Pulmonary Alveolar Proteinosis (PAP)

Epidemiology

  • First described in 1958
  • Rare Disorder: <500 cases reported in the medical literature (although literature probably underestimates true number of cases)
  • Median Age at Diagnosis: 39 y/o
  • Median Duration of Symptoms Prior to Diagnosis: 7 months
  • Male Sex Predominance in Smokers: M:F ratio is 2.65:1
    • No sex predominance exists in non-smokers
  • 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)

Etiology

Primary Pulmonary Alveolar Proteinosis

Adult Idiopathic Pulmonary Alveolar Proteinosis

  • Always associated with presence of anti-GM-CSF autoantibody

Neonatal/Congenital Pulmonary Alveolar Proteinosis

  • First described in 1981
  • May account for 1% of all infant deaths within the first 6 months of life
  • Surfactant Protein B Deficiency (autosomal recessive; heterozygous surfactant protein B deficiency is clinically asymptomatic): presents as respiratory distress in full-term infant that is unresponsive to steroids and/or surfactant therapy (diagnose by PCR for surfactant protein B mutations)
  • GM-CSF Receptor ß-chain Abnormality: usually presents at several months of age/may have associated hematologic abnormalities

Secondary Pulmonary Alveolar Proteinosis

Marrow Disorders

  • PAP may accompany 5.3% of all marrow disorders at some institutions (8.8% in neutropenic patients)
    [Cordonnier; Am J Resp Crit Care Med, 1994]
  • Most patients were neutropenic when they developed PAP
  • Most recovered spontaneously when their marrow recovered
  • Etiologies
    • AML: AML is a common marrow disorder associated with PAP
    • ALL: a case report in a neutropenic ALL patient noted improvement in PAP with GCSF therapy
    • Aplastic Anemia:
    • CML: CML is a common marrow disorder associated with PAP
    • Chronic Lymphocytic Leukemia (see [[Chronic Lymphocytic Leukemia]])
    • Myelodysplastic Syndrome: MDS is a common marrow disorder associated with PAP
    • Multiple Myeloma (see [[Multiple Myeloma]])
    • Non-Hodgkin’s [[Lymphoma]]:
    • Waldenstrom’s Macroglobulinemia:

Other Malignancies

  • Adenocarcinoma:
  • Glioblastoma:
  • Melanoma:

Immune Deficiency Syndromes/Chronic Inflammation

  • HIV Disease (see [[HIV Disease]]): the 2 reported cases both had coexistent opportunistic infection
  • Amyloidosis (see [[Amyloidosis]])
  • Congenital Lymphoplasia:
  • Fanconi’s Syndrome:
  • Hypogammagloublinemia/IgA Deficiency:
  • Idiopathic Thrombocytopenic Purpura (see [[Idiopathic Thrombocytopenic Purpura]])
  • Juvenile Dermatomyositis:
  • Polydermatomyositis (see [[Polydermatomyositis]])
  • Renal Tubular Acidosis (RTA):
  • Subacute Combined Immunodeficiency Syndrome:
    • Solid Organ Transplantation: case reports

Chronic Infections

  • CMV (see [[CMV]])
  • Tuberculosis (see [[Tuberculosis]])
  • Nocardiosis (see [[Nocardiosis]])
  • Pneumocystis Jirovecii (see [[Pneumocystis Jirovecii]]): studies in PCP show alveolar proteinosis in 9 of 26 patients

Drug-Induced Pulmonary Alveolar Proteinosis

  • Busulfan (see [[Busulfan]])
  • Leflunomide (see [[Leflunomide]])
  • Mitomycin-C (see [[Mitomycin]])
  • Sirolimus (see [[Sirolimus]])

Occupational Exposure-Related Pulmonary Alveolar Proteinosis

  • Agricultural Dust:
  • Aluminum Dust (see [[Aluminum]])
  • Bakery Flour Dust:
  • Cement Dust: may be related to silica
  • Chlorine (see [[Chlorine Inhalation]])
  • Cleaning Products:
  • Fertilizer Dust:
  • Gasoline Fumes:
  • Nitrogen Dioxide (see [[Nitrogen Dioxide Inhalation]])
  • Paint/Synthetic Paint Fumes/Varnish:
  • Petroleum:
  • Sawdust:
  • Silica (Silicoproteinosis) (see [[Silicosis]]): this is the most commonly reported exposure associated with PAP
    • Silicotic nodules with alveolar proteinosis occur in setting of intense sandblasting with poor ventilation (typically with fine quartz dust exposure)
    • Silica dioxide (quartz) instilled into rodent airways induces surfactant production and produces PAP-like pathology
  • Titanium Dioxide (see [[Titanium]])

Physiology

-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


Diagnosis

ABG

  • Hypoxemia with respiratory alkalosis

FOB

-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

PFT’s

-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

  • Increased (as compared to other patients with diffuse lung diseases)

CXR/Chest CT Patterns

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

  • Alveolar Infiltrates
    • Usually bilateral, symmetric (some cases are asymmetric)
    • Patchy or reticulonodular
    • Perihilar “Butterfly” Pattern (similar to pulmonary edema or PCP): lower > upper lobes, with characteristic sparing of subpleural areas and areas adjacent to diaphragm
    • ”Crazy Paving” Pattern: branching white linear areas (due to thickened interlobular septa), forming geometric shapes around 10 mm in diameter
    • ”Geographic” Pattern: areas of involvement (not related to to anatomic landmarks) are sharply demarcated
    • Ground-Glass Pattern: background homogenous haze with preserved normal airway and vessel branching
    • Air Bronchograms: variable
    • Absence of Mediastinal Adenopathy: rules out Sarcoidosis
    • Absence of Pleural Effusions: makes CHF less likely
  • Interstital Infiltrates
    • May be superimposed on alveolar infiltrates later in course
  • Honeycombing
    • Small cystic changes (seen best in lower fields): seen late in course
    • Radiographic honeycombing correlates well with pathologic honeycombing

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


Clinical

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)


Treatment

Neonatal/Congenital Pulmonary Alveolar Proteinosis

  • Uniformly fatal within first few months of life, unless treated with lung transplant
  • Lung Transplant: 12/190 lung transplants were done in one study for PAP

Adult Pulmonary Alveolar Proteinosis

  • Bilateral Whole Lung Lavage
    • Preferred treatment
    • Procedure: double-lumen tube in OR -> lavage with up to 3 L of NS, until effluent is clear
    • Only treatment shown to decrease symptoms and improve oxygenation (less impressive effect on degree of restriction and decrease in DLCO)
    • Median Duration of Benefit: 15 months
    • Improves 5-year survival (94% vs. 85% in those not lavaged)
    • Good response to treatment in most cases
    • May require repeat treatment 6-12 months later
    • Indications for Lung Lavage: dyspnea limiting activities, RA pO2 <60, and/or shunt fraction >10-12%
    • Contraindications to Lung Lavage: bacterial pneumonia (may result in septic shock)
    • Complications of Lung Lavage: hydropneumothorax, sepsis, pneumonia, hypoxemia, and ARDS
    • In patients who are unable to tolerate general anesthesia, there are case reports of lavage being done with FOB, in hyperbaric chamber, with CPB, and with liquid ventilation
  • GM-CSF: first trial in 1995
    • Rapid dose escalation to 18 µg/kg/day x 6-12 months: 60% response rate
    • Lag time to response is around 8 weeks
    • Variability in dose and duration of therapy required
    • There is uniform blunted hematopoetic response to GM-CSF
    • There is a decrease in BAL and serum anti-GM-CSF titers with therapy
    • GM-CSF therapy is not curative: relapses may occur
    • Normal LDH: may predict a good clinical response
    • Anti-GM-CSF Titer: inversely correlated with clinical response to GM-CSF therapy
    • Isolated case reports using aerosolized GM-CSF with benefit in some cases: needs to be further studied
  • Lung Transplantation: one case of double-lung transplant had a recurrence in the transplanted lungs 3 years later (without evidence of infection)
  • Bone Marrow Transplantation: there are reported cases of patients with secondary PAP receiving BMT for their underlying marrow disorder having resolution of their PAP
  • Plasmapheresis: one case report of improvement in PAP
  • Steroids: possibly increase mortality
  • SSKI: ineffective
  • Postural Drainage: ineffective

References

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