What is Pulmonary Alveolar Proteinosis?

What is Pulmonary Alveolar Proteinosis?

Pulmonary alveolar proteinosis (PAP) is a rare syndrome caused by accumulation of surfactant proteins and phospholipids in the alveolar spaces, leading to progressive dyspnea, hypoxemia, respiratory failure, and increased risk of secondary infections and pulmonary fibrosis. 1

Pathophysiology and Disease Mechanisms

PAP results from distinct mechanistic pathways that either impair surfactant clearance or cause abnormal surfactant production 1:

• Primary PAP (autoimmune) is driven by disruption of GM-CSF signaling, resulting in alveolar macrophage dysfunction and impaired surfactant clearance 1
• Secondary PAP occurs when underlying diseases reduce the number or function of alveolar macrophages, with hematological disorders being the most common cause 1, 2
• Genetic forms result from mutations in genes encoding surfactant proteins or genes involved in surfactant production and lung development 1

The prevalence of autoimmune PAP is estimated at 6.7-6.9 per million in the general population 1, with secondary PAP accounting for only 4% of all PAP cases 2.

Clinical Presentation

Approximately one-third of patients are asymptomatic or minimally symptomatic at presentation 1:

• Dyspnea is the most common presenting symptom 1
• Cough that is minimally productive of sputum is common 1
• Some patients present with an initial febrile episode followed by progressive symptoms 1
• Hemoptysis is rare 1
• Many patients are active smokers 1
• Typical age of presentation is the third or fourth decade of life 1

Diagnostic Approach

The diagnosis of PAP is based on CT imaging and BAL cytology or lung histology, whereas diagnosis of specific PAP-causing diseases requires GM-CSF antibody testing or genetic analysis 1:

Imaging Findings

• Chest X-ray reveals bilateral, usually asymmetric, patchy airspace consolidation, more pronounced in the lower two-thirds of the lungs 1
• Advanced cases show a dense alveolar pattern known as "bat's wing pattern" or "reverse pulmonary edema pattern" 1
• High-resolution CT demonstrates the characteristic "crazy paving" pattern caused by airspace consolidation and thickened interlobular septae 1
• In secondary PAP, ground glass opacifications typically show a more diffuse pattern compared to the patchy geographic pattern seen in autoimmune PAP 2

Bronchoscopy and Biopsy

• BAL effluent yields sandy-colored or light-brown fluid from affected segments 1
• Bronchoscopic or surgical lung biopsy is diagnostic when needed 1
• Histology reveals alveolar filling by granular lipoproteinaceous substance that stains deep pink with periodic acid-Schiff stain 1

Additional Testing

• GM-CSF antibody testing to identify autoimmune PAP 1
• Genetic testing when hereditary forms are suspected 1
• Pulmonary function tests typically reveal restrictive dysfunction with reduced carbon monoxide diffusion capacity 1

Prognosis and Natural History

Spontaneous improvement occurs in 30% of cases 1:

• The prognosis of secondary PAP is considerably worse than autoimmune PAP, with estimated median survival of less than 20 months 2
• PAP carries risk of respiratory failure and early death if untreated 1
• Increased risk of secondary infections and pulmonary fibrosis 1

Treatment Options

Whole lung lavage (WLL) is considered the main treatment for many, but not all, PAP-causing diseases 1:

Whole Lung Lavage

• Currently the treatment of choice using normal saline solution 1
• Some patients require repeated lavages at intervals of several weeks to months 1
• Treatment is not indicated in all patients given the 30% spontaneous improvement rate 1

GM-CSF Augmentation Therapy

• Inhaled GM-CSF appears to be a promising option for autoimmune PAP 1
• This therapy remains under investigation 1

Other Therapies

• Rituximab for select cases 1
• Plasmapheresis in specific situations 1
• Lung transplantation for progressive respiratory failure 1
• For secondary PAP, the only proven therapy is treatment of the underlying disease, with WLL demonstrating efficacy in a small number of cases 2

Supportive Measures

• Smoking cessation may help hasten resolution 1

Important Clinical Caveats

The supporting evidence for PAP therapies remains limited despite available treatment options 1. Secondary PAP requires identification and treatment of the underlying condition, as its prognosis is significantly worse than primary forms 2. The characteristic "crazy-paving" appearance may not always be present in secondary PAP, making diagnosis more challenging 2.