Clinical manifestations and etiology of pulmonary alveolar proteinosis in adults
- Edward D Chan, MD
Edward D Chan, MD
- Professor of Medicine
- National Jewish Health
- Talmadge E King, Jr, MD
Talmadge E King, Jr, MD
- Editor-in-Chief — Pulmonary and Critical Care Medicine
- Section Editor — Interstitial Lung Disease
- Dean, School of Medicine
- Vice Chancellor, Medical Affairs
- University of California San Francisco
Pulmonary alveolar proteinosis (PAP), also known as pulmonary alveolar phospholipoproteinosis, is a diffuse lung disease characterized by the accumulation of amorphous, periodic acid-Schiff (PAS)-positive lipoproteinaceous material in the distal air spaces [1-3]. There is little or no lung inflammation, and the underlying lung architecture is preserved. The lipoproteinaceous material is composed principally of the phospholipid surfactant and surfactant apoproteins.
The etiology, pathogenesis, and clinical manifestations of PAP in adults will be reviewed here. The presentation and management of PAP in children and the diagnosis, treatment, and prognosis of PAP in adults are discussed separately. (See "Pulmonary alveolar proteinosis in children" and "Diagnosis and treatment of pulmonary alveolar proteinosis in adults".)
ETIOLOGY AND PATHOGENESIS
●The congenital form often presents in the neonatal period and is likely related to mutations in the genes for surfactant, the granulocyte macrophage-colony stimulating factor (GM-CSF) receptor, or a defect in the plasma membrane transport of cationic amino acids (known as lysinuric protein intolerance). (See "Pulmonary alveolar proteinosis in children".)
●The acquired form of PAP is the most common; it is associated with a high prevalence of anti-GM-CSF antibodies that are believed to contribute to macrophage dysfunction and impaired processing of surfactant.
- ROSEN SH, CASTLEMAN B, LIEBOW AA. Pulmonary alveolar proteinosis. N Engl J Med 1958; 258:1123.
- Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med 2003; 349:2527.
- Presneill JJ, Nakata K, Inoue Y, Seymour JF. Pulmonary alveolar proteinosis. Clin Chest Med 2004; 25:593.
- Carey B, Trapnell BC. The molecular basis of pulmonary alveolar proteinosis. Clin Immunol 2010; 135:223.
- Buechner HA, Ansari A. Acute silico-proteinosis. A new pathologic variant of acute silicosis in sandblasters, characterized by histologic features resembling alveolar proteinosis. Dis Chest 1969; 55:274.
- Miller RR, Churg AM, Hutcheon M, Lom S. Pulmonary alveolar proteinosis and aluminum dust exposure. Am Rev Respir Dis 1984; 130:312.
- Keller CA, Frost A, Cagle PT, Abraham JL. Pulmonary alveolar proteinosis in a painter with elevated pulmonary concentrations of titanium. Chest 1995; 108:277.
- Prakash UB, Barham SS, Carpenter HA, et al. Pulmonary alveolar phospholipoproteinosis: experience with 34 cases and a review. Mayo Clin Proc 1987; 62:499.
- Cordonnier C, Fleury-Feith J, Escudier E, et al. Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients. Am J Respir Crit Care Med 1994; 149:788.
- Tsushima K, Koyama S, Saitou H, et al. Pulmonary alveolar proteinosis in a patient with chronic myelogenous leukemia. Respiration 1999; 66:173.
- McDonald JW, Alvarez F, Keller CA. Pulmonary alveolar proteinosis in association with household exposure to fibrous insulation material. Chest 2000; 117:1813.
- Cummings KJ, Donat WE, Ettensohn DB, et al. Pulmonary alveolar proteinosis in workers at an indium processing facility. Am J Respir Crit Care Med 2010; 181:458.
- Cummings KJ, Nakano M, Omae K, et al. Indium lung disease. Chest 2012; 141:1512.
- Shaughnessy GF, Lee AS. Pulmonary Alveolar Proteinosis, Barbecue Smoke, and Granulocyte-macrophage Colony-stimulating Factor Therapy. Am J Med 2016; 129:e7.
- Dranoff G, Crawford AD, Sadelain M, et al. Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science 1994; 264:713.
- Huffman JA, Hull WM, Dranoff G, et al. Pulmonary epithelial cell expression of GM-CSF corrects the alveolar proteinosis in GM-CSF-deficient mice. J Clin Invest 1996; 97:649.
- Reed JA, Ikegami M, Cianciolo ER, et al. Aerosolized GM-CSF ameliorates pulmonary alveolar proteinosis in GM-CSF-deficient mice. Am J Physiol 1999; 276:L556.
- Nishinakamura R, Nakayama N, Hirabayashi Y, et al. Mice deficient for the IL-3/GM-CSF/IL-5 beta c receptor exhibit lung pathology and impaired immune response, while beta IL3 receptor-deficient mice are normal. Immunity 1995; 2:211.
- Dirksen U, Nishinakamura R, Groneck P, et al. Human pulmonary alveolar proteinosis associated with a defect in GM-CSF/IL-3/IL-5 receptor common beta chain expression. J Clin Invest 1997; 100:2211.
- Bewig B, Wang XD, Kirsten D, et al. GM-CSF and GM-CSF beta c receptor in adult patients with pulmonary alveolar proteinosis. Eur Respir J 2000; 15:350.
- Martinez-Moczygemba M, Doan ML, Elidemir O, et al. Pulmonary alveolar proteinosis caused by deletion of the GM-CSFRalpha gene in the X chromosome pseudoautosomal region 1. J Exp Med 2008; 205:2711.
- Suzuki T, Sakagami T, Rubin BK, et al. Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA. J Exp Med 2008; 205:2703.
- 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 2000; 161:1294.
- Kitamura T, Tanaka N, Watanabe J, et al. Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor. J Exp Med 1999; 190:875.
- Uchida K, Nakata K, Trapnell BC, et al. High-affinity autoantibodies specifically eliminate granulocyte-macrophage colony-stimulating factor activity in the lungs of patients with idiopathic pulmonary alveolar proteinosis. Blood 2004; 103:1089.
- Kitamura T, Uchida K, Tanaka N, et al. Serological diagnosis of idiopathic pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2000; 162:658.
- Bonfield TL, Russell D, Burgess S, et al. Autoantibodies against granulocyte macrophage colony-stimulating factor are diagnostic for pulmonary alveolar proteinosis. Am J Respir Cell Mol Biol 2002; 27:481.
- Latzin P, Tredano M, Wüst Y, et al. Anti-GM-CSF antibodies in paediatric pulmonary alveolar proteinosis. Thorax 2005; 60:39.
- Seymour JF, Presneill JJ, Schoch OD, et al. Therapeutic efficacy of granulocyte-macrophage colony-stimulating factor in patients with idiopathic acquired alveolar proteinosis. Am J Respir Crit Care Med 2001; 163:524.
- Inoue Y, Trapnell BC, Tazawa R, et al. Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan. Am J Respir Crit Care Med 2008; 177:752.
- Uchida K, Beck DC, Yamamoto T, et al. GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis. N Engl J Med 2007; 356:567.
- Doerschuk CM. Pulmonary alveolar proteinosis--is host defense awry? N Engl J Med 2007; 356:547.
- Bonfield TL, Farver CF, Barna BP, et al. Peroxisome proliferator-activated receptor-gamma is deficient in alveolar macrophages from patients with alveolar proteinosis. Am J Respir Cell Mol Biol 2003; 29:677.
- Alberti A, Luisetti M, Braschi A, et al. Bronchoalveolar lavage fluid composition in alveolar proteinosis. Early changes after therapeutic lavage. Am J Respir Crit Care Med 1996; 154:817.
- Gonzalez-Rothi RJ, Harris JO. Pulmonary alveolar proteinosis. Further evaluation of abnormal alveolar macrophages. Chest 1986; 90:656.
- Brasch F, Birzele J, Ochs M, et al. Surfactant proteins in pulmonary alveolar proteinosis in adults. Eur Respir J 2004; 24:426.
- Nogee LM, Garnier G, Dietz HC, et al. A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. J Clin Invest 1994; 93:1860.
- Mildenberger E, deMello DE, Lin Z, et al. Focal congenital alveolar proteinosis associated with abnormal surfactant protein B messenger RNA. Chest 2001; 119:645.
- Hoffman RM, Dauber JH, Rogers RM. Improvement in alveolar macrophage migration after therapeutic whole lung lavage in pulmonary alveolar proteinosis. Am Rev Respir Dis 1989; 139:1030.
- Poletti V, Costabel U, Casoni GL, et al. Rare infiltrative lung diseases: a challenge for clinicians. Respiration 2004; 71:431.
- Santamaria F, Brancaccio G, Parenti G, et al. Recurrent fatal pulmonary alveolar proteinosis after heart-lung transplantation in a child with lysinuric protein intolerance. J Pediatr 2004; 145:268.
- Palacín M, Borsani G, Sebastio G. The molecular bases of cystinuria and lysinuric protein intolerance. Curr Opin Genet Dev 2001; 11:328.
- Parto K, Mäki J, Pelliniemi LJ, Simell O. Abnormal pulmonary macrophages in lysinuric protein intolerance. Ultrastructural, morphometric, and x-ray microanalytic study. Arch Pathol Lab Med 1994; 118:536.
- Parto K, Kallajoki M, Aho H, Simell O. Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients. Hum Pathol 1994; 25:400.
- Goldstein LS, Kavuru MS, Curtis-McCarthy P, et al. Pulmonary alveolar proteinosis: clinical features and outcomes. Chest 1998; 114:1357.
- Shah PL, Hansell D, Lawson PR, et al. Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis. Thorax 2000; 55:67.
- Bedrossian CW, Luna MA, Conklin RH, Miller WC. Alveolar proteinosis as a consequence of immunosuppression. A hypothesis based on clinical and pathologic observations. Hum Pathol 1980; 11:527.
- Witty LA, Tapson VF, Piantadosi CA. Isolation of mycobacteria in patients with pulmonary alveolar proteinosis. Medicine (Baltimore) 1994; 73:103.
- Martin RJ, Rogers RM, Myers NM. PUlmonary alveolar proteinosis: shunt fraction and lactic acid dehydrogenase concentration as aids to diagnosis. Am Rev Respir Dis 1978; 117:1059.
- Honda Y, Takahashi H, Shijubo N, et al. Surfactant protein-A concentration in bronchoalveolar lavage fluids of patients with pulmonary alveolar proteinosis. Chest 1993; 103:496.
- Kuroki Y, Tsutahara S, Shijubo N, et al. Elevated levels of lung surfactant protein A in sera from patients with idiopathic pulmonary fibrosis and pulmonary alveolar proteinosis. Am Rev Respir Dis 1993; 147:723.
- Honda Y, Kuroki Y, Shijubo N, et al. Aberrant appearance of lung surfactant protein A in sera of patients with idiopathic pulmonary fibrosis and its clinical significance. Respiration 1995; 62:64.
- Honda Y, Kuroki Y, Matsuura E, et al. Pulmonary surfactant protein D in sera and bronchoalveolar lavage fluids. Am J Respir Crit Care Med 1995; 152:1860.
- Hirakata Y, Kobayashi J, Sugama Y, Kitamura S. Elevation of tumour markers in serum and bronchoalveolar lavage fluid in pulmonary alveolar proteinosis. Eur Respir J 1995; 8:689.
- Fujishima T, Honda Y, Shijubo N, et al. Increased carcinoembryonic antigen concentrations in sera and bronchoalveolar lavage fluids of patients with pulmonary alveolar proteinosis. Respiration 1995; 62:317.
- Usui Y, Takayama S, Nakayama M, et al. Interstitial lattice shadow and mediastinal lymphadenopathy with an elevation of carcinoembryonic antigen in severe pulmonary alveolar proteinosis. Intern Med 1992; 31:422.
- Holbert JM, Costello P, Li W, et al. CT features of pulmonary alveolar proteinosis. AJR Am J Roentgenol 2001; 176:1287.
- Wasserman K, Mason GR. Pulmonary alveolar proteinosis. In: Textbook of Respiratory Medicine, 2nd ed, Murray JF, Nadel JA (Eds), WB Saunders Co, Philadelphia 1994. p.1933.
- Claypool WD, Rogers RM, Matuschak GM. Update on the clinical diagnosis, management, and pathogenesis of pulmonary alveolar proteinosis (phospholipidosis). Chest 1984; 85:550.
- Miller PA, Ravin CE, Smith GJ, Osborne DR. Pulmonary alveolar proteinosis with interstitial involvement. AJR Am J Roentgenol 1981; 137:1069.
- Hudson AR, Halprin GM, Miller JA, Kilburn KH. Pulmonary interstitial fibrosis following alveolar proteinosis. Chest 1974; 65:700.
- Ishii H, Trapnell BC, Tazawa R, et al. Comparative study of high-resolution CT findings between autoimmune and secondary pulmonary alveolar proteinosis. Chest 2009; 136:1348.
- Johkoh T, Itoh H, Müller NL, et al. Crazy-paving appearance at thin-section CT: spectrum of disease and pathologic findings. Radiology 1999; 211:155.
- Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med 2002; 166:215.
- Chou CW, Lin FC, Tung SM, et al. Diagnosis of pulmonary alveolar proteinosis: usefulness of papanicolaou-stained smears of bronchoalveolar lavage fluid. Arch Intern Med 2001; 161:562.
- Lin FC, Chen YC, Chang SC. Clinical importance of bronchoalveolar lavage fluid and blood cytokines, surfactant protein D, and Kerbs von Lungren 6 antigen in idiopathic pulmonary alveolar proteinosis. Mayo Clin Proc 2008; 83:1344.