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A1093 - Differential Diagnosis of Pulmonary Alveolar Proteinosis: Lung Biopsy or Blood Test?
Author Block: C. McCarthy1, B. C. Carey2, M. Nowell-Bostic1, M. Rieman-Klingler1, C. Chalk1, A. Toth1, M. Brelsford3, H. Lee3, T. S. Wang4, J. Krischer3, B. C. Trapnell5; 1Translational Pulmonary Science Center, Cincinnati Children's Hospital, Cincinnati, OH, United States, 2Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH, United States, 3University of South Florida, Tampa, FL, United States, 4UCLA Dept of Pulm / Crit Care, Los Angeles, CA, United States, 5Childrens Hosp Medical Ctr, Cincinnati, OH, United States.
Rationale: Pulmonary alveolar proteinosis (PAP) is not a specific disease but rather a rare syndrome of progressive alveolar surfactant accumulation resulting in hypoxemic respiratory failure that occurs in multiple distinct diseases (cause) including; autoimmune PAP (GM-CSF autoantibodies), hereditary/genetic PAP (mutations in genes required for GM-CSF signaling, alveolar macrophage development, surfactant production) and secondary PAP (myelodysplasia and other hematological conditions, toxic inhalation exposures, or infections affecting alveolar macrophage numbers or function). While a lung biopsy has been used historically to diagnose PAP, it cannot specifically identify any PAP-causing disease. GM-CSF autoantibody testing has a sensitivity and specificity of 100% for autoimmune PAP and genetic tests are available for many of hereditary causes. Importantly, autoimmune PAP accounts for ~90% of all patients with PAP. Methods: Participants in the US National PAP Registry were surveyed to determine the method(s) that had been used for the initial diagnosis of PAP. All participants also completed a comprehensive questionnaire and underwent GM-CSF autoantibody testing with a novel dried blood spot card-based test. Results: Among Registry participants with documented PAP for whom complete data was available, 102 registrants were evaluated in this analysis. Eighty percent had undergone prior GM-CSF autoantibody testing prior to enrollment. Of 102 registrants with confirmed PAP, autoimmune PAP was identified by GM-CSF autoantibody testing in 90 (88%), hereditary PAP was identified by genetic testing in 3 patients (from mutations in CSF2RA (2 patients) or ABCA3 (1 patient)), and PAP of unknown cause was present in 9 patients (9%). Eighty-two percent (82%) of patients had undergone lung biopsy testing, 30% had a surgical lung biopsy, 29% had a transbronchial biopsy, and 23% had both a surgical and a transbronchial biopsy prior. Twenty-three percent (23%) of all biopsies performed in Registry participants were non-diagnostic. Importantly, among Registry participants with autoimmune PAP, 28% had previously undergone a non-diagnostic lung biopsy before autoimmune PAP was diagnosed by blood testing. Conclusion: Results demonstrate that among US National PAP Registry participants, the PAP-causing disease was identified in 91% of patients by a GM-CSF autoantibody blood test or genetic testing. These results and previously reported findings support an approach to the differential diagnosis of PAP (in patients with a history and radiological findings compatible with PAP presenting beyond the neonatal period) that includes a GM-CSF autoantibody test followed by genetic testing as indicated clinically with reservation of lung biopsy testing for those individuals in whom the PAP-causing disease remains unidentified.