Department of Respiratory Medicine, Rare Lung Disease Centre, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland.
Interstitial Lung Disease Unit, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, London, UK.
Curr Opin Pulm Med. 2019 Sep;25(5):450-458. doi: 10.1097/MCP.0000000000000601.
Pulmonary alveolar proteinosis (PAP) can be considered the archetype of ultra-rare diseases with a prevalence of under 10 cases per million. We discuss the classification of PAP, the current diagnostic practice and the supplementary role of genetic testing and granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling in the diagnosis of congenital and hereditary PAP. We report on novel therapeutic approaches such as GM-CSF substitution, stem cell transplantation, pioglitazone, statins and immunomodulation.
The discovery of new genetic mutations underlying this syndrome raises the question whether the classification should be radically revised in the future. Serum GM-CSF autoantibody is the best diagnostic marker for autoimmune PAP, the most common form, but does not correlate with disease severity. Several circulating biomarkers have been investigated to assess disease activity and predict outcome. Imaging techniques have also enormously evolved and offer new tools to quantify disease burden and possibly drive therapeutic decisions. Promising clinical trials are ongoing and will generate new treatment strategies besides or in addition to whole lung lavage in the next future.
Despite impressive advances in understanding pathogenesis, PAP remains a rare syndrome with several unanswered questions impacting diagnosis, management and treatment, and, as a result, patients' quality of life.
肺泡蛋白沉积症（PAP）可被视为罕见病的典型代表，其发病率低于每百万人中有 10 例。我们讨论了 PAP 的分类、目前的诊断实践以及遗传检测和粒细胞-巨噬细胞集落刺激因子（GM-CSF）信号在先天性和遗传性 PAP 诊断中的补充作用。我们报告了新的治疗方法，如 GM-CSF 替代、干细胞移植、吡格列酮、他汀类药物和免疫调节。
该综合征潜在的新基因突变的发现提出了一个问题，即该分类将来是否需要彻底修订。血清 GM-CSF 自身抗体是自身免疫性 PAP（最常见的形式）的最佳诊断标志物，但与疾病严重程度无关。已经研究了几种循环生物标志物来评估疾病活动度和预测预后。成像技术也有了巨大的发展，为定量疾病负担并可能推动治疗决策提供了新的工具。未来，除全肺灌洗外，还将开展有前景的临床试验，以提供除全肺灌洗以外或作为全肺灌洗的替代疗法的新治疗策略。
尽管对发病机制的理解取得了令人瞩目的进展，但 PAP 仍然是一种罕见的综合征，存在许多未解决的问题，影响诊断、管理和治疗，从而影响患者的生活质量。
