Efficacy and safety of whole-lung lavage for pulmonary alveolar proteinosis: A protocol for a systematic review and meta-analysis

Abstract

Pulmonary alveolar proteinosis (PAP) is an ultra-rare syndrome first described by Rosen et al. in 1958. In a recent study, the prevalence of PAP has been estimated to be 6.87 per million in the general population. PAP is characterized by abnormal surfactant homeostasis and resultant accumulation of surfactant in pulmonary alveoli and alveolar macrophages. The typical physiological consequence of PAP is impaired gas exchange, resulting in progressive dyspnoea, hypoxemia, or even respiratory failure and death. PAP can be classified into three different types based on the pathogenetic mechanism. The most frequent form is primary PAP, which includes autoimmune disease type, associated with elevated levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies. Secondary PAP results from alveolar macrophages dysfunction due to hematopoietic disorders, immune dysregulation, environmental exposures, and pharmaceutical agents, while genetic PAP affects almost exclusively children. Autoimmune PAP comprises the most significant share (90–95%) of adult patients, whereas secondary PAP accounts for 5–10% of adult cases. Notwithstanding the considerably evolved understanding of PAP over the past several decades, limited treatment options are available for this disease. By tradition, whole-lung lavage (WLL) has been the gold standard of care in primary PAP and some causes of secondary PAP (but not congenital PAP). Many improvements have been made since its initial introduction in the 1960. In brief, WLL is an invasive procedure. It requires general anesthesia and isolation of the two lungs using a double-lumen endotracheal tube. One lung is mechanically ventilated while the other is repeatedly filled with saline and drained. Each lung is usually washed with 15–20 liters of saline, but the volume can be up to 50 liters. No randomized controlled trial has been reported on WLL, probably due to the extreme rarity of PAP. However, numerous observational studies have been published, and the cumulative experience may be valuable in assessment. Although widely considered as the first-line management for PAP, the clinical efficacy of WLL has not been evaluated systematically. Besides, new therapeutic strategies for PAP have emerged, such as inhaled or subcutaneous GM-CSF, rituximab, plasmapheresis, and statins. Moreover, WLL is not without morbidity. There is a real need to evaluate the efficacy and safety of WLL in this heterogeneous disease. Therefore, to appropriately apply the available evidence to the clinical practice of WLL in PAP, the systematic and meta-analysis of reported observational studies will be performed strictly following the Cochrane Handbook for Systematic Reviews of Interventions