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Pulmonary Alveolar Proteinosis: A Historic Perspective

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Treatment of Cystic Fibrosis and Other Rare Lung Diseases

Part of the book series: Milestones in Drug Therapy ((MDT))

Abstract

Since the first report, the pathogenesis of pulmonary alveolar proteinosis (PAP) had been mysterious. In 1999, we discovered granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody in the blood and lung of idiopathic PAP, which consisted 90 % of acquired PAP and was later named as autoimmune PAP. Ten years later, Trapnell and his colleagues proved the hypothesis that the loss of GM-CSF bioactivity in the lung might lead PAP by developing a PAP model in nonhuman primates caused by injecting with a patient-derived GM-CSF autoantibody. The new technology for seroligical diagnosis revealed that most adult onset PAP is associated with GM-CSF autoantibody, and thus, the conventional name of “idiopathic PAP” was changed to “autoimmune PAP” of which a large cohort study was conducted in Japan by Inoue et al. reporting that PAP is distributed equally among subarctic to subtropical regions, with a 2:1 ratio of males to females and the mean age of 51 years, while efforts to develop novel treatment approaches for PAP have been continued at the same time based on the pathogenesis related to the deficiency of pulmonary GM-CSF bioactivity, aerosolized GM-CSF inhalation therapy to autoimmune PAP achieved a satisfactory success with an overall efficacy of more than 60 %. Rituximab therapy targeting reduction of GM-CSF autoantibody has been ongoing. Secondary PAP is a very rare lung disorder consisting approximately 8–9 % of acquired PAP. Hematological disorders are the most common underlying disease, of which 74 % cases demonstrated myelodysplastic syndrome in Japan and the prognosis was poor with a 2-year survival of <50 %. On the other hand, most pediatric cases of pathologically diagnosed PAP have been proven to have defects in a variety of genes involved in surfactant metabolism, such as surfactant protein B, surfactant protein C, ATP-binding cassette family of transporters, and thyroid transcription factor 1. Not only pediatric but also adult-onset PAP is caused by functional defects in the genes encoding the GM-CSF receptor (CSF2RA and CSF2RB). Thus, in the recent two-decade history of research on PAP, an outstanding progress has been achieved in a "bench-to-bedside" manner, which improved our understandings on the pathogenesis, enabled us to characterize clinical features, and increased the choice of the treatment, but efforts are still necessary to solve the mechanism for GM-CSF autoantibody production.

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Authors and Affiliations

  1. Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Niigata, 951-8520, Japan

    Koh Nakata & Ryushi Tazawa

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  1. Koh Nakata
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  2. Ryushi Tazawa
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Correspondence to Koh Nakata .

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Editors and Affiliations

  1. Div of Pulmonary Medicine, Nippon Medical School Div of Pulmonary Medicine, Tokyo, Japan

    Arata Azuma

  2. Children's Hospital of Richmond, Virginia Commonwealth University Children's Hospital of Richmond, Richmond, Virginia, USA

    Michael S. Schechter

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Nakata, K., Tazawa, R. (2017). Pulmonary Alveolar Proteinosis: A Historic Perspective. In: Azuma, A., Schechter, M. (eds) Treatment of Cystic Fibrosis and Other Rare Lung Diseases. Milestones in Drug Therapy. Springer, Basel. https://doi.org/10.1007/978-3-0348-0977-1_4

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