Invasive Aspergillosis in Solid Organ Transplant Recipients

Abstract

Invasive aspergillosis occurs in 1–15% of the solid organ transplant recipients. Mortality rate in transplant recipients with invasive aspergillosis typically ranges from 65% to 92% (1-4). An estimated 9.3–16.9% of all deaths in transplant recipients in the first year have been considered attributable to invasive aspergillosis (5). Although the outcomes have improved in the current era, invasive aspergillosis remains a significant posttransplant complication in solid organ transplant (SOT) recipients. The review herein discusses the epidemiologic characteristics, risk factors, diagnostic laboratory assays and the approach to antifungal prophylaxis and treatment of invasive aspergillosis in SOT recipients. In this regard, most of the data cited are derived from studies in adults. The extent to which extrapolations can be made to pediatric populations varies depending on the clinical scenarios and the specific drug treatment being employed. A summary of pediatric issues and drugs doses are included in this document. The net state of immunosuppression and the intensity of immunosuppressive regimen is a major determinant of the development of invasive aspergillosis in SOT recipients, regardless of the type of solid organ transplant. However, the incidence of invasive aspergillosis differs and there are unique risk factors for Aspergillus infections for various types of organ transplant recipients as discussed herein (Table 1). Invasive aspergillosis occurs in 1–9.2% of the liver transplant recipients (1, 4-8). A number of well-characterized risk factors have been shown to portend a high risk of invasive aspergillosis after liver transplantation. Retransplantation and renal failure are among the most significant risk factors for invasive aspergillosis in these patients (4, 9-11). Retransplantation confers 30-fold higher risk and renal dysfunction, particularly the requirement of any form of renal replacement therapy, for example, hemodialysis or continuous venovenous hemofiltration is associated with a 15- to 25-fold greater risk of invasive fungal infections in liver transplant recipients (3, 10). Most Invasive fungal infections in these high-risk patients occur within the first month posttransplant; the median time to onset of invasive aspergillosis after renal replacement therapy and retransplantation was 13 and 28 days, respectively in one study (8, 12). Other factors associated with invasive aspergillosis in liver transplant recipients include transplantation for fulminant hepatic failure, cytomegalovirus (CMV) infection, and prolonged intensive unit care stay (6-8, 13-15; Table 2). Historically, invasive aspergillosis in liver transplant recipients has occurred in the early posttransplant period; the median time to onset after transplantation was 17 days in one study (2) and 16 days in another (16). More recently however, Aspergillus infections have been shown to occur in the late posttransplant period. In a study that compared a cohort of patients with invasive aspergillosis from 1998 to 2002 with those from 1990 to 1995, 55% of the infections in the later compared with 23% in the earlier cohort occurred after 90 days of transplantation (3). Improved outcome in the early postoperative period due to technical surgical advances, and delayed onset of posttransplant risk factors such as CMV infection, allograft dysfunction due to recurrent hepatitis C virus hepatitis are proposed to have led to delayed occurrence of invasive aspergillosis in liver transplant recipients in the current era (3). CMV and hepatitis C virus infection are independent risk factors for late-onset invasive aspergillosis in liver transplant recipients (2, 6, 10). Mortality rate in liver transplant recipients with invasive aspergillosis has ranged from 83% to 88% (5, 17). Requirement of dialysis and CMV infection are independent predictors of mortality in SOT recipients, including liver transplant recipients with invasive aspergillosis (12). More recent studies have reported better outcomes with mortality ranging from 33.3% to 65% (3, 18). Mortality rates however, remain high in patients who develop invasive aspergillosis after liver retransplantation (82.4%), particularly in those undergoing retransplantation after 30 days of primary transplant (100%) (12). Invasive aspergillosis has been reported in approximately 0.7% and in up to 4% of the renal transplant recipients (5, 6, 19-24). High doses and prolonged duration of corticosteroids, graft failure requiring hemodialysis and potent immunosuppressive therapy have been shown to be risk factors for invasive aspergillosis after renal transplantation (5, 22, 25). Despite a relatively lower overall incidence as compared to other organ transplant recipients, invasive aspergillosis is a significant contributor to morbidity in renal transplant recipients. Mortality rate in renal transplant recipients with invasive aspergillosis have ranged from 67% to 75% (4, 5). The overall incidence of invasive aspergillosis in lung transplant patients ranges from 4% to 23.3% (26). The median time to onset of invasive aspergillosis in lung transplant recipients in the current era is 483 days posttransplant (27). In lung transplant recipients, the continuous exposure of the organ to the environment, coupled with impaired defenses due to decreased mucociliary clearance and blunted cough reflex, contributes to the vulnerability to IA (28). Other risk factors that confer an increased risk of IA in lung transplant recipients are relative ischemia at the anastomosis (29), receipt of single lung transplant (30), hypogammaglobulinemia (31), placement of a bronchial stent (32) CMV infection (33) and pre/postcolonization of the airways with Aspergillus (34-36). The presence of obliterative bronchiolitis as a risk factor for invasive aspergillosis is not well determined. The mortality rate of IA in lung transplant recipients varies according to the clinical presentation, ranging from 23% to 29% in patients with tracheobronchitis to as high as 67% to 82% in patients with invasive pulmonary disease (9). The incidence of invasive aspergillosis in heart transplant recipients ranges from 1% to 14% (37). The risk factors for the development of IA include the isolation of Aspergillus fumigatus from broncholaveolar lavage, reoperation, CMV disease, posttransplant hemodialysis and existence of an episode of invasive aspergillosis in heart transplant program 2 months before or after heart transplant (38-40). Overall mortality in heart transplant recipients with invasive aspergillosis at 1 year was 66.7% in one study (37). A substantial delay in establishing an early diagnosis remains a major impediment to the successful treatment of invasive aspergillosis. Cultures of the respiratory tract secretions lack sensitivity and fungus may only be detected in clinical samples in late stages of the disease. On the other hand, a positive culture with Aspergillus from respiratory tract samples does not always indicate invasive disease. The significance of a positive culture from an airway sample also varies with the type of organ transplant. Isolation of Aspergillus spp. from the respiratory tract of liver transplant recipients is an infrequent event (∼1.5%). However, it has a high-positive predictive value, ranging from 41% to 72% for the subsequent development of invasive aspergillosis (5). Aspergillus spp. can be detected in airway samples of ∼25–30% of the lung transplant recipients (3, 34, 41). Although, positive airway cultures have a low-positive predictive value for the diagnosis of invasive aspergillosis in lung transplant recipients they portend a higher risk for subsequent invasive infection (5). Recovery of Aspergillus spp. from an airway sample in lung transplant recipients warrants a bronchoscopic examination to exclude the presence of tracheobronchitis because radiographic and imaging studies may be nonrevealing at this stage. In heart transplant recipients, the positive predictive value of culturing Aspergillus from respiratory track samples for the diagnosis of invasive aspergillosis was 60–70% (40). The positive predictive value of recovering A. fumigatus for the diagnosis of invasive aspergillosis was 78–91%, whereas it was 0% for other species (40). The isolation of A. fumigatus from the sputum had a positive predictive value of 50–67% that increased to 88–100% when the sample was a respiratory specimen other than the sputum such as bronchoalveolar lavage (BAL), and bronchial aspirate (40). The utility of the galactomannan test for the early diagnosis of invasive aspergillosis has been assessed in a limited number of studies in SOT recipients. In liver transplant recipients where archived sera were tested, the sensitivity of the test was 55.6% and the specificity was 93.9% (42). A prospective study in 154 liver transplant recipients documented a specificity of 98.5% (43). In lung transplant recipients, the galactomannan test had a specificity of 95%, but a relatively low sensitivity (30%) for the diagnosis of invasive aspergillosis (44). Although the test was able to detect the only case of systemic invasive aspergillosis, and 29% of the cases of pulmonary invasive aspergillosis, it detected none of the cases of Aspergillus tracheobronchitis (44). A meta-analysis showed that galactomannan assay may have greater utility in hematopoietic stem cell transplant recipients than in SOT recipients in whom the sensitivity and specificity of the test was 22% and 84%, respectively (45). Sensitivity of the galactomannan assay for the diagnosis of invasive aspergillosis in SOT recipients may be improved by testing BAL. In one study, BAL had a sensitivity of 67% and specificity of 98% at the index cutoff value of ≥1 for the diagnosis of invasive aspergillosis in lung transplant recipients (46). In another study, BAL had a sensitivity of 100% and specificity of 91% at the same index cutoff value for the diagnosis of invasive aspergillosis in SOT recipients (47). In another study which combined the data from two previously reported studies, the galactomannan sensitivity was 81.8% in patients with aspergillosis and specificity was 95.8% in lung transplant patients who underwent BAL for surveillance for infection or rejection (48). False-positive galactomannan tests have been documented in up to 13% of the liver and 20% of the lung transplant recipients (43, 44). Liver transplant recipients undergoing transplantation for autoimmune liver disease and those requiring dialysis were significantly more likely to have false-positive galactomannan tests (43). In a report in lung transplant recipients, false-reactivity with the Aspergillus EIA was documented in 20% (14/70) of the patients (44). Most false-positive tests occurred in the early posttransplant period, that is, within 3 days of lung transplantation in 43%, within 7 days in 64% and within 14 days of transplantation in 79% of the patients (44). Patients undergoing lung transplantation for cystic fibrosis and chronic obstructive pulmonary disease were more likely to have positive tests in the early posttransplant period (44). False-positive galactomannan tests in 29% of the liver transplant recipients in the first week posttransplantation were attributed to perioperative prophylaxis with β-lactam agents. The utility of 1–3, β-d-glucan for the diagnosis of invasive aspergillosis has not been fully defined. The test, however, was useful for the diagnosis of invasive aspergillosis in living-donor liver allograft recipients in one study (49). A pan fungal PCR in the blood was shown to be helpful and preceded clinical signs of invasive fungal infections in renal transplant recipients by 27 days (50). However, PCR-based molecular diagnostic tests for Aspergillus are not commercially available, remain largely nonstandardized and their precise role in the diagnosis and management of invasive aspergillosis in SOT recipients remains to be determined. General principles for the treatment of invasive aspergillosis in SOT recipients remain the same as in other patient populations. Prompt initiation of antifungal therapy is critical for achieving optimal outcomes in SOT recipients with invasive aspergillosis. Beginning in the early 1990s and for almost a decade, lipid formulations of amphotericin B largely because of a lower potential of nephrotoxicity have been the mainstay for the treatment for invasive aspergillosis in SOT recipients. In a study consisting of 47 SOT patients with invasive aspergillosis who were treated with lipid formulations of amphotericin B (5–7.4 mg/kg/day), the overall 90-day mortality was 49% and the invasive aspergillosis-associated mortality was 43% (12). Another study that compared the efficacy of amphotericin B lipid complex (median dose of 5.2 mg/kg/day) and amphotericin B deoxycholate (median does of 1.1 mg/kg/day) for the treatment of invasive aspergillosis in SOT recipients (51), the overall and invasive aspergillosis-related mortality rate was 33% and 25% in amphotericin B lipid complex group, and 83% and 76% in amphotericin B deoxycholate group (51). Availability of newer triazole agents and the echinocandins that have potent anti-Aspergillus activity and better tolerability profile have led to an expanded armamentarium of antifungal agents for the treatment of invasive aspergillosis. A large, randomized trial that compared voriconazole with amphotericin B deoxycholate as primary therapy of invasive aspergillosis included 11 SOT recipients (52). At week 12, successful outcomes were documented in 52.8% of the patients in the voriconazole group and in 31.6% in the amphotericin B group. The survival rate at 12 weeks was 70.8% in the voriconazole group and 57.9% in the amphotericin B group (hazard ratio, 0.59; 95% CI 0.40–0.88). Voriconazole-treated patients had significantly fewer severe drug-related adverse events, except for transient visual disturbances. Since this study, a number of reports of employing voriconazole for the treatment of invasive aspergillosis in SOT recipients have appeared in the literature. In three studies that included SOT patients with invasive aspergillosis, complete or partial response rates observed with voriconazole were 100%, 100% and 50% (53-55). In another report that included 11 SOT recipients with central nervous system aspergillosis treated with voriconazole, the favorable response rate was 36% (56). Voriconazole was successfully used in heart transplant recipients as first-line and salvage therapy for invasive aspergillosis (57, 58). Intravitreal voriconazole has also been used in a lung transplant patient with Aspergillus endophtlamitis (59). Voriconazole is now regarded as the drug of choice for primary treatment of invasive aspergillosis in all hosts, including SOT recipients, a recommendation endorsed by the recent Clinical Practice Guidelines of the Infectious Diseases Society of America (IDSA) for the treatment of invasive aspergillosis (level I recommendation) (60). Caspofungin is the only echinocandin currently approved by the US Food and Drug administration for the treatment of invasive aspergillosis. In a study that employed caspofungin as primary therapy for invasive aspergillosis in 12 SOT recipients, the response rate was 92% (61). Caspofungin has been used successfully as salvage therapy in invasive aspergillosis as single agent (62) and in combination with other drugs (63-65). To date limited experience exists with the use of posaconazole, micafungin or anidulafungin for the treatment of invasive aspergillosis in SOT recipients (66-68). In patients developing therapy limiting toxicity or with contraindications to voriconazole, liposomal amphotericin B is considered an alternative primary therapy as per IDSA guidelines. Based on the AmBiLoad study in which 3 mg/kg/day showed similar efficacy to 10 mg/kg/day and less toxicity, higher doses are not recommended (69). Amphotericin B lipid complex, itraconazole, caspofungin, posaconazole or micafungin (B-II) are rational choices for alternative therapy for invasive aspergillosis (60). Aspergillus species such as A. terreus are typically resistant to the polyenes but susceptible to voriconazole. However, only 5–6% of invasive aspergillosis in SOT recipients is due to A. terreus (12). New guidelines of the Infectious Disease Society of America recommend voriconazole as initial therapy for the treatment of tracheobronchial aspergillosis (60). Aerosolized amphotericin B deoxycholate or lipid formulations of amphotericin B may have some benefits however, their use for the treatment of tracheobronchial infection has not been standardized and remains investigational (60). There is little experience with caspofungin or other echinocandins in treating tracheobronchial infections. The role of combination antifungal therapy for invasive aspergillosis has not been fully defined. Updated guidelines of the Infectious Disease Society of America suggest reserving this option for salvage therapy (60). A prospective, multicenter study in SOT recipients compared outcomes in 40 patients who received voriconazole plus caspofungin as primary therapy for invasive aspergillosis with those in 47 patients in an earlier cohort who received a lipid formulation of amphotericin B as primary therapy (12). The two groups were well matched, including the proportion with disseminated disease (10% vs. 12.8%), proven invasive aspergillosis (55% vs. 51.1%) or A. fumigatus (71.1% vs. 80.9%). Overall survival at 90 days was 67.5% in the cases and 51% in the control group. Mortality was attributable to invasive aspergillosis in 26% of the cases and in 43% of the controls (p = 0.11). Deaths tended to occur later in cases than in the control patients (mean 49.5 vs. 36.7 days, p < 0.11). In multivariate Cox regression model, CMV infection and renal failure were independently predictive of mortality at 90 days. Combination therapy was associated with a trend toward lower mortality (HR 0.58, 95% CI: 0.30–1.14, p = 0.117) when controlled for CMV infection and renal failure. When 90-day mortality was analyzed in subgroups of patients, combination therapy was independently associated with reduced mortality in patients with renal failure, and in those with A. fumigatus infection), even when adjusted for other factors predictive of mortality in the study population (12). No correlation was found between in vitro antifungal synergistic interactions and outcome. None of the patients required discontinuation of antifungal therapy for intolerance or adverse effects; however, patients in the combination therapy arm were more likely to develop an increase in calcineurin-inhibitor agent level, or gastrointestinal intolerance (12). A retrospective survey documented invasive pulmonary aspergillosis in 7.5% (19/251) of the lung transplant recipients of whom 47% (9/19) had disseminated aspergillosis (70). Mortality rate was 86% (12/14) in patients who received amphotericin B preparations (amphotericin B deoxycholate or a lipid formulation of amphotericin B) and 0% (0/3) in those who received voriconazole plus caspofungin. Two of 19 cases were diagnosed only at autopsy (70). Mortality rate in patients receiving voriconazole plus caspofungin was also lower compared to lipid formulations of amphotericin B (0/3 vs. 8/8, p = 0.006). Although definitive clinical trials are pending, the combination of voriconazole and caspofungin for the treatment of invasive aspergillosis posed a lesser economic burden on institutional resources than 5 mg/kg/day of liposomal amphotericin B (71). A survey of antifungal therapeutic practices for invasive aspergillosis in liver transplant recipients documented that currently combination therapy is used as first-line treatment in 47% and as salvage therapy in 80% of the transplant centers in North America (72). We believe that potential benefits of combination therapy may be best realized when used as initial therapy, particularly in patients with more severe forms of the disease such as disseminated invasive aspergillosis or with poor prognostic factors such as renal failure. Surgical excision or debridement remains an integral part of the management of invasive aspergillosis for both diagnostic and therapeutic purposes (64, 68, 73-76). Specifically, surgery is indicated for persistent, or a life-threatening hemoptysis, for lesions in the proximity of great vessels or pericardium, sino-nasal infections, for single cavitary lung lesions which progress despite adequate treatment, for lesions invading the pericardium, bone, invading the subcutaneous or thoracic tissue (60). Pneumonectomy led to successful outcomes in a lung transplant recipient with progressive, refractory angioinvasive aspergillosis whose disease worsened despite conventional antifungal therapy (77). Surgical resection is also indicated for intracranial abscesses depending upon the location, access ability of the lesion and neurologic sequelae. The optimal duration of therapy for invasive aspergillosis depends upon the response to therapy, and the patient's underlying disease(s) or immune status. Treatment is usually continued for 12 weeks, however, the precise duration of therapy should be guided by clinical response rather than an arbitrary total dose or duration. A reasonable course would be to continue therapy until all clinical and radiographic abnormalities have resolved, and cultures if they can be readily obtained do not yield Aspergillus. Reversal of immunosuppression that includes withdrawal of corticosteroids and a decrease in calcineurin-inhibitor agents is an important adjuvant measure to surgical and medical treatment of invasive aspergillosis. Close monitoring of cyclosporine (CsA) or tacrolimus levels and of allograft function is critical. Drug interactions of a number of antifungal agents with immunosuppressants must be carefully considered when treating transplant recipients with invasive aspergillosis. The triazole agents are potent inhibitors of the CYP34A isoenzymes and have the potential to increase the levels of calcineurin-inhibitor agents and sirolimus (78). Itraconazole has been shown to increase CsA or tacrolimus levels by 40–83% (79, 80). A 50–60% reduction in the dose of calcineurin-inhibitor agents may be necessary with the concurrent use of voriconazole (78). The use of sirolimus is contraindicated in patients receiving voriconazole. In some reports, however, the two agents have been safely coadministered with sirolimus dose reduction by 75–90% (81, 82). Coadministration of posaconazole increased CsA exposure and necessitated dosage reductions of 14–20% for CsA (83). Posaconazole increased the maximum blood concentration and the area under the concentration–time curve for tacrolimus by 121% and 357%, respectively (83). The pharmacokinetics of caspofungin is unaltered by coadministration of tacrolimus, but caspofungin may reduce tacrolimus concentrations by up to 20% and may increase CsA A plasma concentrations by 35% (84). Elevated liver function tests in healthy volunteers receiving caspofungin and CsA A lead to the exclusion of CsA recipients from the initial phase II/III clinical studies of caspofungin (84). In clinical setting however, coadministration of caspofungin with CsA A has been well tolerated (85-87). Nevertheless, it is prudent to monitor hepatic enzymes in CsA recipients treated with caspofungin. There is no interaction between caspofungin and mycophenolate mofetil. Anidulafungin clearance is not affected by drugs that are substrates, inducers or inhibitor of cytochrome P450 hepatic isoenzymes (88). Further, because the drug is negligibly excreted in the urine, drug–drug interactions due to competitive renal elimination are unlikely (88, 89). Coadministration with tacrolimus documented no pharmacokinetic interaction between the two agents (89). When administered with CsA A, a small (22%) increase in andifulafungin concentration was observed after 4 days of dosing with CsA A and was not considered to be clinically relevant (89). Micafungin is a weak substrate and a mild inhibitor of the CYP3A enzyme, but not of P-glycoproteins (90). In healthy volunteers, micafungin was shown to be a mild inhibitor of CsA levels (90, 91). In patients receiving sirolimus, serum concentrations of this agent was increased by 21% with concomitant use of micafungin (92). No drug interactions have been noted between micafungin and mycophenolate mofetil, or CsA (90). Enhancement of the host's immune status with immunomodulatory agents is a potentially attractive therapeutic adjunct in the management of invasive aspergillosis. Evidence from in vitro and animal studies has shown enhanced antifungal activity with cytokine or colony stimulating factors, and modulation of cellular immune responses (93-95). Granulocyte-colony stimulating factor (G-CSF) stimulates proliferation and maturation of committed myeloid precursor cells and also augments neutrophil functions including chemotaxis, phagocytosis and oxidative responses (95, 96). Granulocyte macrophage colony stimulating factor (GM-CSF) stimulates the proliferation and differentiation of multiple lineages of cell such as neutrophils, eosinophil and monocyte progenitor cells (97). G-CSF or GM-CSF has been shown to be effective for invasive aspergillosis as adjuvant therapy for invasive fungal infections in some studies in patients with hematologic malignancies (98). Although GM-CSF use in SOT recipients appears to be safe, there are no studies that have evaluated its efficacy as adjunctive antifungal therapy specifically in these patients. In vitro studies have also demonstrated a potential role of interferon-γ (IFN-γ) against Aspergillus (99-102) and case reports in hosts other than SOT recipients have documented possible beneficial effects of the adjunctive use of IFN-γ in invasive fungal infections, including invasive aspergillosis (103-106). Guidelines of the IDSA suggest a role for IFN-γ as adjunctive antifungal therapy for invasive aspergillosis in immunocompromised nonneutropenic host (60). The use of this cytokine in organ transplant recipients is of concern however, given the risk of potential graft rejection. Presently, prophylaxis against invasive aspergillosis is not routinely recommended in all SOT recipients. A more rational approach is to target antifungal prophylaxis toward high-risk patients such as lung transplant recipients and high-risk liver recipients. Clinical trials of antifungal prophylaxis in liver transplant recipients have comprised small sample sizes in single center studies. An optimal approach to the prevention of invasive fungal infections in these patients, therefore, has not been defined. A meta-analysis of antifungal prophylactic trials in liver transplant recipients documented a beneficial effect on morbidity and attributable mortality, but an emergence of infections due to non-albicans Candida spp. in patients receiving antifungal prophylaxis (107). Because the risk factors and the period of susceptibility to invasive fungal infections is clearly definable, antifungal prophylaxis targeted toward these high-risk patients is also deemed a rational approach for the prevention of invasive aspergillosis after liver transplantation. Targeted antifungal prophylaxis using the lipid formulations of amphotericin B in doses ranging from 1 to 5mg/kg/day has been shown to be effective in observational studies (18, 108-110). The availability of echinocandins with their good tolerability and safety profile has led to an expanded armamentarium of antifungal drugs with a potentially promising role as agents for targeted prophylaxis for invasive fungal infections in high-risk liver transplant recipients (111). Currently, targeted prophylaxis in liver transplant recipients is employed most frequently during the initial hospital stay or for the first month posttransplant (72). Given the potential for significant drug interactions with the immunosuppressive agents, the role of newer triazoles as antifungal prophylaxis in high-risk liver transplant recipients has not yet been defined. The choice of antifungal regimen should also take into consideration that a vast majority of invasive mycoses even in these high-risk patients are due to invasive candidiasis for which fluconazole is an appropriate approach for preventive therapy. An optimal antifungal prophylactic strategy in lung transplant recipients still remains to be determined. Current practices of antifungal prophylaxis in lung transplant recipients are derived from nonrandomized clinical trails of inadequate sample sizes, single center noncomparative case series or case control studies (26, 112-118). Although all but one study (119) have employed universal antifungal prophylaxis, a more rational approach would be to use a risk stratification strategy for antifungal prophylaxis. To date, no data exist on the preemptive treatment of invasive aspergillosis based on positive galactomannon in serum or bronchoalveolar lavage in lung transplant recipients. Among the antifungal drugs, aerosolized amphotericin B allows the direct administration of the drug into the transplanted lung, avoiding systemic side effects and drug–drug interactions. Its use however, is limited by tolerability. Common side effects include cough, bronchospasm and nausea. Amphotericin B deoxycholate and the lipid formulations (lipid complex and liposomal) have been shown to be safe and well tolerated (113, 120); however, aerosolized amphotericin B lipid complex was associated with fewer side effects (113). A disadvantage of aerosolized amphotericin B is the fact that distribution in single lung transplant recipients occurs preferentially in the allograft, with unreliable distribution in the native lung, which could remain as a source of infection (121). It is also important to note that use of aerosolized amphotericin B may fail to prevent systemic fungal infections such as candidemia and pleural candidiasis in lung trasnplant recipients (122). Moreover the data on the long-term safety of aerosolized preparations of amphotericin B is not available. Triazoles including, itraconazole and voriconazole have been shown to decrease the rate of invasive aspergillosis in lung transplant recipients. In one study using voriconazole prophylaxis, liver enzyme abnormalities developed in more than 40% of the patients (26). Itraconazole may be less hepatotoxic than voriconazole in lung transplant recipients receiving antifungal prophylaxis (123). Because of interactions with calcineurin inhibitors, levels of the immunosuppressive agents need to be measured and doses adjusted routinely when voriconazole is used concomitantly. Within recent years, there has been an increase in the number of agents available for the treatment of systemic fungal infections. However, most of the available data on new antifungal agents apply to adult patients. It has been well established that data from adult patients cannot be reliably extrapolated to infants and children due to differences in pharmacokinetic and toxicity profiles. For example, children have a higher capacity for elimination of voriconazole and as such higher doses are required compared with adults. To this end, studies are in progress that are aimed at providing more pediatric pharmacokinetic data that will allow for the use of several newer agents in infants and young children. For older children (>12–13 years of age), adult dosing strategies are often used. Table 3 summarizes currently available agents for use in the treatment and prevention of aspergillus infection in children. Clinicians need to be aware for data that are emerging for several newer agents, including posaconazole and anidulafungin, among others. As such the precise place of these agents in the management of pediatric aspergillosis is yet to be fully defined. The infectious diseases consult service should always be engaged when children are being treatment for invasive aspergillosis after organ transplantation. These recommendations are primarily intended for the first year following the lung transplant. No definite recommendation can be made for the later years of lung transplantation due to the lack of existing data. Based on the current literature, it is reasonable to initiate antifungal prophylaxis if any one of the following risk factors are present in lung transplant recipients (II-2): Pretransplant Aspergillus colonization Posttransplant Aspergillus colonization within a year of transplant Antifungal prophylaxis against invasive aspergillosis may be considered if more than one of the following risk factors are present in lung transplant recipients (II-3, III): Early airway ischemia Induction with alemtuzumab or thymoglobulin Single lung transplant CMV infection Rejection and augmented immunosuppression (particularly use of monoclonal antibody posttransplant) Acquired hypogammaglobulinemia (IgG level <400 mg/dL) Use of serum galactomannnon for the screening of invasive apsergillosis is not recommended in lung transplant recipients (II-2). Use of bronchoalveolar lavage galactomannon as a screening tool for the diagnosis of invasive aspergillosis may be used in centers where the incidence of apsergillosis is higher than 6% (II-2). No recommendation can be made about the reinitiation of prophylaxis after 1 year of lung transplant. With regards to the choice of the drug and duration of antifungal prophylaxis against Aspergillus in lung transplant recipients following recommendation are made. Inhaled amphotericin B or lipid preparation of amphotericin B can be used postoperatively in patients with a risk of developing invasive aspergillosis. Caution should be exercised in single lung transplant recipients (II-2). The dosage of amphotericin B may vary from 20 mg t.i.d. to 25 mg q day. The duration of prophylaxis should be guided by interval airway inspection, respiratory surveillance fungal cultures and clinical risk factors. Nebulized ABLC can be used at a dose of 50 mg once every 2 days for 2 weeks and then once per week for at least 13 weeks (II-3). Nebulized ambisome can be administered as 25 mg 3 times/week for 2 months, followed by weekly administration for 6 months and twice per month thereafter (II-3). In high-risk lung transplant recipients, systemic antifungal agents active against Aspergillus such voriconazole or itraconazole can be used for prophylaxis. The recommended duration is 4 months (II-2). Liver enzymes should be monitored to assess the hepatic toxicity. Further continuation of the prophylaxis should be guided by the continued existence or emergence of a new risk factor of invasive aspergillosis upon evaluation of transplant recipients. Heart Transplant Recipients Targeted prophylaxis with itraconazole or voriconazole 200 mg b.i.d. for 50–150 days is recommended in recipients with one or more of the following risk factors (II-3): Isolation of Aspergillus species in respiratory tract cultures Reoperation CMV disease Post transplant hemodialysis Existence of an episode of invasive aspergillosis in the program 2 months before or after heart transplant Liver Transplant Recipients Targeted prophylaxis with a lipid formulation of amphotericin B in dosages ranging from 3 to 5 mg/kg/day (II-2) or an echinocandin (II-3) may be considered in patients with any of the following high-risk factors: Retransplantation (second or third liver transplant). Renal replacement therapy (hemodialysis or continuous venovenous dialysis) pre- or posttransplantation. Reoperation involving thoracic or intraabdominal cavity, for example, exploratory laparotomy or any intrathoracic surgery. Transplantation for fulminant hepatic failure. Other Solid Organ Transplant Recipients There are insufficient data to routinely recommend anti-Aspergillus prophylaxis in other solid organ transplant recipients. Singh N.: Grant Support, Pfizer. Husain S.: Grant Support, Pfizer, Schering Plough, Merck Frost, Astellas.