Chapter 518

Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by the accumulation of surfactant lipids and proteins within the pulmonary alveoli, resulting in impaired gas exchange and respiratory insufficiency.1 Our understanding of PAP has advanced significantly over the past several decades due to a series of contributions from basic, clinical, and translational research.2,3 These studies have revealed a critical role for pulmonary granulocyte/macrophage-colony stimulating factor (GM-CSF) in the terminal differentiation of alveolar macrophages and in alveolar macrophage-mediated surfactant catabolism, pulmonary surfactant homeostasis, and lung host defense.4-6 PAP comprises part of a larger group of disorders associated with disruption of surfactant homeostasis and includes disorders of surfactant production (hereafter referred to as pulmonary surfactant metabolic dysfunction disorders) and disorders of surfactant clearance (hereafter referred to as PAP; Table 518-1). The distinct epidemiological, pathogenic, clinical, and prognostic features of these two disease categories indicate they are usually considered separately rather than as a continuum of a single disease process. PAP can be further divided into primary and secondary PAP, which, respectively, are associated with either loss of GM-CSF signaling or the presence of an underlying disorder that reduces alveolar macrophage numbers or functions.

Table 518-1. Classification of Disorders Associated with Disruption of Surfactant Homeostasis

### Epidemiology

Epidemiological studies of disorders of surfactant homeostasis are hampered by their rarity and values for incidence, and prevalences provided here are considered estimates. Autoimmune pulmonary alveolar proteinosis (PAP) is the most common clinical form, accounting for 90% of all cases, and has an incidence and prevalence of 0.49 and 6.2 per million, respectively, in the general population.2,15 It is twice as common in males as females, possibly due to an association with smoking, typically presents in the third or fourth decade, and it is rarely observed in children under 10 years old.15,23 Secondary PAP is the next most common, accounting for 9% to 10% of cases, with an incidence and prevalence of 0.05 and 0.5 per million, respectively. Secondary PAP is linked to the occurrence of the underlying clinical conditions that cause it (Table 518-1). Only ...

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