Pulmonary Alveolar Proteinosis (PAP)



Primary Pulmonary Alveolar Proteinosis

Adult Idiopathic Pulmonary Alveolar Proteinosis

Neonatal/Congenital Pulmonary Alveolar Proteinosis

Secondary Pulmonary Alveolar Proteinosis

Marrow Disorders

Other Malignancies

Immune Deficiency Syndromes/Chronic Inflammation

Chronic Infections

Drug-Induced Pulmonary Alveolar Proteinosis

Occupational Exposure-Related Pulmonary Alveolar Proteinosis


-Production of lipoprteinaceous material by type II pneumocytes with accumulation in alveoli
-Surfactant is believed to be cleared by alveolar macrophages (a process-dependent on GM-CSF): mechanism probably involves normal surfactant uptake with decreased catabolism (explains the foamy, vacuolated appearance of alveolar macrophages)
–Macrophage functions (phagocytosis, migration, phagolysosome fusion, and subsequent killing) are impaired by the surfactant with cells

-Animal Models:
a) GM-CSF Knockout Mouse: develops PAP-like lung disease at 8 weeks of age
b) Murine GM-CSF Receptor ß-Chain Deletion: develops PAP-like disease
c) Silica Overload: develops PAP-like disease
d) IL-13 Overexpression: develops PAP-like disease
e) IL-4 Overexpression: develops PAP-like disease
f) SP-D Knockout Mouse: develops PAP-like disease

-Serum Anti-GM-CSF Neutralizing Autoantibody: detected (at levels at least 1:400) in all idiopathic PAP patients [Bonfield; Am J Resp Cell Mol Biol, 2002]
–Sensitivity: 100%
–Specificity: >91%
–Higher titer in active disease and lower in remission
–Suggests that this autoantibody results in an effective decrease in active GM-CSF

-PAP in Marrow Disorders: may be related to the malignant clone affecting the monocyte-alveolar macrophage lineage cells, chemo or XRT effects on macrophages, or steroid use

Pathologic Patterns

1) Alveolar Proteinosis: amorphous eosinophilic-staining (PAS-positive) granular intra-alveolar exudate (rich in surfactant-associated lipids and proteins)
-May occasionally extend into small bronchioles
-Interstitial inflammation generally not seen earlier in course
-Alveolar wall fibrosis seen in chronic cases
-SP-A demonstrates uniform staining in alveoli in primary PAP cases, but patchy staining in alveoli in secondary PAP cases
-Foamy, vacuolated alveolar macrophages
2) Usual Interstitial Pneumonia (UIP): features may be seen in some cases




-BAL: usually grossly milky and opaque, layers into thick sediment and translucent supernatant layer
–Cytospin of Milky Layer:
a) PAS-Positive (Eosinophilic) Lipoproteinaceous Material: this is relatively non-specific
b) Foamy Vacuolated Alveolar Macrophages: most striking finding
c) Fat Globules: by PAP stain
d) Cell Counts (difficult, as cells get trapped in debris): predominantly alveolar macrophages (with lymphocytes, neutrophils, and eosinophils), with normal differential (one study in smokers suggested a lymphocyte-predominance, with increased CD4 and CD8 cells, in that group)
e) Lipids: cholesterol is increased 7-fold, as compared to normals/increased SP-A:phospholipid ratio and increased SP-A:phospholipid ratio
f) EM: granular debris is composed of tubular myelin, concentrically-laminated lamellar bodies, and membrane structures resembling surfactant
-TBB: may be diagnostic (shows granular alveolar filling containing large acellular eosinophilic bodies)
-BAL KL-6 Level (KL-6 is a mucin-like protein secreted by type II pneumocytes): increased


-Restriction: most common abnormality (FVC and TLC are mildly decreased in most studies)
-DLCO: decreased (often out of proportion, as compared to the decrease in FVC and TLC)

Shunt Fraction

CXR/Chest CT Patterns

(chest CT appearances correlate with restrictive PFT’s, decreased DLCO, and hypoxemia)

Serum Anti-GM-CSF Autoantibody: detected (at levels at least 1:400) in all idiopathic PAP patients [Bonfield; Am J Resp Cell Mol Biol, 2002]
–Sensitivity: 100%
–Specificity: >91%

LDH: frequently elevated (non-specific)
-Correlation between LDH and aretrial pO2 is poor

Serum Surfactant Proteins A, B, and D: elevated (non-specific: also elevated in acute lung injury and IPF)

Serum KL-6 Level: increased


Symptoms/Signs: variable and non-specific symptoms (may lead to misdiagnosis as chronic bronchitis)/symptoms are frequently less significant than radiographic findings
1) Dyspnea and Cough: usually insidious/subacute onset
2) Fever: less common
3) Hemoptysis: occasional
4) Constitutional Symptoms: less common
5) Crackles: may be seen
6) Cyanosis: may be seen
7) Clubbing: may be seen

Association with Infection: most associations were from earlier studies and case reports, it is currently believed that PAP does increase the risk of infection
Association with Pulmonary Fibrosis: 3 case reports cite an association between PAP and interstitial fibrosis (likely a rare occurrence)


Neonatal/Congenital Pulmonary Alveolar Proteinosis

Adult Pulmonary Alveolar Proteinosis