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Pulmonary Alveolar Proteinosis

by Harold R. Collard, MD

Pulmonary alveolar proteinosis is accumulation of surfactant in alveoli. Etiology is almost always unknown. Symptoms are dyspnea, fatigue, and malaise. Diagnosis is based on bronchoalveolar lavage, although characteristic x-ray and laboratory test abnormalities occur. Treatment is with whole lung lavage or, in some cases, recombinant granulocyte-macrophage colony stimulating factor. Five-year survival is about 80% with treatment.

Etiology

Pulmonary alveolar proteinosis is most often idiopathic and occurs in otherwise healthy men and women between 30 and 50 yr. Rare secondary forms occur in patients with acute silicosis, Pneumocystis jirovecii infection, hematologic cancers, or immunosuppression by drugs and in patients with significant inhalation exposures to aluminum, titanium, cement, and cellulose dusts. Rare congenital forms that cause neonatal respiratory failure also exist. It is unclear whether idiopathic and secondary cases share a common pathophysiology.

Pathophysiology

Impaired alveolar macrophage processing of surfactant due to abnormal granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling is thought to contribute to the disorder, perhaps due to reduced or absent function of the common β chain of the GM-CSF/IL-13/IL-5 receptor on mononuclear cells (present in some children but not in adults with the disorder). Anti–GM-CSF antibodies have also been found in most patients. Toxic lung injury is suspected but not proved in secondary inhalation causes.

Alveoli are filled with acellular lipoprotein surfactant that stains periodic acid–Schiff (PAS) positive. Alveolar and interstitial cells remain normal. Posterobasal lung segments are mostly affected. The pleura and mediastinum are unaffected.

Symptoms and Signs

Most patients present with progressive exertional dyspnea and weight loss, fatigue, malaise, or low-grade fever. Cough, occasionally producing chunky or gummy sputum, occurs but is less common. Clubbing and cyanosis are uncommon. Inspiratory crackles are rare because alveoli are fluid-filled; when crackles are present, they suggest infection.

Diagnosis

  • Bronchoalveolar lavage

  • Sometimes biopsy

Pulmonary alveolar proteinosis is usually first suspected when a chest x-ray is taken for nonspecific respiratory symptoms. The x-ray shows bilateral mid- and lower-lung field opacities in a butterfly distribution with normal hila.

Bronchoalveolar lavage is done. Lavage fluid is milky or opaque, stains PAS-positive, and is characterized by scattered surfactant-engorged macrophages, an increase in T cells, and high levels of surfactant apoprotein-A. Thoracoscopic or open lung biopsy is done when bronchoscopy is contraindicated or when specimens from lavage fluid are nondiagnostic. Tests typically done before treatment begins include high-resolution CT (HRCT), pulmonary function tests, ABGs, and laboratory tests.

HRCT shows ground-glass opacification, thickened intralobular structures, and interlobular septa in typical polygonal shapes (crazy-paving). This finding is not specific, however, as it may also occur in patients with lipoid pneumonia, bronchoalveolar cell carcinoma, and Pneumocystis jirovecii pneumonia.

Pulmonary function tests show reduction in diffusing capacity for carbon monoxide (DL co ) that is disproportionate to the decreases in vital capacity, residual volume, functional residual capacity, and total lung capacity.

Laboratory test abnormalities include polycythemia, hypergammaglobulinemia, increased serum LDH levels, and increased serum surfactant proteins A and D. Abnormalities are suggestive but nondiagnostic. ABGs may show hypoxemia with mild to moderate exercise or at rest if disease is more severe.

Prognosis

Without treatment, pulmonary alveolar proteinosis remits spontaneously in up to 10% of patients. A single whole lung lavage is curative in up to 40%; other patients require lavage every 6 to 12 mo for many years. Five-year survival is about 80%; the most common cause of death is respiratory failure, typically occurring within the first year after diagnosis. Secondary pulmonary infections with bacterial (eg, Mycobacteria, Nocardia) and other organisms ( Aspergillus, Cryptococcus, and other opportunistic fungi) occasionally develop because of impaired macrophage function; these infections require treatment.

Treatment

  • Whole lung lavage

Treatment is unnecessary for patients without symptoms or for those with only mild symptoms. In patients with troubling dyspnea, whole lung lavage is done by using general anesthesia and a double-lumen endotracheal tube. Lavage of one lung is done up to 15 times with 1 to 2 L saline while the other lung is ventilated. The process is then reversed. Lung transplantation is not done because the disorder recurs in the transplanted lung.

Systemic corticosteroids play no role in management and may increase the risk of secondary infection. The role of GM-CSF (IV or sc) in management remains to be determined. An open-label study showed clinical improvement in 57% of the patients studied.

Key Points

  • Consider pulmonary alveolar proteinosis in otherwise healthy patients between ages 30 and 50 if the chest x-ray shows bilateral mid- and lower-lung field opacities in a butterfly distribution with normal hila.

  • Do bronchoalveolar lavage; if contraindicated or when results are not diagnostic, do lung biopsy.

  • If dyspnea is moderate or severe, treat with whole lung lavage.

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