Pulmonary alveolar proteinosis: diagnostic and therapeutic challenges

In this paper we review the therapeutic strategies which have been proposed for the treatment of PAP patients and the progress which has been made in the understanding of the disease pathogenesis.Pulmonary alveolar proteinosis (PAP) is a diffuse pulmonary disease characterized by the accumulation of periodic acid-Schiff (PAS)-positive lipoproteinaceous material, primarily phospholipid surfactant and surfactant apoproteins, in the distal air spaces, which results in impaired gas transfer.PAP is an extremely rare disorder, occurring worldwide with an estimated prevalence of 0.1 per 100,000 individuals. The clinical course of PAP is variable, ranging from spontaneous remission to respiratory failure. The onset of clinical disease is insidious, with a subacute indolent course that often delays the diagnosis by months to years. This delay is secondary to the time required for sufficient surfactant accumulation in the alveoli to impair gas exchange. In fact, decreased clearance of surfactant from the alveoli has been postulated as the basis of PAP pathogenesis.Major advancements have been achieved in the understanding of the pathogenesis in the last two decades. The first milestone was the discovery in GM-CSF knockout mice that surfactant lipids and proteins progressively accumulate in the alveolar space, as in human PAP [1,2]. These findings revealed an unexpected critical role of GM-CSF in the homeostasis of surfactant in humans. However, unbound immunoreactive GM-CSF is detectable in BAL fluid and plasma of PAP patients [3], thus researchers postulated that an inhibitory circulating factor could play a role in the pathogenesis of the disorder. With this hypothesis they laid the groundwork for the discovery of the neutralizing autoantibodies directed against GM-CSF (Abs) [4] which were proposed as the causative agent for autoimmune PAP, by impairing the function of alveolar macrophages in surfactant clearance. Later, Uchida and coworkers [5] demonstrated that in patient