(HMG-CoA reductase inhibitors) to mouse models of PAP has been shown to increase alveolar macrophage cholesterol effux [31]. This nding was replicated in a case series of patients with autoimmune PAP; patients were treated with rosuvastatin with resultant resolution of PAP lung disease, better lung function, oxygenation, and improvements in radiological ndings [31].

Other strategies targeting GM-CSF autoantibodies include plasmapheresis and B-lymphocyte depletion. Plasmapheresis to remove autoantibodies is challenging because it must be repeated daily for several weeks to lower the GM-CSF autoantibody levels to suf ciently low levels, which limits the practical utility of this approach in clinical practice [147]. The use of rituximab anti-B lymphocyte therapy in autoimmune PAP has been described in case reports and small studies [148–150]. Results suggested initial improvements in AaD02 but bene ts were not sustained over the follow-up period. Thus, the role for rituximab in autoimmune PAP is unclear and it should be reserved for patients who are refractory to other therapies [22]. Corticosteroids are often considered or used in clinical practice despite a lack of convincing evidence. A recent retrospective study demonstrated a worsening in lung disease and increased risk of infection in a cohort of 31 patients with autoimmune PAP [151].

Ultimately, lung transplantation is the only option for patients with autoimmune PAP patients who develop pulmonary brosis as other therapies such as WLL become ineffective. Such measures should be taken with caution as the autoimmune PAP lung disease returns in the donor lung(s) and thus must be treated [152].

Conclusions and Future Directions

Considerable advances have occurred in our knowledge of autoimmune PAP pathogenesis, diagnosis, clinical course, and treatment. Notwithstanding, important questions remain. Although a serum GM-CSF autoantibody test is 100% sensitive and speci c for a diagnosis of autoimmune PAP, antibody levels do not refect disease severity. Thus, robust markers of autoimmune PAP disease severity are needed. Radiographic assessment is promising as such a measure for a several lung diseases, including PAP with promising reports from semi-quantitative approaches [153, 154] and more interestingly a parenchymal pattern analysis method which has been previously used in idiopathic pulmonarybrosis [155–157]. This minimally invasive biomarker has potential as an outcome measure in both clinical and ­academic practice, with utility already demonstrated as a measure of treatment response to inhaled GM-CSF and cholesterol targeted therapy [31, 158].

Disruption of lipid homeostasis is central to autoimmune PAP (and other PAP-causing diseases) and disrupt

the normal cholesterol to phospholipid ratio of surfactant [31, 159], which is expected to alter the biophysical properties of surfactant in PAP. In addition to improving our understanding of the pathogenic mechanisms involved, these observations but may identify additional molecular targets for therapeutic or diagnostic development. Future data may indicate whether the alveolar lipidome correlates with clinical pro le or alters in response to targeted therapies [157, 160].

Internationally agreed clinical practice guidelines for diagnosis and management of PAP are lacking and are needed to help guide physicians and patients so that optimal care can be provided.

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