Pulmonary alveolar proteinosis: from classification to therapy

Abstract

<jats:p>Pulmonary alveolar proteinosis (PAP) is a rare respiratory syndrome characterised by the accumulation of surfactant lipoproteins within the alveoli. According to various pathogenetic mechanisms and aetiologies, PAP is classified as primary, secondary or congenital. Primary PAP is led by a granulocyte–macrophage colony-stimulating factor (GM-CSF) signalling disruption; the autoimmune form is driven by the presence of anti GM-CSF autoantibodies and represents 90% of all the PAP cases; and the hereditary form is the result of mutations in genes encoding GM-CSF receptor. Secondary PAP is associated with various diseases causing a reduction in function and/or number of alveolar macrophages. Congenital PAP emerges as a consequence of corrupted surfactant production, due to mutations in surfactant proteins or lipid transporter, or mutations affecting lung development. The clinical manifestations are various, ranging from insidious onset to acute or progressive respiratory failure, including premature death within the first days of life in neonates with congenital surfactant production disorders. The diagnostic workup includes clinical and radiological assessment (respiratory function test, high-resolution chest computed tomography), laboratory tests (anti-GM-CSF autoantibodies dosage, GM-CSF serum level and GM-CSF signalling test), and genetic tests. Whole-lung lavage is the current gold standard of care of PAP; however, the therapeutic approach depends on the pathogenic form and disease severity, including GM-CSF augmentation strategies in autoimmune PAP and other promising new treatments.</jats:p><jats:sec><jats:title>Educational aims</jats:title><jats:list list-type="bullet"><jats:list-item><jats:p>To update knowledge about a rare respiratory syndrome, pulmonary alveolar proteinosis, in order to promote early diagnosis and correct management.</jats:p></jats:list-item><jats:list-item><jats:p>To highlight recent treatment options based on pathogenesis and disease severity.</jats:p></jats:list-item></jats:list></jats:sec>

Selection Criteria for Lung Transplantation: Controversies and New Developments

“…Pulmonary alveolar proteinosis (PAP) is a rare respiratory syndrome characterized by the accumulation of surfactant in pulmonary alveoli, leading to a variable impairment in pulmonary gas transfer, resulting in hypoxemic respiratory failure, secondary infections, and sometimes pulmonary fibrosis. [149][150][151] PAP is caused by either impaired surfactant clearance or abnormal surfactant production. Disorders in which surfactant clearance is impaired are divided into primary and secondary PAP.…”

“…Congenital PAP consists of a group of surfactant production disorders caused by mutations in genes involved in surfactant production. 149,150 When no known cause is found, the patient is diagnosed with unclassified PAP. Autoimmune PAP accounts for 90% of all PAP cases.…”

“…149 Our main focus is hPAP, which results from mutations involving the GM-CSF receptor (in the CSF2RA or CSF2RB genes that code for the αand βchains, respectively). [149][150][151] GM-CSF is a cytokine produced by type II alveolar epithelial cells that binds to specific receptors on alveolar macrophages; it plays a critical role in the terminal differentiation of alveolar macrophages of the lung and also the degradation of surfactant in alveolar macrophages. 149,152 Currently, whole-lung lavage is the gold standard of care for PAP.…”

“…[149][150][151] GM-CSF is a cytokine produced by type II alveolar epithelial cells that binds to specific receptors on alveolar macrophages; it plays a critical role in the terminal differentiation of alveolar macrophages of the lung and also the degradation of surfactant in alveolar macrophages. 149,152 Currently, whole-lung lavage is the gold standard of care for PAP. [149][150][151][152] However, hPAP may lead to pulmonary fibrosis if insufficiently treated or long lasting.…”

“…149,152 Currently, whole-lung lavage is the gold standard of care for PAP. [149][150][151][152] However, hPAP may lead to pulmonary fibrosis if insufficiently treated or long lasting. Lung transplantation has been reported when hPAP progression leads to end-stage respiratory failure due to pulmonary fibrosis.…”