Pulmonary Alveolar Proteinosis
- Author: Roger B Olade, MD, MPH; Chief Editor: Zab Mosenifar, MD more...
Background
Pulmonary alveolar proteinosis (PAP) is a rare lung disorder of unknown etiology characterized by alveolar filling with floccular material that stains positive using the periodic acid-Schiff (PAS) method and is derived from surfactant phospholipids and protein components (see the image below). PAP was first described in 1958.[1]
A periodic acid-Schiff histochemical stain of transbronchial biopsy: Alveolar spaces contain considerable amounts of granular material. Two forms are recognized, (1) primary (idiopathic) and (2) secondary; due to lung infections, hematologic malignancies and inhalation of mineral dusts such as silica, titanium oxide, aluminum, indium-tin oxide and insecticides. Incidence of PAP is increased in patients with hematologic malignancies and AIDS, suggesting a relationship with immune dysfunction. Associations with Niemann-Pick disease[2] and myelodysplastic syndrome[3] have been reported.
A similar disorder affects neonates deficient in surfactant-associated protein B (SP-B).
The discovery that PAP may be related to granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies or GM-CSF deficiency has been noted.
Pathophysiology
The alveoli in pulmonary alveolar proteinosis (PAP) are filled with proteinaceous material, which has been analyzed extensively and determined to be normal surfactant composed of lipids and surfactant-associated proteins A, B, C, and D (SP-A, SP-C, SP-D). Evidence exists of a defect in the homeostatic mechanism of either the production of surfactant or the clearance by alveolar macrophages and the mucociliary elevator. A clear relationship has been demonstrated between PAP and impaired macrophage maturation or function, which might account for the high association with malignancies and unusual infections, eg, infection with Nocardia asteroides.
Studies of genetically altered mice ("knock-out mice") with targeted gene deletions for GM-CSF yielded animals with PAP-like disease. GM-CSF has been demonstrated to increase the effectiveness of alveolar macrophages in the catabolism of surfactant. Recent studies have demonstrated the presence of neutralizing autoantibodies against GM-CSF in patients with PAP. Also documented is that alveolar macrophages from some PAP patients have decreased levels of the transcription factor peroxisome proliferator-activated receptor–gamma (PPAR-gamma), which normalize after treatment with GM-CSF.[4]
Epidemiology
Frequency
United States
PAP has an estimated prevalence of 1 case per 100,000 population.
International
Frequency is believed to be similar to that in the United States, but notification systems do not exist.
Mortality/Morbidity
Mortality rates of as high as 30% within several years of disease onset have been reported previously, but the actual mortality rate may be less than 10%. Solitary pulmonary PAP is increasingly being seen and may resolve spontaneously over several months.
The natural history of secondary PAP depends on the underlying etiologic entity.
Race
Isolated studies have reported predominance in patients of Arabian origin, but no other definitive studies are available.
Sex
Incidence for males is 4 times higher than for females.
Age
Patients are typically aged 20-50 years at presentation.
Rosen SH, Castleman B, Liebow AA. Pulmonary alveolar proteinosis. N Engl J Med. Jun 5 1958;258(23):1123-42. [Medline].
Griese M, Brasch F, Aldana VR, Cabrera MM, Goelnitz U, Ikonen E, et al. Respiratory disease in Niemann-Pick type C2 is caused by pulmonary alveolar proteinosis. Clin Genet. Feb 2010;77(2):119-30. [Medline].
Xue Y, Han Y, Li T, Chen S, Zhang J, Pan J, et al. Pulmonary alveolar proteinosis as a terminal complication in a case of myelodysplastic syndrome with idic(20q-). Acta Haematol. 2010;123(1):55-8. [Medline].
Bonfield TL, Farver CF, Barna BP, Malur A, Abraham S, Raychaudhuri B, et al. Peroxisome proliferator-activated receptor-gamma is deficient in alveolar macrophages from patients with alveolar proteinosis. Am J Respir Cell Mol Biol. Dec 2003;29(6):677-82. [Medline].
Wardwell NR Jr, Miller R, Ware LB. Pulmonary alveolar proteinosis associated with a disease-modifying antirheumatoid arthritis drug. Respirology. Sep 2006;11(5):663-5. [Medline].
Suzuki T, Sakagami T, Young LR, et al. Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy. Am J Respir Crit Care Med. Nov 15 2010;182(10):1292-304. [Medline]. [Full Text].
Bonfield TL, John N, Barna BP, Kavuru MS, Thomassen MJ, Yen-Lieberman B. Multiplexed particle-based anti-granulocyte macrophage colony stimulating factor assay used as pulmonary diagnostic test. Clin Diagn Lab Immunol. Jul 2005;12(7):821-4. [Medline].
Carraway MS, Ghio AJ, Carter JD, Piantadosi CA. Detection of granulocyte-macrophage colony-stimulating factor in patients with pulmonary alveolar proteinosis. Am J Respir Crit Care Med. Apr 2000;161(4 Pt 1):1294-9. [Medline].
Godwin JD, Müller NL, Takasugi JE. Pulmonary alveolar proteinosis: CT findings. Radiology. Dec 1988;169(3):609-13. [Medline].
Murayama S, Murakami J, Yabuuchi H, Soeda H, Masuda K. "Crazy paving appearance" on high resolution CT in various diseases. J Comput Assist Tomogr. Sep-Oct 1999;23(5):749-52. [Medline].
Choi HK, Park CM, Goo JM, Lee HJ. Pulmonary alveolar proteinosis versus exogenous lipoid pneumonia showing crazy-paving pattern: Comparison of their clinical features and high-resolution CT findings. Acta Radiol. May 2010;51(4):407-12. [Medline].
Tazawa R, Trapnell BC, Inoue Y, Arai T, Takada T, Nasuhara Y, et al. Inhaled Granulocyte/Macrophage-Colony Stimulating Factor as Therapy of Pulmonary Alveolar Proteinosis. Am J Respir Crit Care Med. Feb 18 2010;[Medline].
Abdul Rahman JA, Moodley YP, Phillips MJ. Pulmonary alveolar proteinosis associated with psoriasis and complicated by mycobacterial infection: successful treatment with granulocyte-macrophage colony stimulating factor after a partial response to whole lung lavage. Respirology. Aug 2004;9(3):419-22. [Medline].
Anders P. Pulmonary Alveolar Proteinosis. In: Fishman AP, Elia JA, Fishman JA, Grippi MA, Kaiser LR, Senior RM, eds. Fishman's Pulmonary Diseases and Disorders. 3rd ed. New York, NY: McGraw-Hill; 1998:1223-9.
Carey B, Trapnell BC. The molecular basis of pulmonary alveolar proteinosis. Clin Immunol. Mar 24 2010;[Medline].
Crocker HL, Pfitzner J, Doyle IR, Hague WM, Smith BJ, Ruffin RE. Pulmonary alveolar proteinosis: two contrasting cases. Eur Respir J. Feb 2000;15(2):426-9. [Medline].
Cummings KJ, Donat WE, Ettensohn DB, Roggli VL, Ingram P, Kreiss K. Pulmonary alveolar proteinosis in workers at an indium processing facility. Am J Respir Crit Care Med. Mar 1 2010;181(5):458-64. [Medline].
Ioachimescu OC, Kavuru MS. Pulmonary alveolar proteinosis. Chron Respir Dis. 2006;3(3):149-59. [Medline].
Kitamura T, Uchida K, Tanaka N, Tsuchiya T, Watanabe J, Yamada Y, et al. Serological diagnosis of idiopathic pulmonary alveolar proteinosis. Am J Respir Crit Care Med. Aug 2000;162(2 Pt 1):658-62. [Medline].
Presneill JJ, Nakata K, Inoue Y, Seymour JF. Pulmonary alveolar proteinosis. Clin Chest Med. Sep 2004;25(3):593-613, viii. [Medline].
Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med. Jul 15 2002;166(2):215-35. [Medline].
Venkateshiah SB, Thomassen MJ, Kavuru MS. Pulmonary alveolar proteinosis. Clinical manifestations and optimal treatment strategies. Treat Respir Med. 2004;3(4):217-27. [Medline].

