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.
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.’
Lung biopsy:
- Histologic hallmark consists of an intra-alveolar accumulation of a granular eosinophilic and amorphous material with diffuse and rarely patchy lesions
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