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At a glance

In this disorder, the alveoli are filled with periodic acid–Schiff (PAS)-positive proteinaceous material that is chemically-similar to surfactant. Significant respiratory problems leading to severe hypoxemia, recurrent pulmonary infections, and cardiac problems.

Synonyms

Alveolar Lipoproteinosis; Alveolar Phospholipidosis; Pulmonary Alveolar Phospholipoproteinosis.

History

First described in 1958 by American physicians Samuel H. Rosen. Two forms are recognized: (1) primary or autoimmune and (2) secondary to lung infections, hematologic malignancies, inflammation from mineral dusts such as silica, titanium oxide, aluminum, and insecticides.

Incidence

Rare. The incidence is estimated at 0.2 per 1,000,000. Autoimmune pulmonary alveolar proteinosis accounts for approximately 90% of cases, while 4% is secondary. There is a male predominance (3:1) in adults, but not in children. Mortality rates can be as high as 30% in the secondary form, depending on the underlying cause is less than 10% in the primary form.

Genetic inheritance

Autoimmune disease in vast majority of patients. Autosomal recessive mutations in the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor α or β chains also lead to impaired macrophage maturation in the absence of autoimmunity. A congenital form appears to be transmitted in an autosomal recessive way due to a SFTPB or ABCA3 gene mutation located on 2p11.2 and 16p13, respectively. The late-onset form is usually associated with lymphoproliferative disorders or infection (HIV, tuberculosis).

Pathophysiology

Primary pulmonary alveolar proteinosis is caused by defective clearance of surfactant lipoprotein from the alveolar space due to autoantibodies against GM-CSF or defective signaling by the GM-CSF receptor that results in the diminished expression or function of the α or β subunits of the GM-CSF receptor. The distal lung tissue becomes filled with enlarged alveolar macrophages that are able to ingest surfactant but unable to process it. The net result is an imbalance in the homeostasis between production of surfactant and its clearance by alveolar macrophages and the mucociliary elevator. Ultimately, decreased gaseous exchange results in hypoxemic respiratory failure and defects in host defense.

Diagnosis

Confirmed by bronchoalveolar lavage and/or lung biopsy that shows alveoli filled with PAS-positive proteinaceous material. The bronchoalveolar lavage material looks cloudy or milky and the cytologic examination shows foamy macrophages, reactive pulmonary pneumocytes, and cholesterol crystals. The alveolar architecture and intralobular septae are usually well preserved and the conductive airways unaffected. The congenital form is characterized by absent surfactant protein B. The chest radiograph shows bilateral pulmonary infiltrates (ground-glass aspect) with hilar prominence (bat-wing shape) and progression to fibrosis and a “honeycomb” appearance.

Clinical aspects

  • Neonatal-Onset Form: The neonate presents with acute respiratory distress with marked hypoxemia shortly after birth. Initially, the symptoms are indistinguishable from hyaline membrane disease (neonatal respiratory distress syndrome). Slow resolution of the initial illness, pneumonia, or persistence of ...

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