Pulmonary Alveolar Proteinosis

Angela C. Wang

Pulmonary alveolar proteinosis (PAP) is a heterogeneous group of rare diseases characterized by the accumulation of eosinophilic, periodic acid-Schiff (PAS)-positive material within alveoli, and distal airways resulting in restrictive pulmonary function that can progress to respiratory failure and death. Two general categories of PAP exist: autoimmune and non-autoimmune. The latter can be further classified into hereditary and secondary.

PATHOPHYSIOLOGY

More than 90% of PAP cases are caused by defective granulocyte macrophage colony-stimulating factor (GM-CSF) signaling due to high levels of circulating autoantibodies that prevent GM-CSF binding to its receptor (autoimmune PAP). GM-CSF is a hematopoietic cytokine that regulates the clearance of surfactant lipids and proteins by alveolar macrophages. Impaired host defense results from decreased surfactant catabolism and impaired microbicidal activity by neutrophils. In congenital cases, inherited GM-CSF receptor mutations prevent GM-CSF signaling. All forms result in decreased surfactant catabolism and the accumulation of large, foamy, surfactant-filled macrophages within alveoli. Because GM-CSF also regulates multiple neutrophil functions, PAP also is associated with defective alveolar macrophage- and neutrophil-mediated host defense. Thus, patients are prone to pulmonary and systemic infections.

Three main etiologies of secondary PAP have been identified: (1) lung infections, including Pneumocystis carinii pneumonia in patients with and without AIDS; (2) hematologic malignancies and other immune-altering conditions; and (3) exposure to inhaled chemicals and minerals. Several toxic insults to the lung (e.g., silica, NO₂, ozone, and ONOO-) can result in alveolar proteinosis. PAP has also been produced in laboratory animals by inhalation of inert dusts of extremely fine particulate matter. Presumably, these exposures result in impaired macrophage function.

DIAGNOSIS

PAP occurs in all ethnic groups. The peak age of onset of autoimmune PAP is between 30 and 50 years; however, the disease has been described in all ages. In adults, the male to female ratio is approximately 4:1 and is associated with past or current history of smoking. Although some patients are asymptomatic at the time of diagnosis, PAP most commonly presents insidiously with increasing dyspnea and cough. However, abrupt onset also can occur, usually in the setting of a concomitant respiratory infection. Often, patients present with bilateral, community-acquired pneumonia that fails to clear with antibiotics.

Sputum production is usually scant but on occasion has been described as containing small chunks of material. Other much less-common symptoms include weight loss, weakness, chest pain, and hemoptysis. Physical findings, if present, are nonspecific. Fever usually implies superinfection, although a low-grade fever is present occasionally. Inspiratory crackles occur in up to 50% of patients; in severe cases, cyanosis and clubbing are observed.

The most common laboratory finding is a mildly elevated serum lactate dehydrogenase (LDH). Although nonspecific, LDH may be used to follow disease activity and severity. Patients with severe disease may have secondary polycythemia. The leukocyte count is normal or slightly increased. Serum protein electrophoresis may reveal increased globulins. Pulmonary function tests may be normal but usually reveal a restrictive pattern with decreased static lung compliance and decreased carbon monoxide diffusing capacity (DLCO). Arterial blood gases demonstrate hypoxemia and a widened alveolar–arterial oxygen gradient.

Chest radiographs typically show diffuse, finely nodular, soft infiltrates in a perihilar butterfly pattern, similar in appearance to pulmonary edema; however, other signs of left ventricular failure (cardiomegaly, Kerley B lines) are absent. A miliary, interstitial, or multinodular pattern and lobar consolidation also can be seen. Hilar adenopathy, pleural effusions, and cavitation are rare and suggest superimposed infection. The presence of patchy ground-glass opacities with lobular septal thickening (“crazy paving”) on high-resolution chest CT is highly characteristic of PAP, but may be absent, particularly in patients with secondary PAP. Furthermore, “crazy paving” is not pathognomonic for PAP and can also be seen in alveolar sarcoidosis, lipoid pneumonia, and mucinous bronchoalveolar carcinoma.

The differential diagnosis includes any disease that can produce a diffuse acinar-filling pattern on chest roentgenogram, including cardiogenic and noncardiogenic pulmonary edema, toxic inhalations, pulmonary hemorrhage, viral pneumonia, and P. carinii infection. One of the clues to the diagnosis of PAP is the disparity between extensive radiographic abnormalities and minimal clinical symptomatology. When chest roentgenograms reveal a predominant interstitial pattern, the diagnosis becomes more difficult.

Although open-lung biopsy was previously used as the gold standard for diagnosing PAP, the diagnosis can now be established via bronchoscopy with bronchoalveolar lavage (BAL), combined with appropriate clinical and radiographic findings and the presence of autoantibodies against GM-CSF in BAL fluid/serum. Serum concentration of less than 10 μg/mL has been reported to have good negative predictive value. Typically, the BAL fluid in PAP appears opaque and milky and is PAS-positive. Microscopically, few alveolar macrophages are seen and these cells appear large and foamy. Increased lymphocytes may be seen. Large eosinophilic bodies appear amidst a background of PAS-positive granular debris. The presence of the phospholipid or proteinaceous material within alveoli correlates with a ground-glass appearance.

TREATMENT

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