Description
Pulmonary alveolar proteinosis (PAP) is a rare lung condition characterised by the accumulation of proteinaceous material within the alveoli, resulting in impaired gas exchange and leading to dyspnea and respiratory failure. This accumulated material is largely composed of surfactant, a substance crucial for maintaining alveolar stability.
Pathogenesis
PAP occurs due to impaired clearance of surfactant by alveolar macrophages. There are three known types:
- Primary or idiopathic PAP (accounts for about 90% of cases) results from antibodies against GM-CSF (granulocyte-macrophage colony-stimulating factor), a cytokine that controls surfactant homeostasis.
- Secondary PAP (10%) occurs due to a decreased number or function of alveolar macrophages, commonly in association with haematologic malignancies (leukaemia 60%, lymphoma 30%, and myelodysplastic syndromes 10%) or immunodeficiency states.
- Congenital or hereditary PAP is caused by mutations in surfactant protein genes or the GM-CSF receptor genes.
Epidemiology, Risk Factors & Associations
- PAP is a rare disease, with an estimated prevalence of 3.7 cases per million
- Typically presents in adults aged 30-50 years and has a slight male preponderance.
- Smoking and dust inhalation, particularly silica, have been associated with an increased risk of developing the disease.
Clinical Features
- Progressive dyspnea
- Non-productive cough
- Fatigue
- Weight loss
- Clubbing in severe or long-standing disease
In more severe cases, cyanosis, respiratory failure and cor pulmonale may occur.
Complications
Possible complications of PAP include:
- Progressive respiratory failure
- Opportunistic infections, particularly Nocardia, mycobacteria (tuberculosis, nontuberculous), fungi (Aspergillus, Cryptococcus, Histoplasma, Zygomycetes)
- Lung cancer, particularly in association with smoking
- Pulmonary fibrosis
Subtypes
- Primary/autoimmune: Due to anti-GM-CSF antibodies
- Secondary: Associated with malignancies or immunodeficiency
- Congenital/hereditary: Resulting from genetic mutations affecting surfactant proteins or GM-CSF receptors
Pathological Features
Morphology
Alveoli are filled with an eosinophilic, granular material (the proteinaceous material) that stains positive with periodic acid-Schiff (PAS).
Histopathology
Lung tissue demonstrates alveoli filled with acellular, eosinophilic material, with preserved alveolar architecture. The alveolar walls are not thickened.
Biochemistry
- The proteinaceous material within the alveoli is primarily composed of surfactant proteins and lipids.
- Bronchoalveolar lavage fluid: Milky and turbid with thick sediment. Contains phospholipids and surfactant proteins A, B, and D, with lower concentrations of phosphatidylcholine and phosphatidylglycerol
Serology
- GM-CSF autoantibodies: Diagnostic sensitivity and specificity; 100% and 98%
- Risk of PAP increased when GM-CSF autoantibody threshold > 5 μg/mL
Radiological Features
General Features
The classic radiological manifestation of PAP is bilateral, symmetric, perihilar airspace opacification. The distribution of abnormalities can be quite variable, though characteristically sparing the costophrenic angles.
CT
- HRCT is the best imaging modaltiy
- Crazy-paving pattern: The appearance of ground-glass opacification superimposed by interlobular septal thickening and intralobular lines.
- The presence of consolidative opacities.
- In long-standing disease, traction bronchiectasis (20%), fibrosis, honeycombing (5%) and cystic (20%) changes may be present.
X-Ray
- Diffuse bilateral alveolar filling pattern (ill-defined ground-glass opacities or consolidation)
- Similar distribution to pulmonary oedema (symmetric and perihilar) however may be asymmetric peripheral/lobar and spare apices.
- Reticular or reticularnodule opacities.
- Pneumothorax – ruptured subpleural cysts
Grading and Staging
There is currently no formal grading or staging system for PAP.
Differential Diagnosis
- Pulmonary oedema: Clinical context (acute, often with cardiac history) and imaging features (perihilar distribution, upper lobe diversion) help distinguish it from PAP.
- Pneumocystis jirovecii pneumonia: Typically seen in immunocompromised individuals and can be differentiated by the presence of immunodeficiency (AIDS) and specific microbiological tests.
- Diffuse alveolar haemorrhage: Seen in autoimmune conditions, pulmonary-renal syndrome. Ground-glass opacities with crazy-paving and consolidation. Anaemia and haemoptysis.
- Acute respiratory distress syndrome
Management
- Whole lung lavage – treatment of choice for symptomatic patients with severe disease. Involves the mechanical removal of the accumulated proteinaceous material from the alveoli.
- Inhaled GM-CSF therapy can be considered, particularly in cases of primary PAP, to stimulate the surfactant-clearing function of alveolar macrophages.
- Secondary PAP treatment involves managing the underlying cause.
- Supportive therapy, including supplemental oxygen and treatment of any superimposed infections, is also critical.