Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation.

Tens of thousands of patients with advanced lung diseases may be eligible to be considered as potential candidates for lung transplant around the world each year. The timing of referral, evaluation, determination of candidacy, and listing of candidates continues to pose challenges and even ethical dilemmas. To address these challenges, the International Society for Heart and Lung Transplantation appointed an international group of members to review the literature, to consider recent advances in the management of advanced lung diseases, and to update prior consensus documents on the selection of lung transplant candidates. The purpose of this updated consensus document is to assist providers throughout the world who are caring for patients with pulmonary disease to identify potential candidates for lung transplant, to optimize the timing of the referral of these patients to lung transplant centers, and to provide transplant centers with a framework for evaluating and selecting candidates. In addition to addressing general considerations and providing disease specific recommendations for referral and listing, this updated consensus document includes an ethical framework, a recognition of the variability in acceptance of risk between transplant centers, and establishes a system to account for how a combination of risk factors may be taken into consideration in candidate selection for lung transplantation.

Lymphangioleiomyomatosis Diagnosis and Management: High-Resolution Chest Computed Tomography, Transbronchial Lung Biopsy, and Pleural Disease Management. An Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline.

BACKGROUND: Recommendations regarding key aspects related to the diagnosis and pharmacological treatment of lymphangioleiomyomatosis (LAM) were recently published. We now provide additional recommendations regarding four specific questions related to the diagnosis of LAM and management of pneumothoraces in patients with LAM. METHODS: Systematic reviews were performed and then discussed by a multidisciplinary panel. For each intervention, the panel considered its confidence in the estimated effects, the balance of desirable (i.e., benefits) and undesirable (i.e., harms and burdens) consequences, patient values and preferences, cost, and feasibility. Evidence-based recommendations were then formulated, written, and graded using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. RESULTS: For women who have cystic changes on high-resolution computed tomography of the chest characteristic of LAM, but who have no additional confirmatory features of LAM (i.e., clinical, radiologic, or serologic), the guideline panel made conditional recommendations against making a clinical diagnosis of LAM on the basis of the high-resolution computed tomography findings alone and for considering transbronchial lung biopsy as a diagnostic tool. The guideline panel also made conditional recommendations for offering pleurodesis after an initial pneumothorax rather than postponing the procedure until the first recurrence and against pleurodesis being used as a reason to exclude patients from lung transplantation. CONCLUSIONS: Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed.

Noninfectious Pulmonary Complications of Liver, Heart, and Kidney Transplantation: An Update.

Despite significant advances in surgical techniques, perioperative care, and immunosuppressive therapy, solid organ transplantation still carries considerable risk of complications. Pulmonary complications, in particular, are a major cause of morbidity and mortality. Although infectious complications prevail, the lungs are also vulnerable to a variety of noninfectious complications related to the transplant surgery and adverse effects of the immunosuppressive regimen. This article focuses on noninfectious pulmonary complications associated with the 3 most commonly performed solid organ transplant procedures: liver, kidney, and heart.

Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease that primarily affects women. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of LAM. METHODS: Systematic reviews were performed to summarize evidence pertinent to our questions. The evidence was summarized and discussed by a multidisciplinary panel. Evidence-based recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: After considering the panel's confidence in the estimated effects, the balance of desirable (i.e., benefits) and undesirable (i.e., harms and burdens) consequences of treatment, patient values and preferences, cost, and feasibility, recommendations were formulated for or against specific interventions. These included recommendations for sirolimus treatment and vascular endothelial growth factor D testing and recommendations against doxycycline and hormonal therapy. CONCLUSIONS: Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed.

Birt-Hogg-Dubé Syndrome.

Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder caused by mutations in the Folliculin gene and is characterized by the formation of fibrofolliculomas, early onset renal cancers, pulmonary cysts, and spontaneous pneumothoraces. The exact pathogenesis of tumor and lung cyst formation in BHD remains unclear. There is great phenotypic variability in the clinical features of BHD, and patients can present with any combination of skin, pulmonary, or renal findings. More than 80% of adult patients with BHD have pulmonary cysts on high-resolution computed tomography scan of the chest.

Lung transplantation for obstructive lung diseases.

Chronic obstructive pulmonary disease (COPD) represents one of the most common indications for lung transplantation, accounting for approximately one third of all procedures performed worldwide to date. Despite this extensive experience, questions remain about the appropriate timing of transplantation in the natural history of COPD, the optimal procedure to perform, and the survival benefit achieved. Less commonly encountered obstructive lung disorders for which transplantation is occasionally performed include emphysema due to α-1-antitrypsin deficiency, lymphangioleiomyomatosis, and Langerhans cell histiocytosis. Like COPD, the application of transplantation to these rare disorders also poses several questions. This article explores issues that arise when lung transplantation is utilized for treatment of both common and uncommon obstructive lung disorders.

Post-transplant lymphoproliferative disorder after lung transplantation: a review of 35 cases.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a complication of organ transplantation. The risk of developing PTLD varies depending on a number of factors, including the organ transplanted and the degree of immunosuppression used. METHODS: We report a retrospective analysis of 35 patients with PTLD treated at our center after lung transplantation. Of 705 patients who received allografts, 34 (4.8%) developed PTLD. One patient underwent transplantation elsewhere and was treated at our center. RESULTS: PTLD involved the allograft in 49% of our patients and the gastrointestinal (GI) tract lumen in 23%. Histologically, 39% of tumors were monomorphic and 48% polymorphic. The time to presentation defined the location and histology of disease. Of 17 patients diagnosed within 11 months of transplantation, PTLD involved the allograft in 12 (71%) and the GI tract in 1 (p = 0.01). This "early" PTLD was 85% polymorphic (p = 0.006). Conversely, of the 18 patients diagnosed more than 11 months after transplant, the lung was involved in 5 (28%) and the GI tract in 7 (39%; p = 0.01). "Late" PTLD was 71% monomorphic (p = 0.006). Median overall survival after diagnosis was 18.57 months. Overall survival did not differ between all lung transplant recipients and those who developed PTLD. CONCLUSIONS: PTLD is an uncommon complication after lung transplantation, and its incidence declined remarkably in the era of modern immunosuppression. We report several factors that are important for predisposition toward, progression of, and treatment of PTLD after lung transplantation.

Candidate selection, timing of listing, and choice of procedure for lung transplantation.

Decisions about patient selection, timing of listing, and choice of procedure are important steps in optimizing the outcome of lung transplantation. Selection of candidates for lung transplantation requires an appreciation of the effect of pretransplant patient characteristics on posttransplant outcomes. Familiarity with the natural history of the underlying disease and of disease-specific prognostic factors is essential in making decisions about when to list candidates. Decisions about transplanting 1 or 2 lungs are principally determined by the underlying disease, but in cases in which both procedures are acceptable, factors such as survival benefit, patient's age, and center-specific preferences come into play.

Recurrent spontaneous pneumothorax in a patient with Birt-Hogg-Dubé syndrome.

Recurrent spontaneous pneumothorax is a disorder often managed by thoracic surgeons. Most etiologies are benign in nature; however, there are several syndromes that are associated with potentially fatal pulmonary or systemic manifestations. One such example is Birt-Hogg-Dubé syndrome, a rare inheritable syndrome characterized by papular skin lesions involving the scalp, head, face and neck; pulmonary cysts; and a propensity to develop renal carcinoma. In our report, we describe a patient, who was diagnosed with Birt-Hogg-Dubé syndrome after presenting with a history of recurrent spontaneous pneumothorax, and a family history of spontaneous pneumothorax and renal cell carcinoma. This case is of particular interest to the cardiothoracic surgery community as the patient described as well as several of his family members were managed by multiple thoracic surgeons, who did not appreciate the diagnosis.

Lung transplantation for chronic obstructive pulmonary disease: special considerations.

Since the introduction of lung transplantation nearly half a century ago, more procedures have been performed for chronic obstructive pulmonary disease (COPD) than for any other single indication. Because COPD tends to progress slowly and long-term survival is possible even in the advanced stages, the time at which transplantation should be offered remains unclear. Current recommendations rely on use of the BODE index to provide guidance on listing. Although both single lung transplantation (SLT) and bilateral lung transplantation (BLT) are suitable procedures for the COPD population, BLT has become the preferred procedure, particularly for patients under age 60, for whom it appears to offer superior survival and functional benefits. Whether lung transplantation truly extends survival for patients with COPD is uncertain. Preliminary answers have come from use of survivorship models that suggest a subset of COPD patients do derive a survival benefit, and that the size of this subgroup can be enhanced by selecting patients with extremely severe airflow obstruction and preferentially utilizing BLT. Those undergoing SLT are uniquely at risk for complications related to the remaining native lung-bronchogenic carcinoma and progressive hyperinflation-which are fortunately rare.

Severe venous and lymphatic obstruction after single-chamber pacemaker implantation in a patient with chest radiation therapy.

A 73-year-old woman with a history of paroxysmal atrial fibrillation, sinus node dysfunction, bilateral breast cancer, and extensive chest radiation developed progressive edema, dyspnea, and recurrent pleural effusions soon after single-chamber pacemaker implantation. Thoracentesis yielded a diagnosis of chylothorax, and progressive refractory anasarca developed. A computed tomography angiogram suggested obstruction of the superior vena cava and left subclavian vein despite outpatient therapeutic anticoagulation. Autopsy confirmed venous thrombosis, along with mediastinal fibrosis. The presumed etiology of the chylothorax and anasarca was obstruction of the atretic central venous structures following pacemaker implantation, critically impairing the already tenuous venous and lymphatic drainage. (PACE 2010; 520-524).

Does lung transplantation confer a survival benefit?

PURPOSE OF REVIEW: There are reasonably compelling data documenting the beneficial impact of lung transplantation on functional status, hemodynamics, and quality of life. Demonstration of a survival benefit has been more problematic, largely due to significant constraints on long-term survival. This article reviews the current literature addressing the question of whether transplantation is truly a life-extending procedure. RECENT FINDINGS: Because randomized trials are nonexistent, the question has been approached by comparing observed posttransplant survival to wait list survival, or by simulating survival with and without transplantation by statistical modeling. Studies uniformly suggest that transplantation extends survival for patients with idiopathic pulmonary fibrosis. For patients with chronic obstructive pulmonary disease, studies are conflicting and suggest that survival benefit is largely restricted to a subset of patients with extremely severe airflow obstruction who undergo bilateral lung transplantation. Cystic fibrosis (CF) adults with a predicted 5-year survival of less than 50%, and without Burkholderia cepacia or arthropathy appear most likely to realize a survival benefit. Whether transplantation extends survival for pediatric CF patients remains controversial. SUMMARY: Questions about the survival benefit of lung transplantation linger. In the absence of definitive answers, it may be most appropriate to view transplant as a procedure that enhances the quality but not necessarily the duration of life.

Central airways obstruction due to Aspergillus fumigatus after lung transplantation.

Aspergillus fumigatus may affect immunocompromised lung transplant patients in many ways. We report a new pulmonary manifestation of A fumigatus in 3 patients who underwent bilateral lung transplantation. All 3 subjects developed rapid decreases in pulmonary function and were found to have large central airways obstruction with thick plugs of mucus, heavily laden with Aspergillus species. All 3 patients presented with atypical features of Aspergillus infection, but all responded to treatments with either steroids, anti-fungals or both.

Lung transplant outcomes in white and African American recipients: special focus on acute and chronic rejection.

BACKGROUND: The effects of lung transplant recipient race on post-transplant outcomes have not been adequately evaluated. This cohort study seeks to determine the characteristics of African American lung transplant recipients and the effects of African American race on post-transplant outcomes, particularly acute and chronic rejection, compared with white recipients, at a single center. METHODS: There were 485 first-time lung transplantations (431 white, 47 African American, 5 Hispanic and 2 Asian recipients) performed at the University of Pennsylvania between 1991 and 2006. All white and African American recipients were compared based on pre-transplant diagnoses and post-transplant survival. The cohort from 1998 to 2006 (239 white and 25 African American recipients) was also compared based on acute rejection score (ARS) and development of bronchiolitis obliterans syndrome (BOS). RESULTS: Chronic obstructive pulmonary disease was the most common diagnosis leading to lung transplantation in both groups, but sarcoidosis was a much more common indication in African American recipients (white, 1%; African American, 28%; p < 0.001). Survival was similar in the two groups (white vs African American groups: 1 month, 90.0% vs 87.2%; 1 year, 74.9% vs 74.5%; 5 years, 52.3% vs 50.5%, respectively; p = 0.84). Freedom from BOS at 3 years (white, 60.3%; African American, 62.8%; p = 0.30) and ARS per biopsy (white, 0.83 +/- 0.82; African American, 0.63 +/- 0.77; p = 0.31) were similar in both groups. CONCLUSIONS: White and African American patients seek lung transplantation for different diseases, but post-transplant outcomes were found to be similar. Larger, multi-center studies are needed to confirm these results.

Selection of candidates for lung transplantation.

The selection of candidates for lung transplantation requires an appreciation of the natural history of lung disease to determine when the disease has entered an advanced and imminently life-threatening stage. It also requires an understanding of the impact of preexisting medical comorbidities on transplant outcomes. Finally, selection is influenced by the particular metric by which outcomes are judged to be successful (e.g., maximizing short-term net survival benefit versus maximizing post-transplant longevity). This article will discuss general and disease-specific criteria used to select patients for lung transplantation and determine the appropriate timing of listing. It will highlight current guidelines put forth by the International Society of Heart and Lung Transplantation and will explore the published data upon which these guidelines are based.

Association between elevated whole blood Epstein-Barr virus (EBV)-encoded RNA EBV polymerase chain reaction and reduced incidence of acute lung allograft rejection.

BACKGROUND: Accurate functional assessment of patient immunosuppression after solid-organ transplantation remains elusive. Despite therapeutic serum immunosuppressive drug levels many lung transplant recipients still develop allograft rejection. We investigated the hypothesis that detection of latent Epstein-Barr virus (EBV) in peripheral blood may be a functional marker for the net effects of administered immunosuppression. METHODS: A retrospective analysis was performed on data obtained from a prospective trial investigating the ability of a novel EBV polymerase chain reaction (PCR) panel for LMP (latent membrane protein 1), EBNA (EBV nuclear antigen) and EBER (EBV-encoded RNA) to predict future development of post-transplant lymphoproliferative disorder (PTLD). Thirty-one lung transplant patients were followed for up to 2 years after transplantation with EBV PCR panels performed on plasma and whole blood. Patients were assessed for occurrences of Grade 2 or higher acute rejection and episodes of infection. RESULTS: Patients with whole blood EBER-positive PCR had a statistically significant lower incidence (45% vs 83%) of Grade 2 or higher acute allograft rejection than patients with no positive assays (odds ratio [OR] = 0.17, 95% confidence interval [CI] 0.021 to 1.2, p = 0.048). Positive whole blood EBER PCR did not correlate with increased risk for infectious complications (OR = 1.6, 95% CI 0.22 to 11, p = 0.69). CONCLUSIONS: These results suggest that whole blood EBER EBV PCR load may represent an important functional measure of immunosuppression in solid-organ transplant patients.