eMedicine Specialties > Pulmonology > Idiopathic Lung Disorders

Pulmonary Alveolar Proteinosis

Author: Roger B Olade, MD, MPH, Medical Director, Providence Health Group
Coauthor(s): 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; Ali Hmidi, MD, Staff Physician, Department of Internal Medicine, Brooklyn Hospital Center, Cornell University; Oluwatoyin E Ijitola, MD, PhD, Adjunct Professor, International University for Graduate Studies (IUGS)
Contributor Information and Disclosures

Updated: Nov 19, 2008

Introduction

Background

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder of unknown etiology characterized by alveolar filling with floccular material that stains positive using the periodic acid-Schiff (PAS) method and is derived from surfactant phospholipids and protein components (see Media File 1). PAP was first described in 1958.1

Two forms are recognized, (1) primary (idiopathic) and (2) secondary (due to lung infections; hematologic malignancies; and inhalation of mineral dusts such as silica, titanium oxide, aluminum, and insecticides). Incidence of PAP is increased in patients with hematologic malignancies and AIDS, suggesting a relationship with immune dysfunction.

A similar disorder affects neonates deficient in surfactant-associated protein B (SP-B).

The discovery that PAP may be related to granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies or GM-CSF deficiency has been noted.

A related Medscape CME course is Nontuberculous Mycobacteria: Update on Diagnosis and Treatment.

Pathophysiology

The alveoli in pulmonary alveolar proteinosis (PAP) are filled with proteinaceous material, which has been analyzed extensively and determined to be normal surfactant composed of lipids and surfactant-associated proteins A, B, C, and D (SP-A, SP-C, SP-D). Evidence exists of a defect in the homeostatic mechanism of either the production of surfactant or the clearance by alveolar macrophages and the mucociliary elevator. A clear relationship has been demonstrated between PAP and impaired macrophage maturation or function, which might account for the high association with malignancies and unusual infections, eg, infection with Nocardia asteroides.

Studies of genetically altered mice ("knock-out mice") with targeted gene deletions for GM-CSF yielded animals with PAP-like disease. GM-CSF has been demonstrated to increase the effectiveness of alveolar macrophages in the catabolism of surfactant. Recent studies have demonstrated the presence of neutralizing autoantibodies against GM-CSF in patients with PAP. Also documented is that alveolar macrophages from some PAP patients have decreased levels of the transcription factor peroxisome proliferator-activated receptor–gamma (PPAR-gamma), which normalize after treatment with GM-CSF.2

Frequency

United States

PAP has an estimated prevalence of 1 case per 100,000 population.

International

Frequency is believed to be similar to that in the United States, but notification systems do not exist.

Mortality/Morbidity

  • Mortality rates of as high as 30% within several years of disease onset have been reported previously, but the actual mortality rate may be less than 10%. Solitary pulmonary PAP is increasingly being seen and may resolve spontaneously over several months.
  • The natural history of secondary PAP depends on the underlying etiologic entity.

Race

  • Isolated studies have reported predominance in patients of Arabian origin, but no other definitive studies are available.

Sex

  • Incidence for males is 4 times higher than for females.

Age

  • Patients are typically aged 20-50 years at presentation.

Clinical

History

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

Physical findings are usually nonspecific. Symptoms include the following:

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

Causes

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, and other inorganic dusts
  • Hematologic malignancies, mostly myeloid disorders
  • Lysinuric protein intolerance (rare)
  • HIV infection (AIDS)
  • Leflunomide - Case report (disease-modifying antirheumatic arthritis therapy)3

More on Pulmonary Alveolar Proteinosis

Overview: Pulmonary Alveolar Proteinosis
Differential Diagnoses & Workup: Pulmonary Alveolar Proteinosis
Treatment & Medication: Pulmonary Alveolar Proteinosis
Follow-up: Pulmonary Alveolar Proteinosis
Multimedia: Pulmonary Alveolar Proteinosis
References
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References

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

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

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

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

  5. 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. Apr 2000;161(4 Pt 1):1294-9. [Medline].

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

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

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

  9. Anders P. Pulmonary Alveolar Proteinosis. In: Fishman AP, Elia JA, Fishman JA, Grippi MA, Kaiser LR, Senior RM, eds. Fishman's Pulmonary Diseases and Disorders. 3rd ed. New York, NY: McGraw-Hill; 1998:1223-9.

  10. Crocker HL, Pfitzner J, Doyle IR, Hague WM, Smith BJ, Ruffin RE. Pulmonary alveolar proteinosis: two contrasting cases. Eur Respir J. Feb 2000;15(2):426-9. [Medline].

  11. Ioachimescu OC, Kavuru MS. Pulmonary alveolar proteinosis. Chron Respir Dis. 2006;3(3):149-59. [Medline].

  12. Kitamura T, Uchida K, Tanaka N, Tsuchiya T, Watanabe J, Yamada Y, et al. Serological diagnosis of idiopathic pulmonary alveolar proteinosis. Am J Respir Crit Care Med. Aug 2000;162(2 Pt 1):658-62. [Medline].

  13. Presneill JJ, Nakata K, Inoue Y, Seymour JF. Pulmonary alveolar proteinosis. Clin Chest Med. Sep 2004;25(3):593-613, viii. [Medline].

  14. Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med. Jul 15 2002;166(2):215-35. [Medline].

  15. Venkateshiah SB, Thomassen MJ, Kavuru MS. Pulmonary alveolar proteinosis. Clinical manifestations and optimal treatment strategies. Treat Respir Med. 2004;3(4):217-27. [Medline].

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Further Reading

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Keywords

pulmonary alveolar proteinosis, PAP, alveolar filling with floccular material, periodic acid-Schiff, PAS, surfactant-associated protein B deficiency, SP-B deficiency, GM-CSF antibodies, GM-CSF deficiency, inhalation of silica dust, acute silicoproteinosis, insecticide exposure, aluminum dust exposure, titanium dioxide exposure, inorganic dust exposure, hematologic malignancy, myeloid disorder, lysinuric protein intolerance, HIV infection, AIDS

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Contributor Information and Disclosures

Author

Roger B Olade, MD, MPH, Medical Director, Providence Health Group
Roger B Olade, MD, MPH is a member of the following medical societies: American College of Occupational and Environmental Medicine and American College of Physicians
Disclosure: Nothing to disclose.

Coauthor(s)

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 Society for Artificial Internal Organs, American Thoracic Society, Physicians for Social Responsibility, and Society of Critical Care Medicine
Disclosure: sepracor Ownership interest None

Ali Hmidi, MD, Staff Physician, Department of Internal Medicine, Brooklyn Hospital Center, Cornell University
Disclosure: Nothing to disclose.

Oluwatoyin E Ijitola, MD, PhD, Adjunct Professor, International University for Graduate Studies (IUGS)
Oluwatoyin E Ijitola, MD, PhD is a member of the following medical societies: American Academy of Tropical Medicine, American College of Healthcare Executives, American Society of Tropical Medicine and Hygiene, HIV Medicine Association of America, and International AIDS Society
Disclosure: Nothing to disclose.

Medical Editor

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, and American Thoracic Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Gregg T Anders, DO, Medical Director, Great Plains Regional Medical Command , Brook Army Medical Center; Clinical Associate Professor, Department of Internal Medicine, Division of Pulmonary Disease, University of Texas Health Science Center at San Antonio
Gregg T Anders, DO is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society
Disclosure: Nothing to disclose.

CME Editor

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine
Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians
Disclosure: Nothing to disclose.

Chief Editor

Zab Mosenifar, MD, Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center; Professor of Medicine, David Geffen School of Medicine at UCLA
Zab Mosenifar, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, and American Thoracic Society
Disclosure: Nothing to disclose.

 
 
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