Multicenter International Cross-Sectional Evaluation of Pulmonary Alveolar Proteinosis Trial

Overview

The purpose of this study is to (1) compare a technically improved assay with an existing assay used to measure serum anti-GM-CSF antibodies in stored serum samples previously obtained from patients diagnosed with either primary, secondary, congenital or idiopathic pulmonary alveolar proteinosis (PAP), other chronic diseases or disease-free, healthy individuals; (2) determine the prevalence and levels of anti-GM-CSF autoantibodies and (3) define the breadth of the autoimmune antibody responses in primary PAP patients from the United States, Japan, Australia, and Europe using previously collected serum samples; and (4) using a chart review approach, compare the clinical, radiologic and laboratory features of primary PAP patients to determine if differences exist among patients in these globally geographically distributed regions.

The Rare Lung Disease Consortium (RLDC), a group of geographically-dispersed clinical research sites, has been established to conduct collaborative clinical research regarding rare lung diseases. The collaborative work includes diagnostic, therapeutic and other studies in patients with pulmonary alveolar proteinosis (PAP), lymphangioleiomyomatosis (LAM), alpha-1 antitrypsin deficiency (AATD), or hereditary interstitial lung diseases. These patients can have delayed or incorrect diagnoses, and sub-optimal clinical management. The present protocol is focused to individuals with PAP. PAP occurs as primary, secondary, congenital and idiopathic forms. RLDC investigators have previously shown that primary PAP is strongly associated with high levels of circulating, neutralizing anti-GM-CSF autoantibodies. Absence of GM-CSF bioactivity is thought to impair alveolar macrophage and blood neutrophil functions including reduced surfactant catabolism (alveolar macrophages - thought to result in surfactant accumulation in primary PAP) and immune dysfunction (neutrophil dysfunction, and possibly macrophage dysfunction - thought to increase the risk of infection in primary PAP). Secondary PAP is caused by an underlying condition believed to impair alveolar macrophage surfactant catabolism. Secondary PAP is related to other conditions, including myelogenous leukemias, infections and environmental exposures. Congenital PAP is caused by mutations in the genes encoding surfactant protein (SP)-B, SP-C or the ABCA3 transporter. Idiopathic PAP is that which results from unknown mechanisms. Anti-GM-CSF autoantibodies appear to be absent in secondary, congenital and idiopathic PAP. This cross sectional study protocol is designed to evaluate the autoimmune aspect of PAP in patients that are currently being followed by clinical investigators in the Rare Lung Disease Consortium (RLDC). The study involves a retrospective chart review and serological analysis of preexisting, stored serum samples from individuals diagnosed with PAP. Thus, this study will not involve any direct interactions or contact with PAP patients or any other study participants. It will yield diagnostic information regarding the use of anti-granulocyte macrophage-colony stimulating factor (GM-CSF) autoantibody testing in patients with PAP. It will also yield information about the extent of the autoimmune response in primary PAP. In addition, the study will compare/contrast the clinical phenotypes of individuals with anti-GM-CSF autoantibody-positive PAP in various regions of the world. A stringent evaluation of the autoimmune aspects of PAP including rigorous anti-GM-CSF antibody testing will provide a better understanding of PAP and is expected to confirm the usefulness of serum anti-GM-CSF antibody testing in the clinical diagnosis of PAP. The study will evaluate the rate of serious or opportunistic infections and other clinical and demographic data from patients in various regions of the world to determine if significant differences exist, which will provide important knowledge regarding infectious and other complications associated with PAP.