Pulmonary alveolar proteinosis
Synonyms and keywords:Pulmonary alveolar phospholipoproteinosis

# Overview
Pulmonary alveolar proteinosis ( PAP) was first discovered by Samuel Rosen, Benjamin Castleman, and Averill Liebow, in 1958. Pulmonary alveolar proteinosis ( PAP) may be classified into 2 subtypes, primary and secondary pulmonary alveolar proteinosis. The pathogenesis of pulmonary alveolar proteinosis is characterized by the intraalveolar accumulation of surfactant phospholipid and apoproteins. Pulmonary alveolar proteinosis develop because of reduced granulocyte-macrophage colony-stimulating factor (GM-CSF) levels or function and/or impaired alveolar macrophage function. On gross pathology after lung washings, fluid with the milky composition are the characteristic finding of pulmonary alveolar proteinosis. On microscopic histopathological analysis, terminal bronchioles and alveoli are filled with a lipoproteinaceous material that will be pink after periodic acid-Schiff (PAS) stain. The exact etiology of pulmonary alveolar proteinosis (PAP) is unknown, but it may be associated with exposure to insecticides, hematologic malignancies, or HIV infection. Pulmonary alveolar proteinosis must be differentiated from other diseases that cause ground glass opacities in radiography. Pulmonary alveolar proteinosis is more commonly observed among patients aged 40- 50 years old. Men are more commonly affected with pulmonary alveolar proteinosis than women. Common risk factors in the development of pulmonary alveolar proteinosis are current or former cigarette smokers and HIV infection. If left untreated, patients with pulmonary alveolar proteinosis may progress to develop pulmonary fibrosis, cor pulmonale. Symptoms of pulmonary alveolar proteinosis may include dyspnea on exertion, cough. The physical examination is often normal. Laboratory findings are serum anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in autoimmune pulmonary alveolar proteinosis and elevated serum level of GM-CSF in hereditary pulmonary alveolar proteinosis. Imaging studies include chest x-ray and high resolution computed tomography (HRCT). Treatment include whole-lung lavage (WLL), recombinant GM-CSF and lung transplantation.

# Historical Perspective
- Pulmonary alveolar proteinosis ( PAP) was first discovered by Samuel Rosen, Benjamin Castleman, and Averill Liebow, in 1958, during pathologic investigations of material filling the alveoli. 
- In 1960, the first  therapeutic bronchoalveolar lavage by repeated segmental flooding was developed by Dr. Jose Ramirez-Rivera to treat pulmonary alveolar proteinosis. 

# Classification
Pulmonary alveolar proteinosis ( PAP) may be classified into 2 subtypes:
- Autoimmune and hereditary PAP: Disruption of Granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling
Clearance of surfactant by alveolar macrophages is regulated by GM-CSF
Autoimmune PAP: The most common type of PAP in adults
Effect of GM-CSF on alveolar macrophages is neutralized by antibodies to GM-CSF
Hereditary PAP: GM-CSF is intact but recessive variants of the GM-CSF receptor alpha and beta genes (CSF2RA and CSF2RB) impair signaling by GM-CSF
- Clearance of surfactant by alveolar macrophages is regulated by GM-CSF
- Autoimmune PAP: The most common type of PAP in adults
Effect of GM-CSF on alveolar macrophages is neutralized by antibodies to GM-CSF
- Effect of GM-CSF on alveolar macrophages is neutralized by antibodies to GM-CSF
- Hereditary PAP: GM-CSF is intact but recessive variants of the GM-CSF receptor alpha and beta genes (CSF2RA and CSF2RB) impair signaling by GM-CSF
- Congenital PAP: Disorders of surfactant production
Variants of surfactant proteins B and C (SFTPB, SFTPC)
Variants of ATP-binding cassette, subfamily A (ABCA3)
Variant of NK2 homeobox-1 (NKX2.1) 
Variants in the gene SLC7A7
Variants of the MARS (methionyl-tRNA synthetasegene ): Prevalent on Reunion Island
- Variants of surfactant proteins B and C (SFTPB, SFTPC)
- Variants of ATP-binding cassette, subfamily A (ABCA3)
- Variant of NK2 homeobox-1 (NKX2.1) 
- Variants in the gene SLC7A7
- Variants of the MARS (methionyl-tRNA synthetasegene ): Prevalent on Reunion Island
- High level dust exposures (titanium, silica, indium-tin oxide, aluminum)
- Hematologic dyscrasias such as GATA2 gene deficiency, myelodysplastic syndrome and hematologic malignancy 
- After allogeneic hematopoietic cell transplantation for myeloid malignancies 

# Pathophysiology
- The pathogenesis of pulmonary alveolar proteinosis is characterized by the intraalveolar accumulation of surfactant phospholipid and apoproteins. Pulmonary alveolar proteinosis develop because of reduced granulocyte-macrophage colony-stimulating factor (GM-CSF) levels or function and/or impaired alveolar macrophage function.
- Genes involved in the pathogenesis of pulmonary alveolar proteinosis include:
Surfactant proteins B and C (SFTPB, SFTPC), ATP-binding cassette, subfamily A (ABCA3), SLC7A7, MARS (methionyl-tRNA synthetasegene ) and GM-CSF receptor alpha and beta genes (CSF2RA and CSF2RB) genes mutation in production of surfactant.
- Surfactant proteins B and C (SFTPB, SFTPC), ATP-binding cassette, subfamily A (ABCA3), SLC7A7, MARS (methionyl-tRNA synthetasegene ) and GM-CSF receptor alpha and beta genes (CSF2RA and CSF2RB) genes mutation in production of surfactant.
- On gross pathology after lung washings, fluid with milky composition are characteristic finding of pulmonary alveolar proteinosis. 
- On microscopic histopathological analysis, terminal bronchioles and alveoli are filled with a lipoproteinaceous material that will be pink after periodic acid-Schiff (PAS) stain. Oil red-O positive, PAS-positive macrophages and cholesterol crystals are another characteristic findings of pulmonary alveolar proteinosis. Multilamellated structures in the alveoli can be seen in electron microscopy.

# Causes
The exact etiology of pulmonary alveolar proteinosis (PAP) is unknown, but it may be associated with:
- Exposure to insecticides, titanium dioxide, indium-tin oxide and silica dust
- Hematologic malignancies
- HIV infection (AIDS)
- Leflunomide, case report
- Recessive CSF2RA mutations

# Differentiating pulmonary alveolar proteinosis from other Diseases
- Pulmonary alveolar proteinosis must be differentiated from other diseases that cause ground glass opacities in radiography such as:
- Infection (Pneumocystis jirovecii or Mycoplasma)
- Acute interstitial pneumonia
- Cardiogenic pulmonary edema
- Noncardiogenic pulmonary edema
- Lipoid pneumonia
- Drug-related hypersensitivity reactions

# Epidemiology and Demographics
- The prevalence of pulmonary alveolar proteinosis is approximately 1 per 100,000 individuals worldwide.
- The incidence of pulmonary alveolar proteinosis is estimated to be 0.33 cases per 100,000 individuals in united states. 

## Age
- Pulmonary alveolar proteinosis is more commonly observed among patients aged 40- 50 years old.

## Gender
- Men are more commonly affected with pulmonary alveolar proteinosis than women. The men to women ratio is approximately 2 to 1.

## Race
- There is no racial predilection for pulmonary alveolar protoeinosis.

# Risk Factors
- Common risk factors in the development of pulmonary alveolar proteinosis are:
Current or former cigarette smokers
HIV infection
- Current or former cigarette smokers
- HIV infection

# Natural History, Complications and Prognosis
- If left untreated, patients with pulmonary alveolar proteinosis may progress to develop pulmonary fibrosis, cor pulmonale. The natural history of secondary pulmonary alveolar proteinosis is related to underlying etiologies.
- Common complications of pulmonary alveolar proteinosis include lung infections with Pneumocystis carinii, Mycobacterium avium-intracellulare, Nocardia asteroides. 
- Prognosis is generally good for primary pulmonary alveolar proteinosis with whole lung lavage. Congenital pulmonary alveolar proteinosis respond well to lung transplantation. Prognosis for secondary pulmonary alveolar proteinosis is related to underlying etiologies.

# Diagnosis

## Symptoms
- One third of patients are usually asymptomatic.
- Symptoms of pulmonary alveolar proteinosis may include the following:
- Dyspnea on exertion
- Cough (productive or nonproduvtive)
- Fatigue
- Weight loss
- Low-grade fever

## Physical Examination
- The physical examination is often normal. 
- Physical examination may be remarkable for:
- Crackles, but may be absent in pulmonary alveolar proteinosis with completely fluid-filled distal alveoli
- Clubbing
- Cyanosis

## Laboratory Findings
- Serum anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in autoimmune pulmonary alveolar proteinosis.
- Complete blood count and differential in secondary pulmonary alveolar proteinosis due to hematologic malignancy.
- Elevated serum level of GM-CSF in hereditary pulmonary alveolar proteinosis.
- Nonspecific laboratory findings:
Hypergammaglobulinemia
Polycythemia
Increased lactate dehydrogenase (LDH) levels
Elevated levels of lung surfactant proteins A and D (SP-A and SP-D)
Elevated levels of tumor markers (carcinoembryonic antigen , sialyl SSEA-1 , carbohydrate antigens sialyl Lewis-a ) 
- Hypergammaglobulinemia
- Polycythemia
- Increased lactate dehydrogenase (LDH) levels
- Elevated levels of lung surfactant proteins A and D (SP-A and SP-D)
- Elevated levels of tumor markers (carcinoembryonic antigen , sialyl SSEA-1 , carbohydrate antigens sialyl Lewis-a ) 

## Imaging Findings
- Bat wing distribution of bilateral symmetric alveolar opacities in mid and lower lung zones.
- Segmental atelectasis due to bronchiolar obstruction.
- In chronic cases, focal fibrosis may be seen.
- Ground-glass opacification with crazy-paving pattern (interlobular septal thickening).

## Other Diagnostic Studies
- Reduction in the diffusing capacity for carbon monoxide (DLCO).
- Maybe decrease in forced vital capacity.
- It is done via flexible bronchoscopy.
- Milky or opaque appearance because of abundant lipoproteinaceous material.
- It is done via video-assisted thoracoscopic biopsy.

# Treatment

## Interventional therapy
- Whole-lung lavage (WLL) with normal saline under general anesthesia: 
Indication:
Resting PaO2 <65 mmHg
Alveolar-arterial O2 gradient 40 mmHg at rest
Severe dyspnea
Hypoxemia 
Contraindication:
Clotting disorders
Anesthetic risks
Cardiopulmonary instability
- Indication:
Resting PaO2 <65 mmHg
Alveolar-arterial O2 gradient 40 mmHg at rest
Severe dyspnea
Hypoxemia
- Resting PaO2 <65 mmHg
- Alveolar-arterial O2 gradient 40 mmHg at rest
- Severe dyspnea
- Hypoxemia
- Contraindication:
Clotting disorders
Anesthetic risks
Cardiopulmonary instability
- Clotting disorders
- Anesthetic risks
- Cardiopulmonary instability

## Medical therapy
- Recombinant GM-CSF ( sargramostim) by inhaled or subcutenous injections:
For patients with failed whole-lung lavage (WLL)
- For patients with failed whole-lung lavage (WLL)
- Rituximab ( anti-CD20 monoclonal antibody): for refractory autoimmune pulmonary alveolar proteinosis.
- Therapeutic plasma exchange: for patients with failed whole lung lavage.

## Surgery
- Lung transplantation in refractory cases especially for congenital pulmonary alveolar proteinosis.

## Prevention
- Avoiding further exposure is the effective measure for the secondary prevention of pulmonary alveolar proteinosis due to inorganic dust or insecticides.
- Annual influenza vaccination and age approriate pneumococcal pneumonia vaccination.