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)的了解有了巨大的进步，但这是一种罕见的疾病 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，没有纵向研究 已经确定了其自然病史，没有临床或患者报告的结果在APAP患者中得到验证， 而且目前还没有FDA批准的治疗方法。目前，APAP的治疗方法是全肺灌洗，一种侵入性的， 需要全身麻醉和机械通风的低效程序，旨在物理上去除多余的 表面活性物质，每个肺用多达50升的生理盐水洗掉。我们阐明了APAP的发病机制，建立了 目前，准确的血液检测是诊断的金标准，并参与了多项临床试验 吸入GM-CSF是治疗APAP的一种有前途的药物治疗。尽管如此，一段定义不清的自然历史(就 疾病进展)和缺乏有效的结果衡量标准是药物治疗发展的关键障碍。 这项提议的目的是利用我们现有的美国国家PAP登记处来进行追溯自然历史 APAP研究根据患者的情况、功能、治疗要求和程度来确定疾病进展 开发和测试新的工具来测量和监测APAP肺的严重程度的变化 疾病。中心假设是使用包含如何进行的结果度量来定义APAP的自然历史 患者的感觉、功能和呼吸作为其肺部疾病的严重程度的函数，并开发出测量工具 临床结果将加速APAP药物治疗的发展。建议进行这项研究的理由是 定义APAP自然病史的信息的可用性和反映患者感觉的结果衡量标准 和功能(和生活质量)将加速药物治疗的发展，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一假设：1)行为 对APAP的回顾、纵向、基于医学图表的自然历史研究；2)开发和测试一种新的患者-- 报告结果衡量-APAP疾病严重程度评分(APAP-DSS)，反映患者的感觉、功能(和质量 生命)，他们对补充氧疗的需求，以及气体交换损害的客观衡量标准( 肺对二氧化碳的扩散能力(DLCO%)；3)开发和测试一种新的患者报告的结果测量方法 APAP疾病严重程度(5分钟台阶试验)能更好地引起/证明氧气输送障碍 六分钟步行测试。这项拟议的研究具有创新性，因为它与现有的 方法(例如，未在APAP中验证的横断面研究和临床试验终点的使用，没有反映 患者的感觉、功能或生存)通过定义自然病史、开发和测试工具来测量疾病 严重性(APAP-DSS)和远程测量功能限制(5分钟阶跃测试)预计具有较小的变异性和 比6分钟步行测试更灵敏。拟议中的研究将推动该领域的发展，因为它将克服 发展APAP药物疗法的关键障碍。此外，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.