Retrospective Autoimmune PAP Natural History and Patient-Reported Outcomes Study

摘要 尽管我们对自身免疫性肺泡蛋白沉积症（aPAP）的认识取得了巨大进展， 巨噬细胞功能障碍、肺泡表面活性物质积聚和低氧性呼吸衰竭，无纵向研究 已经定义了其自然史，尚未在aPAP患者中验证临床或患者报告的结局指标， 目前还没有FDA批准的治疗方法。目前，aPAP的治疗方法是全肺灌洗，这是一种侵入性的， 需要全身麻醉和机械通气的低效手术，旨在物理去除多余的 表面活性剂，用每肺50升盐水冲洗。我们阐明了aPAP的发病机制，建立了一个 准确的血液检测诊断现在作为金标准，并参加了多个临床试验， 吸入GM-CSF是一种有前途的aPAP药物治疗方法。尽管如此，一个定义不清的自然历史（就 疾病进展）和缺乏有效的结果测量是药物开发的关键障碍。 本建议的目的是利用我们现有的美国国家PAP登记处进行回顾性自然史 aPAP研究，根据患者的功能、治疗要求和程度定义疾病进展 肺损伤的严重程度;并开发和测试新的工具来测量和监测aPAP肺严重程度的变化 疾病中心假设是，使用结果测量来定义aPAP的自然史， 患者的感觉、功能和呼吸是其肺部疾病严重程度的函数， 临床结果将加速aPAP的药物开发。拟议研究的基本原理是 定义aPAP自然史的信息的可用性和反映患者感受的结果指标 和功能（和生活质量）将通过提供更合适的临床 试验终点和如何解释它们的知识。我们计划在3个具体目标中解决这个假设：1）行为 回顾性、纵向、基于病历的aPAP自然史研究; 2）开发和测试新患者- 报告的结局指标-反映患者感觉、功能（和质量）的aPAP疾病严重程度评分（aPAP-DSS） 他们对补充氧气治疗的需求，以及对气体交换受损的客观测量（ 肺二氧化碳弥散量（DLCO%）; 3）开发和测试一种新的患者报告结局指标 aPAP疾病严重程度（5分钟台阶试验）的患者能够更好地引出/证明氧输送受损， 六分钟步行测试。拟议中的研究是创新的，因为它代表了对现有研究的显著偏离。 方法（例如，横断面研究和临床试验终点的使用未在aPAP中得到验证， 患者的感觉、功能或生存），并开发和测试测量疾病的工具 严重度（aPAP-DSS）和远程测量功能限制（5分钟步进试验）预期具有较小变异性， 比6分钟步行测试更敏感。拟议中的研究将推动该领域的发展，因为它将克服 开发aPAP药物治疗的关键障碍。此外，有待开发/测试的新工具 可用于评估aPAP以外的肺部疾病，包括各种罕见和常见的肺部疾病。

ABSTRACT Despite enormous advances in our understanding of autoimmune pulmonary alveolar proteinosis (aPAP), a rare disorder of macrophage dysfunction, alveolar surfactant accumulation, and hypoxemic respiratory failure, no longitudinal studies have defined its natural history, no clinical or patient-reported outcome measures have been validated in aPAP patients, and no FDA-approved therapy is currently available. Currently, aPAP is treated by whole lung lavage, an invasive, inefficient procedure requiring general anesthesia and mechanical ventilation that aims to physically remove the excess surfactant by washing it out with up to 50 litters saline per lung. We elucidated the pathogenesis of aPAP, established an accurate blood test for diagnosis now serving as the gold-standard, and participated in multiple clinical trials identifying inhaled GM-CSF as a promising pharmacotherapy of aPAP. Notwithstanding, a poorly defined natural history (in terms of disease progression) and lack of validated outcome measures are critical barriers to pharmacotherapeutic development. The objective of this proposal is to use our existing US National PAP Registry to conduct a retrospective natural history study of aPAP to define disease progression in terms of how patients, function, their treatment requirements and degree of lung impairment; and to develop and test novel tools to measure and monitor changes in the severity of aPAP lung disease. The central hypothesis is that defining the natural history of aPAP using an outcome measure incorporating how patients feel, function, and breathe as a function of the severity of their lung disease and developing tools to measure clinical outcomes will accelerate pharmacotherapeutic development for aPAP. The rationale for the proposed research is that availability of information defining the natural history of aPAP and outcome measures reflecting how patients feel and function (and quality of life) will accelerate pharmacotherapeutic development by providing more appropriate clinical trial end points and knowledge how to interpret them. We plan to address this hypothesis in 3 Specific Aims: 1) conduct of a retrospective, longitudinal, medical chart-based natural history study of aPAP; 2) develop and test a novel patient- reported outcome measure - aPAP disease severity score (aPAP-DSS) that reflects how patients feel, function (and quality of life), their requirement for supplemental oxygen therapy, and an objective measure of impairment in gas exchange (the diffusing capacity of the lungs for carbon dioxide (DLCO%); 3) develop and test a novel patient-reported outcome measure of aPAP disease severity (5-minute step test) better able to elicit/demonstrate the impairment in oxygen delivery than the six-minute walk test. The proposed research is innovative because it represents a marked departure from existing approaches (e.g., cross-sectional studies and use of clinical trial end points not validated in aPAP that don’t reflect how patients feel, function, or survive) by defining the natural history, and developing and testing tools to measure disease severity (aPAP-DSS) and remotely measure functional limitation (5-minute step test) expected to have less variability and greater sensitivity than the 6-minute walk test. The proposed research will move the field forward because it will overcome critical barriers to the development of pharmacotherapeutics for aPAP. Further, the novel tools to be developed/tested may be useful for evaluation of lung diseases beyond aPAP, including a variety of rare and common lung diseases.