What is Pulmonary Alveolar Proteinosis?
Pulmonary alveolar proteinosis (PAP) is a rare syndrome caused by abnormal 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
PAP results from distinct mechanistic pathways that either impair surfactant clearance or cause abnormal surfactant production 1:
- Primary (autoimmune) PAP is driven by disruption of GM-CSF signaling, resulting in alveolar macrophage dysfunction and impaired surfactant clearance 1
- The autoimmune form accounts for the vast majority of cases and is caused by autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF), which impairs catabolism and clearance of surfactant 2
- Secondary PAP occurs due to underlying diseases or conditions that reduce the numbers and/or functions of alveolar macrophages, with hematological disorders being the most common trigger 3
- Drug-induced PAP results from reduction in alveolar macrophage numbers and/or impairment of their surfactant clearance function, distinguishing it from autoimmune PAP 4
Epidemiology
The prevalence of autoimmune PAP is estimated at 6.7-6.9 per million in the general population 1.
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
- Clinical manifestations range from asymptomatic to severe respiratory failure 5
Disease Activity Indicators
PAP is considered active in the presence of 6:
- Continuous or progressive symptoms such as dyspnea, cough, sputum production, chest pain, weight loss
- Lung function decline in forced vital capacity (FVC) or diffusing capacity of carbon monoxide (DLco)
- Hypoxemia measured by arterial blood gas (PaO2, SaO2, AaDO2)
- New or worsening PAP-characteristic infiltrates on high resolution CT (HRCT), including ground glass and crazy paving patterns
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:
- High-resolution CT demonstrates the characteristic "crazy paving" pattern caused by airspace consolidation and thickened interlobular septae 1
- Bronchoalveolar lavage (BAL) should be performed as part of the diagnostic work up, including differential cell count, periodic-acid-Schiff (PAS)-staining, and microbiology 6
- BAL fluid is typically reported as milky white, opalescent 6
- GM-CSF autoantibody testing is critical to differentiate autoimmune PAP from secondary or drug-induced forms 3, 4
Treatment Options
Whole lung lavage (WLL) is considered the main treatment for many, but not all, PAP-causing diseases 1:
- WLL is the current standard of care and plays a critical role as a modifier factor of the natural history of proteinosis 5
- Inhaled GM-CSF appears to be a promising option for autoimmune PAP 1
- Inhaled GM-CSF therapy is not indicated for drug-induced secondary PAP, unlike autoimmune PAP 4
- For drug-induced PAP, the only proven therapy is immediate discontinuation of the offending medication, with spontaneous resolution often occurring after drug withdrawal 4
- Lung transplantation is considered for progressive respiratory failure 1
Common Pitfalls
- Failing to distinguish between autoimmune and secondary PAP: Always perform GM-CSF autoantibody testing, as this fundamentally alters management 3, 4
- Overlooking underlying causes: In secondary PAP, identify and treat hematological disorders, infections, drug exposures, or occupational exposures 3, 4
- Assuming all PAP requires treatment: Approximately one-third of patients are asymptomatic and may not require immediate intervention 1