Medscape is available in 5 Language Editions – Choose your Edition here.


Pulmonary Alveolar Proteinosis Workup

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

Laboratory Studies

Serologic studies are generally not useful for pulmonary alveolar proteinosis (PAP). Flexible bronchoscopy with bronchoalveolar lavage (BAL) remains the criterion standard. Elevated levels of the proteins SP-A and SP-D in serum and BAL fluid may be useful. Elevated titer of neutralizing autoantibody against GM-CSF (immunoglobulin G [IgG] isotype) in serum and BAL fluid may be useful. Recent studies have proposed that deficiency of GM-CSF causes pulmonary alveolar proteinosis (PAP); all patients studied had the antibody to GM-CSF.[11, 12] Serum lactate dehydrogenase (LDH) level is usually elevated, but this finding is nonspecific.

Recent studies have shown a correlation between the levels of some tumor markers such as carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and squamous cell carcinoma (SCC) and severity of PAP.[13]

The diagnosis can be made by BAL only if PAS staining is requested. Therefore, PAP is probably underdiagnosed.

Lung biopsy findings are classic for PAP. Alveoli are filled with nonfoamy material. Transbronchial biopsies are adequate, and open lung biopsy is not required.


Imaging Studies

Chest radiography in pulmonary alveolar proteinosis (PAP) shows bilateral perihilar infiltrates with consolidation in a "bat-wing" configuration, which may mimic pulmonary edema, although with a typical absence of cardiomegaly or pleural effusion. Unilateral involvement occurs occasionally, and lymphadenopathy is rarely present. Typically, changes progress over weeks to months into a diffuse reticulogranular pattern.

High-resolution computed tomography (HRCT) scan of the chest demonstrates areas of patchy ground-glass opacification with smooth interlobular septal thickening and intralobular interstitial thickening, which produces a polygonal pattern referred to as "crazy paving." The crazy-paving pattern also can be observed in exogenous lipoid pneumonia, sarcoidosis, mucinous bronchoalveolar cell carcinoma, and acute respiratory distress syndrome (ARDS).[14, 15] PAP may also present as ground-glass opacity (GGO), mimicking carcinoma.[16] HRCT findings have been able to show several distinctive differences between exogenous lipoid pneumonia and PAP, which had previously only been distinguished pathologically.[17]



Bronchoscopy with transbronchial biopsy and BAL may be helpful. Transbronchial biopsies of affected lung segments, coupled with findings on BAL, are sufficient to make the diagnosis. Use PAS reagent for BAL. Bronchoalveolar lavage fluid appears "milky." Papanicolaou staining may reveal green and orange globules that are diagnostic for PAP. Electron microscopy of BAL may reveal characteristic multilamellar structures.

Transbronchial biopsy may increase the yield. Surgical lung biopsy rarely is necessary for definitive diagnosis.


Histologic Findings

Light microscopy of the lung parenchymal tissue shows alveoli filled with a granular PAS base-reactive and diastase-resistant eosinophilic material. Electron microscopy of the material in the alveoli shows multilamellated structures and membranous vesicles.

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.
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.