Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of surfactant in pulmonary alveoli resulting in respiratory failure and increased infection risk in most patients due to the defective granulocyte/macrophage-colony stimulating factor (GM-CSF) signaling. Disruption is caused by GM-CSF autoantibodies (GMAbs) in autoimmune PAP (aPAP) accounting for 90% of cases or by mutations in the GM-CSF receptor a or p genes [CSF2RA, CSF2RB] in hereditary PAP (hPAP) in 5% or less. Historically, a diagnosis of PAP has required a lung biopsy. However, while a lung biopsy can determine if PAP is present, it cannot identify the disease responsible and therefore does not inform prognosis or therapeutic alternatives. This is a critical limitation since therapeutic options, treatment responses, and prognosis vary widely depending on which disease caused PAP. We developed a set of blood tests that can diagnose aPAP and hPAP with high specificity and sensitivity. We recently developed an approach using a dried blood spot card (DBSC) for blood collection, which patients can use to collect their own samples and send them by mail in an envelope to the test center. While a pivotal study has demonstrated that inhaled GM-CSF therapy of aPAP is effective, further studies are needed to optimize the protocol in a larger group of patients. Importantly, to translate these novel findings into clinical practice, it will be necessary to organize the PAP patient community and establish the natural history of PAP. The long term goal of this research is to improve the diagnosis and therapy of PAP. The objectives of this application are to evaluate blood-based diagnostics, identify novel disease mechanisms and HLA associations. measure the incidence and prevalence of PAP in the United States (US), and define the natural history of aPAP and hPAP. Our central hypothesis is that an observational study with cross-sectional and longitudinal components will inform the epidemiology, pathogenesis, and natural history of PAP and will facilitate the conduct of planned, future therapeutic trials in people with PAP. This hypothesis will be addressed in the following Aims.
In Aim 1, we will optimize and validate DBSC testing for the diagnosis of aPAP and study the epidemiology of PAP in the US.
In Aim 2, we will identify human alleles associated with an increased risk of developing PAP.
In Aim 3, we will utilize DSBC testing to conduct prospective, longitudinal observation study to evaluate the natural history of PAP. Anticipated results will validate novel blood-tests for the diagnosis of PAP, and identify new mutation(s) as a novel cause of hPAP, define the incidence and prevalence of PAP, potential HLA allele-specific associations of aPAP, and comprise the first prospective natural history study of PAP. This project will impact the field by transforming how PAP is diagnosed: using a simple, inexpensive, self-administered test that improves access for patients in remote locations, and by organizing the patient community for planned therapeutic trials. Finally, we will help organize the PAP patient community for planned therapeutic trials by creating a National PAP registry using inexpensive methods integrated with our CCTST.
We will validate a novel blood test for diagnosis of aPAP, define the incidence and prevalence of PAP in the US, improve knowledge of PAP pathogenesis, identify aPAP-specific HLA allelic associations, and comprise the first prospective natural history study of PAP. These results will impact the field by transforming how PAP is diagnosed - using a simple, inexpensive, self-administered test that improves access for patients in remote locations, and by organizing the patient community for planned therapeutic trials.
|Vicary, Glenn W; Vergne, Yeidyly; Santiago-Cornier, Alberto et al. (2016) Pulmonary Fibrosis in Hermansky-Pudlak Syndrome. Ann Am Thorac Soc 13:1839-1846|
|Sahin, Mustafa; Henske, Elizabeth P; Manning, Brendan D et al. (2016) Advances and Future Directions for Tuberous Sclerosis Complex Research: Recommendations From the 2015 Strategic Planning Conference. Pediatr Neurol 60:1-12|
|O'Brien, Kevin J; Lozier, Jay; Cullinane, Andrew R et al. (2016) Identification of a novel mutation in HPS6 in a patient with hemophilia B and oculocutaneous albinism. Mol Genet Metab 119:284-287|
|El-Chemaly, Souheil; Young, Lisa R (2016) Hermansky-Pudlak Syndrome. Clin Chest Med 37:505-11|
|Fan, Leland L; Dishop, Megan K; Galambos, Csaba et al. (2015) Diffuse Lung Disease in Biopsied Children 2 to 18 Years of Age. Application of the chILD Classification Scheme. Ann Am Thorac Soc 12:1498-505|
|Saito, Atsushi; Nikolaidis, Nikolaos M; Amlal, Hassane et al. (2015) Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment. Sci Transl Med 7:313ra181|
|Trapnell, Bruce C (2015) A lymphocyte-mediated cause of secondary PAP. Blood 125:215-6|
|Suzuki, Takuji; Arumugam, Paritha; Sakagami, Takuro et al. (2014) Pulmonary macrophage transplantation therapy. Nature 514:450-4|