infections are invasive candidiasis (table 1). The risk factors for candidal infections in intestinal transplant recipients, however, have not been well defined. Antifungal prophylaxis, if highly effective, inexpensive, nontoxic, and easily administered, would be far less controversial. The foremost issue pertinent to antifungal prophylaxis, therefore, is who should receive it. In my opinion, high incidence coupled with significant mortality support the use of prophylaxis for invasive aspergillosis in liver and lung transplant recipients and for invasive candidiasis in liver and pancreas transplant recipients. Currently, given the relatively low incidence of invasive fungal infections and uncertain clinical benefits of prophylaxis, routine employment of antifungal prophylaxis cannot be justified for other solid organ transplant recipients. I believe that strategies for antifungal prophylaxis should not be universal but instead should be targeted toward high-risk patients. Liver transplant recipients. In liver transplant recipients, the risk factors for invasive aspergillosis and the period of vulnerability to aspergillus infection have been precisely defined. Thus, a targeted or preemptive prophylactic approach lends itself well to these patients. The following key facts, however, need to be borne in mind. First, detection of Aspergillus species in respiratory samples from liver transplant recipients almost always indicated invasive disease [5]. Indeed, the infection may already have widely disseminated beyond a pulmonary focus by the time Aspergillus is detected in respiratory cultures [27]. Therefore, liver transplant recipients with airway specimen cultures positive for Aspergillus should not be considered candidates for prophylaxis but should be considered for therapy for invasive aspergillosis. Second, liver transplant recipients at risk for invasive aspergillosis are often critically ill, and invasive infection ensues very rapidly in these high-risk patients [27–29]. Prophylactic antifungal agents in this setting must be potent and be able to rapidly achieve the systemic drug levels considered adequate for activity against Aspergillus. The efficacy of prophylaxis for aspergillosis with itraconazole (in capsule or solution form) and low-dose amphotericin B deoxycholate (AmBd) in dosages of 0.1–0.5 mg/kg/d is unconvincing in liver transplant recipients. The capsule formulation of itraconazole has an absolute of An environment and the of in the Although itraconazole tend to be lower in all immunocompromised poor can be particularly in critically liver transplant recipients, in whom the of the is is and a is not in the early transplantation in has significantly the of has compared the solution of itraconazole with for of systemic fungal infections in liver transplant recipients The study, however, was to demonstrate the efficacy of itraconazole against invasive there were documented aspergillus infections in patients who received itraconazole or in who received In a that included patients, however, the rate of systemic infections due to Aspergillus not between patients who received the solution of itraconazole of and those who received of An of itraconazole in has efficacy as prophylaxis and therapy in clinical trials including transplant recipients. dosages of are of efficacy as prophylaxis for aspergillosis. Regardless, the potential for the use of in these dosages for transplant recipients. The of amphotericin the other have several characteristics that antifungal agents for prophylaxis for high-risk liver transplant recipients. These are less and are at or perhaps to in efficacy against invasive mycelial infections amphotericin B the antifungal that were with high of Although in and a in efficacy between of amphotericin B in the transplant setting has not been study including liver transplant recipients, however, found in efficacy or between amphotericin B complex and amphotericin B Therefore, and, to a would probably the between these 3 of are substantially more than is the most less and amphotericin B the B however, is associated with a higher rate of than are and of of amphotericin B as prophylaxis for aspergillus infections in the transplant setting have also not been defined. study that compared dosages of and for the of invasive aspergillosis in and transplant patients found in efficacy between However, case and reports of cases in liver transplant recipients have documented failure of prophylaxis with at a of mg/kg/d for aspergillus infection Thus, although recommendations regarding prophylaxis for infections due to Aspergillus cannot be without prophylaxis for invasive aspergillosis in liver transplant recipients, if deemed may be is a formulation of amphotericin B at a of 3 5 targeted toward high-risk patients in table for a period of after transplantation. The need for prophylaxis beyond this period should be the basis of the of risk However, I that of are and there are to support these Lung transplant recipients. The of aspergillus infections in lung transplant recipients is not as precisely as in liver transplant recipients. The period of greatest vulnerability several Thus, the and of a antifungal for a time render this a less for include agents and antifungal that most aspergillus infections are pulmonary and airway colonization or invasive infections in lung transplant recipients, prophylaxis would appear to be a rational In an of immunocompromised of days before infection death in all in the following whereas of the it is proposed that is more to the higher lung as an than by the systemic of at a of in the lung whereas the was with only of at to were in without and serum The of amphotericin B by an was more as prophylaxis for aspergillus infection than was alone It has been proposed that of may enhance the of in the lung Lung with the of amphotericin B were higher than those of Although randomized trials have not been a number of reports have significant in the frequency of aspergillus infections in lung transplant recipients treated with was also reported to be in a study of lung transplant recipients Thus, although the efficacy of amphotericin B remains to be the of this approach include of systemic low of and of a need to drug levels or have been itraconazole has generally been against the less of invasive aspergillosis in lung transplant recipients (e.g., and as prophylaxis for colonized patients Therefore, an for prophylaxis for lung transplant recipients is amphotericin B for several after transplantation or the bronchial anastomosis has (in one report all anastomotic infections occurred within days of lung transplantation It should be that Aspergillus that the small and have a of The of the is in are likely to be in the and may not the lower respiratory preemptive prophylaxis with itraconazole for months or without amphotericin may be considered for patients with airway specimen cultures that are positive for Aspergillus within months of transplantation. of tracheobronchitis or of invasive disease in colonized patients has generally been with a of itraconazole and this of prophylaxis the period of greatest vulnerability to infection the 6 months after Patients with airway specimen cultures positive for Aspergillus who have all of invasive aspergillosis, including anastomotic site infections and tracheobronchitis, should be from this these patients should receive and not prophylaxis for aspergillosis. The solution of itraconazole may be to of its greater Although of itraconazole may be more predictive of efficacy than are serum it has been that serum levels of itraconazole of at are for antifungal prophylaxis for patients The itraconazole used to achieve may be considered for lung transplant recipients. It should be that itraconazole or levels by Other drug itraconazole therapy for transplant recipients should also be borne in For use of and itraconazole has been associated with in a lung transplant recipient At randomized studies have the efficacy of as prophylaxis for invasive fungal infections in liver transplant recipients randomized from compared with for days after transplantation as antifungal prophylaxis for liver transplant recipients Although the incidence of colonization with Candida and fungal infections was lower among recipients a in the frequency of invasive candidiasis was not observed between the has often been alone as part of bowel for liver transplant recipients. However, its efficacy in systemic fungal infections is a high incidence of invasive candidiasis has been documented among patients who received therapy study found that for was associated with a significant decrease in the incidence of invasive fungal infections However, this study reported an high incidence of invasive mycoses most of were fungal infections. The frequency of invasive candidiasis in this group was to the frequency among patients at other who received systemic antifungal prophylaxis The need for prophylaxis, in my opinion, should be the basis of institutional in the incidence of invasive prophylaxis is and should be the low frequency of invasive candidiasis at many liver transplant and the potential for the of prophylaxis should be When it is prophylaxis should be only to high-risk patients in table and for only after transplantation. prophylaxis has been reported to be after pancreas transplantation [14, the significant and patient that are associated with candidal infections, prophylaxis with for may be considered for high-risk pancreas transplant recipients. for candidal infections may also be for small bowel transplant however, the risk factors for candidemia have not been well in this of patients. The potential for the of fungi is among the most to antifungal prophylaxis and is particularly in the context of use is the most significant factor to an toward Candida species and the of Candida infection. to demonstrate infection due to Candida in in one report is not the of often and an with prophylaxis are The potential due to infections with Candida and the of these infections far in the The reports antifungal prophylaxis are largely studies with small (table studies have frequently to patients by variables (e.g., of table and, at have been to fungal infections. In this a by the for and of to and for invasive fungal infections in patients is Finally, the of the efficacy of prophylaxis with clinical is an important However, mortality have not been reported in published studies. Patients at risk for invasive fungal infections are often critically and may of their illness regardless of the efficacy of At 3 randomized studies not an impact a significant in invasive fungal infections in liver transplant recipients. these have noteworthy for future For the studies by et al. and et al. their the of efficacy of low-dose as prophylaxis for invasive aspergillosis, that higher need to be considered in clinical trials including liver transplant recipients. The approaches for antifungal prophylaxis are upon the of prophylaxis to high-risk patients for the period to transplantation risk is to be Although it should be that these recommendations are my and a of literature. of the efficacy of these approaches in future and of their are should studies The recommendations should not be as a of but merely as for of major invasive fungal infections among organ transplant recipients and of those infections that are due to Aspergillus and characteristics of Aspergillus infections in organ transplant recipients. approach to antifungal prophylaxis for organ transplant recipients. from published studies systemic antifungal prophylaxis for solid organ transplant recipients.