Pulmonary alveolar proteinosis is a rare disease characterized by an accumulation of a lipoproteinaceous material within the alveoli. It can be idiopathic or secondary. It is also known as pulmonary alveolar phospholipoproteinosis and alveolar lipoproteinosis.
Pulmonary alveolar proteinosis may be idiopathic or secondary. Secondary cases may accompany the following disorders:
Other conditions such as surfactant deficiency and Fanconi's anemia also have associations with the disorder.
The incidence and prevalence of alveolar proteinosis are not known. Pulmonary alveolar proteinosis is a rare disease mainly observed in males, with a sex ratio of 2:1. Estimates of the mean age of these patients run between 30 and 50 years with exceptional pediatric cases. A small number of case reports in infants and children exist. Many patients are former or current smokers.
The pathogenesis of this disease continues to be unclear, but many theories have been proffered in the literature, including an impairment in the ability of macrophages to clear secretions or an overproduction of surfactant dealing with a deficient clearance activity of macrophages.
The macrophages themselves are a potential contributing factor in the formation of the amorphous material upon dying. The theory of impaired macrophage function is sustained by the association of this disease to immunodeficiency diseases that cause dysfunction of macrophages. Moreover, reports of the presence of antibodies of immunoglobulin isotype G against granulocyte-macrophage-colony-stimulating factor (GM-CSF) in pulmonary proteinosis also exist.
The diagnosis of alveolar proteinosis may be made based on the bronchoalveolar fluid findings but is frequently made based on tissue samples including open or transbronchial biopsy.
Bronchoalveolar lavage fluid is characteristic when it has a milky appearance. The presence of alveolar macrophages engorged with Periodic Acid Schiff (PAS) positive material, acellular eosinophilic bodies in a background of eosinophilic granules are key-features. The bronchoalveolar lavage formula characteristically presents with a decrease in the number of alveolar macrophages and a slight increase in T lymphocytes (with a tendency toward a high CD4/CD8 ratio). Elevated levels of several tumor markers (carcinoembryonic antigen (CEA), carbohydrate antigens sialyl Lewis (CA19-9) have been found in bronchoalveolar lavage fluid form in some patients with alveolar proteinosis. It is possible that these markers may reflect disease activity without a real consensus. Serum or BAL KL-6 has proven useful for the diagnosis of alveolar proteinosis and the estimation of its activity.
Gross features consist of a yellow-tan discolorated parenchyma. The architecture of the lung appears preserved, and the process appears to fill the alveolar spaces. The abnormality primarily affects the right and appears to fill the alveolar spaces.
In tissue specimens, the histologic hallmark consists of an intra-alveolar accumulation of a granular eosinophilic and amorphous material with diffuse and rarely patchy lesions. Within this material, rounded empty spaces, cholesterol clefts, and small dense globular eosinophilic material are distinctive features of the diagnosis. Interstitial fibrosis or inflammation is commonly absent. If observed, the association to an infection or a neoplasm has to be suspected by the pathologist. In case of an association to silicosis, the polarization microscopy may show birefringent needle-like particles. In long-standing cases, observable tissue changes may include interstitial fibrosis.
With electron microscopy, the characteristic features consist of multilamellar structures of trilaminar membranes separated by amorphous material. Electron-dense bodies and membranous vesicles are often found at the center of the multilamellar structures. Even if these features can be helpful, electron microscopy isn't a routine exam.
Pulmonary proteinosis is asymptomatic in one-third of the patients. In symptomatic patients, symptoms are non-specific consisting mainly of cough, dyspnea, fatigue, weight loss, hemoptysis and chest pain. In very rare cases, patients may report an expectoration of 'chunky' gelatinous material. Physical examination is often normal. Auscultation of crackles may be a feature on chest examination, but lung auscultation is often normal because of the absence of gas movement due to complete filling of distal airspaces.
The characteristic findings on high resolution computed tomography consist of bilateral ground-glass opacities often associated with interlobular septal thickening with a characteristic feature of 'crazy paving.' In less typical cases, radiologic findings consist of bilateral and symmetrical areas of airspace consolidation or ground-glass opacities. In patients with less severe disease, the radiologic features may consist of hazy areas of ground-glass opacities rather than consolidation. The abnormalities tend to involve mainly the perihilar regions and lower lobes.
The major differential diagnoses consist in:
Pulmonary edema is characterized by edematous material that lacks coarse granules, cholesterol clefts, and foamy macrophages.
Pneumocystis pneumonia consists of intra-alveolar eosinophilic exudate with 'bubbles' corresponding to cysts of organisms that can be highlighted using Grocott special stain.
Approximately 30% to 40% of the patients require only one lavage. Other patients may require repeat lung lavages at intervals of 6 to 12 months.
Complications have been rarely reported and consist mainly in malpositioning of the endotracheal tube, saline spillover into the unlavaged ventilated lung, and hydropneumothorax.
Alveolar lipoproteinosis is a rare disease with non-specific diagnostic features. A multi-disciplinary approach including pathologists and pulmonologists is mandatory to assess the diagnosis competently. The pulmonologist has to suspect the diagnosis when performing a bronchoalveolar lavage to a patient explored for an interstitial disease. The gross appearance of the liquid can be suggestive of the diagnosis. On the other hand, the pathologist can make the diagnosis on liquid or tissue samples. In the bronchoalveolar lavage, the granular material with the presence of eosinophilic bodies and granules are key-features. In tissue samples, the presence of alveoli filled with PAS-positive eosinophilic material is a hallmark. The presence of fibrosis or inflammatory infiltrates have to highlight the possibility of an associated disease.