Lung Donation After Controlled Circulatory Determination of Death: A Review of Current Practices and Outcomes.

BACKGROUND: Since the first reported series in 1995, transplantation of lungs recovered through donation after circulatory determination of death (DCDD) has steadily increased. In some European and Australian centers, controlled DCDD accounts for 15% to 30% of all transplanted lungs. Several transplant centers have reported early and midterm outcomes similar to those associated with the use of donors after brain death. Despite these encouraging reports, less than 2% of all lung transplants in the United States are performed using donors after circulatory determination of death. METHODS: An electronic search from January 1990 to January 2014 was performed to identify series reporting lung transplant outcomes using controlled DCDD. Data from these publications were analyzed in terms of donor characteristics, donation after circulatory determination of death protocols, recipients' characteristics, and early and midterm outcomes. RESULTS: Two hundred twenty-two DCDDs were transplanted into 225 recipients. The rate of primary graft dysfunction grade 3 ranged from 3% to 36%. The need for extracorporeal membrane oxygenation support after transplantation ranged from 0% to 18%. The average intensive care unit stay ranged from 4 to 8.5 days and the average hospital stay ranged from 14 to 35 days. Thirty-day mortality ranged from 0% to 11% and 1-year survival from 88% to 100%. CONCLUSION: Under clinical protocols developed and strictly applied by several experienced lung transplant programs, lungs from controlled DCDD have produced outcomes very similar to those observed with brain death donors.

Successful lung salvage by ex vivo reconditioning of neurogenic pulmonary edema: case report.

Liberalization in donor selection criteria allowed centers to increase the number of lung transplants, yet less than 25% of all donors had lungs utilized for transplantation in the United States in 2013. Less than 5% of all transplanted donors deviate 3 or more criteria from the ideal donor. Ex vivo lung perfusion (EVLP) provides the opportunity to increase the percentage of used donors by acting on modifiable selection criteria such as oxygenation, contusion and pulmonary infiltrates. We report the pre-transplant use of EVLP in the salvage of lungs from a donor that developed neurogenic pulmonary edema -PaO2 188 mmHg-. The recipient had a lung allocation score of 69.3. The post-operative course was excellent and was discharged home after 15 days. He is alive and doing well 780 days after transplant. In this report the pre-transplant use of EVLP led not only to transplanting lungs that otherwise would not have been used by many centers, but also to a very short and typical period of post-operative mechanical ventilation and hospital stay.

Preservation of post-transplant lung function with aerosol cyclosporin.

Post-lung transplant use of aerosol cyclosporin (ACsA) is considered by examining the relationship between deposited aerosol dose and effect. In a sub-study of placebo controlled trials of ACsA as a rejection prophylaxis, 15 drug subjects received aerosol dose quantification tests to gage their ability to effectively deposit the nebulised drug in their transplanted lung(s). A total of seven placebo subjects received mock deposition tests. The deposited doses and mock doses were compared to changes in the forced expiratory volume in one second, at six time points during the 2-yr trial period (ACsA was started within 6 weeks post-transplant). Linear relationships were demonstrated between deposited dose and improvement in lung function in the drug subjects at all intervals. Mock dose data from placebo subjects did not demonstrate similar correlation. Based on these results, subjects were grouped by dose and compared. Subjects depositing > or = 5 mg of the drug in the periphery of their transplant(s) had improving pulmonary function on average. Low-dose and placebo subjects demonstrated declines, more A2-A4 rejection events in the latter portion of the trial, and more chronic rejection beyond the end of the trial. A dose-to-effect relationship is demonstrated for aerosol cyclosporin in terms of pulmonary function and biopsy proven rejection.

Aerosol cyclosporin therapy in lung transplant recipients with bronchiolitis obliterans.

The majority of patients who develop bronchiolitis obliterans, after lung transplantation, die within 2-3 yrs after onset since treatment with conventional immunosuppression is typically ineffective. A case/control study was conducted in lung transplant recipients with biopsy-documented bronchiolitis obliterans to determine whether aerosol cyclosporin use contributed to increased survival. The cases comprised 39 transplant recipients who received open-label aerosol cyclosporin treatment in addition to conventional immunosuppression. The controls were transplant recipients treated with conventional immunosuppression alone. There were 51 controls from the University of Pittsburgh Medical Center and 100 from a large multicentric database (Novartis Lung Transplant Database). Forced expiratory volume in one second expressed as a percentage of the predicted value was an independent predictor of survival in all patients with bronchiolitis obliterans. Cox proportional-hazards analysis revealed a survival advantage for aerosol cyclosporin cases compared to the Pittsburgh control group. A survival advantage was also seen when comparing study cases to multicentric controls. Aerosol cyclosporin, given with conventional immunosuppression to lung transplant recipients with bronchiolitis obliterans, provides a survival advantage over conventional therapy alone.

Incidence of clinically unsuspected pulmonary embolism in mechanically ventilated lung transplant recipients.

BACKGROUND: The incidence of pulmonary embolism (PE) in lung transplant recipients has not been well established. The purpose of this study was to describe the incidence of clinically unsuspected PE in a cohort of lung transplant recipients requiring mechanical ventilatory support. These patients underwent surgical lung biopsy (SLBx) for progressive deterioration in the absence of a specific diagnosis. METHODS: We retrospectively reviewed all SLBx pathology reports for mechanically ventilated lung transplant recipients with clinical deterioration, progressive radiographic abnormalities, or both at any time after transplantation. Our objective was to determine the incidence of clinically unsuspected PE in this patient population during an 11-year period. RESULTS: Clinically unsuspected PE was identified in 8 (19.5%) of 41 mechanically ventilated lung transplant recipients after a median of 20 days (interquartile range: 16.3, 148.8 days) after transplantation. There was a tendency for clinically unsuspected PE to occur in the early postoperative period, with the majority of events (75%) occurring within 14 weeks of transplantation. Pulmonary infarction occurred in 37.5% of cases and occurred uniformly during the postoperative period. The finding of pulmonary emboli on SLBx lead to confirmatory investigations in five (62.5%) of eight patients and changed management in seven (87.5%) of eight patients. CONCLUSIONS: A high index of suspicion and reliance on ancillary diagnostic testing may be insufficient to establish the diagnosis of postoperative pulmonary emboli. PE is an underappreciated complication contributing to respiratory failure in the early postoperative period in lung transplant recipients, warranting identification of putative risk factors and consideration for prophylaxis.

Diagnostic properties of transbronchial biopsy in lung transplant recipients who require mechanical ventilation.

INTRODUCTION: Bronchoscopy with transbronchial biopsy (TBBx) and bronchoalveolar lavage is useful and safe for diagnosing acute rejection and infection in lung transplant recipients. However, its role is less well defined in determining the etiology of allograft dysfunction in the setting of respiratory failure necessitating mechanical ventilation. METHODS: We retrospectively identified 41 mechanically ventilated patients with respiratory failure in whom 42 TBBx were followed within a 10 day period by surgical lung biopsy (SLBx) to determine the sensitivity, specificity, and positive and negative predictive values of TBBx compared with SLBx. RESULTS: The sensitivity, specificity, and positive and negative predictive values of TBBx for all episodes of acute rejection and for significant episodes of acute cellular rejection were 53.3% and 36.0%; 91.7% and 94.1%; 94.1% and 90.0%; 44.0% and 50.0%, respectively. A significantly higher histologic grade was noted on SLBx compared with TBBx specimens obtained within a 10-day period (2.39 +/- 1.02 vs 0.97 +/- 0.11, p

Improving drug delivery from medical nebulizers: the effects of increased nebulizer flow rates and reservoirs.

Drug delivery from jet nebulizers can be considered in terms of the dose inhaled and the respirability of that dose. It is proposed that dose respirability and dose per breath can be controlled through specification of the driving gas flowrate, and that the dose inhaled per breath can also be increased through the use of nebulizer reservoirs. When a Hudson Micromist nebulizer was used and assessments of respirability were made utilizing phase Doppler interferometry, it was noted that the portion of the spray mass in droplet sizes of

Neutrophils, unopposed neutrophil elastase, and alpha1-antiprotease defenses following human lung transplantation.

Neutrophils are sequestered in the newly transplanted lung after reperfusion or with infection, rejection, and chronic graft dysfunction. Because unopposed (free) neutrophil elastase (NE) released into bronchoalveolar secretions may injure the lung allograft and impair bacterial clearance, we assessed total neutrophil numbers, myeloperoxidase activity as an index of neutrophil influx and degranulation, alpha1-antiprotease (alpha1-AP) concentrations, and unopposed NE activity in bronchoalveolar secretions from lung transplant recipients. Unopposed NE activity was present in bronchoalveolar lavage fluid (BALF) from recipients transplanted for emphysema associated with alpha1-AP deficiency as well as recipients without such deficiency (171 of 2,137 BALF; 8%). Ten of 17 (59%) recipients with alpha1-AP deficiency who were followed for at least 1 yr after transplant with multiple surveillance and diagnostic bronchoscopies had at least one BALF containing unopposed NE, usually associated with the presence of > or = 10(5) colony forming units/ml BALF of aerobic bacteria. In contrast, 19 of 58 (33%) with emphysema not associated with alpha1-AP deficiency, 8 of 32 (25%) recipients with cystic fibrosis (CF), 6 of 16 (38%) with idiopathic pulmonary fibrosis (IPF), and 11 of 36 (31%) with other indications for transplant had unopposed NE in BALF. alpha1-AP levels were significantly elevated in the early posttransplant time period and could be augmented considerably in alpha1-AP-deficient recipients with episodes of infection or rejection. Our findings indicate that unopposed NE activity can be found in both alpha1-AP-deficient and alpha1-AP-sufficient recipients after transplantation, usually in association with endobronchial bacterial infection.

Dactylaria gallopava infection presenting as a pulmonary nodule in a single-lung transplant recipient.

We describe the first case of a pulmonary nodule caused by Dactylaria gallopava in a lung-transplant recipient. An asymptomatic lung-allograft recipient was found to have a 2-cm nodule in the native lung 450 days after transplantation. Culture of a transthoracic needle biopsy of the solitary pulmonary nodule revealed Dactylaria gallopava. Treatment was initiated with amphotericin B for a period of 21 days followed by oral itraconazole for an 8-month period.

The anatomic distribution of acute cellular rejection in the allograft lung.

BACKGROUND: Transbronchial lung biopsy (TBLB) is used for routine monitoring and diagnosing of acute cellular rejection (ACR) in the lung allograft, and yet the optimal anatomic site for lung biopsy has not been investigated. We examined our clinical data to clarify the distribution of ACR in the lung allograft monitored by TBLB. METHODS: A retrospective case-series study was done reviewing the pathology files and slides of TBLB performed on lung allograft recipients. In 73 patients, transbronchial biopsies were taken from more than one lobe. RESULTS: Identical grades of ACR were seen in 33 of 73 (45%) patients, and a single-grade difference in ACR was noted 34 of 73 (47%) patients. Six cases demonstrated two or more grade differences on biopsies taken from two separate lobes. Among cases with different grades of ACR, the "upper" lobes had a higher grade in 35% (14/40) and the "lower" lobes had a higher grade in 65% (26/40). CONCLUSIONS: If limitations on the site for transbronchial biopsy exist, biopsies of the lower lobes appear more informative.

Segmental nonanastomotic bronchial stenosis after lung transplantation.

BACKGROUND: Nonanastomotic distal bronchial stenosis has been observed in some patients after lung transplantation. We investigated its relationship with acute cellular rejection (ACR), infection, and ischemia. METHODS: Between January 1994 and December 1997, 246 lung transplantations were performed at our hospital. These cases were retrospectively reviewed and evaluated to identify those patients with nonanastomotic bronchial stenosis. RESULTS: Six patients had bronchial stenosis within the grafted airway distal to the uninvolved anastomotic site. The average ACR before stenosis was 1.9 compared with 1.6 in a control group. ACR at the time of first recognition of the stenosis ranged from A2 to A3.5, with an average value of A2.9. All 6 patients demonstrated alloreactive airway inflammation before and at the time of stenosis. Four patients had evidence of ischemic damage in the perioperative period. CONCLUSIONS: Segmental nonanastomotic large airway stenosis after lung transplantation should be assessed separately from anastomotic complications. Although the pathogenesis is unclear, certainly one should consider alloreactive injury, ischemic damage, and infection as individual and coercive causes.

Balloon dilation and endobronchial stent placement for bronchial strictures after lung transplantation.

PURPOSE: To evaluate the effect of balloon dilation and endobronchial stent placement for bronchial fibrous stenoses and bronchomalacia after lung transplantation. MATERIALS AND METHODS: Bronchial dilation and/or stent placement was performed on 25 lung transplant recipients. Indications included severe dyspnea with postobstructive pneumonia (n = 24) and respiratory failure (n = 1). All patients underwent pulmonary function testing (PFT) before and after bronchial dilation, the results of which were evaluated for changes. A total of 63 procedures were performed between February 1996 and December 1998. Thirty-five lesions were treated (18 were due to bronchomalacia, 17 were due to fibrosis). Areas treated included the left mainstem bronchus (n = 11), bronchus intermedius (n = 10), right mainstem bronchus (n = 7), left upper lobe bronchus (n = 4), right lower lobe bronchus (n = 2), and right middle lobe bronchus (n = 1). Bronchoscopic and/or bronchographic follow-up ranged from 1 to 34 months (mean, 15 months). RESULTS: Six-month primary patency of stents placed for bronchomalacia was 71% (10 of 14), with three of the four occlusions caused by mechanical failure of Palmaz stents in the mainstem bronchi. Six-month primary patency for treatment of fibrous strictures was 29%. Secondary patency at 1 year was 100% for both bronchomalacia and fibrous strictures. After treatment, there was a significant improvement in mean PFT results (P = .01-.0001). There was one acute complication, obstruction of the left lower lobe bronchus by a Wallstent treated by dilating a hole in the side of the stent. CONCLUSIONS: Balloon dilation and stent placement are safe and effective for bronchial strictures and bronchomalacia after lung transplantation, resulting in significant improvement in PFT results. However, there is almost universal restenosis in patients treated for fibrous strictures necessitating reintervention for prolonged patency.

Lung transplantation for end-stage pulmonary sarcoidosis.

BACKGROUND: Sarcoidosis is a multi-system granulomatous disease which can cause significant pulmonary morbidity and occasionally be fatal. The long term benefit of lung transplantation for this disorder are unknown. METHODS: A retrospective review was made of nine single lung transplant procedures performed at the University of Pittsburgh between March 1991 and March 1995 in patients with end-stage lung disease secondary to sarcoidosis. Two contemporaneous groups of recipients receiving transplants for COPD (n = 30) and inflammatory lung disease (n = 13) served as control groups. Surviving recipients underwent sequential surveillance bronchoscopy with transbronchial biopsy. RESULTS: All recipients survived beyond post-operative day (POD) 30, with 5 recipients currently alive. One year survival for this group was 6/9 (67%). Eight of the 9 sarcoidosis recipients had sequential lung biopsy procedures. Five of these 8 recipients (62.5%) had recurrence of granulomata in the lung allograft with the mean time to diagnosis of recurrent sarcoidosis being POD 224.2 +/- 291.3 (range POD 21-719). None of these 5 recipients had radiographic evidence or clinical symptoms related to granulomatous inflammation in the allograft. Pre-operative and post-operative spirometric values were available on 8 recipients. Vital capacity significantly improved in all recipients from 1.54 +/- 0.43 litres to 2.55 +/- 0.63 litres by POD 180 and was maintained through the fourth postoperative year (p < 0.05 Wilcoxon Signed Rank). Spirometric values were also compared before and after transplantation in the 5 recipients with granulomata in the allograft. Vital capacity significantly improved in these 5 recipients from 1.53 +/- 0.48 litres to 2.71 +/- 0.71 litres by POD 180 and was maintained throughout the first postoperative year (p < 0.05, Wilcoxon Signed Rank). The prevalence of high grade acute cellular rejection [ACR (histologic grades III and IV)] did not differ from that seen in a contemporaneous group of 30 single lung recipients who received allografts for COPD (p < 0.05 Mann-Whitney U), nor when compared to a group of 13 single lung recipients who received allografts for immunologically mediated lung disease (p < 0.05 Mann-Whitney U). The prevalence of chronic rejection (histologic obliterative bronchiolitis [OB]) in the sarcoidosis recipients was 4/8 (50%). In the controls with COPD recipients the prevalence of OB was 10/30 (33.3%), and in the 13 controls with immunologic disease it was 6/13 (46.2%). There was no significant difference in the prevalence of OB between the sarcoidosis recipients and controls. When analyzed to the fifth year after transplantation, freedom from the development of OB also failed to differ between these 3 groups (p = 0.25, Logrank, Mantel-Cox). CONCLUSIONS: Although granulomatous inflammation in the lung allograft is common following transplantation for sarcoidosis, it is not clinically or radiographically relevant. In addition, the prevalence of high grade ACR and histologic OB is no different when compared to other single lung recipients. For these reasons lung transplantation is a viable alternative for end-stage lung disease secondary to sarcoidosis.

Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.

STUDY OBJECTIVE: To define the prevalence of colonization and infection of the lower respiratory tract (LRT) with Aspergillus in lung transplant recipients with and without cystic fibrosis (CF). DESIGN: Retrospective review. SETTING: Large university lung transplant center. MATERIALS AND METHODS: The postoperative course of 31 CF and 53 non-CF double lung or double lobar transplant recipients receiving allografts from April 1991 to February 1996 was reviewed. All recipients were subjected to surveillance bronchoscopy and biopsy at predetermined intervals and when clinically indicated. BAL fluid (BALF) and biopsy material were examined by appropriate fungal culture and staining techniques. Infection was defined by the finding of tissue-invasive disease on biopsy specimens. RESULTS: Seven of the 31 CF recipients (22%) had Aspergillus isolated from cultures of sputum prior to transplantation. Following transplantation, 15 CF recipients (48%) had Aspergillus isolated from either sputum or BALF, including 4 of the 7 recipients identified with the fungus prior to transplantation. By contrast, 21 of the 53 non-CF recipients (40%) had Aspergillus isolated from the LRT following transplantation, none having had the fungus isolated prior to transplantation. The prevalence of Aspergillus did not differ between these groups (p = 0.51). Infections with Aspergillus occurred in 4 of the CF recipients (27%) and did not differ from the 3 infections (14%) identified in the non-CF recipients (p = 0.36). However, three of the four infections in the CF recipients involved the healing bronchial anastomosis and occurred prior to postoperative day 60. All three of these recipients had Aspergillus preoperatively. Postoperative infection was more common in the CF recipients having Aspergillus preoperatively than in those CF recipients without preoperative Aspergillus (p = 0.02). CONCLUSIONS: Isolation of Aspergillus from the LRT following double lung transplantation is common and generally not associated with tissue-invasive disease. Those CF recipients with Aspergillus isolated in cultures of sputum preoperatively are at risk for postoperative infections with this agent. The healing bronchial anastomosis is particularly vulnerable.

Allograft colonization and infections with pseudomonas in cystic fibrosis lung transplant recipients.

OBJECTIVE: To assess the incidence of pseudomonal infection, colonization, and inflammation in the allograft of lung transplant recipients with cystic fibrosis (CF) as compared with recipients with other end-stage lung disease. DESIGN: Retrospective review. SETTING: University medical center transplant service. PATIENTS: All patients with CF and chronic pseudomonal infection (n=62) and patients with nonseptic end-stage lung disease (n=52) receiving a double lung transplant between October 1983 and March 1996. RESULTS: Fifty lung transplant recipients with CF survived beyond postoperative day (POD) 15 and were subject to sequential bronchoscopy with BAL. Forty-four CF lung transplant recipients had Pseudomonas isolated from the allograft by median POD 15 as compared with 21 non-CF lung transplant recipients (p<0.001) with isolation at median POD 158 (p<0.0001). Thirteen CF lung transplant recipients had histologic evidence of infection when Pseudomonas was isolated as compared with only three of the non-CF lung transplant recipients (p<0.01). These infections occurred earlier in the CF lung transplant recipients (median POD 10 vs 261) (p<0.01). When compared with non-CF lung transplant recipients, CF lung transplant recipients with Pseudomonas isolated but without concomitant histologic infection (colonized) were demonstrated to have increased number of polymorphonuclear cells (PMNs) in the BAL fluid recovered from the allograft (17.66+/-24.94 x 10(6) cells vs 3.46+/-4.73 x 10(6)) (p<0.05). Non-CF lung transplant recipients who became colonized with Pseudomonas also had a greater number of PMNs recovered when compared with non-CF lung transplant recipients who did not have Pseudomonas (22.32+/-34.00 x 10(6) cells vs 0.21+/-0.18 x 10(6)) (p<0.01). Nine of 32 (28%) lung transplant recipients with CF have died from pseudomonal allograft infections, but this is no greater than 4 of 21 (19%) deaths related to Pseudomonas infection in recipients without CF (p=0.34). CONCLUSIONS: Isolation of Pseudomonas from the lung allograft occurs more frequently and earlier after transplantation in recipients with CF. While infections related to Pseudomonas also occur more frequently in recipients with CF, there is no increase in mortality. There is an intense inflammatory response in the lung allograft associated with the isolation of Pseudomonas in recipients with and without CF.

Dose-related reversal of acute lung rejection by aerosolized cyclosporine.

This study evaluated the effectiveness of aerosolized cyclosporine as rescue therapy for refractory acute rejection in lung-transplant patients that is unresponsive to conventional therapy. Over 2 yr, nine allograft recipients with histologic evidence of persistent acute rejection and worsening pulmonary function were enrolled. Twenty-two patients with similar degrees of unremitting rejection served as historical controls. Aerosolization of cyclosporin A (300 mg in 4.8 ml propylene glycol) using an AeroTech II jet nebulizer was instituted daily for 12 consecutive days followed by a maintenance regimen of 3 d/wk. Cyclosporine and tacrolimus blood and plasma levels were maintained within therapeutic ranges throughout this trial. Efficacy was assessed by histologic grade of rejection, interleukin-6 (IL-6) mRNA expression by graft bronchoalveolar lavage cells, and pulmonary function testing before and during cyclosporine therapy. In seven patients, results were correlated to deposition of cyclosporine aerosol in the allograft(s) as measured by radioisotopic techniques. At a mean of 37 d after initiation of aerosolized cyclosporine, graft histology improved in eight of the nine patients. Cellular IL-6 mRNA expression decreased significantly in seven patients (mean IL-6/actin +/- SD, 40.96 +/- 118 versus 0.33 +/- 0.57 [p = 0.038]). Pulmonary function (FEV1), which had decreased posttransplant (over a mean of 347 d of observation) from a best value of 1.98 +/- 0.8 L to 1.59 +/- 0.6 L (p = 0.0077), improved over time (152 d) to a posttransplant value of 1.90 +/- 0.8 (p = 0.025). In the control subjects, FEV1 inexorably declined over a comparable period of observation (best posttransplant value 2.36 +/- 0.86 to 1.32 +/- 0.53, p < 0.0001). There was a strong correlation between cyclosporine deposition in the allograft and improvement in FEV1 (r = 0.900, p < 0.01). Fewer cycles of pulsed corticosteroids (1.4 +/- 0.9 versus 0.2 +/- 0.4, p = 0.011) and anti-thymocyte globulin 0.8 +/- 0.4 versus 0, p = 0.018) and reduced doses of oral prednisone (10.8 +/- 3.1 versus 6.1 +/- 4.2 mg/d, p = 0.026) were observed during treatment with aerosolized cyclosporine. Episodes of pneumonia also were reduced significantly during aerosol therapy (2.6 versus 0.95 episodes/100 d, p = 0.029). Nephrotoxicity and hepatotoxicity did not occur, and no patients withdrew from the study. Aerosolized cyclosporine appears to be safe and effective therapy for refractory acute rejection, but confirmation by a larger, randomized trial is necessary. The correlation observed between deposition of cyclosporine aerosol and physiologic improvement of lung function suggests that there is a dose-response relationship between the concentration of cyclosporine in the allograft and immunologic tolerance.

Spirometry values in stable lung transplant recipients.

To clarify the usefulness of spirometry to assess the function of the lung allograft post-transplant, we retrospectively reviewed 351 sequential spirometry measurements performed by 65 healthy recipients after the 80th postoperative day when the clinical evaluation and fiberoptic bronchoscopy with transbronchial biopsies and bronchoalveolar lavage excluded significant rejection or infection in the allograft. The mean coefficients of variation (CV) and significant values for change (SC) for the FVC, FEV1, and FEF25-75% were calculated according to the type of transplant procedure (heart-lung and double-lung [HL-DL] versus single-lung [SL]), and to the time after transplant when the spirometry measurements were obtained < or = 1 yr versus > 1 yr). The SC for the FVC decreased with time after transplantation for both HL-DL (< or = 1 yr: 17% versus > 1 yr: 7%) and SL recipients (< or = 1 yr: 13% versus > 1 yr: 8%). The higher degree of variability within the first year was primarily due to increasing values especially in the HL-DL recipients. The SC for the FEV1 also decreased over time for HL-DL recipients (< or = 1 yr: 18% versus > 1 yr: 9%) but was similar for SL recipients at both intervals (13%). Our results suggest that decreases of > or = 11% in FVC or 12% in FEV1 in HL-DL recipients and > or = 12% in FVC or 13% in FEV1 for SL recipients indicate a significant decrease in allograft function that may be due to infection or rejection.

Lung and heart-lung transplantation at the University of Pittsburgh.

The application of lung transplantation as a treatment modality for patients with severe pulmonary disease has changed dramatically since its inception. At the University of Pittsburgh, the criteria for recipient selection continues to evolve and, in an effort to maximize scarce donor organs, the criteria for donor lung acceptance have been extended. Patient survival during the first 3 years after transplantation continues to improve but longer term survival is limited by infectious complications and chronic rejection. In early studies, the utilization of cyclosporine delivered directly to the lungs via aerosol has resulted in dramatic improvement in pulmonary function in recipients with immune mediated allograft injury and has allowed a reduction in systemic immunosuppression. We are hopeful that interventions such as this will result in prolongation of patient survival with less toxicity.

Aerosolized cyclosporine in lung recipients with refractory chronic rejection.

This study evaluated aerosolized cyclosporine as rescue therapy for lung transplant recipients with unremitting chronic rejection. Nine patients with histologic active obliterative bronchiolitis and progressively worsening airway obstruction refractory to conventional immune suppression received aerosolized cyclosporine. Improvement in rejection histology was seen in seven of nine patients. We compared the changes in the FVC and FEV1 over time using linear regression analysis in these seven histologic responders and nine historical control patients. During the pretreatment period for both the experimental and control groups, the FVC and FEV1 declined at comparable rates. After aerosolized cyclosporine there was stabilization of pulmonary function, whereas in the controls there was continued decline. Cyclosporine blood levels were less than 50 ng/ml 24 h after an aerosolized dose of 300 mg in five patients receiving oral tacrolimus. Nephrotoxicity, hepatotoxicity, and a greater than expected rate of infection was not observed. This study suggests that aerosolized cyclosporine is safe and may be effective therapy for refractory chronic rejection in lung transplant recipients.

Clinical trial of tacrolimus versus cyclosporine in lung transplantation.

BACKGROUND: A prospective clinical trial was undertaken to compare the efficacy of tacrolimus (FK 506) versus cyclosporine as the primary immunosuppressive agent after lung transplantation. METHODS: Between October 1991 and May 1994, 133 single-lung and bilateral-lung recipients were randomized to receive either cyclosporine (n = 67) or tacrolimus (n = 66). The two groups were similar in age, sex, and underlying disease. RESULTS: One-year and 2-year survival rates were similar in the two groups, although the trend was toward increased survival with tacrolimus. Acute rejection episodes per 100 patient-days were fewer (p = 0.07) in the tacrolimus group (0.85) than in the cyclosporine group (1.09). Obliterative bronchiolitis developed in significantly fewer patients in the tacrolimus group (21.7%) compared with the cyclosporine group (38%) (p = 0.025), and there was greater freedom from obliterative bronchiolitis over time for patients receiving tacrolimus (p < 0.03). Significantly more cyclosporine-treated patients (n = 13) required crossover to tacrolimus than tacrolimus-treated patients to cyclosporine (n = 2) (p = 0.02). The switch to tacrolimus controlled persistent acute rejection in 6 of 9 patients. The overall incidence of infections was similar in the two groups, although bacterial infections were more common with cyclosporine (p = 0.0375), whereas the risk of fungal infection was higher with tacrolimus (p < 0.05). CONCLUSIONS: This trial demonstrates the advantage of tacrolimus in reducing the risk of obliterative bronchiolitis, the most important cause of long-term morbidity and mortality after lung transplantation.