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Rare disorder with accumulation of lipoproteinaceous material in the lung alveoli.
Alveoli filled with periodic-Schiff (PAS) positive lipoproteinaceous material.
Pulmonary Alveolar Proteinosis manifests as filling of the alveoli by a proteinaceous material that is positive at periodic acid–Schiff staining and rich in lipid, in association with an inflammatory response in the adjacent interstitium.
Characterized by pulmonary surfactant accumulation within pulmonary alveoli, that causes progressive respiratory insufficiency.
Approximately 90% of cases are autoimmune, associated with a high level of auto antibodies against granulocyte-macrophage collony stimulating factor (GM-CSF).
These autoantibodies neutralize GM-CSF biologic activity and impair the clearance of surfactant that leads into clinical disease.
Pulmonary alveolar proteinosis is most common in adults between 20 and 50 years of age, although it has been reported in a wide range of ages.
Alveolar filling with lipid rich proteinaceous material accompanied by large, foamy, alveolar macrophages and relatively few inflammatory cells.
Accumulation of surfactant derived components in the lungs.
Incidence estimated to be 0.36 case per million population and a prevalence of 3.7 cases per million.
Susceptibility to pulmonary infections.
Can be congenital, secondary or acquired.
Widely variable course from spontaneous resolution to respiratory failure.
Prevalence of acquired disease estimated to be 0.37 per 1000,000 persons.
More than 90% of cases are acquired.
Median age at diagnosis is 39 years with most patients being male.
72% of patients have a smoking history.
Most patients present with dyspnea on exertion and insidious onset of cough and weight loss.
Patients may present with fever, chest pain or hemoptysis.
Clinical exam may reveal crackles in 50% of patients, cyanosis in 25% and clubbing in a small number of individuals.
Laboratory tests are generally normal, but the lactate dehydrgenase level is usually elevated and is a useful marker for the severity of the disease.
Radiographs of the chest usually reveal bilateral airspace disease with nodular or confluent pattern often with a perihilar pulmonary edema pattern.
In pulmonary alveolar proteinosis classic radiographic finding is bilateral, symmetric alveolar consolidation or ground-glass opacity, particularly in a perihilar or hilar distribution resembling pulmonary edema.
Crazy paving is the classical finding on CT scan, although that finding is much more common associated with other processes including infection, ARDS, and pulmonary edema.
CT scan appearance often shows homogeneous ground glass changes with thickened interlobular septa forming a “crazy paving” pattern.
Elevated serum levels of pulmonary epithelial cell derived products include cytokeratin 19, surface proteins A, B, and D.
Pulmonary function tests reveal a restrictive pattern and a disproportionately reduced diffusion capacity.
Patients frequently manifest hypoxia.
Partial pressure of oxygen in arteries is elevated compared with that in the alveoli.
Diagnosis requires lung biopsy with findings of alveoli and distal bronchioles filled with surfactant derived material tat is acellular, acidophilic, amorphous and periodic acid Schiff positive and diastase resistant.
Management of pulmonary alveolar proteinosis (PAP) depends on the progression of the illness, coexisting infections, and degree of physiological impairment.
The standard of care for PAP is mechanical removal of the lipoproteinaceous material by whole-lung lavage.
Historically, patients have been treated with systemic steroids, mucolytics (aerosol), and proteinase (aerosol) without much success.
Indications for this procedure are a histologic diagnosis in combination with any of the following: (1) an alveolar-arterial oxygen gradient greater than or equal to 40 mm Hg, (2) dyspnea and hypoxemia at rest or with exercise, or (3) a PaO2 of less than 65 mm Hg.
Bronchoalveolar lavage yields milky opaque fluid positive on PAS staining.
Lung biopsy is generally not needed for diagnosis and is noted for preserved lung architecture with alveolar filling by histologically distinctive coarse and densely eosinophilic material positive on a periodic acid-Schiff stain
In secondary PAP, appropriate treatment of the underlying cause is warranted. Inhaled and systemic GM-CSF has been shown to be safe and effective in providing a sustained therapeutic effect in autoimmune PAP.
Whole-lung lavage is performed with a double-lumen endotracheal tube designed to allow simultaneous ventilation and lavage.
Lung lavage is performed under general anesthesia, and the lung is ventilated briefly with 100% oxygen before lavage with isotonic sodium chloride solution.
The standard is lavage with up to 50 L of saline to physically remove the surfactant sediment.
Upon completion of the procedure, the lung is suctioned of most of the isotonic sodium chloride solution and allowed to recover before lavaging the other lung.
Lung lavage has been performed in hyperbaric chambers, which has made lavage of both lungs possible on the same day.
Lung lavage may require several hours.
In most cases, repeated treatments are required because of the re-accumulation of surfactant.
Rarely, hyperbaric chamber or extracorporeal membrane oxygenation (ECMO) has been used to perform whole-lung lavages in cases of severe hypoxemia.
It’s natural history is variable ranging from stability, persistent symptoms, progressive deterioration, or spontaneous remission.
Spontaneous remission occurs in 5-7% of patients.
In a retrospective analysis five-year survival was 75%.
The major causes of death included progressive respiratory failure and pulmonary infections.
Can be an hereditary, secondary, or autoimmune process.
Less than 1% of cases are hereditary.
Hereditary cases arise from mutations in surfactant protein B or C, the receptor for GM-CSF,
ABCA3, thyroid transcription factor 1or other of mutations.
Secondary pulmonary alveolar proteinosis, which accounts for 9% of cases develops when alveolar macrophage dysfunction or deficiency occur, such as inhalation exposure to silica dust or toxic fumes , Immunosuppression, infections, or cancer such as myelodysplastic syndrome and acute myeloid leukemia.
The autoimmune form is responsible for approximately 90% of cases and results from the development of antibodies that target GM-CSF.
Antibodies against GM-CSF lead to dysfunction in alveolar macrophages resulting in impaired catabolism and accumulation of surfactant lipids and proteins.
Testing for serum GM-CSF is available and the combination of autoantibody testing and bronchoalveolar lavage obviates thevneed for lung biopsy in most patients.
Treatment approach to pulmonary alveolar proteinosis depends on the cause: for hereditary pulmonary alveolar proteinosis, treatment includes supportive care with a lung transplanttion and whole lung lavage is usually ineffective.
For secondary pulmonary alveolar proteinosis the treatment targets are the underlying condition.
For autoimmune pulmonary alveolar proteinosis the treatment is whole-lung lavage.
Whole-lung lavage requires general anesthesia, isolation of the lung with the double lumen endotracheal tube and single lung ventilation and instillation of the other lung with one-liter aliquots of normal saline followed by chest physiotherapy in the drainage of proteinaceous effluent with the help of postural positioning: The average number of lavages performed is 2:5 over a 5 year period, and the average volume of saline is 15 L used per lung.
Whole-lung lavage is associated with reduced mortality.
Subcutaneous or inhaled GM-CSF therapy may result in improvement in the alveolar-oxygen gradient and quality-of-life.
In a randomized trial human inhaled GM-CSF was associated with a moderate effect in outcome on arterial oxygen tension, improves lung function, and radiologic findings.