Lung transplantation

First performed in 1963, lung transplantation is approaching the half-century mark. With more than 32,000 procedures having been performed worldwide, lung transplantation has become the standard of care for select patients with advanced lung diseases of various nonmalignant etiologies. Indications for transplantation have broadened over the years, and selection criteria have become less restrictive. A relatively scarce donor pool limits wider application of this therapy, but this is being addressed in part through relaxation of donor selection criteria, donor management protocols that preserve and optimize lung function, and development of ex vivo perfusion techniques to "recondition" suboptimal organs. Bilateral lung transplantation has become the procedure of choice for most indications, although its preferential use in patients with idiopathic pulmonary fibrosis remains controversial. Post-transplantation survival has steadily improved, but significant constraints on long-term survival persist as evidenced by a median survival rate that currently stands at 5.7 years. This has brought into focus the question of whether and for whom transplantation actually confers a survival advantage, a question that in the absence of randomized trials can only be answered with statistical modeling. Primary graft dysfunction, infection, and bronchiolitis obliterans syndrome are common complications encountered by the lung transplant recipient and are major impediments to long-term survival. This review provides an overview of the current status of lung transplantation, highlighting both the many advances that have taken place and the challenges that remain.     

Prognostication in chronic obstructive pulmonary disease: implications for lung transplantation

Chronic obstructive pulmonary disease (COPD) is the most common disease for which single lung transplantation (SLT) is performed and is a frequent reason for bilateral lung transplantation (BLT). Recent data suggest a favorable survival advantage for patients with COPD undergoing lung transplantation compared with other diagnoses. This has led some investigators to question whether transplantation leads to improved survival in COPD patients compared with alternative treatment and whether this surgical therapy is appropriate in these individuals. These viewpoints may reflect the difficulties inherent in accurately predicting short- and long-term survival in patients with advanced COPD. Our review of the available data suggests that clinical, physiological, and radiographic features allow the identification of COPD patients with increased mortality despite maximal medical therapy. In these high risk individuals transplantation remains a viable therapeutic option.     

Lung transplant outcomes: a review of survival, graft function, physiology, health-related quality of life and cost-effectiveness.

The success of lung transplantation has improved over time as evidenced by better long-term survival and functional outcomes. Despite the success of this procedure, there are numerous problems and complications that may develop over the life of a lung transplant recipient. With proper monitoring and treatment, the frequency and severity of these problems can be decreased. However, significant improvement for the overall outcomes of lung transplantation will only occur when better methods exist to prevent or effectively treat chronic rejection.     

Conventional and novel approaches to immunosuppression

Immunosuppressive therapy has contributed significantly to improved survival after solid organ transplantation. Nevertheless, treatment-related adverse events and persistently high risk of chronic graft rejection remain major obstacles to long-term survival after lung transplantation. The development of new agents, refinements in techniques to monitor immunosuppression, and enhanced understanding of transplant immunobiology are essential for further improvements in outcome. In this article, conventional immunosuppressive regimens, novel approaches to preventing graft rejection, and investigational agents for solid organ transplantation are reviewed.     

Graft ischemic time and outcome of lung transplantation: a multicenter analysis

RATIONALE: The effect of graft ischemic time on early graft function and long-term survival of patients who underwent lung transplantation remains controversial. Consequently, graft ischemic time has not been incorporated in the decision-making process at the time of graft acceptance. OBJECTIVES: To investigate the relationship between graft ischemic time and (1) early graft function and (2) long-term survival after lung transplantation. MEASUREMENTS AND MAIN RESULTS: The data from 752 patients who underwent single lung transplantation (n = 258), bilateral lung transplantation (n = 247), and heart-lung transplantation (n = 247) in seven French transplantation centers during a 12-year period were reviewed. Independent data quality control was done to ensure the quality of the collected variables. Mean graft ischemic time was 245.8 +/- 96.4 minutes (range 50-660). After adjustment on 11 potential confounders, graft ischemic time was associated with the recipient Pa(O2)/FI(O2) ratio recorded within the first 6 hours and with long-term survival in patients undergoing single or double lung transplantation but not in patients undergoing heart-lung transplantation. The relationship between graft ischemic time and survival appears to be of cubic form with a cutoff value of 330 minutes. These results were unaffected by the preservation fluid employed. CONCLUSIONS: The results of this large cohort of patients suggest a close relationship between graft ischemic time and both early gas exchange and long-term survival after single and double lung transplantation. Such relationship was not found in patients undergoing heart-lung transplantation. The expected graft ischemic time should be incorporated in the decision-making process at the time of graft acceptance.     

Update on cystic fibrosis: selected aspects related to lung transplantation

Survival after lung transplantation for cystic fibrosis has improved substantially. To date, 1-year survival is as much as 80-90% and 5-year survival 60-70%. Experience of surgical techniques, periand postoperative management and long-term follow-up care has grown. High risk patients for whom transplantation was contraindicated ten years ago are today being transplanted. Prerequisites for a successful outcome are appropriate timing of referral, careful consideration of medical issues in other organs, and psychosocial support systems. Panresistant organisms are a special problem in candidates with cystic fibrosis, and advances in microbiological testing and characterisation of these organisms are warranted. Living donor lobar transplantation has become an option in rapidly deteriorating children and young adults. Selected aspects of the evolving field of lung transplantation are discussed.     

Lung transplantation for interstitial lung disease

For selected parenchymal lung disease patients who fail to respond to medical therapy and demonstrate declines in function that place them at increased risk for mortality, lung transplantation should be considered. Lung transplantation remains a complex medical intervention that requires a dedicated recipient and medical team. Despite the challenges, lung transplantation affords appropriate patients a reasonable chance at increased survival and improved quality of life. Lung transplantation remains an appropriate therapeutic option for selected patients with parenchymal lung disease.     

Bilateral sequential lung transplantation: technical aspects

The surgical technique for lung transplantation has evolved dramatically over the last three decades. Significant improvements in short term outcomes in the early years of lung transplantation were due, in large part, to techniques developed to reduce airway anastomotic complications in single lung transplantation. Following development of the technique of en bloc double lung transplantation, evolution to the bilateral sequential technique further reduced airway complications for double lung transplantation. More recently, some programs have utilized the en bloc double lung transplant technique with bronchial artery revascularization to aid airway healing and potentially improve short- and long-term outcomes. The experience with bronchial artery revascularization remains limited to a few series, with the technique having not been widely adopted by most lung transplant programs. With the implementation of priority allocations schemes in many countries, patients with higher risk profiles are being prioritized for transplantation which results in more complex procedures in fragile recipients with multiple comorbidities. This includes the increased need for concomitant cardiac procedures as well as performing lung transplantation after prior cardiothoracic surgery. Different surgical approaches have been described for bilateral sequential lung transplantation with or without intra-operative mechanical circulatory support (MCS), such as sternotomy, clamshell (bilateral anterior thoracotomies with transverse sternotomy), and bilateral thoracotomy incisions. Herein, we aim, not only to describe the various surgical approaches for double lung transplantation, but to provide a comprehensive review of other aspects related to the recipient pathology and different anatomical variants as well as handling technical challenges that might be encountered during the procedure.     

Special considerations in pediatric lung transplantation

More than 1300 lung or heart-lung transplants have been performed in children to date, resulting in many years of improved quality of life. Increasing experience has demonstrated that this therapy is unique and differs from adult lung transplantation in terms of indications, complications, pharmacokinetics, and monitoring. Unlike adult lung transplant recipients, cystic fibrosis and pulmonary vascular disease are very common indications. Complications such as graft dysfunction and bronchiolitis obliterans occur similarly in children as in adults, but others such as posttransplant lymphoproliferative disorders, growth retardation, respiratory tract infections, and medical nonadherence appear to be more common in pediatric lung transplant recipients. In addition, infants and adolescents are two very distinct populations that require special attention. Although the new lung allocation system grants some preference to children, donor shortage remains a limiting factor. Living donor lobar transplantation is an alternative for select candidates. Survival rates are similar between adult and pediatric transplant recipients. Support for collaborative studies is critical if we are to improve long-term outcomes for our young patients.     

Outcome of lung transplantation in patients with mycetomas.

BACKGROUND: Lung transplantation has become an acceptable treatment option for many end-stage lung diseases. Pulmonary mycetomas are found in patients with end-stage lung diseases, especially sarcoidosis. The clinical course and long-term outcome of these patients after transplantation remains unknown. METHODS: We reviewed retrospectively the pathology reports of the explanted lungs from all lung and heart-lung transplantations performed at our institution between January 20, 1992, and June 26, 2000. Patients were included in our study if mycetomas were present on the specimens. Information on transplant date and type, diagnosis, information on antifungal therapy and fungal infections pretransplant and posttransplant, and clinical course after transplantation was recorded. RESULTS: Mycetomas were present in 3.0% of transplant recipients (9 of 303 patients). The underlying pulmonary diagnoses were sarcoidosis (six patients), and emphysema, idiopathic pulmonary fibrosis, and pneumoconiosis (one patient each). Seven patients received bilateral lung transplants, one patient received a heart/lung transplant, and one patient received a single lung transplant. Aspergillus was isolated from culture in five patients pretransplant and from five patients posttransplant. Six patients received treatment with itraconazole, or IV or inhaled amphotericin B prior to transplantation. All patients who survived transplantation received posttransplant antifungal therapy. Four patients died in the first month after transplantation. Two patients died at 17 months and 24 months posttransplant, respectively; one patient received a second transplant 30 months later; and two patients are alive and free from fungal infections 17 months and 18 months, respectively, after transplantation. All of the medium-term survivors received lengthy therapy with inhaled and systemic amphotericin B and itraconazole before and after transplantation. CONCLUSIONS: Lung transplant recipients with mycetomas have significantly reduced posttransplant survival. Careful selection of patients and aggressive antifungal therapies before and after transplantation have led to improved outcomes in patients with mycetomas. Additional research is needed to define the best therapeutic strategy for these patients during transplantation.     

Chronic allograft rejection (obliterative bronchiolitis)

Lung and heart-lung transplantation are currently recognized as effective treatment for selected patients with end-stage lung or heart-lung disease. Although the survival rates have improved in recent years, long-term survival is still hampered by the development of chronic rejection. Histologically chronic rejection is manifested by obliterative bronchiolitis (OB), a process that leads to airways obstruction, with a gradual decline in pulmonary function tests. Extensive research efforts have attempted to unravel the pathophysiology of OB and identify key cytokines and growth factors involved in the process. Since the histological diagnosis of chronic rejection remains difficult, a clinical grading system has been proposed, determined as bronchiolitis obliterans syndrome (BOS), divided into four and, more recently, five categories, depending on the severity of airflow obstruction. This paper reviews the current knowledge of chronic rejection after heart-lung and lung transplantation.     

Lung transplantation]

Lung transplantation began to expand in 1983, after the advent of cyclosporin and the publication of the Toronto lung transplant group study. Single lung transplantation was first performed in patients with interstitial pneumopathy to be extended later to pulmonary emphysema, then to primary or secondary pulmonary arterial hypertension. Double lung transplantation provides patients suffering from chronic lung infection (e.g. cystic fibrosis) with a useful alternative to their ordinary treatment. The experience acquired throughout these years has resulted in wider criteria for patients' inclusion. More than acute rejection, bacterial infections directly condition the immediate prognosis. The frequency and severity of cytomegalovirus lung diseases lead to a discussion on the possibility of prophylactic and curative antiviral therapy. The occurrence of obliterative broncholitis, which reflects chronic lung rejection, jeopardizes the long-term results of transplantation. The functional results of the various types of lung grafting are analysed, and the position of lung transplantation in thoracic surgery is reassessed.     

Special considerations for patients with cystic fibrosis undergoing lung transplantation

This article reviews lung transplantation in patients with cystic fibrosis (CF). Lung transplantation is commonly utilized for patients with end-stage CF. There are several characteristics of CF that present unique challenges before and after lung transplantation. There is new information available that can be utilized to predict outcomes in patients with end-stage CF, and therefore can help in decisions of referral and listing for lung transplantation. The new lung allocation score, which allocates organs to patients who are on the lung transplant waiting list in the United States, presents new challenges and opportunities for patients with end-stage CF. In addition, the effect of the presence of microbiological flora prior to lung transplantation has been better linked to outcomes after lung transplantation. It is now known that, other than those patients harboring Burkholderia cepacia in their lungs before transplantation, most CF patients can undergo transplantation successfully. Nutrition remains an important issue among CF patients, and diabetes is a common problem after lung transplantation. In contrast, liver disease does not usually present major problems but, if it is severe, can necessitate liver and lung transplantation. Mechanical ventilation prior to transplantation might not be an absolute contraindication for CF patients. CF lung transplant recipients have good outcomes after lung transplantation compared with those of other lung transplant recipients. Quality of life is dramatically improved. However, they are still prone to common complications that all lung transplant recipients are prone to, including primary graft dysfunction, acute and chronic rejection, a variety of infections and malignancies, and renal failure.     

Lung transplantation: opportunities for research and clinical advancement

Lung transplantation is the only definitive therapy for many forms of end-stage lung diseases. However, the success of lung transplantation is limited by many factors: (1) Too few lungs available for transplantation due to limited donors or injury to the donor lung; (2) current methods of preservation of excised lungs do not allow extended periods of time between procurement and implantation; (3) acute graft failure is more common with lungs than other solid organs, thus contributing to poorer short-term survival after lung transplant compared with that for recipients of other organs; (4) lung transplant recipients are particularly vulnerable to pulmonary infections; and (5) chronic allograft dysfunction, manifest by bronchiolitis obliterans syndrome, is frequent and limits long-term survival. Scientific advances may provide significant improvements in the outcome of lung transplantation. The National Heart, Lung, and Blood Institute convened a working group of investigators on June 14-15, 2004, in Bethesda, Maryland, to identify opportunities for scientific advancement in lung transplantation, including basic and clinical research. This workshop provides a framework to identify critical issues related to clinical lung transplantation, and to delineate important areas for productive scientific investigation.     

Medical complications after lung transplantation

Despite remarkable progress in short-term functional and survival outcomes following lung transplantation, long-term outcomes remain limited due to a multitude of medical complications caused predominantly by immunosuppressive protocols. Although chronic allograft rejection and infection account for the majority of deaths beyond the first year after lung transplantation, a large number of other medical problems contribute significantly to excess mortality and morbidity. This article reviews the most frequent and important medical complications of lung transplantation, other than rejection and infection, with an emphasis on complications that involve the respiratory tract.     

Medical complications and management of lung transplant recipients

Lung transplantation is associated with a great number of major medical complications that act in concert to limit the long-term success of this difficult treatment option for advanced lung disease. Close and parallel attention to pulmonary and nonpulmonary medical complications and management of lung transplant recipients by a multidisciplinary team are the most important ingredients of optimal long-term outcomes.     

Unilateral lung transplantation in end-stage pulmonary emphysema

Patients with end-stage pulmonary emphysema are usually proposed for either heart-lung or double-lung transplantation. The single-lung transplantation is reversed for patients with pulmonary fibrosis. Patients with emphysema are thought to be unsuitable for single-lung transplantation because of the ventilation-perfusion imbalance that is supposed to occur, the ventilation being preferentially distributed to the native lung when the perfusion is distributed to the transplanted lung. We now report a preliminary success with single-lung transplantation in two consecutive patients with end-stage pulmonary emphysema. Despite the persistence after transplantation of an obstructive syndrome, the clinical status was good, the blood gases were markedly improved, and ventilation-perfusion imbalance did not occur on lung scans. After discharge from the hospital, the patients could return to an almost normal life. Thus, our data support the feasibility of single-lung transplantation in patients with end-stage pulmonary emphysema, and we consider that single-lung transplantation could be the optimal form of lung transplantation in these patients.     

Lung transplantation in cystic fibrosis.

Lung transplantation has emerged in the last decade as a valid therapeutic endeavor for patients with end-stage lung disease. Although the presence of highly resistant organisms in the airway and sinuses of patients with cystic fibrosis (CF) increases the perioperative risk of infection following lung transplantation, transplant procedures can be undertaken in properly selected CF patients with acceptable morbidity and mortality at experienced centers. The introduction of a modification in the technique of double-lung transplantation has resulted in improved operative survival of CF patients undergoing lung transplantation. Whereas problems with posttransplant obliterative bronchiolitis, infection, and lymphoproliferative disorders contribute to morbidity, it is clear that lung transplantation can offer CF patients with end-stage lung disease improvement in both the quality and quantity of life. The most serious impediment to more widespread application of this therapy in CF is the inadequate number of donor organs.     

Prognostic Value of RV Function Before and After Lung Transplantation

ObjectivesWe investigated the effects of lung transplantation on right ventricular (RV) function as well as the prognostic value of pre- and post-transplantation RV function.BackgroundAlthough lung transplantation success has improved over recent decades, outcomes remain a challenge. Identifying predictors of mortality in lung transplant recipients may lead to improved long-term outcomes after lung transplantation.MethodsEighty-nine (age 60 ± 6 years, 58 men) consecutive patients who underwent single or double lung transplantation and had pre- and post-transplantation echocardiograms between July 2001 and August 2012 were evaluated. Echocardiographic measurements were performed before and after lung transplantation. Left ventricular (LV) and RV longitudinal strains were analyzed using velocity vector imaging. Cox proportional prognostic hazard models predicting all-cause death were built.ResultsThere were 46 all-cause (52%) and 17 cardiac (19%) deaths during 43 ± 33 months of follow-up. After lung transplantation, echocardiography showed improved systolic pulmonary artery pressure (SPAP) (50 ± 19 mm Hg to 40 ± 13 mm Hg) and RV strain (−17 ± 5% to −18 ± 4%). No pre-transplantation RV parameter predicted all-cause mortality. After adjustment for age, sex, surgery type, and etiology of lung disease in a Cox proportional hazards model, both post-transplantation RV strain (hazard ratio: 1.13, 95% confidence interval: 1.04 to 1.23, p = 0.005), and post-transplantation SPAP (hazard ratio: 1.03, 95% confidence interval: 1.01 to 1.05, p = 0.011) were independent predictors of all-cause mortality. When post-transplantation RV strain and post-transplantation SPAP were added the clinical predictive model based on age, sex, surgery type, and etiology, the C-statistic improves from 0.60 to 0.80 (p = 0.002).ConclusionsAlterations of RV function and pulmonary artery pressure normalize, and post-transplantation RV function may provide prognostic data in patients after lung transplantation. Our study is based on a highly and retrospectively selected group. We believe that larger prospective studies are warranted to confirm this result.     

Lung transplantation

Advances in solid organ transplantation over the last several decades have made human lung transplantation a realistic possibility for selected patients with end-stage lung disease. A review of clinical indications, proper patient selection, and long-term management is presented. Infection and rejection continue to represent 2 major areas of posttransplantation complications and merit particular attention.