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Internal Medicine

Pulmonary alveolar proteinosis (PAP)

Disease of alveolar accumulation of phospholipoproteinaceous material that results in gas exchange impairment leading to dyspnea and alveolar infiltrates.

Disease of alveolar accumulation of phospholipoproteinaceous material that results in gas exchange impairment leading to dyspnea and alveolar infiltrates.


Classification

Congenital PAP

Due to mutation of surfactant protein SP-B gene

Idiopathic (primary) PAP (M/C type):

Antibodies formed against GM-CSF leads to alveolar macrophage dysfunction

90% of PAP cases are autoimmune, only 1.7% of patients have other identified autoimmune diseases

  • Smoking (53-85%)
  • Occupational exposures (39-48%)

Acquired (secondary) PAP:

  • Infections: infectious causes can include bacteria (Nocardia), fungi, viruses, Mycobacteria, or Pneumocystis carinii
  • Neoplasms including lymphomas and leukemias
  • Inorganic dust exposure including silicosis and aluminum
  • Immunodeficiencies such as HIV infection, lung transplantation, and IgA deficiency

Pathophysiology

The macrophages themselves are a potential contributing factor in the formation of the amorphous material upon dying. The theory of impaired macrophage function is sustained by the association of this disease to immunodeficiency diseases that cause dysfunction of macrophages. Moreover, reports of the presence of antibodies of immunoglobulin isotype G against granulocyte-macrophage-colony-stimulating factor (GM-CSF) in pulmonary proteinosis also exist.

Categories, etiologies and pathophysiology of the various forms of pulmonary alveolar proteinosis (PAP). | GM-CSF Granulocyte macrophage-colony stimulating factor | Patel, S. M., Sekiguchi, H., Reynolds, J. P., & Krowka, M. J. (2012). Pulmonary alveolar proteinosis. Canadian respiratory journal, 19(4), 243–245. https://doi.org/10.1155/2012/841530

Clinical features

Asymptomatic presentation

One-third of the patients are asymptomatic at the time of presentation

Non-specific symptoms:

Clinical presentation of PAP varies from indolent to emergent and symptoms are often non-specific
  • Dyspnea (M/C, 39% cases)
  • Cough (21% cases)
  • Hemoptysis, fever, and chest pain (rare)
  • Fever (24% of secondary PAP patients due to concomitant hematological malignancies or opportunistic infections)
  • Expectoration of ‘chunky’ gelatinous material (rare)

Clinical examination:

  • Auscultation of crackles (but lung auscultation is often normal because of the absence of gas movement due to complete filling of distal airspaces)
  • Clubbing (30% cases)
  • Cyanosis (25-30% cases)

Diagnosis

Serum biomarkers:

Non-specific findings
  • ↑ Serum LDH (50% cases)
  • ↑ Serum CEA
  • ↑ Serum surfactant proteins A, B, and D (associated with disease severity)

Enzyme-linked immunosorbent assay (ELISA):

GOLD STANDARD
  • IgG anti-GM-CSF antibodies ≥ 2.8µg/ml

Bronchoalveolar lavage:

  • Characteristic chunky, gelatinous milky appearance
  • Foamy macrophages with amorphous material that stains PAS-positive
  • BALF cellularity: Lymphocyte-predominant

Pulmonary function test (PFT):

not necessary for diagnosis, nor is it specific for PAP
  • Restrictive spirometry pattern

Chest radiography:

  • Bilateral alveolar opacities in a peri-hilar and basilar distribution without air-bronchograms “batwing distribution

High resolution computed tomography (HRCT):

  • Bilateral ground-glass opacities often associated with interlobular septal thickening with a characteristic feature of ‘crazy paving.’
A Chest x-ray (posteroanterior view) demonstrating hazy, diffuse, bilateral alveolar infiltrates. B High-resolution computed tomography scan showing diffuse, bilateral, geographical ground-glass opacities with associated inter- and intralobular septal thickening with interspersed areas of normal lung that are indicative of ‘crazy-paving’ | Patel, S. M., Sekiguchi, H., Reynolds, J. P., & Krowka, M. J. (2012). Pulmonary alveolar proteinosis. Canadian respiratory journal, 19(4), 243–245. https://doi.org/10.1155/2012/841530

Lung biopsy:

  • Histologic hallmark consists of an intra-alveolar accumulation of a granular eosinophilic and amorphous material with diffuse and rarely patchy lesions
A Biopsy demonstrating dilated air spaces, thickened interlobular septae and relatively acellular, eosinophilic debris within the alveoli. Hematoxylin and eosin stain, original magnification ×100. B Higher power inspection of the alveoli demonstrating thick, amorphous material with scattered pulmonary macrophages. Hematoxylin and eosin stain, original magnification ×400. Note: Grocott’s methanamine silver staining was negative and ruled out pneumocystis pneumonia in the differential of ‘crazy-paving’ | Patel, S. M., Sekiguchi, H., Reynolds, J. P., & Krowka, M. J. (2012). Pulmonary alveolar proteinosis. Canadian respiratory journal, 19(4), 243–245. https://doi.org/10.1155/2012/841530

Differential diagnosis:

  • Pulmonary oedema: Characterized by edematous material that lacks coarse granules, cholesterol clefts, and foamy macrophages
  • Pneumocystis carinii pneumonia: Intra-alveolar eosinophilic exudate with ‘bubbles’ corresponding to cysts of organisms that can be highlighted using Grocott special stain.
  • Alveolar mucinosis: Intra-alveolar accumulation of mucin are potentially observable in association with mucinous adenocarcinomas or bronchiectasis or honeycomb fibrosi

Management

No immediate treatment is necessary in some cases because of the potential for spontaneous remission.

Therapeutic whole lung lavage (WLL) via a double-lumen endotracheal tube:

Current standard of care which helps to clear the alveolar space to help improve respiratory physiology

GM-CSF replacement therapy:

Therapeutic targets that replace granulocyte macrophage colony stimulating factor or remove these antibodies are being actively developed

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