Assessing the accuracy of the lung allocation score.

BACKGROUND: The United States (US) Lung Allocation Score (LAS) relies on the performance of 2 survival models that estimate waitlist and post-transplant survival. These models were developed using data from 2005 to 2008, and it is unknown if they remain accurate. METHODS: We performed an observational cohort study of US lung transplantation candidates and recipients greater than 12 years of age between February 19, 2015 and February 19, 2019. We evaluated the LAS waitlist and post-transplant models with the concordance probability estimate and by comparing predicted vs observed 1-year restricted mean survival times by risk decile. We then compared a nonparametric estimate of the observed LAS with the predicted LAS for each percentile of recipients. RESULTS: The waitlist model ranked candidates (N = 11,539) in the correct risk order 72% of the time (95% CI 71%-73%), and underestimated candidate one-year survival by 136 days for the highest risk decile (p < 0.001). The post-transplant model ranked recipients (N = 9,377) in the correct risk order 57% of the time (95% CI 55-58%), and underestimated recipient one-year survival by 70 days for the highest risk decile (p < 0.001). Overall, the LAS at transplant explained only 56% of the variation in observed outcomes, and was increasingly inaccurate at higher predicted values. CONCLUSIONS: The waitlist and the post-transplant models that constitute the LAS are inaccurate, limiting the ability of the system to rank candidates on the waitlist in the correct order. The LAS should therefore be updated and the underlying models should be modernized.

Association of Transplant Center With Survival Benefit Among Adults Undergoing Heart Transplant in the United States.

Importance: In the United States, the number of deceased donor hearts available for transplant is limited. As a proxy for medical urgency, the US heart allocation system ranks heart transplant candidates largely according to the supportive therapy prescribed by transplant centers. Objective: To determine if there is a significant association between transplant center and survival benefit in the US heart allocation system. Design, Setting, and Participants: Observational study of 29 199 adult candidates for heart transplant listed on the national transplant registry from January 2006 through December 2015 with follow-up complete through August 2018. Exposures: Transplant center. Main Outcomes and Measures: The survival benefit associated with heart transplant as defined by the difference between survival after heart transplant and waiting list survival without transplant at 5 years. Each transplant center's mean survival benefit was estimated using a mixed-effects proportional hazards model with transplant as a time-dependent covariate, adjusted for year of transplant, donor quality, ischemic time, and candidate status. Results: Of 29 199 candidates (mean age, 52 years; 26% women) on the transplant waiting list at 113 centers, 19 815 (68%) underwent heart transplant. Among heart transplant recipients, 5389 (27%) died or underwent another transplant operation during the study period. Of the 9384 candidates who did not undergo heart transplant, 5669 (60%) died (2644 while on the waiting list and 3025 after being delisted). Estimated 5-year survival was 77% (interquartile range [IQR], 74% to 80%) among transplant recipients and 33% (IQR, 17% to 51%) among those who did not undergo heart transplant, which is a survival benefit of 44% (IQR, 27% to 59%). Survival benefit ranged from 30% to 55% across centers and 31 centers (27%) had significantly higher survival benefit than the mean and 30 centers (27%) had significantly lower survival benefit than the mean. Compared with low survival benefit centers, high survival benefit centers performed heart transplant for patients with lower estimated expected waiting list survival without transplant (29% at high survival benefit centers vs 39% at low survival benefit centers; survival difference, -10% [95% CI, -12% to -8.1%]), although the adjusted 5-year survival after transplant was not significantly different between high and low survival benefit centers (77.6% vs 77.1%, respectively; survival difference, 0.5% [95% CI, -1.3% to 2.3%]). Overall, for every 10% decrease in estimated transplant candidate waiting list survival at a given center, there was an increase of 6.2% (95% CI, 5.2% to 7.3%) in the 5-year survival benefit associated with heart transplant. Conclusions and Relevance: In this registry-based study of US heart transplant candidates, transplant center was associated with the survival benefit of transplant. Although the adjusted 5-year survival after transplant was not significantly different between high and low survival benefit centers, compared with centers with survival benefit significantly below the mean, centers with survival benefit significantly above the mean performed heart transplant for recipients who had significantly lower estimated expected 5-year waiting list survival without transplant.

Geographic Variation in the Treatment of U.S. Adult Heart Transplant Candidates.

BACKGROUND: The current U.S. priority ranking for heart candidates is based on treatment intensity, not objective markers of severity of illness. This system may encourage centers to overtreat candidates. OBJECTIVES: This study sought to describe national variation in the intensity of treatment of adult heart transplantation candidates and identify center-level predictors of potential overtreatment. METHODS: The registrations of all U.S. adult heart transplantation candidates from 2010 to 2015 were collected from the SRTR (Scientific Registry of Transplant Recipients). "Potential overtreatment" was defined as treatment of a candidate who did not meet American Heart Association cardiogenic shock criteria with either high-dose inotropes or an intra-aortic balloon pump. Multilevel logistic regression and propensity score models were used to adjust for candidate variability at each center. Center-level variables associated with potential overtreatment were identified. RESULTS: From 2010 to 2015, 108 centers listed 12,762 adult candidates who were not in cardiogenic shock for heart transplantation. Of these, 1,471 (11.6%) were potentially overtreated with high-dose inotropes or intra-aortic balloon pumps. In the bottom quartile of centers, only 2.1% of candidates were potentially overtreated compared with 27.6% at top quartile centers, an interquartile difference of 25.5% (95% confidence interval: 21% to 30%). Adjusting for candidate differences did not significantly alter the interquartile difference. Local competition with 2 or more centers increased the odds of potential overtreatment by 50% (adjusted odds ratio: 1.50; 95% confidence interval: 1.07 to 2.11). CONCLUSIONS: There is wide variation in the treatment practices of adult heart transplantation centers. Competition for transplantable donor hearts is associated with the potential overtreatment of hemodynamically stable candidates. Overtreatment may compromise the fair and efficient allocation of scarce deceased donor hearts.

Trends in the Use of Inotropes to List Adult Heart Transplant Candidates at Status 1A.

BACKGROUND: The number of adult heart transplant candidates waiting at the most urgent status 1A has increased over time despite the expansion of geographic sharing of hearts in 2006. We aimed to determine whether candidates listed with inotropes contribute to the excess status 1A candidates. METHODS AND RESULTS: The initial registrations of all adult heart-only candidates listed from 2000 to 2015 were analyzed using the Scientific Registry of Transplant Recipients data set. Trends in listing status, justifications, and candidate factors were measured. Adjusted trends in listing status pre- and post-geographic sharing were estimated using multilevel logistic regression. Competing risks models provided trends in transplant-free waitlist survival. There were 46 853 adult heart-alone listings during 2000 to 2015. Pre-sharing, status 1A listing was unchanged over time (adjusted odds ratio, 0.98; 95% confidence interval, 0.78-1.23). Post-sharing, the adjusted odds of status 1A listing increased 117% over 9 years (adjusted odds ratio 2.17, 95% confidence interval, 1.82-2.58). The number of candidates listed as status 1A with inotropes increased by 193 a year, whereas the dobutamine, dopamine, and milrinone doses used decreased 49%, 55%, and 29% (P<0.001). The risk of waitlist death or deterioration of status 1A inotrope candidates relative to status 2 candidates decreased 62% for 2006 to 2010 and 70% for 2011 to 2015 compared with that for 2003 to 2006. CONCLUSIONS: After the wider geographic sharing of hearts in 2006, transplant programs used multiple inotropes to list candidates at status 1A more frequently with progressively lower doses. Concurrently, the status 1A inotrope candidate waitlist outcomes improved substantially. These trends suggest that overtreatment with multiple inotropes contributes to the current critical excess of status 1A candidates.

Lung Transplantation: The State of the Airways.

CONTEXT: Lung transplantation has become a viable option for definitive treatment of several end-stage lung diseases for which there are no other options available. However, long-term survival continues to be limited by chronic lung allograft dysfunction, which primarily affects the airways. OBJECTIVE: To highlight the complications occurring mainly in the airways of the lung transplant recipient from the early to late posttransplant periods. DATA SOURCES: Review literature focusing on the airways in patients with lung transplants and clinical experience of the authors. CONCLUSIONS: Postsurgical complications and infections of the airways have decreased because of better techniques and management. Acute cellular rejection of the airways can be distinguished from infection pathologically and on cultures. Separating small from large airways need not be an issue because both are risk factors for bronchiolitis obliterans. Grading of airway rejection needs to be standardized. Chronic lung allograft dysfunction consists of both bronchiolitis obliterans and restrictive allograft syndrome, neither of which can be treated very effectively at present.

Impact of the lung allocation score.

The number of donors falls short of the number of patients on the wait list for lung transplantation making it necessary to ration the available donor organs. The ideal allocation system is guided by ethical principles and scientifically accurate at identifying patients who will gain the greatest degree of benefit from receiving the organ, in terms of both pre- and posttransplantation survival. The lung allocation score (LAS) was developed in 2005 to reduce mortality on the wait list, prioritize candidates based on urgency, minimize the role of geography, and maximize transplant benefit. The LAS has not made much of an impact on the geographic disparity of listing patients for lung transplantation, but it did achieve the goal of reducing wait-list mortality and prioritizing patients based on urgency. In prioritizing patients with the most urgent status, a new controversy has come into the forefront: whether or not the increased number of critically ill recipients maximizes transplant benefit. Despite the controversy, the LAS system is an improvement compared with the traditional first-come, first-served system, and it has even been adopted by Eurotransplant. In the future, as modifications are made to improve the LAS, the issue of critically ill patients and maximizing posttransplant benefit will be the focus.

Decreased incidence of cytomegalovirus infection with sirolimus in a post hoc randomized, multicenter study in lung transplantation.

BACKGROUND: Cytomegalovirus (CMV) is the most common opportunistic infection in lung transplantation. A recent multicenter, randomized trial (the AIRSAC study) comparing sirolimus to azathioprine in lung transplant recipients showed a decreased incidence of CMV events in the sirolimus cohort. To better characterize this relationship of decreased incidence of CMV events with sirolimus, we examined known risk factors and characteristics of CMV events from the AIRSAC database. METHODS: The AIRSAC database included 181 lung transplant patients from 8 U.S.-based lung transplant centers that were randomized to sirolimus or azathioprine at 3 months post-transplantation. CMV incidence, prophylaxis, diagnosis and treatment data were all prospectively collected. Prophylaxis and treatment of CMV were at the discretion of each institution. RESULTS: The overall incidence of any CMV event was decreased in the sirolimus arm when compared with the azathioprine arm at 1 year after lung transplantation (relative risk [RR] = 0.67, confidence interval [CI] 0.55 to 0.82, p < 0.01). This decreased incidence of CMV events with sirolimus remained significant after adjusting for confounding factors of CMV serostatus and CMV prophylaxis. CONCLUSIONS: These data support results from other solid-organ transplantation studies and suggest further investigation of this agent in the treatment of lung transplant recipients at high risk for CMV events.

Interobserver variability in grading transbronchial lung biopsy specimens after lung transplantation.

BACKGROUND: Acute rejection remains a major source of morbidity after lung transplantation. Given the importance of this diagnosis, an international grading system was developed to standardize the diagnosis of acute lung-allograft rejection. The reliability of this grading system has not been adequately assessed by previous studies. METHODS: We examined the level of agreement in grading transbronchial biopsy specimens obtained from a large multicenter study (AIRSAC [Comparison of a Tacrolimus/Sirolimus/Prednisone Regimen vs Tacrolimus/Azathioprine/Prednisone Immunosuppressive Regimen in Lung Transplantation] trial). Biopsy specimens were initially graded for acute rejection and lymphocytic bronchiolitis by the site pathologist and subsequently graded by a central pathologist. Reliability of interobserver grading was evaluated using Cohen κ coefficients. RESULTS: A total of 481 transbronchial biopsy specimens were graded by both the site and central pathologists. The overall concordance rates were 74% and 89% for grade A and grade B biopsy specimens, respectively. When samples from biopsies performed at different time points after transplantation were assessed, there was a higher level of agreement early (≤ 6 weeks) after transplant compared with later time points for acute rejection. However, there was still only moderate agreement for both grade A (κ score 0.479; 95% CI, 0.29-0.67) and grade B (κ score 0.465; 95% CI, 0.08-0.85) rejection. CONCLUSIONS: These results expand upon previous reports of interobserver variability in grading transbronchial biopsy specimens after lung transplantation. Given the variability in grading these specimens, we advocate further education of the histopathologic findings in lung transplant biopsy specimens, as well as revisiting the current criteria for grading transbronchial biopsy specimens to improve concordance among lung transplant pathologists. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT00321906; URL: www.clinicaltrials.gov.

SaLUTaRy: survey of lung transplant rejection.

BACKGROUND: The International Society for Heart and Lung Transplantation (ISHLT) guidelines on the interpretation of lung rejection in pulmonary allograft biopsy specimens were revised most recently in 2007. The goal of our study was to determine how these revisions, along with nuances in the interpretation and application of the guidelines, affect patient care. METHODS: A Web-based survey was e-mailed to pathologists and pulmonologists identified as being part of the lung transplant team at institutions in the United States with active lung transplant programs as determined from the Organ Procurement and Transplantation Network Web site (http://optn.transplant.hrsa.gov/members/directory.asp). RESULTS: Grades B1 and B2 in asymptomatic patients would fall into the same treatment group under the 2007 classification, which combines B1 and B2 into B1R. Also, some pulmonologists would not interpret a pathologic diagnosis of lymphocytic bronchiolitis as grade B rejection, resulting in under-treatment of these patients. Regarding bronchiolitis obliterans, most pulmonologists would treat the patient differently if there were an active mononuclear inflammatory infiltrate, and most pathologists would comment on the presence of such an infiltrate, contrary to the 2007 guidelines, which discourage reporting this infiltrate. We also found discrepancies among pathologists in their interpretation of airway lymphocytic infiltrates, whether eosinophils can be present in bronchial-associated lymphoid tissue, and whether airway inflammation represents rejection or bacterial infection. CONCLUSIONS: The issue of grading and treating airway inflammation in pulmonary allograft biopsy specimens continues to be problematic, despite revised ISHLT guidelines. Clarification of guidelines for pathologists and pulmonologists using evidence-based criteria could lead to improved communication and patient care.

Myocardial damage in patients with sarcoidosis and preserved left ventricular systolic function: an observational study.

AIMS: Late gadolinium enhanced cardiovascular magnetic resonance (LGE-CMR) is a valuable test to detect myocardial damage in patients with sarcoidosis; however, the clinical significance of LGE in sarcoidosis patients with preserved left ventricular ejection fraction (LVEF) is not defined. We aim to characterize the prevalence of LGE, its associated cardiac findings, and its clinical implications in sarcoidosis patients with preserved LVEF. METHODS AND RESULTS: One hundred and fifty-two patients with biopsy proven extra-cardiac sarcoidosis, no known cardiac sarcoidosis, and LVEF ≥ 50% referred for LGE-CMR were included in this observational study. The presence of LGE in the left ventricular myocardium was considered diagnostic for cardiac sarcoidosis. The cohort was divided into two groups based on the presence or absence of LGE. Twenty-nine patients (19%) had LGE involving 11 ± 9% of the left ventricle. The modified Japanese Ministry of Health and Welfare (JMHW) criteria for diagnosing cardiac sarcoidosis only had a sensitivity of 52% and specificity of 83% for identifying myocardial LGE in these patients. Compared with those patients without LGE, those with LGE had a higher heart rate (84 ± 19 vs. 76 ± 18 b.p.m., P= 0.002), greater prevalence of an abnormal electrocardiogram (76 vs. 31%, P< 0.001), diastolic dysfunction (67 vs. 33%, P= 0.05), reduced right ventricular ejection fraction (49 ± 8 vs. 55 ± 6%, P= 0.012), and evidence of non-sustained ventricular tachycardia (33 vs. 6%). CONCLUSIONS: In patients with sarcoidosis and preserved systolic function, myocardial damage is commonly present and may increase the risk of ventricular tachy-arrhythmias. The JMHW Criteria were neither sensitive nor specific for predicting the presence of myocardial LGE.

Differentiated transplant derived airway epithelial cell cytokine secretion is not regulated by cyclosporine.

BACKGROUND: While lung transplantation is an increasingly utilized therapy for advanced lung diseases, chronic rejection in the form of bronchiolitis obliterans syndrome (BOS) continues to result in significant allograft dysfunction and patient mortality. Despite correlation of clinical events with eventual development of BOS, the causative pathophysiology remains unknown. Airway epithelial cells within the region of inflammation and fibrosis associated with BOS may have a participatory role. METHODS: Transplant derived airway epithelial cells differentiated in air liquid interface culture were treated with IL-1ß and/or cyclosporine, after which secretion of cytokines and growth factor and gene expression for markers of epithelial to mesenchymal transition were analyzed. RESULTS: Secretion of IL-6, IL-8, and TNF-α, but not TGF-ß1, was increased by IL-1ß stimulation. In contrast to previous studies using epithelial cells grown in submersion culture, treatment of differentiated cells in ALI culture with cyclosporine did not elicit cytokine or growth factor secretion, and did not alter IL-6, IL-8, or TNF-α production in response to IL-1ß treatment. Neither IL-1ß nor cyclosporine elicited expression of markers of the epithelial to mesenchymal transition E-cadherin, EDN-fibronectin, and α-smooth muscle actin. CONCLUSION: Transplant derived differentiated airway epithelial cell IL-6, IL-8, and TNF-α secretion is not regulated by cyclosporine in vitro; these cells thus may participate in local inflammatory responses in the setting of immunosuppression. Further, treatment with IL-1ß did not elicit gene expression of markers of epithelial to mesenchymal transition. These data present a model of differentiated airway epithelial cells that may be useful in understanding epithelial participation in airway inflammation and allograft rejection in lung transplantation.

Lung allocation in the United States.

Lung allocation in the United States has changed significantly with the introduction of the Lung Allocation Score (LAS) system in May 2005. Since then, organ allocation is no longer based on waiting time but on a measure of transplant benefit (the difference between survival with vs without a transplant). The LAS system has met its primary goal of reducing time and mortality on the waiting list. Better understanding of pretransplant factors that influence long-term posttransplant outcomes of the individual patient will be instrumental in improving the LAS system in the future.

Decreased percentage of CD4+FoxP3+ cells in bronchoalveolar lavage from lung transplant recipients correlates with development of bronchiolitis obliterans syndrome.

BACKGROUND: Lung transplantation, in patients with end-stage lung disease, is limited by chronic rejection, which occurs with an incidence and severity exceeding most other transplanted organs. Alloimmune responses play an important role in progression to chronic rejection that manifests as bronchiolitis obliterans syndrome (BOS), but no biomarker can currently predict the progression to BOS. Studies in animal models suggest that intragraft T regulatory cells (Tregs) are important in maintaining transplantation tolerance, and FoxP3 is the protoypic Treg marker. METHODS: Leukocytes in blood and bronchoalveolar lavage (BAL) fluid were compared for expression of FoxP3 by flow cytometry in 14 stable lung transplant recipients and 6 lung transplant recipients who eventually developed BOS. RESULTS: Stable patients, compared with patients who subsequently developed BOS, consistently had a significantly increased percentage of FoxP3 cells among CD4 cells in BAL and greater levels of the Treg-attracting chemokine CCL22. These differences were observed in limited sequential analyses, before, at the time of acute rejection, and postacute rejection. In this pilot study, a threshold of 3.2% CD4/FoxP3 cells in the BAL distinguished stable recipients from those subsequently developing BOS within the first 2 years posttransplantation. CONCLUSION: The proportion of FoxP3 cells among CD4 cells in BAL may help to predict lung allograft outcome and guide therapeutic immunosuppression in lung transplant recipients.

Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations.

BACKGROUND: Telomerase is an enzyme that catalyzes the addition of nucleotides on the ends of chromosomes. Rare loss of function mutations in the gene that encodes the protein component of telomerase (TERT) have been described in patients with idiopathic pulmonary fibrosis (IPF). Here we examine the telomere lengths and pulmonary fibrosis phenotype seen in multiple kindreds with heterozygous TERT mutations. METHODS AND FINDINGS: We have identified 134 individuals with heterozygous TERT mutations from 21 unrelated families. Available medical records, surgical lung biopsies and radiographs were evaluated retrospectively. Genomic DNA isolated from circulating leukocytes has been used to measure telomere lengths with a quantitative PCR assay. We find that telomere lengths of TERT mutation carriers decrease in an age-dependent manner and show progressive shortening with successive generations of mutation inheritance. Family members without TERT mutations have a shorter mean telomere length than normal, demonstrating epigenetic inheritance of shortened telomere lengths in the absence of an inherited TERT mutation. Pulmonary fibrosis is an age-dependent phenotype not seen in mutation carriers less than 40 years of age but found in 60% of men 60 years or older; its development is associated with environmental exposures including cigarette smoking. A radiographic CT pattern of usual interstitial pneumonia (UIP), which is consistent with a diagnosis of IPF, is seen in 74% of cases and a pathologic pattern of UIP is seen in 86% of surgical lung biopsies. Pulmonary fibrosis associated with TERT mutations is progressive and lethal with a mean survival of 3 years after diagnosis. Overall, TERT mutation carriers demonstrate reduced life expectancy, with a mean age of death of 58 and 67 years for males and females, respectively. CONCLUSIONS: A subset of pulmonary fibrosis, like dyskeratosis congenita, bone marrow failure, and liver disease, represents a "telomeropathy" caused by germline mutations in telomerase and characterized by short telomere lengths. Family members within kindreds who do not inherit the TERT mutation have shorter telomere lengths than controls, demonstrating epigenetic inheritance of a shortened parental telomere length set-point.

The impact of the lung allocation score.

The lung allocation score (LAS) was developed in an effort to facilitate lung transplantation to more urgent and ill patients, to decrease wait time, and to change the allocation process to a more merit-based system. Four years after the implementation of the LAS, we now evaluate the impact and outcomes of this system. We have found that registrations on the wait list as well as wait time have decreased. Mortality on the wait list has decreased. There has been significant change in the distribution of diagnoses receiving transplantation with no significant difference in survival in most areas. Patients with higher LAS scores have increased short-term mortality. The LAS has affected the allocation process as well as significant outcomes in the transplant patient population.

Early readmission is a predictor of overall survival following isolated lung transplantation.

Causes of early readmissions following lung transplantation are not well understood, and the impact is poorly reported. We reviewed 221 consecutive lung transplantations and identified patients readmitted within 90 days. A case control analysis was performed to determine the characteristics that predict readmission and the impact of readmission on survival. Ninety (44%) of the 205 operative survivors required a total of 125 readmissions during the 90 days after transplantation. Twenty-eight patients (13.7%) required multiple readmissions. Causes for readmissions were pulmonary complication (59%), gastrointestinal (18%), cardiac (5%), metabolic (2.5%), neurological (2.5%), hematological (2%), and miscellaneous (11%). The sex, native disease, or type of transplant did not predict readmission. Requirement of cardiopulmonary bypass for transplantation showed a trend toward significance (P = 0.08). The 90-day conditional survival at 1, 3, and 5 years for those patients readmitted within 90 days were 76%, 59%, and 52%, respectively, compared to 93%, 80%, and 76% for patients not readmitted (P = 0.01). Requirement for readmission within 90 days following transplantation is associated with increased mortality. Sex, native disease, and type of transplant are not predictors of readmission or survival.