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Pulmonary Alveolar Proteinosis Clinical Presentation

  • Author: Roger B Olade, MD, MPH; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
Updated: Dec 17, 2015


Patients with pulmonary alveolar proteinosis (PAP) typically present with a gradual onset of symptoms. As many as 30% of patients are asymptomatic, even with diffuse chest radiograph (CXR) abnormalities. Symptoms include the following:

  • Persistent dry cough (or scant sputum production)
  • Progressive dyspnea
  • Fatigue and malaise
  • Weight loss
  • Intermittent low-grade fever and/or night sweats
  • Pleuritic chest pain
  • Cyanosis (rare)
  • Hemoptysis (rare)


Physical findings are usually nonspecific. Symptoms include the following:

  • Fine end-inspiratory crackles
  • Clubbing (25%)
  • Cyanosis (20%)
  • Pulmonary hypertension and cor pulmonale (rare)


The etiology of pulmonary alveolar proteinosis (PAP) is unknown, but it has been associated with a number of other processes, implying a causal relationship. Causes may include the following:

  • Inhalation of silica dust (acute silicoproteinosis)
  • Exposure to insecticides, aluminum dust, titanium dioxide, indium-tin oxide and other inorganic dusts[5, 6, 7]
  • Hematologic malignancies, mostly myeloid disorders
  • Lysinuric protein intolerance (rare)
  • HIV infection (AIDS)
  • Leflunomide - Case report (disease-modifying antirheumatic arthritis therapy)[8]

Recessive CSF2RA mutations may cause a rare, hereditary form of PAP. GM-CSF signaling may be absent or severely reduced, and the GM-CSF receptor alpha chain may be absent or abnormal, paralleling the GM-CSF signaling defects. This is unlike secondary PAP, in which a deficiency of GM-CSF and increased autoantibodies are noted. Genetic analysis may reveal multiple distinct CSF2RA abnormalities, including missense, duplication, frameshift, and nonsense mutations; exon and gene deletion; and cryptic alternative splicing.[9, 10]

Contributor Information and Disclosures

Roger B Olade, MD, MPH Medical Director, Genesis Health Group

Roger B Olade, MD, MPH is a member of the following medical societies: American College of Occupational and Environmental Medicine, American College of Physicians

Disclosure: Nothing to disclose.


Klaus-Dieter Lessnau, MD, FCCP Clinical Associate Professor of Medicine, New York University School of Medicine; Medical Director, Pulmonary Physiology Laboratory; Director of Research in Pulmonary Medicine, Department of Medicine, Section of Pulmonary Medicine, Lenox Hill Hospital

Klaus-Dieter Lessnau, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Medical Association, American Thoracic Society, Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Oluwatoyin E Ijitola, MD, PhD Dean and Professor, International University for Graduate Studies (IUGS)

Oluwatoyin E Ijitola, MD, PhD is a member of the following medical societies: American Medical Association, American Society of Tropical Medicine and Hygiene, International AIDS Society, American College of Healthcare Executives, HIV Medicine Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Zab Mosenifar, MD, FACP, FCCP Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Zab Mosenifar, MD, FACP, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Thoracic Society

Disclosure: Nothing to disclose.

Additional Contributors

Gregory Tino, MD Director of Pulmonary Outpatient Practices, Associate Professor, Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania Medical Center and Hospital

Gregory Tino, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Thoracic Society

Disclosure: Nothing to disclose.


Gregg T Anders, DO Medical Director, Great Plains Regional Medical Command , Brooke Army Medical Center; Clinical Associate Professor, Department of Internal Medicine, Division of Pulmonary Disease, University of Texas Health Science Center at San Antonio

Disclosure: Nothing to disclose.

Ali Hmidi, MD Staff Physician, Department of Internal Medicine, Brooklyn Hospital Center, Cornell University

Disclosure: Nothing to disclose.

  1. Rosen SH, Castleman B, Liebow AA. Pulmonary alveolar proteinosis. N Engl J Med. 1958 Jun 5. 258(23):1123-42. [Medline].

  2. 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. 2010 Feb. 77(2):119-30. [Medline].

  3. 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].

  4. 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. 2003 Dec. 29(6):677-82. [Medline].

  5. 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. 2010 Mar 1. 181(5):458-64. [Medline]. [Full Text].

  6. Cummings KJ, Nakano M, Omae K, et al. Indium lung disease. Chest. 2012 Jun. 141(6):1512-21. [Medline]. [Full Text].

  7. 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. 2010 Mar 1. 181(5):458-64. [Medline].

  8. Wardwell NR Jr, Miller R, Ware LB. Pulmonary alveolar proteinosis associated with a disease-modifying antirheumatoid arthritis drug. Respirology. 2006 Sep. 11(5):663-5. [Medline].

  9. Suzuki T, Sakagami T, Young LR, et al. Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy. Am J Respir Crit Care Med. 2010 Nov 15. 182(10):1292-304. [Medline]. [Full Text].

  10. Carey B, Trapnell BC. The molecular basis of pulmonary alveolar proteinosis. Clin Immunol. 2010 May. 135(2):223-35. [Medline]. [Full Text].

  11. 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. 2005 Jul. 12(7):821-4. [Medline].

  12. 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 Apr. 161(4 Pt 1):1294-9. [Medline].

  13. Fang SC, Lu KH, Wang CY, Zhang HT, Zhang YM. Elevated tumor markers in patients with pulmonary alveolar proteinosis. Clin Chem Lab Med. 2013 Jan 11. 1-6. [Medline].

  14. Godwin JD, Müller NL, Takasugi JE. Pulmonary alveolar proteinosis: CT findings. Radiology. 1988 Dec. 169(3):609-13. [Medline].

  15. Murayama S, Murakami J, Yabuuchi H, Soeda H, Masuda K. "Crazy paving appearance" on high resolution CT in various diseases. J Comput Assist Tomogr. 1999 Sep-Oct. 23(5):749-52. [Medline].

  16. Sunadome H, Nohara J, Noguchi T, Matsui C, Kono T, Terada Y. [A case of pulmonary alveolar proteinosis that showed solitary ground-glass opacity in the subpleural area]. Nihon Kokyuki Gakkai Zasshi. 2010 Jul. 48 (7):516-9. [Medline].

  17. 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. 2010 May. 51(4):407-12. [Medline].

  18. 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. 2010 Feb 18. [Medline].

  19. Hasan N, Bagga S, Monteagudo J, Hirose H, Cavarocchi NC, Hehn BT, et al. Extracorporeal membrane oxygenation to support whole-lung lavage in pulmonary alveolar proteinosis: salvage of the drowned lungs. J Bronchology Interv Pulmonol. 2013 Jan. 20(1):41-4. [Medline].

  20. 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. 2004 Aug. 9(3):419-22. [Medline].

  21. Rosen LB, Freeman AF, Yang LM, et al. Anti-GM-CSF Autoantibodies in Patients with Cryptococcal Meningitis. J Immunol. 2013 Apr 15. 190(8):3959-66. [Medline].

  22. Trapnell BC, Suzuki T. Pulmonary Alveolar Proteinosis. Fishman AP, Elia JA, Fishman JA, Grippi MA, Kotloff R, Senior RM, Pack A, eds. Fishman's Pulmonary Diseases and Disorders. 5th ed. New York, NY: McGraw-Hill Educational; 2015. 1028-37.

A periodic acid-Schiff histochemical stain of transbronchial biopsy: Alveolar spaces contain considerable amounts of granular material.
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