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(Chest. 2003;123:800-808.)
© 2003 American College of Chest Physicians

Aspergillus Infection in Lung Transplant Recipients With Cystic Fibrosis*

Risk Factors and Outcomes Comparison to Other Types of Transplant Recipients

Mohamed Helmi, MD; Robert B. Love, MD, FCCP; Debbie Welter, RN; Richard D. Cornwell, MD and Keith C. Meyer, MD, FCCP

* From the Department of Medicine (Drs. Helmi, Cornwell, and Meyer), Section of Pulmonary and Critical Care Medicine, and the Department of Surgery (Dr. Love and Ms. Welter), Section of Cardiothoracic Surgery, University of Wisconsin, Madison, WI.

Correspondence to: Keith C. Meyer, MD, FCCP, Department of Medicine, K4/930 Clinical Sciences Center, 600 Highland Ave, Madison, WI 53792-9988; e-mail: kcm{at}medicine.wisc.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To characterize Aspergillus infections in lung transplant recipients with cystic fibrosis (CF).

Design: A retrospective analysis of 32 consecutive lung transplant recipients with CF who underwent bilateral lung transplant at the University of Wisconsin from 1994 to 2000 to determine the incidence, risk factors, and consequences of Aspergillus infection. The findings were compared to 101 non-CF recipients of lung transplants (93) and heart-lung transplants (8) for other transplant indications.

Setting: A university hospital.

Patients or participants: Lung transplant recipients with CF or other indications for transplantation.

Interventions: None.

Measurements and results: Seventeen of 32 CF recipients (53%) had Aspergillus fumigatus isolated from their respiratory secretions prior to undergoing transplantation. Ten of these 17 (59%) recipients had A fumigatus persistently found in their respiratory secretions posttransplant vs 6 of 15 CF patients (40%) who had not been colonized pretransplant and 28 of 101 of the non-CF recipients (28%). Four of the preoperatively colonized CF recipients developed tracheobronchial aspergillosis (TBA) just distal to the bronchial anastomoses, and one recipient had dehiscence of the involved anastomosis. None of the CF recipients developed disseminated aspergillosis or pneumonia. Prophylactic antifungal therapy did not prevent TBA, and IV amphotericin B therapy was required to clear the infection in all four patients, with endobronchial debridement of necrotic tissue required in two of them. In contrast, 10 of the non-CF (10%) recipients developed Aspergillus infections posttransplant (TBA, 4 recipients; pneumonitis, 6 recipients), and only 3 patients had successful treatment and long-term survival (TBA, 2 patients; pneumonia, 1 patient). Donor lung ischemia time, cytomegalovirus infection or pneumonia, or pretransplant mechanical ventilation did not increase the risk of developing TBA in CF recipients.

Conclusions: The risk of TBA for patients receiving lung transplants for CF warrants early surveillance bronchoscopy to detect TBA, particularly in recipients with pretransplant colonization.

Key Words: Aspergillus • respiratory tract infection • lung transplantation


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Fungal infections can be a serious and often fatal complication of lung transplantation. Aspergillus fumigatus frequently colonizes the respiratory tract of patients with cystic fibrosis (CF),1 and the prevalence of Aspergillus spp in sputum has been reported to be as high as 63% in patients being considered for lung transplantation.2 Patients with CF may develop allergic bronchopulmonary aspergillosis3 4 or aspergillomas,5 but Aspergillus rarely causes invasive respiratory mycosis in patients who are not immunocompromised. Posttransplant immunosuppression therapy, however, places transplant recipients with CF at increased risk for opportunistic fungal infection. Pulmonary aspergillosis is the most frequently observed fungal infectious complication of heart-lung or isolated lung transplantation,6 7 8 and invasive infection is often fatal. A fumigatus is the species usually isolated from the respiratory secretions or tissues of recipients who develop aspergillosis.8 Airway colonization, tracheobronchial aspergillosis (TBA), aspergilloma, pneumonia, and disseminated infection due to A fumigatus all have been observed in lung transplant recipients.7

Various case series have been reported in the literature that have examined the incidence of posttransplant A fumigatus infection,6 7 8 9 10 11 12 13 14 15 16 17 and respiratory tract colonization with A fumigatus has been identified as a risk factor for developing posttransplant pulmonary aspergillosis.9 10 11 Although immediate prophylactic postoperative antifungal therapy with nebulized amphotericin B, oral imidazoles, or both18 19 20 21 has been reported to diminish the likelihood of infection posttransplant in groups of recipients with diverse indications for lung transplantation, the data supporting the efficacy of these strategies are limited.

The currently available data do not conclusively define the risk factors that predispose lung transplant recipients with CF to pulmonary aspergillosis or recommend a clearly effective approach to preventive prophylactic therapy. Because large numbers of young adult patients with CF have respiratory tract colonization with Aspergillus, we analyzed the records of 32 consecutive patients with CF who received bilateral lung transplants at the University of Wisconsin (UW) to determine the incidence of preoperative and postoperative A fumigatus colonization, the incidence and nature of postoperative A fumigatus infection, and the risk factors for postoperative pulmonary aspergillosis. We compared our findings on postoperative colonization and infection in our recipients with CF to that of 101 consecutive patients who underwent transplantations for other indications.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient Population
We retrospectively analyzed the data from all consecutive primary lung transplants (125) and heart-lung transplants (8) that had performed at UW between 1988 and September 2000. Thirty-two recipients had CF, and 9 of these 32 patients had been receiving mechanical ventilation prior to transplantation due to ventilatory failure. All records were reviewed for microbiological examination of respiratory secretions, operative reports, pretransplant and posttransplant antifungal therapies, bronchoscopic procedure reports, surveillance BAL culture and lung biopsy reports, autopsy reports, and causes and time of death. All patients with CF had at least three cultures of respiratory secretions prior to transplant, but patients who had undergone transplantations for other indications usually had their respiratory secretions cultured only if they had a history of productive cough. All respiratory tract secretions were cultured in the Clinical Microbiology Laboratory of the UW Hospital and Clinics.

One hundred thirty-three patients received 141 lung transplants at our institution between October 1988 and September 2000. All of the 32 recipients with CF, who comprised a subset of these 141 recipients, received bilateral lung transplants between February 1994 and September 2000. Sixty-three non-CF patients received single-lung transplants, 30 received bilateral lung transplants, and 8 underwent heart-lung transplants (Table 1 ). Other data including age, sex, and transplant indication are given in Table 1 .


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  		Table 1. Demographics of the Study Population*

 
Transplant recipients were considered to be colonized if A fumigatus was isolated from respiratory secretions on two or more specimens that included expectorated or induced sputum, tracheal aspirates from patients with tracheostomy, or BAL fluid. TBA was defined as (1) the presence of extensive necrosis with ulceration and purulent secretions just distal to the bronchial anastomosis, and (2) the presence of invasive or semi-invasive A fumigatus found in endobronchial biopsy specimens from the affected area confirmed by positive cultures of endobronchial secretions and/or tissue. Aspergillus pneumonia was defined as the presence of radiologically progressive infiltrates that were compatible with pulmonary aspergillosis accompanied by the isolation of A fumigatus from respiratory secretions, a lack of clinical or radiologic improvement in response to broad-spectrum antibacterial chemotherapy, the presence of metastatic A fumigatus infection, or the identification of aspergillosis on postmortem examination.

Ischemia time for the donor lung was obtained from the transplant operative procedure notes and the transplant records. The ischemic times for the comparison groups were determined as the minutes from harvest to reperfusion for individual lungs or the average times to the reperfusion of both lungs. Cytomegalovirus (CMV) infection without pneumonia was defined as the presence of positive shell vial cultures for CMV from respiratory secretions in the absence of pneumonitis and CMV inclusion bodies found in transbronchial lung biopsy specimens, and CMV pneumonia was defined as the presence of CMV inclusion bodies in transbronchial lung biopsy specimens.

Lung Transplant Protocols
The maintenance immunosuppressive regimens were cyclosporine-based or tacrolimus-based. The initial target trough cyclosporine levels were 300 to 350 ng/mL as determined by a diagnostic monoclonal whole-blood assay (Toshiba; Tokyo, Japan), and they tapered to 250 to 300 ng/mL at 26 weeks posttranpslant. The initial trough tacrolimus target levels were 10 to 15 ng/mL with subsequent tapering to 5 to 10 ng/mL at 6 to 12 months posttransplant. All recipients also received therapy with azathioprine (initially 2 mg/kg and subsequently titrated to blood leukocyte counts between 3,500 and 8,500 cells/µL) and prednisone (0.3 mg/kg daily initially tapered to 0.05 mg/kg daily by 6 to 9 months posttransplant). IV antibiotic agents were administered in the early posttransplant period based on the pretransplant flora that were present in native and/or transplanted grafts and on the early results of posttransplant cultures of respiratory secretions. Ganciclovir was administered to nearly all recipients for CMV prophylaxis, and CMV Ig was administered to high-risk recipients or recipients with active CMV infection. Trimethoprim-sulfamethoxazole (or nebulized pentamidine for sulfa-allergic recipients) and topical clotrimazole were administered to all recipients, and inhaled nebulized antibacterial or antifungal agents were administered to selected patients. Beginning in early 1995, all recipients were given therapy with prophylactic fluconazole (100 mg) IV for the first week following transplantation. All but the first two CF patients who underwent transplantation at our center received prophylactic fluconazole.

Initial postoperative surveillance was intense with at least daily spirometry following extubation until hospital discharge. Patients were subsequently monitored with daily spirometry and with frequent blood sampling to monitor drug levels and leukocyte counts. Pulmonary function testing was intermittently performed in the hospital pulmonary function laboratory by registered pulmonary function technologists adhering to American Thoracic Society criteria, and any decline in lung function detected via home monitoring was verified and quantitated in the pulmonary function laboratory. Surveillance bronchoscopy with BAL and transbronchial biopsy were obtained to detect infection, and transbronchial biopsies were performed to detect allograft rejection or infection. Bronchoscopy with BAL and transbronchial biopsy were typically performed at 10 to 14 days and at 30 days following transplantation for many of the transplant recipients. Additional BAL and transbronchial biopsies typically were performed at 3, 6, 9, and 12 months during the first year after transplantation and also for clinical indications at any time point. BAL fluids were examined for the presence of aerobic bacteria, fungi, Pneumocystis carinii, mycobacteria, CMV, and other pathogenic viruses. Total and differential cell counts were performed as previously described.22 Bronchiolitis obliterans syndrome (BOS) was defined as a > 20% decline in FEV1 from the best posttransplant value that did not improve despite enhanced immunosuppression, and acute rejection or obliterative bronchiolitis were diagnosed via transbronchial lung biopsy using the histologic criteria of Yousem et al.23

Measurements of Outcome and Statistical Analysis
We attempted to define the factors that predispose transplant recipients with CF to the development of TBA, including pretransplant colonization of the respiratory tract with A fumigatus, donor lung ischemia time, mechanical ventilation at the time of transplantation, or CMV infection. All data were analyzed on electronic spreadsheets (SuperCalc4; Computer Associates; San Jose, CA; and EXCEL; Microsoft, Inc; Redmond, WA) and with a database-statistics package for microcomputers (Abstat 4.1; Anderson-Bell, Parker, CO; and SAS; SAS Institute; Cary, NC). The values are expressed as the mean ± SEM unless otherwise stated. Independent t tests (two-tailed) were performed as appropriate.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The demographics of the recipients are given in Table 1 . The indications for transplantation in the non-CF recipients included 43 patients with emphysema without {alpha}1-antitrypsin deficiency, 15 patients with emphysema with {alpha}1-antitrypsin deficiency, 20 patients with idiopathic pulmonary fibrosis, 3 patients with bronchiectasis, 8 patients with pulmonary vascular disease, and 12 patients with other indications. Retransplantation was performed in six recipients without CF. Sixty-three patients received single-lung transplants, 62 patients received bilateral lung transplants, and 8 patients received heart-lung transplants. As noted in Table 2 , 17 of the 32 patients with CF (53%) had been colonized preoperatively with A fumigatus. Only 6 of the 15 CF recipients who had not been colonized with A fumigatus prior to undergoing transplantation had A fumigatus isolated from their respiratory secretions posttransplant, and this was usually a transient finding. In contrast, 10 of the 17 patients who had been colonized prior to undergoing transplantation had A fumigatus isolated posttransplant, usually repeatedly, although this detection appeared to wane at later time points following transplantation (Fig 1 ). Other fungi were isolated from CF patients (Table 3 ) including one patient who had Blastomyces dermatitidis isolated from BAL fluid that had been obtained during routine surveillance bronchoscopy 4 years after undergoing transplantation.


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  		Table 2. Characteristics of Recipients With CF*

 


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  		Figure 1. Fungal isolates from respiratory secretions posttransplant. Top, A: recipients with CF. Bottom, B: recipients with other transplant indications. N = total number of recipients providing specimens during a given time period.

 

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  		Table 3. Summary of Fungal Isolates From All Recipients

 
All but two recipients with CF have survived for at least 1 year following transplantation. One of the CF recipients who died early had succumbed to bilateral anastomotic breakdown 2 weeks posttransplant but had no evidence of Aspergillus infection, and the other recipient had died of refractory Mycobacterium abscessus infection 4 months posttransplant. Neither of these recipients had been colonized with A fumigatus pretransplant. The other three recipients who had not been colonized with A fumigatus pretransplant but had died of causes unrelated to fungal infection included one who succumbed to obliterative bronchiolitis at 42 months, one who died at 15 months due to medical noncompliance leading to refractory rejection, and one who had an anterior wall myocardial infarction and cerebrovascular accident at 48 months posttransplant. Of the three patients who had been colonized preoperatively and had died postoperatively, one died of obliterative bronchiolitis at 49 months, one died of colon carcinoma at 21 months, and one died of inadequate cyclosporine dosing leading to refractory rejection at 16 months.

Four of the 32 recipients (12.5%) with CF developed TBA following transplantation, and all of the 4 recipients had been colonized with A fumigatus prior to transplant. As noted in Table 4 , TBA was detected in all four recipients within 1 month of their undergoing transplantation, and none of these four individuals had received mechanical ventilation prior to undergoing transplantation. These four subjects developed dusky-appearing, ulcerative areas just distal to the bronchial anastomoses, predominantly involving the medial bronchial walls, and had extensive areas of bronchial ischemia and pseudomembrane formation. Three of the four recipients had these changes bilaterally, but one recipient only had involvement of the right allograft bronchus. All of the four recipients received daily therapy with IV fluconazole for the first week after transplantation, and two recipients began receiving nebulized amphotericin B immediately posttransplant. The two recipients who had not been receiving inhaled nebulized amphotericin B when the lesions were detected immediately began receiving it, and two of the four subjects with TBA also received therapy with oral itraconazole when the lesions were detected. Despite receiving therapy with topical amphotericin B with or without itraconazole, all required the administration of systemic amphotericin B to clear the lesions. The fourth recipient, who had involvement of only the right bronchus, also began receiving systemic amphotericin B therapy but then experienced a dehiscence of the bronchial anastomosis, which required emergent surgical repair. He subsequently finished his course of amphotericin B and did not have any recurrence of aspergillosis. Two of the three individuals with bilateral airway involvement required rigid bronchoscopy with debridement of exuberant granulation tissue, which partially occluded the involved airways for 4 to 6 weeks after the therapy with systemic amphotericin B had been initiated. For the 17 CF transplant recipients who had been preoperatively colonized with A fumigatus, the mean time for ischemia in the allograft airways in which TBA developed (445 ± 44 min; 7 anastomoses) was no different from that in the airways of patients who did not develop TBA (450 ± 23 min; 27 anastomoses). Seven of the 32 recipients with CF developed CMV infection without pneumonia posttransplant, and 2 developed CMV pneumonia. None of the 4 CF recipients with TBA developed CMV pneumonia.


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  		Table 4. Summary of Aspergillus Infections*

 
Seventy-eight of the 101 non-CF recipients survived for at least 1 year posttransplant. Of the 23 recipients who did not survive to 1 year posttransplant, 4 had perioperative deaths, and 19 succumbed to various complications prior to 1 year. Ten serious A fumigatus infections occurred in the 101 recipients with transplant indications other than CF. Four recipients (4%) developed TBA, and six recipients (6%) developed pneumonia. Thirty-four of the non-CF recipients had CMV infection without pneumonia, and 11 developed CMV pneumonia. Only 1 of the 11 recipients with CMV pneumonia also developed pulmonary aspergillosis. Eight of the non-CF recipients had persistent A fumigatus (A fumigatus cultured from multiple sequential BAL specimens), and all developed BOS. None of the non-CF recipients who developed TBA required debridement or dilatation. Anastomotic complications did not occur more frequently in recipients who had A fumigatus isolated from respiratory secretions but no evidence of TBA posttransplant vs those who did not. Individuals who had fungal isolates including A fumigatus found in their respiratory secretions posttransplant, but who were clinically stable with no airway lesions or radiologic abnormalities on chest CT scanning, were not treated for Aspergillus infections. Interestingly, those individuals who had been colonized with fungi (usually A fumigatus) who had no evidence of infection, rejection, or BOS had increased numbers of neutrophils found in their BAL fluid from surveillance bronchoscopy specimens that had been obtained >= 2 months posttransplant when they were clinically stable (Fig 2 ). However, there was no difference in the FEV1 percent predicted values for posttransplant colonized vs noncolonized recipients with CF 1 year following transplant.



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  		Figure 2. Neutrophils in the BAL fluid of patients who have been colonized with fungus (positive culture) but who are clinically stable (>= 2 months posttransplant) without evidence of rejection, infection, or BOS.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Pulmonary aspergillosis, which is a potentially fatal complication of lung transplantation, can be occult and may become apparent only when a serious or fatal complication such as pulmonary hemorrhage occurs.10 24 Due to the direct communication of the lung allograft with the external environment, recipients are prone to colonization of their transplanted lungs with this environmentally ubiquitous organism. Many recipients with CF (and some individuals with other transplant indications) are already colonized with this organism prior to transplantation. Fifty-three percent of our recipients with CF had been colonized pretransplant, and other investigators2 10 12 25 have found a high incidence of A fumigatus colonization in patients with CF who are listed for transplantation. Airway colonization with A fumigatus posttransplant may be related to persistent pretransplant colonization, lung preservation/reperfusion injury, disruption of lymphatic drainage of the lung, depressed mucociliary clearance, impaired cough clearance, the presence of other infections such as CMV or bacterial tracheobronchitis, anastomotic dysfunction, or leukocyte dysfunction. The incidence of posttransplant colonization with A fumigatus was 50% in our recipients with CF and 28% in our non-CF recipients, and a high prevalence of A fumigatus in respiratory secretions posttransplant also has been reported by other lung transplant centers.2 7 8 9 10 11 12 16 24 26 27

Aspergillus infections occurred in 14 of the 133 recipients (11%) whose records we examined, and 4 non-CF recipients died of their infections. Although pneumonia or invasive infection has been reported for recipients with CF,10 12 28 we did not encounter this complication in our cohort of recipients with CF. Fortunately, no deaths occurred as a consequence of Aspergillus pulmonary infection following lung transplantation in our CF patients, but the posttransplant courses of four patients were significantly complicated by TBA. All of these patients had A fumigatus cultured from expectorated sputum prior to transplant, and none had been receiving mechanical ventilation prior to transplantation. Lesions that were suggestive of TBA were visualized in all affected recipients just distal to the bronchial anastomoses. These lesions occurred early following transplantation in all four patients and were characterized by areas of ulceration and pseudomembrane formation that were darkly pigmented. Testing of biopsy specimens from these areas demonstrated Aspergillus infiltrating the bronchial mucosa. These infections occurred despite prophylactic therapy and could not be cleared without the administration of IV amphotericin B.

Although Husni et al13 identified CMV infection as a risk factor for invasive aspergillosis, we could not identify CMV infection, allograft ischemia time, or invasive pretransplant mechanical ventilation as risk factors for Aspergillus infection in either the CF or non-CF recipients. Interestingly, all of the six non-CF recipients who developed Aspergillus pneumonia eventually developed BOS. When we examined total neutrophil concentrations in the BAL fluid of CF or non-CF recipients who had Aspergillus in their secretions (colonization) but lacked evidence of bacterial, viral, or fungal infection and had no evidence of significant rejection or bronchiolitis obliterans on lung biopsy or clinical criteria for BOS, individuals colonized with A fumigatus or other fungi had significantly greater numbers of neutrophils found in their BAL. Although it would be difficult to link Aspergillus colonization to an increased risk of developing BOS, this finding is of some interest, considering the association of increased neutrophil counts in BAL fluids with poorer outcome for lung transplant recipients.29 We did not find any difference in values for FEV1 percent predicted for colonized vs noncolonized (posttransplant) recipients with CF at 1 year following transplantation.

In all of our recipients with CF, tracheobronchial infection occurred in the early postoperative period, a finding that was also reported by Nunley et al10 as an early postoperative complication in their cohort of CF recipients. Pretransplant colonization appeared to be a risk factor for posttransplant TBA in CF recipients, a finding that is similar to that of Nunley et al.10 The presence of A fumigatus in the pulmonary secretions of those recipients who did not develop TBA did not appear to correlate with a greater incidence of airway complications, in contrast to the findings of Nathan et al.11 The endobronchial infection was found bilaterally in three of our four CF recipients, and the systemic administration of amphotericin was needed to clear the infection, accompanied by endobronchial debridement in two patients.

Some lung transplant programs have reported a reduction in posttransplant aspergillosis with the administration of prophylactic antifungal agents. A prophylactic regimen of aerosolized amphotericin B given to 126 heart, heart-lung, or lung transplant recipients significantly reduced the incidence of Aspergillus infections.19 Calvo et al20 reported that fluconazole plus aerosolized amphotericin B in the early postoperative period prevented all fungal infections accompanied by negative results of sputum cultures in all recipients, although some of their recipients appear to have developed Aspergillus infections, and inadequate details were given concerning the length of therapy and surveillance. Patterson et al18 reported that 400 mg itraconazole daily was well-tolerated giving median serum concentrations of 0.5 µg/mL, and none of the 12 subjects treated prophylactically developed invasive aspergillosis. Other centers have reported treating recipients with A fumigatus airway colonization when such colonization was identified posttransplant with imidazole agents alone,7 8 9 26 an imidazole agent in combination with aerosolized amphotericin B,9 12 or aerosolized amphotericin B alone,9 with few patients progressing to TBA or invasive aspergillosis. The treatment of patients with established TBA, as reviewed by Mehrad et al,8 reveals that treatment with itraconazole alone or in combination with aerosolized or systemic amphotericin B can be successful and can prevent progression of the disease to invasive aspergillosis, but the infection progressed to invasive disease in some individuals at various lung transplant centers, even when recipients were treated with systemic amphotericin B. Our experience suggests that TBA cannot be uniformly prevented with the prophylactic administration of nebulized amphotericin B that we employed for many of our recipients with CF, and initial attempts to clear the infection without the use of systemic amphotericin B were unsuccessful.

Because individuals who develop TBA have complicated postoperative courses and are at risk for life-threatening complications such as massive pulmonary hemorrhage or bronchial dehiscence, we feel that aggressive early surveillance utilizing bronchoscopy is mandated in recipients with CF, particularly in those who are colonized with A fumigatus prior to transplantation. Effective prophylactic therapy to prevent this complication of lung transplantation would be quite useful. Preoperative and perioperative therapy with itraconazole may have preventive value, but this has not been definitively demonstrated. Perioperative and early postoperative treatment with systemic amphotericin B would likely give effective prophylaxis, but the potential toxicity of such an approach makes this an unattractive option. Multicenter trials with newer, less toxic antifungal agents with good activity against A fumigatus are needed.

In summary, we have found that TBA occurs early in recipients with CF and can develop despite early postoperative antifungal therapy with aerosolized amphotericin B. In our experience, the TBA, once established in our recipients with CF, did not appear to resolve without systemic therapy with amphotericin B with or without endobronchial debridement of extensive granulation tissue. None of our recipients with CF developed pneumonia or disseminated aspergillosis, in contrast to recipients with other transplant indications. Early surveillance bronchoscopic airway evaluation appears to be essential for the timely detection of TBA, and pretransplant colonization is a risk factor for posttransplant TBA in recipients with CF. It remains to be demonstrated whether more effective posttransplant prophylaxis directed against A fumigatus will decrease the incidence of serious Aspergillus pulmonary infections in both CF and non-CF recipients.


   Footnotes
 
Abbreviations: BOS = bronchiolitis obliterans syndrome; CF = cystic fibrosis; CMV = cytomegalovirus; TBA = tracheobronchial aspergillosis

Presented in part in abstract form at the American Thoracic Society International Meeting in San Diego, CA, April 27, 1999.

Received for publication December 20, 2001. Accepted for publication September 9, 2002.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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