Frailty and patient centered outcomes in candidates for lung transplantation

项目摘要/摘要 对于患有终末期肺部疾病的成人，肺移植旨在延长生存时间，缓解 残疾，并改善与健康有关的生活质量。2005年器官分配政策的全面改革 优先考虑在不影响一年存活率的情况下对病情较重的老年人和老年人进行肺移植--主要措施 移植的效果。然而，这种彻底改革是付出了巨大代价的，包括最近的趋势 残疾增加，HRQL更差，长期死亡率增加。迫切需要区别对待 有可能在手术后存活的候选人的残疾和HRQL有所改善，并确定了新的信息丰富的预 移植因素，以帮助候选人的决策。最近，我们发现脆弱很普遍，而且 与残疾相关的。与其他实体器官移植群体相比，只有两个成熟的 脆弱的衡量标准预测了肺移植候选人等待死亡/退市的风险。另外，我们的早期 数据表明，已建立的衡量脆弱程度的标准可能会被肺部疾病混淆，导致 分类错误。我们还表明，代表脆弱可能途径的蛋白质生物标记物(即系统性 炎症、衰老和恶病质)是肺移植候选患者的重要因素。这些通路是否会导致 虚弱在不同的肺部疾病中是普遍存在的，或者是虚弱的亚型(所谓的 具有不同的病理生物学、结果风险和治疗反应的内型)是未知的。在此，我们 建议在美国三个大型肺移植中心进行前瞻性队列研究，以解决三个基本和 脆弱可能给肺移植领域带来启示的新领域。在624名肺移植患者中，我们将 评估现有的脆弱指标以及绩效、生物标记物和拟人化指标(包括 石棺减少症)与肺部疾病有关。在这些候选人中，480人最终将接受移植 我们将在移植一年后评估存活率、残疾和HRQL。在目标1中，我们将使用运营性 肺疾病相关脆弱域的测量以设计一种新的肺移植脆弱指数。我们 假设这一指数将比现有措施更好地量化脆弱可归因于压力源的脆弱性 在社区居住的老年人口中开发。在目标2中，我们将利用潜在类分析(LCA)来 识别脆弱的内在类型。我们假设考虑临床和生物标记物测量的LCA 导致虚弱的机制将识别肺部疾病中不同的内型。在目标3中，我们将开发一种临床 建立预测模型，以确定肺移植后有残疾、HRQL差和死亡风险的人。我们假设 与不包括脆弱的模型相比，包含脆弱的模型将更好地预测残疾和HRQL改善的患者的存活率。 总而言之，这项提议将产生一种与接受肺移植的成年人相关的新的虚弱衡量标准， 可能，那些患有肺部疾病的人正在接受其他大手术；这将为 肺部疾病虚弱的病理生物学；最后，通过考虑生存和以患者为中心的结果，将 建立一个预测模型，以一种目前不可能的方式，立即帮助做出明智的决策。

PROJECT ABSTRACT/SUMMARY For adults suffering from from end-stage lung disease, lung transplantation aims to extend survival, relieve disability, and improve health-related quality of life (HRQL). An overhaul in organ allocation policy in 2005 prioritized lung transplant for sicker and older adults without impacting one-year survival – the primary measure of transplant efficacy. This overhaul has come at substantial cost, however, including recent trends towards increased disability, poorer HRQL, and increased longer-term mortality. There is an urgent need to discriminate candidates likely to survive after surgery with improved disability and HRQL and to identify new informative pre- transplant factors to aid in candidacy decision-making. Recently, we found that frailty was prevalent and associated with disability. In contrast to other solid organ transplant populations, only one of two well-established measures of frailty predicted risk of waitlist death/delisting in lung transplant candidates. Additionally, our early data suggests that established measures of frailty may be confounded by lung disease, resulting in misclassification. We also showed that protein biomarkers representing putative pathways of frailty (i.e., systemic inflammation, aging, and cachexia) are important in lung transplant candidates. Whether the pathways causing frailty are universal across heterogeneous lung diseases or whether sub-phenotypes of frailty (so called “endotypes”) with distinct pathobiology, outcome risks, and treatment responses exist are unknown. Herein, we propose a prospective cohort study in three large U.S. lung transplant centers to address three fundamental and new areas in which frailty may inform the field of lung transplantation. In 624 lung transplant candidates, we will assess existing frailty measures as well as performance, biomarker, and anthropomorphic measures (including sarcopenia) relevant in lung disease. Of these candidates, 480 will ultimately undergo transplantation in whom we will evaluate survival, disability, and HRQL one year after transplant. In Aim 1, we will use operational measures of frailty domains relevant in lung disease to design a novel frailty index for lung transplantation. We hypothesize that this index will better quantify frailty-attributable vulnerability to stressors than existing measures developed in community-dwelling older adult populations. In Aim 2, we will utilize latent class analysis (LCA) to identify endotypes of frailty. We hypothesize that LCA that considers clinical and biomarker measures of mechanisms driving frailty will identify distinct endotypes in lung disease. In Aim 3, we will develop a clinical prediction model to identify those at risk for disability, poor HRQL, and death after lung transplant. We hypothesize that a model that includes frailty will better predict survival with improved disability and HRQL than a model without. In sum, this proposal will yield a novel measure of frailty relevant for adults undergoing lung transplantation and, possibly, those with lung disease undergoing other major surgeries; will provide new knowledge into the pathobiology of frailty in lung disease; and, finally, by considering survival and patient-centered outcomes, will yield a prediction model that will immediately aid informed decision making in a way that is not presently possible.