Specialty pulmonology ICD-9-CM 516.0 MedlinePlus 000114 | ICD-10 J84.0 DiseasesDB 29642 | |
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OMIM 265120 610913 610921 610910 | ||
Pulmonary alveolar proteinosis (abbreviated PAP), is a rare lung disease in which abnormal accumulation of pulmonary surfactant occurs within the alveoli, interfering with gas exchange. PAP can occur in a primary form or secondarily in the settings of malignancy (especially in myeloid leukemia), pulmonary infection, or environmental exposure to dusts or chemicals. Rare familial forms have also been recognized, suggesting a genetic component in some cases.
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Signs and symptoms
The symptoms of PAP include:
The clinical course of PAP is unpredictable. Spontaneous remission is recognized; some patients have stable symptoms. Death may occur due to progression of PAP or due to the underlying disease associated with PAP. Individuals with PAP are more vulnerable to infection of the lung by bacteria or fungi.
Mechanism
Although the cause of PAP remains obscure, a major breakthrough in the understanding of the cause of the disease came by the chance observation that mice bred for experimental study to lack a hematologic growth factor known as granulocyte-macrophage colony stimulating factor (GM-CSF) developed a pulmonary syndrome of abnormal surfactant accumulation resembling human PAP.
The implications of this finding are still being explored, but significant progress was reported in February, 2007. Researchers in that report discussed the presence of anti-GM-CSF autoantibodies in patients with PAP, and duplicated that syndrome with the infusion of these autoantibodies into mice.
Genetics
Abnormalities in CSF2 receptor alpha have been shown to cause hereditary pulmonary alveolar proteinosis. This gene is located on chromosome 5 in the 5q31 region. This gene product is also known as granulocyte macrophage colony-stimulating factor receptor.
Diagnosis
Chest x-rays of affected individuals typically reveal nonspecific alveolar opacities. Diagnosis is generally made by surgical or endoscopic biopsy of the lung, revealing the distinctive pathologic finding. The current gold standard of PAP diagnosis involves histopathological examination of alveolar specimens obtained from bronchoalveolar lavage and transbronchial lung biopsy.
Microscopically, the distal air spaces are filled with a granular, eosinophilic material that is positive with the PAS stain and the PAS diastase stain. The main histomorphologic differential diagnosis is pulmonary edema, which does not have dense bodies.
An ELISA to measure antibodies against GM-CSF has been validated for routine clinical diagnosis of autoimmune PAP.
Treatment
The first advance in the treatment of Pulmonary Alveolar Proteinosis came in November 1960, when Dr. Jose Ramirez-Rivera at the Veterans' Administration Hospital in Baltimore applied repeated "segmental flooding" as a means of physically removing the accumulated alveolar material.
The standard treatment for PAP is whole-lung lavage, in which sterile fluid is instilled into the lung and then removed, along with the abnormal surfactant material. This is generally effective at ameliorating symptoms, often for prolonged periods. Since the mouse discovery noted above, the use of GM-CSF injections has also been attempted, with variable success. Lung transplantation can be performed in refractory cases.
Epidemiology
The disease is more common in males and in tobacco smokers.
In a recent epidemiologic study from Japan, Autoimmune PAP has an incidence and prevalence higher than previously reported and is not strongly linked to smoking, occupational exposure, or other illnesses.
Endogenous lipoid pneumonia and non-specific interstitial pneumonitis has been seen prior to the development of PAP in a child.
Clinical Research
PAP is one of the rare lung diseases currently being studied by The Rare Lung Diseases Consortium (RLDC). The RLDC is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), of the National Center for Advancing Translational Sciences (NCATS). The RLDC is dedicated to developing new diagnostics and therapeutics for patients with rare lung diseases, through collaboration between the NIH, patient organizations and clinical investigators.
Patient Registry
PAP patients, families, and caregivers are encouraged to join the NIH Rare Lung Diseases Consortium Contact Registry. This is a privacy protected site that provides up-to-date information for individuals interested in the latest scientific news, trials, and treatments related to rare lung diseases.
History
PAP was first described in 1958 by the physicians Samuel Rosen, Benjamin Castleman, and Averill Liebow. In their case series published in the New England Journal of Medicine on June 7 of that year, they described 27 patients with pathologic evidence of periodic acid Schiff positive material filling the alveoli. This lipid rich material was subsequently recognized to be surfactant.