Secondary Pulmonary Alveolar Proteinosis

Introduction to Secondary PAP

• Secondary Pulmonary Alveolar Proteinosis (PAP) occurs due to underlying diseases or conditions that reduce the numbers and/or functions of alveolar macrophages, with hematological disorders being the most common trigger 1, 2

Hematological Disorders

• The European Respiratory Society acknowledges that acute leukemias, including acute lymphocytic leukemia and acute myeloid leukemia, are well-established triggers for secondary PAP 3
• Chronic leukemias, such as chronic lymphocytic leukemia and chronic myeloid leukemia, can also trigger secondary PAP, with CML accounting for 15.2% of published sPAP cases 3
• Plasma cell disorders, including multiple myeloma and Waldenstrom's macroglobulinemia, are associated with secondary PAP 3
• Lymphomas are recognized as a trigger for secondary PAP 3
• Aplastic anemia is identified as a cause of secondary PAP 3
• GATA2 deficiency is linked to secondary PAP 3

Immune Deficiency and Chronic Inflammatory Conditions

• Acquired immunodeficiency syndrome (AIDS) can trigger secondary PAP by impairing macrophage function 3
• Primary immunodeficiencies, such as agammaglobulinemia and severe combined immunodeficiency disease, are associated with secondary PAP 3
• Autoimmune/inflammatory disorders, including juvenile dermatomyositis and amyloidosis, can trigger secondary PAP 3
• Metabolic disorders, such as Fanconi's syndrome and renal tubular acidosis, are linked to secondary PAP 3

Occupational and Environmental Exposures

• Inhalational exposures to metals like aluminum, silica, titanium, and indium can damage or overwhelm alveolar macrophages, leading to secondary PAP 3
• Industrial materials, including cement, fertilizer, and sawdust, are recognized as triggers for secondary PAP 3
• Chemical fumes, such as chlorine, gasoline/petroleum, nitrogen dioxide, paint, varnish, and synthetic plastic fumes, can cause secondary PAP 3
• Organic dusts, including flour, are associated with secondary PAP 3

Chronic Infections

• Cytomegalovirus infection can impair macrophage clearance function, leading to secondary PAP 3
• Mycobacterium tuberculosis (TB) infection is a common underlying cause of secondary PAP, particularly in Chinese cohorts, with a favorable prognosis when treated 3
• Nocardia infection is linked to secondary PAP 3
• Pneumocystis jirovecii infection can trigger secondary PAP 3

Genetic Disorders Affecting Mononuclear Phagocytes

• Lysinuric protein intolerance is associated with secondary PAP 3
• Mutations in methionyl-tRNA synthetase (MARS) are linked to secondary PAP 3

Key Diagnostic Distinctions

• The European Respiratory Society recommends GM-CSF autoantibody testing to differentiate secondary PAP from autoimmune PAP 1