Autoimmune Pulmonary Alveolar Proteinosis

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Abstract: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by abnormal accumulation of surfactant in alveoli. Pathogenetically, in aPAP, the presence of granulocyte macrophage-colony stimulating factor (GM-CSF) autoantibodies hinders physiological binding of GM-CSF to its receptor, disrupting terminal differentiation of alveolar macrophages and the activation GM-CSF-PU.1-PPARG1-ABCG1 axis, resulting in a primary reduction in cholesterol efflux from alveolar macrophages and a secondary reduction in surfactant clearance through macrophages from the alveolar surface. APAP is the most common, accounting for more than 90 to 95% of all patients included under the PAP term, which encompasses and classifies all forms of PAP according to etiopathogenetic mechanisms, as primary, secondary, congenital, and unclassified. APAP is worldwide distributed with an estimated prevalence fluctuating between 7.0 and 9.7 cases/million and an annual incidence of 1.65, affecting middle-aged men and women. Clinical manifestation may be gradual and insidious, mainly manifesting with progressive dyspnea, but the natural history is variable, since some patients stabilize for a long period, while others progress to respiratory failure and death; in a minority, spontaneous resolution may be observed, while some develop lung and/or systemic infections, and rarely pulmonary fibrosis. Until recently, whole lung lavage (WLL) was universally accepted as the gold-standard therapeutic modality in aPAP. However, after considerable progress in the past 25 years and the publication of several positive studies, replacing the use of inhaled-GM-CSF as the standard of care for aPAP and conceding WLL a rescue option is becoming more and more concrete. In conclusion, aPAP is the classic paradigm of a scientific disease progressing from the "bench-to-bedside," since several discoveries made in the laboratory setting have become necessary to clarify its pathogenetic mechanisms, define diagnostic tools, and implement new therapeutic modalities, which established the disease as treatable and fully reversible, literally, moving patients from "hell to heaven."

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