Fig. 22.1  Imaging of a PAP. Computed tomography of the chest showing the radiographic ndings in autoimmune PAP in a 59-year-old man. (a–d) Cross-sectional CT chest images showing ground-glass opaci - cation involving some but not all secondary lobules resulting in a distinctive “geographic” pattern. Also, note the distinctive pattern of

interlobular septal thickening superimposed on ground-glass opaci cation, often referred to as “crazy paving.” There is relative sparing of the lower lobes of the lung. (e) Sagittal CT chest image revealing ground-­ glass opaci cation in a patchy distribution with relative sparing of subpleural space and the costophrenic angles

Introduction

Pulmonary alveolar proteinosis (PAP) is a rare syndrome de ned by abnormal accumulation of surfactant in pulmonary alveoli and can result in hypoxemic respiratory failure. It comprises a heterogeneous group of mechanistically distinct diseases, which are usefully considered to be disorders of surfactant production or clearance [1–3]. The latter can be subdivided into primary PAP and secondary PAP. Primary PAP is caused by disrupted GM-CSF signaling, which causes dysfunction of alveolar macrophages and neutrophils and includes two diseases, autoimmune (caused by GM-CSF autoantibodies) and hereditary PAP (caused by genetic mutations in CSF2RA or CSF2RB, encoding the alpha and beta chain of the GM-CSF receptor, respectively). Secondary PAP is caused by a reduction in the number and/or function of alveolar macrophages due the presence of another underlying disease, exposure to environmental inhaled toxins, or pharmaceutical agents. Congenital PAP includes multiple diseases caused by genetic mutations in the genes required for normal surfactant production that also referred to as pulmonary surfactant metabolic dysfunction (PSMD) disorders. Rarely, the etiology of PAP cannot be determined, resulting in a diagnosis of unclassi ed PAP. Recent advances have improved our understanding of PAP pathogenesis, epidemiology, [4–6] and have resulted in new methods to diagnose,

evaluate, and treat patients [7]. Because of the numerous advances, this chapter will speci cally focus to the pathogenesis, classi cation, clinical presentation, and management of autoimmune PAP except where otherwise noted.

Historical Note

The physical properties of surfactant were described in the early 1950s [8] and shortly afterward PAP was rst described, a disease caused by excessive pulmonary surfactant accumulation [9]. Enlarged, foamy alveolar macrophages lled with lipids were later identi ed with dysfunctional chemotaxis, adhesion, and microbial killing in addition to reduced survival, suggesting that the alveolar microenvironment was abnormal [10]. BAL from patients with PAP were consistently­ abnormal with increased levels of a 40-kDa protein which altered macrophage function and numbers [11] supporting the concept of an abnormal protein-led pathogenesis [12]. Interestingly, whole-lung lavage (WLL) therapy improved alveolar macrophage functions [13]. Further studies discovered that PAP spontaneously developed in GM-CSF-de cient mice [14, 15]. Subsequently, the macrophage function-­ inhibiting protein of concern in the BAL fuid (and serum) of patients with PAP was found to be an immunoglobulin that bound and neutralized GM-CSF [16, 17]. The identi cation