Alternative titles; symbols
SNOMEDCT: 707443007; ORPHA: 747;
Pulmonary alveolar proteinosis is a pathologic entity characterized by intraalveolar surfactant accumulation. There are 3 clinically distinct forms: hereditary (usually congenital), secondary, and acquired. The acquired form of pulmonary alveolar proteinosis is the most common form, accounting for approximately 90% of cases. The mean age at diagnosis is 39 years and it is associated with smoking in 72% of cases. The estimated incidence and prevalence are 0.36 and 3.70 cases per million, respectively (Trapnell et al., 2003; Seymour and Presneill, 2002).
Secondary pulmonary alveolar proteinosis develops in association with conditions involving functional impairment or reduced numbers of alveolar macrophages. Such conditions include some hematologic cancers, pharmacologic immunosuppression, inhalation of inorganic dust or toxic fumes, and certain infections. Congenital pulmonary alveolar proteinosis is a rare, severe, often fatal disorder of newborns associated with pulmonary surfactant metabolism dysfunction caused by mutations in genes involved in surfactant metabolism (see, e.g., SMDP1, 265120) (Trapnell et al., 2003).
See 300770 for information on congenital PAP due to CSF2RA (306250) deficiency.
Acquired pulmonary alveolar proteinosis was first described by Rosen et al. (1958). There are only rare references to possible familial occurrence (Seard et al., 1970; Tsubura et al., 1974; Webster et al., 1980).
The clinical course of the disease is variable, with most patients presenting as adults with progressive exertional dyspnea and cough. Less commonly, patients may have fever, chest pain, or hemoptysis, especially if secondary infection is present. Inspiratory crackles are present in 50%, cyanosis in 25%, and digital clubbing in a smaller percentage. Chest radiograph shows bilateral patchy airspace disease and ground-glass opacifications with a superimposed interlobular septal and intralobular thickening, a pattern commonly referred to as 'crazy paving.' Lung biopsy shows preserved lung architecture with alveoli filled with granular, eosinophilic PAS-positive material with degenerating macrophages (Trapnell et al., 2003).
Arcasoy and Lanken (2002) reported a 26-year-old man with nonproductive cough, exertional dyspnea, acrocyanosis, and pulse oximetry of 79% when walking. Chest radiography showed patchy alveolar and interstitial disease in a perihilar 'batwing' distribution. High-resolution CT scan showed extensive bilateral air-space disease and a 'crazy paving' appearance within affected airspaces. Pulmonary function tests showed a restrictive ventilatory defect and reduction in lung volume and diffusion capacity. Lung biopsy showed alveolar filling with amorphous, granular eosinophilc material and preserved alveolar septal architecture consistent with pulmonary alveolar proteinosis. Sequential bilateral whole-lung lavage resulted in clinical and radiographic improvement.
Uchida et al. (2007) reported detailed clinical features of 12 patients with PAP. The mean age at diagnosis in pediatric (3 patients) and adult (9 patients) was 14 and 43 years, respectively. Patients presented with either dyspnea of insidious onset or a persistently abnormal chest radiograph suggestive of pneumonia but without response to antibiotics. Six of 9 adults had a history of smoking. Variable features included digital clubbing and polycythemia. Eight patients had opportunistic pulmonary infections, including Nocardia asteroides (2 patients), Mycobacterium avium complex (3 patients), and Mycobacterium tuberculosis (1 patient). All patients had significantly increased serum autoantibodies to granulocyte/macrophage colony-stimulating factor (GMCSF, CSF2; 138960). Whole-lung lavage resulted in significant clinical improvement in all cases.
Acquired pulmonary alveolar proteinosis is virtually always attributable to neutralizing autoantibodies against GMCSF, which prevent the binding of GMCSF to GMCSF receptors on alveolar macrophages (Doerschuk, 2007). The hypothesis that pulmonary alveolar proteinosis is due to ineffective signaling by GMCSF receptors was first put forward by Stanley et al. (1994) and Dranoff et al. (1994), who simultaneously reported mice in which both alleles of the gene for GMCSF was disabled. These Gmcsf -/- mice had striking pulmonary pathologic characteristics that closely resembled those of patients with pulmonary alveolar proteinosis, suggesting that the intracellular signaling initiated by the binding of GMCSF to its receptor is critical to pulmonary surfactant homeostasis. Signaling in macrophages initiated by GMCSF receptors is mediated through hematopoietic transcription factor PU.1 (SPI1; 165170), which modulates the expression of many genes that are important in the terminal differentiation of alveolar macrophages.
In cellular studies, Uchida et al. (2007) found that neutrophil function was impaired in patients with PAP. Although PAP neutrophils had normal ultrastructure and differentiation markers, they showed impaired basal functions and antimicrobial functions at baseline and even in response to administration of GMCSF compared to control cells. The findings supported previous observations that some patients with PAP have a systemic predisposition to opportunistic infections.
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Rosen, S. H., Castleman, B., Liebow, A. A. Pulmonary alveolar proteinosis. New Eng. J. Med. 258: 1123-1142, 1958. [PubMed: 13552931] [Full Text: https://doi.org/10.1056/NEJM195806052582301]
Seard, C., Wasserman, K., Benfield, J. R., Cleveland, R. J., Costley, D. O., Heimlich, E. M. Simultaneous bilateral lung lavage (alveolar washing) using partial cardiopulmonary bypass: report of two cases in siblings. Am. Rev. Resp. Dis. 101: 877-884, 1970. [PubMed: 5419972] [Full Text: https://doi.org/10.1164/arrd.1970.101.6.877]
Seymour, J. F., Presneill, J. J. Pulmonary alveolar proteinosis: progress in the first 44 years. Am. J. Resp. Crit. Care Med. 166: 215-235, 2002. [PubMed: 12119235] [Full Text: https://doi.org/10.1164/rccm.2109105]
Stanley, E., Lieschke, G. J., Grail, D., Metcalf, D., Hodgson, G., Gall, J. A. M., Maher, D. W., Cebon, J., Sinickas, V., Dunn, A. R. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc. Nat. Acad. Sci. 91: 5592-5596, 1994. [PubMed: 8202532] [Full Text: https://doi.org/10.1073/pnas.91.12.5592]
Trapnell, B. C., Whitsett, J. A., Nakata, K. Pulmonary alveolar proteinosis. New Eng. J. Med. 349: 2527-2539, 2003. [PubMed: 14695413] [Full Text: https://doi.org/10.1056/NEJMra023226]
Tsubura, E., Kawase, I., Yamamura, Y. Hereditary metabolic diseases of the lung. Rec. Med. 26: 1727 only, 1974. Note: Cited by: Webster et al.: Am. J. Med. 69: 786-789, 1980.
Uchida, K., Beck, D. C., Yamamoto, T., Berclaz, P.-Y., Abe, S., Staudt, M. K., Carey, B. C., Filippi, M.-D., Wert, S. E., Denson, L. A., Puchalski, J. T., Hauck, D. M., Trapnell, B. C. GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis. New Eng. J. Med. 356: 567-579, 2007. [PubMed: 17287477] [Full Text: https://doi.org/10.1056/NEJMoa062505]
Webster, J. R., Jr., Battifora, H., Furey, C., Harrison, R. A., Shapiro, B. Pulmonary alveolar proteinosis in two siblings with decreased immunoglobulin A. Am. J. Med. 69: 786-789, 1980. [PubMed: 7435514] [Full Text: https://doi.org/10.1016/0002-9343(80)90453-2]