What triggers secondary Pulmonary Alveolar Proteinosis (PAP) in adults, particularly those with a history of hematological disorders?

Secondary Pulmonary Alveolar Proteinosis: Triggers and Underlying Causes

Secondary PAP occurs because of 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 (Most Common Category)

The following hematological conditions are well-established triggers for secondary PAP 1:

• Acute leukemias: Acute lymphocytic leukemia and acute myeloid leukemia 1
• Chronic leukemias: Chronic lymphocytic leukemia and chronic myeloid leukemia (CML accounts for 15.2% of published sPAP cases) 1, 3
• Myelodysplastic syndromes (MDS): The most frequent hematological cause, accounting for 34.1% of published sPAP cases 3
• Plasma cell disorders: Multiple myeloma and Waldenstrom's macroglobulinemia 1
• Lymphomas 1
• Aplastic anemia 1
• GATA2 deficiency 1

Critical caveat: Patients with sPAP secondary to MDS have extremely poor prognosis, with median survival less than 20 months and all patients in one series surviving less than 2 years after diagnosis. 2, 3

Immune Deficiency and Chronic Inflammatory Conditions

These conditions trigger sPAP by impairing macrophage function 1:

• Acquired immunodeficiency syndrome (AIDS) 1
• Primary immunodeficiencies: Agammaglobulinemia and severe combined immunodeficiency disease 1
• Autoimmune/inflammatory disorders: Juvenile dermatomyositis and amyloidosis 1
• Metabolic disorders: Fanconi's syndrome and renal tubular acidosis 1

Occupational and Environmental Exposures

Inhalational exposures that damage or overwhelm alveolar macrophages include 1:

• Metals: Aluminum, silica, titanium, and indium 1
• Industrial materials: Cement, fertilizer, and sawdust 1
• Chemical fumes: Chlorine, gasoline/petroleum, nitrogen dioxide, paint, varnish, and synthetic plastic fumes 1
• Organic dusts: Flour 1

Chronic Infections

Persistent infections that impair macrophage clearance function 1:

• Cytomegalovirus 1
• Mycobacterium tuberculosis (TB infection was a common underlying cause in Chinese cohorts, with favorable prognosis when treated) 1, 3
• Nocardia 1
• Pneumocystis jirovecii 1

Genetic Disorders Affecting Mononuclear Phagocytes

• Lysinuric protein intolerance 1
• Mutations in methionyl-tRNA synthetase (MARS) 1

Key Diagnostic Distinctions

When evaluating suspected PAP, GM-CSF autoantibody testing is essential to differentiate secondary PAP from autoimmune PAP (which accounts for >90% of all PAP cases). 1, 4 Negative GM-CSF autoantibodies in the presence of PAP should prompt investigation for the underlying conditions listed above. 3

Clinical Pearls

• sPAP accounts for only 4% of all PAP cases but has significantly worse prognosis than autoimmune PAP 2
• The incidence of secondary PAP in hematologic patients with pulmonary symptoms is approximately 5.3% overall and 10% in those with myeloid disorders 5
• sPAP may be reversible if complete remission of the underlying disease is achieved, particularly in leukemia patients recovering from neutropenia or after bone marrow transplantation 5
• Radiologically, sPAP often presents with diffuse ground-glass opacities without the characteristic interlobular septal thickening ("crazy paving" pattern) commonly seen in autoimmune PAP 3