Cadaveric Lung Transplantation Research Articles

Epidemiology and clinical implications of atypical mycobacterial infections in cadaveric lung transplants: the role of surveillance bronchoscopy and bronchoalveolar lavage phenotype

Epidemiology and clinical implications of atypical mycobacterial infections in cadaveric lung transplants: the role of surveillance bronchoscopy and bronchoalveolar lavage phenotype

Successful treatment of relapsed PTLD with YT-90/anti-CD20 radioimmunotherapy

Background: Posttransplant lymphoproliferative disease (PTLD), is a major cause of morbidity and mortality following lung transplantation, responsible for 4% of mortality after 30 days post-transplant in pediatric recipients. Chemotherapy related mortality in thoracic organ recipients is reported from 30–70%. Therefore, initial treatment is usually reduced immunosuppression and anti-CD20 monoclonal antibody (rituximab). Rituximab is well tolerated and achieves a 60–70% response rate. However, rituximab refractory relapse may occur, requiring the use of chemotherapy. The Zevalin therapeutic protocol (ZTP), including radioimmunotherapy with a Yttrium-90 tagged anti-CD20 antibody (ibritumomab tiuxetan; Zevalin), is a minimally toxic, effective therapy for relapsed or refractory low grade, follicular, or transformed B-cell nonHodgkin’s lymphoma (NHL). We found no published reports of radioimmunotherapy for PTLD. We report the successful use of ZTP in a 16-yr-old bilateral cadaveric lung transplant recipient. Abdominal PTLD was diagnosed 8 months post-transplant. Remission was achieved with reduced immunosuppression and rituximab. Relapse occurred 28 months posttransplant. Procedures: Relapsed CD20 positive, monomorphic B-cell PTLD was diagnosed by biopsy of sinus and esophagus. The patient received 1 dose of rituximab and reduced immunosuppression, with some improvement in symptoms. Once available, she received ZTP, including 0.3 mCi/kg Yt-90 ibritumomab tiuxetan. Efficacy was monitored with PET, CT and endoscopic biopsies (GI and lung). The anticipated hypogammaglobulinemia has been treated with IVIG. Results: Treatment with ZTP resulted in a complete remission without evidence of graft dysfunction. At 8 months post-treatment, there was no evidence of recurrent PTLD. There has been no significant infection. Conclusions: In our patient, ZTP was effective treatment of relapsed PTLD. Although further study is needed to confirm this observation, minimal toxicity makes ZTP an attractive alternative to chemotherapy for relapsed or rituximab refractory PTLD.

Predictors of Lung Transplant Survival in Eurotransplant

This study was undertaken to assess the influence of patient/donor and center factors on lung transplantation outcome. Outcomes of all consecutive first cadaveric lung transplants performed at 21 Eurotransplant centers in 1997–99 were analyzed. The risk-adjusted center effect on mortality was estimated. A Cox model was built including donor and recipient age and gender, primary disease, HLA mismatches, patient's residence, cold ischemic time, donor's cause of death, serum creatinine, type of lung transplant, respiratory support status, clinical condition and percentage predicted FEV1. The center effect was calculated (expressed as the standardized difference between the observed and expected survival rates), and empirical and full Bayes methods were applied to evaluate between-center differences. A total of 590 adults underwent lung transplantation. The primary disease (p=0.01), HLA-mismatches (p = 0.02), clinical condition(p < 0.0001) and the patient's respiratory support status (p = 0.05) were significantly associated with survival. After adjusting for case-mix, no between-center differences could be found. An in-depth empirical Bayes analysis showed the between-center variation to be zero. Similar results were obtained from the full Bayes analysis. Based on these data, there is no scientific basis to support a hypothesis of possible association between center volume and lung survival rates.

Bacterial colonization of the donor lower airways is a predictor of poor outcome in lung transplantation.

At the time of lung transplant, we routinely perform bronchoalveolar lavage (BAL) of the donor lungs on the recipient operating table immediately before implantation, for bacterial and fungal cultures. We sought to determine whether the results correlate with the outcome. We retrospectively analysed 115 consecutive cadaveric lung transplants (single lung: 42; bilateral lung: 63; heart-lung: 10) performed over 4 years. Fifty-three (46%) grafts had positive BAL (bacteria: 33; fungus: 10; mixed: 10) and 62 (54%) were negative. Recipients with donor BAL culture positive for bacteria had lower mean oxygenation index in the first 6 h compared with those with negative bacterial culture (36.5+/-14.73 vs. 44.1+/-16.79 kPa) (P=0.019). They also had longer median intensive treatment unit stay (2.5 vs. 1.5 days) (P=0.035), and median time of mechanical ventilation (37.5 vs. 23.0 h) (P=0.008), as well as inferior 6-month, 1-year, 2-year and 4-year cumulative survival (79, 77, 74, 60% vs. 93, 92, 88, 79% respectively) (P=0.04). There was no difference in the above parameters between recipients with Gram-negative (n=18) and recipients with Gram-positive bacteria (n=19) in the donor BAL. Incidence of acute rejection within the first 2 weeks and time of onset of bronchiolitis obliterans syndrome (BOS) were similar in the bacteria-positive and bacteria-negative groups. Recipients with donor BAL positive for fungi alone had similar outcome with the negatives. There was no difference in the donor oxygenation index and age, recipient age, transplant type and ischaemic time between compared groups. There was a significant difference in the median length of donor mechanical ventilation between donors with Gram-positive and donors with Gram-negative bacteria in the BAL (24 vs. 48 h) (P=0.01), as well as between donors with fungi alone in the BAL and donors with negative BAL (67 vs. 48 h) (P=0.04). Donor lungs with lower airways colonized with bacteria result in inferior recipient outcome. Bacterial colonization of the donor lower airways could therefore be used as a marker of donor lung injury, but evidence from a prospective study is necessary.

Living-donor lobar lung transplantation for various lung diseases

Objective We report on our early experience in living-donor lobar lung transplantation for patients with various lung diseases including restrictive, obstructive, septic, and hypertensive lung diseases. Methods From October 1998 to March 2002, living-donor lobar lung transplantation was performed in 14 patients with end-stage lung diseases. There were 11 female patients and 3 male patients, with ages ranging from 8 to 53 years, including 4 children and 10 adults. Diagnoses included primary pulmonary hypertension (n = 6), idiopathic interstitial pneumonia (n = 2), bronchiolitis obliterans (n = 2), bronchiectasis (n = 2), lymphangioleiomyomatosis (n = 1), and cystic fibrosis (n = 1). Bilateral living-donor lobar lung transplantation was performed in 13 patients and right single living-donor lobar lung transplantation was performed for a 10-year-old boy with primary pulmonary hypertension. Results All the 14 patients are currently alive with a follow-up period of 4 to 45 months. Although their forced vital capacity (1327 ± 78 mL, 50.2% of predicted) was limited at discharge, arterial oxygen tension on room air (98.5 ± 1.8 mm Hg) and systolic pulmonary artery pressure (24.8 ± 1.6 mm Hg) were excellent. Forced vital capacity improved gradually and reached 1894 ± 99 mL, 67.4% of predicted, at 1 year. All donors have returned to their previous lifestyles. Conclusions Living-donor lobar lung transplantation can be applied to restrictive, obstructive, septic, and hypertensive lung diseases. This type of procedure can be an alternative to conventional cadaveric lung transplantation for both pediatric and adult patients who would die soon otherwise.

Single center comparison of pediatric living donor lobar and cadaveric lung transplant

Living donor lobar transplant (LDLT) has been used to address the ongoing shortage of cadaveric lungs and unpredictable course of end-stage lung disease. Because LDLT involves putting two healthy patients at risk, we compared outcomes between cadaveric lung transplant and LDLT. From July 1994 to May 2002, 38 LDLTs were performed at this center. A cohort of cadaveric recipients, also transplanted here during that era, matched by age at transplant, sex and underlying disease was selected to serve as a controls. LDLT recipients were less stable at the time of transplant: more patients (12/38) in the LDLT cohort were mechanically ventilated compared to 2/38 in the controls. The average ischemic times were significantly shorter in the LDLT patients (1:32) compared to controls (4:46). One and 3 year survival for the LDLT recipients was 60 % and 48% compared to 89% and 58% for the control cohort. The difference in Kaplan-Meier survival curves was statistically significant (P=0.03). There was no difference in the incidence of acute rejection between the LDLT and control cohorts. Post-transplant FEV1 and FVC were not significantly different. However, freedom from bronchiolitis obliterans syndrome (BOS) at 1 and 3 years was 92% and 85% compared to 75% and 53% in the cadaveric cohort (P=0.03). Not surprisingly, the causes of death in the LDLT population reflected this difference. Only 2/24 (8%) of deaths in the LDLT cohort were due to BOS compared to 8/18 (45%) of deaths in the control cohort. In contrast, 11/24 (46%) of deaths in the LDLT cohort were related to infection compared to 2/18 (11%) in the control population. Based on this comparison, we conclude that LDLT can be performed successfully in pediatric patients. Although the decreased incidence of BOS makes us optimistic about the long-term survival of LDLT recipients, efforts focusing on minimizing infectious complications are necessary to improve overall survival.

Pulmonary venous Doppler patterns in pediatric cadaveric and living-donor lung transplantation

Pulmonary venous Doppler patterns in pediatric cadaveric and living-donor lung transplantation

Bronchiolitis obliterans is not the primary cause of death in pediatric living donor lobar lung transplant recipients

Background: Obliterative bronchiolitis (OB) is the chief cause of mortality in cadaveric lung transplant patients (CL). But, is OB the primary cause of mortality for living donor lobar recipients? To answer this question, we reviewed the causes of mortality in our pediatric patients who underwent living donor lobar lung transplantation (LD) and compared them with our pediatric patients who received whole cadaveric lungs (CL). Methods Data collected included demographics, transplant type, hospital days, immunosuppression regimen, and cause of death. Statistical analysis was done using Fisher’s Exact test and Student’s t-test (mean ± SD). Results From May 1993 to December 1999, 53 patients underwent lung transplantation (21 males, 32 females; mean age 12.4 ± 5.4 years). Twenty-nine patients had LD procedures (12 males, 17 females; mean age 14.4 ± 3.6 years) and 24 patients had CL surgery (9 males, 15 females; p = .78 [not significant]; mean age 9.8 ± 6.3 years; p = .001). All patients received triple immunosuppression without induction. During the study period, 9 LD (6 males, 3 females; mean age 15.7 ± 5.0 years) and 14 CL (3 males, 11 females; mean age 11.3 ± 6.9 years) patients died. There was no significant difference between patients in the LD and CL groups who died with regard to gender ( p = .08), age at the time of death ( p = .12), mortality rate ( p = .06), number of hospital days ( p = .09), immunosuppressive medications ( p > .08), incidence of non-specific graft failure ( p = .26), or incidence of infection ( p = .18). However, there was a significant difference in the incidence of OB between LD and CL recipients ( p = .002). Conclusions OB was not found to be the chief cause of mortality in pediatric LD recipients. We speculate that prevention of infections, possibly by a modest reduction in immunosuppressive therapy and aggressive antimicrobial therapy, may improve long-term survival in pediatric living donor lobar lung transplant recipients.

Alternatives to cadaveric lung transplantation

Alternatives to cadaveric lung transplantation

Does human leukocyte antigen matching influence the outcome of lung transplantation? an analysis of 3,549 lung transplantations

Background and Objective: Human leukocyte antigen (HLA) compatibility has been shown to improve the outcome of renal and cardiac transplantation. However, its impact on outcome following lung transplantation is not clear, with several single-center studies reporting inconsistent results. We studied the influence of HLA matching on survival and the development of rejection and obliterative bronchiolitis after lung transplantation, using data from the United Network for Organ Sharing/International Society for Heart and Lung Transplantation registry. Methods The study population included adult patients who received cadaveric lung transplants between October 1987 and June 1997 for whom HLA data were available. Two cohorts were examined, depending on the era of transplantation: (1) October 1987 to June 1997 ( n = 3,549): Differences in actuarial survival as stratified by either the total number of HLA mismatches or the number of mismatches at each HLA locus were determined using a log-rank test. Multivariate logistic regression models were developed to determine independent predictors of survival at 1, 3, and 5 years following lung transplantation. (2) April 1994 to June 1997 ( n = 1,796): The association of HLA mismatching with acute rejection and obliterative bronchiolitis was determined using a chi-squared analysis. Results Only 164 patients (4.6%) received lung grafts with 2 or fewer HLA mismatches. Univariate analyses demonstrated a significant difference in post-transplant survival by mismatch level, with the total number of HLA mismatches ( p = 0.0008) and mismatching at the HLA-A locus ( p = 0.002) associated with worse survival. Multivariate logistic regression demonstrated that the number of mismatches at the HLA-A and HLA-DR loci predicted 1-year mortality (incremental odds ratios 1.18, p = 0.01, and 1.15, p = 0.03, respectively). The total number of HLA mismatches predicted 3- and 5-year mortality (incremental odds ratios 1.13 at 3 years, p = 0.0004, and 1.14 at 5 years, p = 0.0002). However, other covariates such as repeat transplantation, transplantation for congenital heart disease, advanced recipient age, and an early era of transplantation were stronger predictors of mortality. We found no significant association between HLA mismatching and the development of obliterative bronchiolitis, although there was an association between mismatching at the HLA-A locus and acute rejection episodes requiring hospital admission ( p = 0.008). We also found no association between mismatching at the HLA-B locus and rejection episodes requiring either hospitalization or the alteration of anti-rejection medications ( p = 0.034). Conclusion Although the number of HLA mismatches at the HLA-A and HLA-DR loci predicted 1-year mortality and the total number of mismatches predicted 3- and 5-year mortality following lung transplantation, the effect of each covariate was small in this multicenter study of 3,549 patients. Further close follow-up of registry patients is necessary to determine the effect of HLA matching on long-term survival and freedom from obliterative bronchiolitis and rejection following lung transplantation. A prospective study of HLA matching for lung transplantation should not yet be considered in view of the small number of grafts with 2 or fewer mismatches and the modest effect of HLA matching on outcome.

Comparison of outcomes between living donor and cadaveric lung transplantation in children

Background. Long-term survival in lung transplant is limited by bronchiolitis obliterans (BOS). We compared outcomes in pediatric living donor bilateral lobar (LL) vs cadaveric lung transplant (CL).Methods. Children were studied who had LL or CL with at least 1 year follow-up. Data collected included acute rejection episodes, pulmonary function tests (PFT), BOS, and survival. Mean age was 13.36 ± 3.16 years in LL and 12.00 ± 4.19 years in CL patients (p = 0.37, ns).Results. There was no difference in rejection (p = 0.41, ns). CL had rejection earlier (2.48 ± 3.84 months) than LL (13.60 ± 10.74 months; p = 0.02). There was no difference in 12 month PFT. But at 24 months, LL had greater forced expiratory volume in 1 second (FEV1) (p = 0.001) and FEF25–75% (p = 0.01) than CL. BOS was found in 0/14 LL vs 9/11 (82%) CL after 1 year (p = 0.04). After 2 years, 0/8 LL and 6/7 (86%) CL had BOS (p < 0.05). LL had 85% survival vs 79% for CL at 12 months. At 24 months, LL survival was 77% vs 67% for CL.Conclusions. Pediatric LL had less BOS and better pulmonary function than CL. As BOS is a determinant of long-term outcome, we believe LL is the preferred lung transplant method for children.

Influence of graft ischemic time and donor age on survival after lung transplantation

Background: Increased graft ischemic time and donor age are risk factors for early death after heart transplantation, but the effect of these variables on survival after lung transplantation has not been determined in a large, multinational study. Methods: All recipients of cadaveric lung transplantations performed between October 1, 1987 and June 30, 1997 which were reported to the United Network for Organ Sharing/International Society for Heart and Lung Transplantation (UNOS/ISHLT) Registry were analyzed. Patient survival rates were estimated using Kaplan-Meier methods. Multivariate logistic regression was used to determine the impact of donor and recipient characteristics on patient survival after transplantation. To examine whether the impact of donor age varied with ischemic time, interactions between the 2 terms were examined in a separate multivariate logistic regression model. Results: Kaplan-Meier survival did not differ according to the total lung graft ischemia time, but recipient survival was significantly adversely affected by young (≤10 years) or old (≥51 years) donor age (p = 0.01). On multivariate analysis, neither donor age nor lung graft ischemic time per se were independent predictors of early survival after transplantation, except if quadratic terms of these variables were included in the model. The interaction between donor age and graft ischemia time, however, predicted 1 year mortality after lung transplantation (p = 0.005), especially if donor age was greater than 55 years and ischemic time was greater than 6 to 7 hours. Conclusions: Graft ischemia time alone is not a risk factor for early death after lung transplantation. Very young or old donor age was associated with decreased early survival, whereas the interaction between donor age and ischemic time was a significant predictor of 1 year mortality after transplantation. Cautious expansion of donor acceptance criteria (especially as regards ischemic time) is advisable, given the critical shortage of donor lung grafts.