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Semin Respir Crit Care Med
DOI: 10.1055/a-2737-7719
Review Article

Autoimmune Pulmonary Alveolar Proteinosis

Authors

  • Spyros A. Papiris

    1   Athens Medical School, National and Kapodistrian University of Athens, Athens, Greece

  • Maria Kallieri

    2   2nd Pulmonary Medicine Department, General University Hospital “Attikon,” Medical School, National and Kapodistrian University of Athens, Athens, Greece

  • Maurizio Zompatori‡   ‡

    3   Radiologia, Villa Erbosa, Gruppo San Donato, Bologna, Italy

  • Sarah H. Forde‡   ‡

    4   School of Medicine, University College Dublin, Dublin, Ireland

  • Spyridon Prountzos‡   ‡

    5   2nd Department of Radiology, General University Hospital “Attikon,” Medical School, National and Kapodistrian University of Athens, Athens, Greece

  • Lykourgos Kolilekas

    6   7th Pulmonary Department, Athens Chest Hospital “Sotiria,” Athens, Greece

  • Andriana I. Papaioannou

    7   1st Respiratory Medicine Department, National and Kapodistrian University of Athens, Medical School, Sotiria Chest Diseases Hospital, Athens, Greece

  • Matthias Griese

    8   Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany
    9   German Center for Lung Research (DZL), Comprehensive Pneumology Center Munich, Munich, Germany

  • Effrosyni D. Manali

    2   2nd Pulmonary Medicine Department, General University Hospital “Attikon,” Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Abstract

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by abnormal accumulation of surfactant in alveoli. Pathogenetically, in aPAP, the presence of granulocyte macrophage-colony stimulating factor (GM-CSF) autoantibodies hinders physiological binding of GM-CSF to its receptor, disrupting terminal differentiation of alveolar macrophages and the activation GM-CSF–PU.1–PPARG1–ABCG1 axis, resulting in a primary reduction in cholesterol efflux from alveolar macrophages and a secondary reduction in surfactant clearance through macrophages from the alveolar surface. APAP is the most common, accounting for more than 90 to 95% of all patients included under the PAP term, which encompasses and classifies all forms of PAP according to etiopathogenetic mechanisms, as primary, secondary, congenital, and unclassified. APAP is worldwide distributed with an estimated prevalence fluctuating between 7.0 and 9.7 cases/million and an annual incidence of 1.65, affecting middle-aged men and women. Clinical manifestation may be gradual and insidious, mainly manifesting with progressive dyspnea, but the natural history is variable, since some patients stabilize for a long period, while others progress to respiratory failure and death; in a minority, spontaneous resolution may be observed, while some develop lung and/or systemic infections, and rarely pulmonary fibrosis. Until recently, whole lung lavage (WLL) was universally accepted as the gold-standard therapeutic modality in aPAP. However, after considerable progress in the past 25 years and the publication of several positive studies, replacing the use of inhaled-GM-CSF as the standard of care for aPAP and conceding WLL a rescue option is becoming more and more concrete. In conclusion, aPAP is the classic paradigm of a scientific disease progressing from the “bench-to-bedside,” since several discoveries made in the laboratory setting have become necessary to clarify its pathogenetic mechanisms, define diagnostic tools, and implement new therapeutic modalities, which established the disease as treatable and fully reversible, literally, moving patients from “hell to heaven.”

Keywords

PAP - GMCSF - autoantibodies - WLL - foamy macrophage - cholesterol

‡ These authors contributed equally to this article.




Publication History

Received: 26 July 2025

Accepted: 04 November 2025

Accepted Manuscript online:
06 November 2025

Article published online:
25 November 2025

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