Pulmonary alveolar proteinosis is a rare lung disorder characterized by an abnormal accumulation of surfactant-derived lipoprotein compounds within the alveoli of the lung. The accumulated substances interfere with the normal gas exchange and expansion of the lungs, ultimately leading to difficulty breathing and a predisposition to developing lung infections. The causes of PAP may be grouped into primary and secondary causes, although the most common cause is a primary autoimmune condition.
The abnormal accumulation of lipoproteinaceous compounds in PAP is due to impaired surfactant regulation and clearance. This is usually related to impaired alveolar macrophage function. In adults, the most common cause of PAP is an autoimmunity to granulocyte-macrophage colony stimulating factor, a critical factor in development of alveolar macrophages. Decreased bioavailability of GM-CSF results in poor alveolar macrophages development and function, which results in accumulation of surfactant and related products. Secondary causes of PAP are those in which the accumulation of lipoproteinaceous compounds is secondary to another disease process. This has been recognized in the settings of certain cancers, lung infections, or environmental exposure to dusts or chemicals. Although the cause of PAP was not originally understood, 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 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. Familial or sporadic inactivating mutations in one of the two parental GATA2 genes produces an autosomal dominant disorder termed GATA2 deficiency. The GATA2gene produces the GATA2 transcription factor which is critical for the embryonic development, maintenance, and functionality of blood-forming, lympathic-forming, and other tissue-forming cells. Individuals with a single GATA2inactivating mutation present with a wide range of disorders including pulmonary alveolar proteinosis. GATA2 mutation-based pulmonary alveolar proteinosis is associated with normal levels of GM-CSF and commonly improves or is avoided in afflicted individuals who successfully receive a hematopoietic stem cell transplantation.
The diagnosis of PAP is made using a combination of a person's symptoms, chest imaging, and microscopic evaluation of lung washing/tissue. Additional testing for serum anti-GM-CSF antibodies are helpful for confirmation. Although both the symptoms and imaging findings are stereotypical and well-described, they are non-specific and indistinguishable from many other conditions. For example, chest x-ray may show alveolar opacities, and a CT may show a crazy paving lung pattern, both of which are seen more commonly in numerous other conditions. Thus, the diagnosis primarily depends on the pathology findings. Lung washings or tissue for histopathologic analysis are most commonly obtained using bronchoalveolar lavage and/or lung biopsy. Characteristic biopsy findings show filling of the alveoli with an amorphous eosinophilic material, which stains strongly positive on PAS stain and the PAS diastase stain. The surrounding alveoli and pulmonary interstitium remain relatively normal. Electron microscopy of the sample, although not typically performed due to impracticality, shows lamellated bodies representing surfactant. An alternative diagnosis with similar histomorphologic findings is Pneumocystis jirovicii pneumonia. Lung washings characteristically yield a fluid which is "milky"composition. Under the microscope, samples show 20-50 micrometer PAS-positive globules on a background of finely granular or amorphous PAS-positive material. There is typically a low numbers of macrophages and inflammatory cells.
Treatment
The standard treatment for PAP is whole-lung lavage, in which the lung is filled with sterile fluid with subsequent removal of the fluid along with the abnormal surfactant material. This is generally effective at improving PAP symptoms, often for a prolonged period of time. Since the mouse discovery noted above, the use of GM-CSF injections has also been attempted, with variable success. Lung transplantation may 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.
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 EnglandJournal 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. The reported treatment of PAP using therapeutic bronchoalveolar lavage was in 1960 by Dr. Jose Ramirez-Rivera at the Veterans' Administration Hospital in Baltimore, who described repeated "segmental flooding" as a means of physically removing the accumulated alveolar material.
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