Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Treatment and prognosis of pulmonary alveolar proteinosis in adults

Edward D Chan, MD
Talmadge E King, Jr, MD
Section Editor
Kevin R Flaherty, MD, MS
Deputy Editor
Helen Hollingsworth, MD


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].

The most common symptoms are dyspnea and cough. Radiographic imaging typically reveals bilateral symmetric alveolar opacities located centrally in mid and lower lung zones, often in a "bat wing" distribution. Three forms of PAP are recognized: primary (autoimmune, receptor variants), secondary (hematologic/immunologic disease, inhalational exposures, metabolic), and congenital (surfactant production disorders) (table 1).

The treatment and prognosis of PAP will be reviewed here. General approaches to adult and pediatric interstitial lung disease and the clinical manifestations and diagnosis of pulmonary alveolar proteinosis in adults are described separately. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Approach to the infant and child with diffuse lung disease (interstitial lung disease)" and "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults".)


In order to determine the appropriate treatment, severity of PAP is assessed using a combination of symptoms, serum level of lactic dehydrogenase (LDH), titer of serum antibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in autoimmune PAP, pulmonary function tests, and extent of opacities on high resolution computed tomography (HRCT) imaging [4,5]. Pulmonary function tests, including lung volumes, diffusing capacity, and six-minute walk, are used to assess the degree of impairment and to provide a baseline for long-term monitoring. (See "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults", section on 'Pulmonary function tests'.)

Serial measurements of bronchoalveolar lavage (BAL) or serum antibodies to GM-CSF may prove useful in monitoring disease activity and response to treatment in autoimmune PAP, although further study of this approach is needed [6,7]. In one study, BAL fluid levels of anti-GM-CSF antibodies correlated better with the severity of PAP compared to serum titers [8].

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Sep 2017. | This topic last updated: Aug 08, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Shah PL, Hansell D, Lawson PR, et al. Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis. Thorax 2000; 55:67.
  2. Kariman K, Kylstra JA, Spock A. Pulmonary alveolar proteinosis: prospective clinical experience in 23 patients for 15 years. Lung 1984; 162:223.
  3. Milleron BJ, Costabel U, Teschler H, et al. Bronchoalveolar lavage cell data in alveolar proteinosis. Am Rev Respir Dis 1991; 144:1330.
  4. 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.
  5. Sui X, Du Q, Xu KF, et al. Quantitative assessment of Pulmonary Alveolar Proteinosis (PAP) with ultra-dose CT and correlation with Pulmonary Function Tests (PFTs). PLoS One 2017; 12:e0172958.
  6. Bonfield TL, Kavuru MS, Thomassen MJ. Anti-GM-CSF titer predicts response to GM-CSF therapy in pulmonary alveolar proteinosis. Clin Immunol 2002; 105:342.
  7. Luisetti M, Rodi G, Perotti C, et al. Plasmapheresis for treatment of pulmonary alveolar proteinosis. Eur Respir J 2009; 33:1220.
  8. Lin FC, Chang GD, Chern MS, et al. Clinical significance of anti-GM-CSF antibodies in idiopathic pulmonary alveolar proteinosis. Thorax 2006; 61:528.
  9. Suzuki T, Trapnell BC. Pulmonary Alveolar Proteinosis Syndrome. Clin Chest Med 2016; 37:431.
  10. Zhao YY, Huang H, Liu YZ, et al. Whole Lung Lavage Treatment of Chinese Patients with Autoimmune Pulmonary Alveolar Proteinosis: A Retrospective Long-term Follow-up Study. Chin Med J (Engl) 2015; 128:2714.
  11. Leth S, Bendstrup E, Vestergaard H, Hilberg O. Autoimmune pulmonary alveolar proteinosis: treatment options in year 2013. Respirology 2013; 18:82.
  12. Ohkouchi S, Akasaka K, Ichiwata T, et al. Sequential Granulocyte-Macrophage Colony-Stimulating Factor Inhalation after Whole-Lung Lavage for Pulmonary Alveolar Proteinosis. A Report of Five Intractable Cases. Ann Am Thorac Soc 2017; 14:1298.
  13. Claypool WD, Rogers RM, Matuschak GM. Update on the clinical diagnosis, management, and pathogenesis of pulmonary alveolar proteinosis (phospholipidosis). Chest 1984; 85:550.
  15. Beccaria M, Luisetti M, Rodi G, et al. Long-term durable benefit after whole lung lavage in pulmonary alveolar proteinosis. Eur Respir J 2004; 23:526.
  16. Bonella F, Bauer PC, Griese M, et al. Pulmonary alveolar proteinosis: new insights from a single-center cohort of 70 patients. Respir Med 2011; 105:1908.
  17. Borie R, Danel C, Debray MP, et al. Pulmonary alveolar proteinosis. Eur Respir Rev 2011; 20:98.
  18. Michaud G, Reddy C, Ernst A. Whole-lung lavage for pulmonary alveolar proteinosis. Chest 2009; 136:1678.
  19. Gay P, Wallaert B, Nowak S, et al. Efficacy of Whole-Lung Lavage in Pulmonary Alveolar Proteinosis: A Multicenter International Study of GELF. Respiration 2017; 93:198.
  20. Campo I, Luisetti M, Griese M, et al. Whole lung lavage therapy for pulmonary alveolar proteinosis: a global survey of current practices and procedures. Orphanet J Rare Dis 2016; 11:115.
  21. Tan Z, Tan KT, Poopalalingam R. Anesthetic Management for Whole Lung Lavage in Patients with Pulmonary Alveolar Proteinosis. A A Case Rep 2016; 6:234.
  22. Hammon WE, McCaffree DR, Cucchiara AJ. A comparison of manual to mechanical chest percussion for clearance of alveolar material in patients with pulmonary alveolar proteinosis (phospholipidosis). Chest 1993; 103:1409.
  23. Vymazal T, Krecmerova M. Respiratory strategies and airway management in patients with pulmonary alveolar proteinosis: a review. Biomed Res Int 2015; 2015:639543.
  24. Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med 2002; 166:215.
  25. Kavuru MS, Sullivan EJ, Piccin R, et al. Exogenous granulocyte-macrophage colony-stimulating factor administration for pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2000; 161:1143.
  26. Venkateshiah SB, Yan TD, Bonfield TL, et al. An open-label trial of granulocyte macrophage colony stimulating factor therapy for moderate symptomatic pulmonary alveolar proteinosis. Chest 2006; 130:227.
  27. Latzin P, Tredano M, Wüst Y, et al. Anti-GM-CSF antibodies in paediatric pulmonary alveolar proteinosis. Thorax 2005; 60:39.
  28. Tazawa R, Trapnell BC, Inoue Y, et al. Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2010; 181:1345.
  29. Seymour JF, Dunn AR, Vincent JM, et al. Efficacy of granulocyte-macrophage colony-stimulating factor in acquired alveolar proteinosis. N Engl J Med 1996; 335:1924.
  30. Barraclough RM, Gillies AJ. Pulmonary alveolar proteinosis: a complete response to GM-CSF therapy. Thorax 2001; 56:664.
  31. de Vega MG, Sánchez-Palencia A, Ramírez A, et al. GM-CSF therapy in pulmonary alveolar proteinosis. Thorax 2002; 57:837.
  32. Seymour JF, Doyle IR, Nakata K, et al. Relationship of anti-GM-CSF antibody concentration, surfactant protein A and B levels, and serum LDH to pulmonary parameters and response to GM-CSF therapy in patients with idiopathic alveolar proteinosis. Thorax 2003; 58:252.
  33. Tanner LM, Kurko J, Tringham M, et al. Inhaled Sargramostim Induces Resolution of Pulmonary Alveolar Proteinosis in Lysinuric Protein Intolerance. JIMD Rep 2016.
  34. Khan A, Agarwal R, Aggarwal AN. Effectiveness of granulocyte-macrophage colony-stimulating factor therapy in autoimmune pulmonary alveolar proteinosis: a meta-analysis of observational studies. Chest 2012; 141:1273.
  35. Tazawa R, Hamano E, Arai T, et al. Granulocyte-macrophage colony-stimulating factor and lung immunity in pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2005; 171:1142.
  36. Wylam ME, Ten R, Prakash UB, et al. Aerosol granulocyte-macrophage colony-stimulating factor for pulmonary alveolar proteinosis. Eur Respir J 2006; 27:585.
  37. Robinson TE, Trapnell BC, Goris ML, et al. Quantitative analysis of longitudinal response to aerosolized granulocyte-macrophage colony-stimulating factor in two adolescents with autoimmune pulmonary alveolar proteinosis. Chest 2009; 135:842.
  38. Ohashi K, Sato A, Takada T, et al. Reduced GM-CSF autoantibody in improved lung of autoimmune pulmonary alveolar proteinosis. Eur Respir J 2012; 39:777.
  39. Ohashi K, Sato A, Takada T, et al. Direct evidence that GM-CSF inhalation improves lung clearance in pulmonary alveolar proteinosis. Respir Med 2012; 106:284.
  40. Seymour JF, Begley CG, Dirksen U, et al. Attenuated hematopoietic response to granulocyte-macrophage colony-stimulating factor in patients with acquired pulmonary alveolar proteinosis. Blood 1998; 92:2657.
  41. Borie R, Debray MP, Laine C, et al. Rituximab therapy in autoimmune pulmonary alveolar proteinosis. Eur Respir J 2009; 33:1503.
  42. Amital A, Dux S, Shitrit D, et al. Therapeutic effectiveness of rituximab in a patient with unresponsive autoimmune pulmonary alveolar proteinosis. Thorax 2010; 65:1025.
  43. Kavuru MS, Malur A, Marshall I, et al. An open-label trial of rituximab therapy in pulmonary alveolar proteinosis. Eur Respir J 2011; 38:1361.
  44. Malur A, Kavuru MS, Marshall I, et al. Rituximab therapy in pulmonary alveolar proteinosis improves alveolar macrophage lipid homeostasis. Respir Res 2012; 13:46.
  45. Kavuru MS, Bonfield TL, Thomassen MJ. Plasmapheresis, GM-CSF, and alveolar proteinosis. Am J Respir Crit Care Med 2003; 167:1036; author reply 1036.
  46. Garber B, Albores J, Wang T, Neville TH. A plasmapheresis protocol for refractory pulmonary alveolar proteinosis. Lung 2015; 193:209.
  47. Parker LA, Novotny DB. Recurrent alveolar proteinosis following double lung transplantation. Chest 1997; 111:1457.
  48. Miyazaki T, Tagawa T, Yamasaki N, et al. Two case reports of successful withdrawal of mycofenolate mofetil after living donor lobar lung transplantation. Transplant Proc 2013; 45:356.
  49. Tagawa T, Yamasaki N, Tsuchiya T, et al. Living-donor lobar lung transplantation for pulmonary alveolar proteinosis in an adult: report of a case. Surg Today 2011; 41:1142.
  50. Trukalj M, Perica M, Ferenčić Ž, et al. Successful Treatment of Autoimmune Pulmonary Alveolar Proteinosis in a Pediatric Patient. Am J Case Rep 2016; 17:641.
  51. Mucci A, Kunkiel J, Suzuki T, et al. Murine iPSC-Derived Macrophages as a Tool for Disease Modeling of Hereditary Pulmonary Alveolar Proteinosis due to Csf2rb Deficiency. Stem Cell Reports 2016; 7:292.
  52. Lachmann N, Happle C, Ackermann M, et al. Gene correction of human induced pluripotent stem cells repairs the cellular phenotype in pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2014; 189:167.
  53. 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.
  54. Akasaka K, Tanaka T, Kitamura N, et al. Outcome of corticosteroid administration in autoimmune pulmonary alveolar proteinosis: a retrospective cohort study. BMC Pulm Med 2015; 15:88.
  55. Chaulagain CP, Pilichowska M, Brinckerhoff L, et al. Secondary pulmonary alveolar proteinosis in hematologic malignancies. Hematol Oncol Stem Cell Ther 2014; 7:127.
  56. 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.
  57. Ishii H, Seymour JF, Tazawa R, et al. Secondary pulmonary alveolar proteinosis complicating myelodysplastic syndrome results in worsening of prognosis: a retrospective cohort study in Japan. BMC Pulm Med 2014; 14:37.
  58. Hisata S, Moriyama H, Tazawa R, et al. Development of pulmonary alveolar proteinosis following exposure to dust after the Great East Japan Earthquake. Respir Investig 2013; 51:212.
  59. 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.
  60. Chew R, Nigam S, Sivakumaran P. Alveolar proteinosis associated with aluminium dust inhalation. Occup Med (Lond) 2016; 66:492.
  61. Gaine SP, O'Marcaigh AS. Pulmonary alveolar proteinosis: lung transplant or bone marrow transplant? Chest 1998; 113:563.
  62. Takaki M, Tanaka T, Komohara Y, et al. Recurrence of pulmonary alveolar proteinosis after bilateral lung transplantation in a patient with a nonsense mutation in CSF2RB. Respir Med Case Rep 2016; 19:89.
  63. 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.
  64. Witty LA, Tapson VF, Piantadosi CA. Isolation of mycobacteria in patients with pulmonary alveolar proteinosis. Medicine (Baltimore) 1994; 73:103.
  65. Punatar AD, Kusne S, Blair JE, et al. Opportunistic infections in patients with pulmonary alveolar proteinosis. J Infect 2012; 65:173.
  66. Rosen LB, Rocha Pereira N, Figueiredo C, et al. Nocardia-induced granulocyte macrophage colony-stimulating factor is neutralized by autoantibodies in disseminated/extrapulmonary nocardiosis. Clin Infect Dis 2015; 60:1017.
  67. Chan ED, Iseman MD. Underlying host risk factors for nontuberculous mycobacterial lung disease. Semin Respir Crit Care Med 2013; 34:110.
  68. Goldstein LS, Kavuru MS, Curtis-McCarthy P, et al. Pulmonary alveolar proteinosis: clinical features and outcomes. Chest 1998; 114:1357.
  69. Akira M, Inoue Y, Arai T, et al. Pulmonary Fibrosis on High-Resolution CT of Patients With Pulmonary Alveolar Proteinosis. AJR Am J Roentgenol 2016; 207:544.