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Diagnosis and treatment 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: congenital, secondary, and acquired (table 1). A more detailed discussion of the etiology and clinical manifestations of PAP is provided separately. (See "Clinical manifestations and etiology of pulmonary alveolar proteinosis in adults".)

This review will provide an approach to the diagnosis and treatment of PAP. General approaches to adult and pediatric interstitial lung disease 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)".)


Our diagnostic algorithm for suspected PAP is shown in the figure (algorithm 1). When findings suggestive of PAP are noted on HRCT scan in patients with a compatible clinical presentation, we proceed to fiberoptic bronchoscopy to obtain bronchoalveolar lavage (BAL) fluid and, when possible, transbronchoscopic biopsies. Unless contraindicated, transbronchoscopic biopsies should be obtained following the BAL procedure. The diagnosis of PAP is confirmed with a positive PAS stain from BAL or transbronchial biopsy. To exclude the presence of concurrent infection, special stains and cultures for opportunistic infections (eg, Nocardia, mycobacteria, fungi) are also obtained during bronchoscopy. (See "Clinical manifestations and etiology of pulmonary alveolar proteinosis in adults", section on 'Associated infections'.)

A transbronchial or surgical lung biopsy is the definitive diagnostic test for PAP. In many cases, the diagnostic accuracy of PAS staining of fluid obtained by BAL and tissue obtained by transbronchial biopsy has obviated the need for open or thoracoscopic lung biopsy when clinical and CT findings are consistent with the condition [1-7]. As an example, in the largest series, the diagnosis was made by HRCT and BAL in 59 percent; HRCT, BAL and transbronchial biopsy in 34 percent; and video-assisted transthoracic biopsy in 7 percent [8].


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Literature review current through: Nov 2016. | This topic last updated: Tue Mar 24 00:00:00 GMT+00:00 2015.
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  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. Rubinstein I, Mullen JB, Hoffstein V. Morphologic diagnosis of idiopathic pulmonary alveolar lipoproteinosis-revisited. Arch Intern Med 1988; 148:813.
  5. Burkhalter A, Silverman JF, Hopkins MB 3rd, Geisinger KR. Bronchoalveolar lavage cytology in pulmonary alveolar proteinosis. Am J Clin Pathol 1996; 106:504.
  6. Masuda T, Shimura S, Sasaki H, Takishima T. Surfactant apoprotein-A concentration in sputum for diagnosis of pulmonary alveolar proteinosis. Lancet 1991; 337:580.
  7. Wang BM, Stern EJ, Schmidt RA, Pierson DJ. Diagnosing pulmonary alveolar proteinosis. A review and an update. Chest 1997; 111:460.
  8. 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.
  9. Kitamura T, Uchida K, Tanaka N, et al. Serological diagnosis of idiopathic pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2000; 162:658.
  10. 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.
  11. Uchida K, Nakata K, Suzuki T, et al. Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects. Blood 2009; 113:2547.
  12. Lin FC, Chang GD, Chern MS, et al. Clinical significance of anti-GM-CSF antibodies in idiopathic pulmonary alveolar proteinosis. Thorax 2006; 61:528.
  13. 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.
  14. Luisetti M, Rodi G, Perotti C, et al. Plasmapheresis for treatment of pulmonary alveolar proteinosis. Eur Respir J 2009; 33:1220.
  15. Leth S, Bendstrup E, Vestergaard H, Hilberg O. Autoimmune pulmonary alveolar proteinosis: treatment options in year 2013. Respirology 2013; 18:82.
  16. Claypool WD, Rogers RM, Matuschak GM. Update on the clinical diagnosis, management, and pathogenesis of pulmonary alveolar proteinosis (phospholipidosis). Chest 1984; 85:550.
  18. 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.
  19. 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.
  20. Borie R, Danel C, Debray MP, et al. Pulmonary alveolar proteinosis. Eur Respir Rev 2011; 20:98.
  21. 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.
  22. 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.
  23. 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.
  24. Latzin P, Tredano M, Wüst Y, et al. Anti-GM-CSF antibodies in paediatric pulmonary alveolar proteinosis. Thorax 2005; 60:39.
  25. 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.
  26. 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.
  27. Barraclough RM, Gillies AJ. Pulmonary alveolar proteinosis: a complete response to GM-CSF therapy. Thorax 2001; 56:664.
  28. de Vega MG, Sánchez-Palencia A, Ramírez A, et al. GM-CSF therapy in pulmonary alveolar proteinosis. Thorax 2002; 57:837.
  29. 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.
  30. 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.
  31. 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.
  32. Wylam ME, Ten R, Prakash UB, et al. Aerosol granulocyte-macrophage colony-stimulating factor for pulmonary alveolar proteinosis. Eur Respir J 2006; 27:585.
  33. 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.
  34. 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.
  35. Parker LA, Novotny DB. Recurrent alveolar proteinosis following double lung transplantation. Chest 1997; 111:1457.
  36. Kavuru MS, Bonfield TL, Thomassen MJ. Plasmapheresis, GM-CSF, and alveolar proteinosis. Am J Respir Crit Care Med 2003; 167:1036; author reply 1036.
  37. Borie R, Debray MP, Laine C, et al. Rituximab therapy in autoimmune pulmonary alveolar proteinosis. Eur Respir J 2009; 33:1503.
  38. 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.
  39. Garber B, Albores J, Wang T, Neville TH. A plasmapheresis protocol for refractory pulmonary alveolar proteinosis. Lung 2015; 193:209.
  40. 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.
  41. 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.
  42. Gaine SP, O'Marcaigh AS. Pulmonary alveolar proteinosis: lung transplant or bone marrow transplant? Chest 1998; 113:563.
  43. Goldstein LS, Kavuru MS, Curtis-McCarthy P, et al. Pulmonary alveolar proteinosis: clinical features and outcomes. Chest 1998; 114:1357.