Pulmonary alveolar proteinosis: time to shift?

Abstract

Pulmonary alveolar proteinosis (PAP) is categorized into hereditary, secondary and autoimmune PAP (aPAP) types. The common pathogenesis is the ability of the alveolar macrophages to catabolize phagocytized surfactant is affected. Hereditary PAP is caused by mutations involving the GM-CSF signaling, particularly in genes for the GM-CSF receptor and sometimes by GATA2 mutations. Secondary PAP occurs in hematologic malignancies, other hematologic disorders, miscellaneous malignancies, fume and dust inhalation, drugs, autoimmune disorders and immunodeficiencies. aPAP is related to the production of GM-CSF autoantibodies. PAP is characterized morphologically by the inappropriate and progressive ‘occupation’ of the alveolar spaces by an excessive amount of unprocessed surfactant, limiting gas exchange and gradually exhausting the respiratory reserve. Myeloid cells’ immunity deteriorates, increasing the risk of infections. Treatment of PAP is based on its etiology. In aPAP, recent therapeutic advances might shift the treatment option from the whole lung lavage procedure under general anesthesia to the inhalation of GM-CSF ‘as needed’.

Keywords:

• autoimmune pulmonary alveolar proteinosis
• granulocyte macrophage-colony stimulating factor
• granulocyte macrophage-colony stimulating factor receptors a and b
• hereditary pulmonary alveolar proteinosis
• inhaled granulocyte macrophage-colony stimulating factor
• lung and systemic infections
• pulmonary alveolar proteinosis
• secondary pulmonary alveolar proteinosis
• surfactant
• whole lung lavage

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Pulmonary alveolar proteinosis (PAP) is categorized as hereditary, secondary and autoimmune PAP (aPAP).

• Hereditary PAP is caused by mutations involving the GM-CSF signaling, particularly in genes for the GM-CSF receptor and sometimes by mutations in GATA2, NPC, SFTPB, SFTPC, ABCA3 and TTF1.

• Secondary PAP occurs in hematologic malignancies, other hematologic disorders, miscellaneous malignancies, fume and dust inhalation, drugs, autoimmune disorders and immunodeficiencies.

• aPAP is related to production of GM-CSF autoantibodies.

• Anti–GM-CSF autoantibodies have high affinity and avidity for their target, neutralizing its entire bioactivity on the alveolar macrophages and, thereby, their ability to catabolize phagocytized surfactant, leading to its alveolar accumulation and related airspace-occupying consequences.

• aPAP is an ultra-rare disease with a worldwide distribution.

• Treatment of PAP certainly relates to its etiology.

• Hereditary disease due to mutations in the GM-CSF receptor require mechanical removal of the inappropriate surfactant accumulated through whole lung lavage procedures as needed.

• Secondary PAP treatment requires the resolution of the etiologic determinant plus the administration of whole lung lavage, if needed, until the achievement of the primary objective and the remission of the disease.

• In aPAP, both whole lung lavage and the exogenous administration of GM-CSF, singularly administered or in combination, may benefit patients, and the definition of the best treatment modality is under development.