Pulmonary alveolar proteinosis: from classification to therapy

Abstract

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.

Educational aims: To update knowledge about a rare respiratory syndrome, pulmonary alveolar proteinosis, in order to promote early diagnosis and correct management.To highlight recent treatment options based on pathogenesis and disease severity.

Figure 1

PAP pathogenesis. In normal surfactant homeostasis (bottom right), surfactant is synthesised by type II alveolar epithelial cells and secreted into the alveolar space to generate a thin layer. GM-CSF is a cytokine produced by type II alveolar epithelial cells that binds specific receptors on macrophages; GM-CSF induces the terminal differentiation of alveolar macrophages, allowing an effective surfactant catabolism. In primary PAP (bottom left), altered macrophage activation, due to a dysfunction in GM-CSF signalling, leads to impaired surfactant clearance and to the consequent accumulation of surfactant. In autoimmune PAP, GM-CSF signalling is inhibited by the presence of neutralising GM-CSF autoantibodies; the hereditary form is the result of mutations involving the GM-CSF receptor. In secondary PAP (top left), various underlying conditions can affect the number and/or the function of the alveolar macrophages, causing reduced surfactant clearance and surfactant accumulation within the alveoli. In congenital PAP (top right), mutations in SFTPB, SFTPC, ABCA3 and TTF1 interfere with the production of surfactant which, in turn, is ineffective and prone to accumulation.

Figure 2

Chest HRCT findings in PAP. a) Interlobular septal thickening within interspersed ground glass (“crazy paving” pattern) is spread symmetrically to all five lobes with a perihilar predominance. b) After whole-lung lavage treatment, the crazy paving pattern is still appreciable but with reduced distribution and lower alveolar infiltration.

Figure 3

Diagnostic algorithm of PAP syndrome. PAP can be suspected based on a congruent clinical picture, compatible chest HRCT findings and an evocative BAL fluid. BAL fluid cytological analysis can confirm the diagnosis of PAP syndrome; subsequently, the diagnostic effort is directed to the identification of the specific PAP-causing disease. In the absence of a clear PAP-causing disease, GM-CSF autoantibody measurement should be performed to identify autoimmune PAP, the most frequent aetiology of PAP. Low levels of GM-CSF autoantibodies exclude the diagnosis of autoimmune PAP and dictate further investigations: accurate research of possible secondary PAP-causing disease, serum GM-CSF measurement and GM-CSF signalling test. High levels of serum GM-CSF indicate GM-CSF receptor dysfunction, highlighting hereditary PAP, which can be confirmed by the GM-CSF signalling test and specific gene analysis. Normal levels of serum GM-CSF and a GM-CSF signalling test within normality suggest the presence of congenital PAP that should be assessed with specific genetic tests [4]. LDH: lactate dehydrogenase.

Figure 4

WLL schematic procedure. WLL is an invasive procedure almost universally performed under general anaesthesia, in an intensive care unit. In this example, the patient lies in the full lateral position; selective ventilation is assured by using a double-lumen endobronchial intubation. The lung above undergoes the lavage, while the other is selectively ventilated; an aliquot of warm saline is infused by gravity into the nonventilated lung and the collection tube is clamped. Subsequently, the aliquot is drained from the lavaged lung and received by gravity by the fluid collector. These passages are repeated until the collected fluid turns clears or until achievement of the programmed total infusion volume for each lung. Chest percussion can be associated during the procedure in order to emulsify the surfactant sediment.