Retrospective Autoimmune PAP Natural History and Patient-Reported Outcomes Study

点击翻译按钮获取中文摘要

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.