Pulmonary alveolar proteinosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mahda Alihashemi M.D. [2] [3] [4]

Synonyms and Keywords: Pulmonary alveolar phospholipoproteinosis

Overview

Pulmonary alveolar proteinosis ( PAP) was first discovered by Samuel Rosen, Benjamin Castleman, and Averill Liebow, in 1958. Pulmonary alveolar proteinosis ( PAP) may be classified into 2 subtypes, primary and secondary pulmonary alveolar proteinosis. The pathogenesis of pulmonary alveolar proteinosis is characterized by the intraalveolar accumulation of surfactant phospholipid and apoproteins. Pulmonary alveolar proteinosis develop because of reduced granulocyte-macrophage colony-stimulating factor (GM-CSF) levels or function and/or impaired alveolar macrophage function. On gross pathology after lung washings, fluid with the milky composition are the characteristic finding of pulmonary alveolar proteinosis. On microscopic histopathological analysis, terminal bronchioles and alveoli are filled with a lipoproteinaceous material that will be pink after periodic acid-Schiff (PAS) stain. The exact etiology of pulmonary alveolar proteinosis (PAP) is unknown, but it may be associated with exposure to insecticides, hematologic malignancies, or HIV infection. Pulmonary alveolar proteinosis must be differentiated from other diseases that cause ground glass opacities in radiography. Pulmonary alveolar proteinosis is more commonly observed among patients aged 40- 50 years old. Men are more commonly affected with pulmonary alveolar proteinosis than women. Common risk factors in the development of pulmonary alveolar proteinosis are current or former cigarette smokers and HIV infection. If left untreated, patients with pulmonary alveolar proteinosis may progress to develop pulmonary fibrosis, cor pulmonale. Symptoms of pulmonary alveolar proteinosis may include dyspnea on exertion, cough. The physical examination is often normal. Laboratory findings are serum anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in autoimmune pulmonary alveolar proteinosis and elevated serum level of GM-CSF in hereditary pulmonary alveolar proteinosis. Imaging studies include chest x-ray and high resolution computed tomography (HRCT). Treatment include whole-lung lavage (WLL), recombinant GM-CSF and lung transplantation.

Historical Perspective

  • Pulmonary alveolar proteinosis ( PAP) was first discovered by Samuel Rosen, Benjamin Castleman, and Averill Liebow, in 1958, during pathologic investigations of material filling the alveoli. [1]
  • In 1960, the first therapeutic bronchoalveolar lavage by repeated segmental flooding was developed by Dr. Jose Ramirez-Rivera to treat pulmonary alveolar proteinosis. [2]

Classification

Pulmonary alveolar proteinosis ( PAP) may be classified into 2 subtypes:

Primary Pulmonary alveolar proteinosis:
Secondary pulmonary alveolar proteinosis:

Pathophysiology

Causes

The exact etiology of pulmonary alveolar proteinosis (PAP) is unknown, but it may be associated with:

Differentiating pulmonary alveolar proteinosis from other Diseases

  • Pulmonary alveolar proteinosis must be differentiated from other diseases that cause ground glass opacities in radiography such as:[17]

Epidemiology and Demographics

  • The prevalence of pulmonary alveolar proteinosis is approximately 1 per 100,000 individuals worldwide.
  • The incidence of pulmonary alveolar proteinosis is estimated to be 0.33 cases per 100,000 individuals in united states. [18]

Age

  • Pulmonary alveolar proteinosis is more commonly observed among patients aged 40- 50 years old.[19]

Gender

  • Men are more commonly affected with pulmonary alveolar proteinosis than women. The men to women ratio is approximately 2 to 1.

Race

  • There is no racial predilection for pulmonary alveolar protoeinosis.

Risk Factors

  • Common risk factors in the development of pulmonary alveolar proteinosis are:
    • Current or former cigarette smokers[20]
    • HIV infection[15]

Natural History, Complications and Prognosis

  • Prognosis is generally good for primary pulmonary alveolar proteinosis with whole lung lavage. Congenital pulmonary alveolar proteinosis respond well to lung transplantation. Prognosis for secondary pulmonary alveolar proteinosis is related to underlying etiologies.

Diagnosis

Symptoms

  • One third of patients are usually asymptomatic.[22]
  • Symptoms of pulmonary alveolar proteinosis may include the following:[23]

Physical Examination

  • The physical examination is often normal. [24]
  • Physical examination may be remarkable for:[25][26]

Laboratory Findings

Imaging Findings

Chest X-ray:
High resolution computed tomography (HRCT):
  • Ground-glass opacification with crazy-paving pattern (interlobular septal thickening).[34][35]

Other Diagnostic Studies

Pulmonary function test:
 Bronchoalveolar lavage (BAL):
  • It is done via flexible bronchoscopy.
  • Milky or opaque appearance because of abundant lipoproteinaceous material.[38]
Surgical lung biopsy:
  • It is done via video-assisted thoracoscopic biopsy.[39]

Treatment

Interventional therapy

  • Whole-lung lavage (WLL) with normal saline under general anesthesia: [40]
    • Indication:[41]
      • Resting PaO2 <65 mmHg
      • Alveolar-arterial O2 gradient ≥40 mmHg at rest
      • Severe dyspnea
      • Hypoxemia 
    • Contraindication:[42]
      • Clotting disorders
      • Anesthetic risks
      • Cardiopulmonary instability

Medical therapy

  • Recombinant GM-CSF ( sargramostim) by inhaled or subcutenous injections:[43]
    • For patients with failed whole-lung lavage (WLL)
  • Rituximab ( anti-CD20 monoclonal antibody): for refractory autoimmune pulmonary alveolar proteinosis.[44]
  • Therapeutic plasma exchange: for patients with failed whole lung lavage.[45]

Surgery

Prevention

  • Avoiding further exposure is the effective measure for the secondary prevention of pulmonary alveolar proteinosis due to inorganic dust or insecticides.[47]

References

  1. Rosen, Samuel H.; Castleman, Benjamin; Liebow, Averill A.; Enzinger, Frank M.; Hunt, Richard T. N. (1958). "Pulmonary Alveolar Proteinosis". New England Journal of Medicine. 258 (23): 1123–1142. doi:10.1056/NEJM195806052582301. ISSN 0028-4793.
  2. Ramirez-R., Jose; Nyka, Walenty; McLaughlin, Joseph (1963). "Pulmonary Alveolar Proteinosis". New England Journal of Medicine. 268 (4): 165–171. doi:10.1056/NEJM196301242680401. ISSN 0028-4793.
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