Aspergillus is the most common cause of fungal infection following lung transplantation, with incidence rates as high as 40.5 cases/1000 patient-years (Minari, 2002). Manifestations of aspergillosis in the lung transplant recipient include classic nodular pneumonia and, unique to lung transplant, ulcerative tracheobronchitis/anastamotic site infection (TBA) (Gordon, 2001; Kramer, 1991). Tracheobronchitis is reported to occur in approximately 5% of lung transplant recipients and have a response rate to antifungal therapy of 71-82% (Mehrad, 2001; Paterson, 1999). Pulmonary aspergillosis has a much worse outcome than TBA, with a response rate of 26-41% in the largest reported series (Mehrad, 2001; Paterson, 1999). As with all invasive aspergillosis, A. fumigatus is the most common pathogen, however other pathogenic species such as A. terreus and A. flavus cause disease as well. Epidemiology of aspergillosis in lung transplant recipients is fairly well-defined; the challenge remains both diagnosis and treatment of this disease.
Risk Factors
Many unique risk factors in lung transplant patients lead to a higher risk of aspergillosis than other solid organ transplant (SOT) recipients. Lung transplant recipients typically remain on higher doses of immunosuppression for longer periods of time than other SOT recipients. The transplanted lung is at risk of many infections as it is exposed to inhaled pathogens; additionally, the lung transplant recipient has difficulty clearing inhaled pathogens due to an impaired cough reflex resulting from denervated lung. Additional risk is incurred from pre- transplant colonization, particularly in the cystic fibrosis patient and in the native lung of single lung transplant recipients. The relative risk of aspergillosis after lung transplantation is not uniform. For cystic fibrosis patients colonized with Aspergillus pre-transplant, the risk of tracheobronchitis is approximately 25%, as demonstrated by several retrospective cohort analyses (Avery, 2004; Helmi, 2003; Nunley, 1998). This unique risk leads to recommendations for frequent early surveillance bronchoscopies to examine the anastomotic site, as well as the use of inhaled antifungal prophylaxis (see below).
Additional risk factors for invasive aspergillosis in lung transplantation are common to risks of invasive aspergillosis in other SOT recipients including CMV infection, use of high-dose corticosteroids, and use of anti-T cell immunotherapy (OKT3, RAT-G). Chronic rejection (bronchiolitis obliterans) is also a risk factor for the development of aspergillosis. Recipients of single lung transplants (overwhelmingly for chronic obstructive pulmonary disease) are at risk for aspergillosis in the native lung. Aspergillosis in the native lung typically occurs later (median 5.2 months after transplantation) and this type of invasive aspergillosis (IA) is associated with a higher mortality than IA in other lung transplant recipients (Singh, 2003).
Manifestations of disease
Tracheobronchial aspergillosis (TBA): TBA is unique to lung transplant recipients and manifests in a range of symptoms from simple bronchitis, obstructing bronchial aspergillosis, ulcerative tracheobronchitis to necrotizing pseudomembranous TBA with bronchopleural fistulae. In a large review of aspergillosis in lung transplant recipients, TBA was the most common form of aspergillosis, occurring in 45/78 (58%) of the reported cases of Aspergillusinfections among lung transplant recipients (Singh, 2003). Episodes of ulcerative tracheobronchitis typically occur one to three months post transplant and are noted on routine bronchoscopy (Paterson, 1999).
Mortality rates in cases of TBA can be up to 24%. TBA may also progress to disseminated disease. It is rarely accompanied by fever (Singh, 2003).
Pulmonary Disease: Pulmonary aspergillosis generally occurs later than TBA. The median time to diagnosis of IA is approximately 6 months post-transplant (Pappas, 2003). Unlike other types of SOT recipients, lung transplant recipients may develop IA even after the first year post transplant.
Disseminated Disease: Like IA in other immunocompromised hosts, lung transplant recipients may suffer from disseminated disease. In a large series of lung transplant patients with IA, disseminated disease comprised 22% of cases (Singh, 2003). The most typical site of dissemination is the central nervous system. As with all cases of documented pulmonary aspergillosis, one should perform either CT scan or MRI of the central nervous system to evaluate for dissemination.
Diagnosis
Tracheobronchial aspergillosis: TBA generally occurs early post transplant, and is most often diagnosed by routine surveillance bronchoscopy. Particular note should be taken of risk factors, including pre-transplant Aspergillus colonization and lack of early fungal prophylaxis. Fever is a rare manisfestation of TBA (Singh, 2003). Bronchoscopic exam may reveal erythema, pseudomembranes or ulcerations. Data is sparse on the performance of serum antigen testing as an adjunct to the diagnosis of TBA.
Pulmonary Aspergillosis: History, including that of prior colonization and a comprehensive assessment of associated risk factors (exposure, CMV infection, recent rejection) is the first step in diagnosis. Symptoms include fever, cough and dyspnea. Physical exam may reveal fever and changes in the pulmonary exam, such as crackles or rhonchi. Radiographic imaging (CT scan) and bronchoscopy with culture remain the cornerstone of diagnosis, with perhaps an emerging role for serum galactomannan testing (see below). Radiographically, the presentation can range from consolidation (40%) to cavitary lesions (30%) to nodular or mass-like lesions (30%) (Singh, 2003). Bronchoscopy with culture has been reported to have a sensitivity ranging from 17-58% for the diagnosis of invasive disease (Horvath, 1996; Perfect, 2001).
The future of Aspergillus diagnostics will likely include Aspergillus PCR on both serum and BAL samples (Musher, 2004). Some experts have evaluated the role of galactomannan andAspergillus PCR testing on bronchoalveolar lavage fluid (Klont, 2004; Musher, 2004; Sanguinetti, 2003). Although this is not routinely performed at present, this test holds promise for the future of pulmonary Aspergillus detection. At present, however, diagnosis generally relies on a combination of radiography and bronchoscopy with biopsy and culture. The addition of newer diagnostic modalities such as galactomannan antigenemia are promising, but require additional validation in this population, as false positives are a considerable problem. Data is limited in the lung transplant population, however one study evaluated prospective monitoring in a lung transplant population. Prospective monitoring with biweekly galactomannan antigenemia assays had a sensitivity of 30%, a specificity of 93%, a positive likelihood ratio of 4.2 and a negative likelihood ratio of 0.75. False positives typically occurred in the first week post transplant (Husain S, 2004). One should remember that the galactomannan test may detect non-Aspergillus fungi (Wheat, 2003) and have false positive results due to concomitant use of beta-lactam antibiotics, including piperacillin-tazobactam and amoxicillin-clavulanate (Sulahian, 2003; Viscoli, 2004).
Caveats
Aspergillus colonization does occur in lung transplant; the challenge remains prediction of who will go on to develop invasive disease. Frequent routine bronchoscopies performed in the lung transplant patient often leads to the “unexpected” finding of Aspergillus in the BAL culture with no other signs of invasive disease. Data regarding the management and outcome of incidentally discovered Aspergillus is sparse, however in a large series, 20% of patients had evidence of IA on the first positive culture and an additional 6% progressed to invasive disease in the following months (Singh, 2003). Our practice is to treat patients who have incidental findings of A. fumigatus on culture from surveillance bronchoscopy with negative chest imaging with 3 months of oral itraconazole solution (400 mg PO BID x 2 days loading, then 200 mg PO BID) and weekly inhaled ABLC (50 mg), with repeat chest imaging and bronchoscopy at the end of therapy. Colonization with other Aspergillus species is treated on a case-by-case basis, with A. flavus and A. terreus observed more closely that colonization with other Aspergillus species. A large survey of US transplant centers revealed that all centers treated positive Aspergillus cultures if they remained positive a median of 4.5 months (Dummer, 2004).
Prophylaxis
Prophylaxis against IA and TBA is a common practice in lung transplantation, practiced by 76% of US transplant centers (Dummer, 2004). Common prophylaxis regimens include inhaled amphotericin (25 mg/week) or inhaled amphotericin B lipid complex (ABLC) (50mg/week) for up to three months post transplant or itraconazole solution 200 mg PO BID. Prophylaxis has been shown to reduce the incidence of aspergillosis from 18.2% to 4.9% (P < 0.05) at one large US transplant center (Minari, 2002). A regimen of nebulized amphotericin B (6 ml of a 1mg/ml solution) q8 hours for 120 days post transplant and then daily for life has been shown to decrease the incidence of invasive aspergillosis (OR 0.13, 95% CI 0.02 – 0.69) in a cohort of lung transplant patients (Monforte, 2001). Imaging studies using radiolabeled amphotericin B show excellent distribution in patients without bronchiolitis obliterans syndrome; however distribution was not uniform in the small number of BOS patients studied. (BOS) (Monforte, 2003). Prophylaxis during the early post-transplant period is particularly critical to preventing TBA. Inhaled amphotericin B or inhaled ABLC have the advantage of direct delivery to the at-risk anastomotic site. Inhaled ABLC daily for 4 days post transplant and then weekly for 7 weeks following transplant has been shown to be well-tolerated and effective at preventing early disease (Drew, 2004). In high risk patients (i.e. cystic fibrosis patients with prior colonization), extension of prophylaxis to at least 3 months post transplant is prudent. As Aspergillus diagnostics improve, the practice of pre-emptive therapy may replace universal prophylaxis.
Treatment
Tracheobronchial aspergillosis:
Treatment of TBA consists of debridement as well as parenteral and inhaled antifungal therapy. Treatment outcome has been described in a small number of patients Historically, patients have been treated with combinations of intravenous amphotericin B and oral itraconazole (Yeldandi, 1995), aersolized amphotericin B and oral itraconazole (Westney, 1996) and amphotericin B alone (Yeldandi, 1995). Surgical resection and stent placement may be necessary in conjunction with antifungal therapy if dehiscence of the anastomosis occurs (Horvath, 1993). Itraconazole alone appears to be unsuccessful (Kramer, 1991). However, the current era of antifungal therapy has likely made these reports obsolete. Although reports of therapy of TBA with voriconazole are rare (3 patients in a large open label study, one of which was a lung transplant) (Denning, 2002), the performance of this agent in invasive aspergillosis is impressive enough to recommend the use of voriconazole combined with inhaled amphotericin B or ABLC for the treatment of TBA. Inhaled agents are a valuable adjunct as the anastomotic site is devascularized making it difficult for parenteral therapies to achieve therapeutic concentrations. Duration of therapy for TBA is not well studied. Standard of care dictates 3 months of treatment with voriconazole and inhaled amphotericin B or ABLC for uncomplicated cases, however in cases where stents are placed over sites of disease necessitate longer therapy, with consideration of lifelong suppression. Chest X-ray and CT images of TBA and an infected stent can be viewed in the Image Bank section “Airways Aspergillosis”.
Invasive pulmonary aspergillosis and disseminated disease: Voriconazole has quickly become the therapy of choice for invasive aspergillosis. Voriconazole is a FDA-approved derivative of fluconazole with enhanced activity against fluconazole resistant Candida species (C. krusei, C. glabrata) as well as filamentous fungi (Aspergillus species, Fusarium species, manyScedosporium apiospermum isolates, Paecilomyces species, Bipolaris species, and Alternariaspecies) (Johnson, 2003). Although most clinical trial data regarding voriconazole is in patients with hematologic malignancies, reports of success in solid organ transplant patients are available (Denning, 2002; Fortun, 2003). In a series of 84 immunocompromised patients enrolled in a compassionate use protocol for voriconazole, a favorable response was seen in 60% (Denning, 2002). Only six patients in this series were SOT recipients (1 lung transplant). A second compassionate use trial found 20% complete response and 38% partial response among 45 patients treated with voriconazole. Approximately one-third of the patients in this series were SOT recipients (Baden, 2003). As these were compassionate use trials, they encompassed patients who were heavily pre-treated with amphotericin B products. A comparative trial of 394 patients given amphotericin B versus voriconazole for primary treatment of aspergillosis also noted an improved response rate (survival at 12 weeks 70.8% in voriconazole group versus 57.9% in amphotericin B group) as well as a significant improvement in the probability of survival (Herbrecht, 2002). Again, only 14 patients in this trial were solid organ transplant recipients and most patients had a hematologic malignancy as their underlying disease.
Voriconazole is available in both an intravenous and oral formulation and demonstrates wide tissue distribution including the central nervous system. Significant drug interactions can occur with voriconazole due to its inhibition of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A4 (Pearson, 2003). Interactions with the calcineurin inhibitors is significant, with experts recommending a 50% decrease in dose of either cyclosporine or tacrolimus with close monitoring of drug levels (Johnson, 2003). Sirolimus is contraindicated during voriconazole therapy, however one investigator reported successful use in 2 renal transplant recipients following a 75-87.5% dose reduction of sirolimus (Mathis, 2004). Physicians should be aware of other drug-drug interactions involving voriconazole as well, including interactions with HMG-CoA reductase inhibitors and warfarin (Johnson, 2003; Purkins, 2003d). Unlike itraconazole tablets, the absorption and kinetics of voriconazole are not affected by decreases in gastric acid (Purkins, 2003b; Wood, 2003). Voriconazole does not affect the steady-state kinetics of digoxin (Purkins, 2003c), however phenytoin decreases the mean steady-state and area under the curve (AUC) of voriconazole. This can be ameliorated by increasing the voriconazole dose to 400 mg BID. Conversely, phenytoin levels are increased by 80% with co-administration of voriconazole; therefore monitoring and dose adjustment should occur (Purkins, 2003a). Side effects of voriconazole include reversible changes in color vision, rash/photosensitivity, and transaminase elevation.
Voriconazole is administered as 400 mg IV/PO q12 hours for 4 doses then 200 mg IV/PO q12 hours thereafter, with standard treatment duration of 3 – 6 months, depending on clinical, radiographic and culture response.
Alternatives to voriconazole therapy include the echinocandin antifungals caspofungin, micafungin, and anidulafungin. Caspofungin is currently approved for use in the US, although micafungin and anidulafungin are not. As a class, echinocandins are lipopeptides that inhibit β-(1à3) glucan synthesis, an important part of the fungal cell wall. These agents are fungistatic against moulds. Caspofungin is available parenterally and is typically administered as a 70 mg loading dose followed by a 50 mg/day maintenance dose. Dose reduction to 35 mg/day is recommended in patients with significant hepatic dysfunction. A major advantage of caspofungin is its relative paucity of drug interactions. However, potentially important reactions with immunosuppressive agents must be noted. Caspofungin levels are increased by 35% when co-administered with cyclosporine A, and healthy volunteers experienced elevations in transaminases when these drugs were co-administered. . The caspofungin package insert encourages the close monitoring of liver function if the benefit of co-administration of the two drugs is deemed to outweigh the risk. Tacrolimus levels are decreased by 20% by caspofungin and should also be monitored. There are no noted interactions with mycophenolate (Sable, 2002). Notably, only small amounts of caspofungin accumulate in the urine.
There are no published randomized trials comparing caspofungin to other antifungal agents for the treatment of IA and, as with voriconazole, the bulk of clinical data regarding caspofungin for the treatment of aspergillosis is in patients with hematologic malignancies. Salvage therapy trials note a favorable response to caspofungin in 37/83 (45%) of patients refractory to or intolerant of amphotericin B products (Maertens J, 2002). In this trial, 11% of patients were solid organ transplant recipients. There is a case report of successful salvage therapy with caspofungin for a heart-lung transplant recipient with IPA (Carby, 2004).
Additional alternative therapies include amphotericin B and lipid amphotericin B products. Posaconazole, an advanced-generation triazole, may represent an option for patients intolerant of voriconazole. Posaconazole does not offer specific therapeutic advantages over voriconazole for the treatment of aspergillosis, but does not share the side-effects of photosensitivity and color-vision changes. Posaconazole has been reported to have successfully cured one case of disseminated aspergillosis in a lung transplant recipient (Lodge, 2004). Combination parenteral therapy for invasive aspergillosis in lung transplant patients has not been evaluated at present.
Aimee Zaas MD
Associate ProfessorÂ
Department of Medicine
0557 Hospital South
Box 3353 DUMC
Durham, N.C. 27710
USA