Pulmonary alveolar proteinosis

What every physician needs to know:

Pulmonary alveolar proteinosis (PAP) is a rare lung syndrome characterized by an accumulation of surfactant within the alveoli, leading to pulmonary symptoms, increased infection risk, and in severe cases, hypoxic respiratory failure. The most common type is autoimmune PAP, which is associated with autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) that impair clearance of surfactant from the lung.

Classification:

The underlying pathology of PAP can be categorized into abnormalities of surfactant production or surfactant clearance.

Surfactant production disorders are less common and typically occur in infants and children. They generally involve mutations in genes which encode proteins involved in surfactant lipid metabolism.

Surfactant clearance disorders are most commonly seen in adults and can be further categorized into primary and secondary disorders.

Primary PAP involves disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) and is comprised of autoimmune PAP and hereditary PAP. Hereditary PAP is the rarer type and related to recessive variants of the GM-CSF receptor genes that result in disruption of GM-CSF signaling. Autoimmune PAP is the most common type of primary PAP, representing ~90% of PAP patients. It affects men more than women and is associated with autoantibodies against GM-CSF that impair clearance of surfactant by alveolar macrophages.

Are you sure your patient has Pulmonary alveolar proteinosis (PAP)? What should you expect to find?

The most common symptoms of PAP are progressive dyspnea on exertion, cough, fatigue, weight loss, and sputum production. Patients often develop symptoms once the surfactant has filled a substantial proportion of the alveolar space. About one-third of affected patients are asymptomatic.

The physical examination is generally unremarkable, but patients can have tachypnea, crackles, cyanosis, and clubbing. In most PAP cases, there is a significant discrepancy between the auscultatory findings and radiographic findings, which generally involve extensive airspace disease.

Beware: there are other diseases that can mimic Pulmonary alveolar proteinosis (PAP):

· Infections, especially with atypical organisms like Mycoplasma and Pneumocystis jirovecii

· Cardiogenic and noncardiogenic pulmonary edema

· Lipoid pneumonia

· Drug-related hypersensitivity reactions

· Organizing pneumonia

· Acute interstitial pneumonia (AIP)

· Diffuse alveolar damage superimposed on usual interstitial pneumonitis (UIP)

How and/or why did the patient develop Pulmonary alveolar proteinosis (PAP)?

It is unclear how or why patients develop higher levels of GM-CSF autoantibodies in autoimmune PAP or acquire malfunctioning alveolar macrophages related to dust exposure or malignancies in secondary PAP.

Which individuals are of greatest risk of developing Pulmonary alveolar proteinosis (PAP)?

Cigarette smoking appears to be a common factor in autoimmune PAP with approximately 50-80% patients being current or former cigarette smokers. Dust or fume exposure have been reported in 20-50% of patients with autoimmune PAP. A small cohort of patients has other autoimmune diseases, such as hemolytic anemia, polymyalgia rheumatica, and granulomatosis with polyangiitis.

Patients with secondary PAP typically have underlying hematologic malignancies, myelodysplastic syndrome (MDS) being the most common, as well as non-hematologic malignancies, infections (cytomegalovirus, Mycobacterium tuberculosis, Nocardia, Pneumocystis jirovecii), immunodeficiency syndromes, and toxic level inhalation exposures to substances such as silica, aluminum, cement, titanium, indium-tin oxide, bakery flour, and fertilizer.

What Laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Most routine laboratory tests are normal. LDH (lactate dehydrogenase) and alveolar-arterial oxygen gradient (A-aDO2) are typically elevated and moderately correlated to the severity of the disease. Other biomarkers that are elevated include SP-A, SP-B, SP-D, DL-6, CEA, KL-6, M-CSF, and MCP-1, but these are not yet utilized clinically.

Measurement of anti-GM-CSF antibody is essential in the diagnosis of autoimmune PAP and is elevated in this setting with a reported sensitivity and specificity of 100%. Serum samples need to be sent to specialty laboratories for testing, such as the Cincinnati Children’s Hospital.

Obtaining a complete blood count (CBC) with differential may be warranted for patients with suspected secondary PAP to evaluate for underlying hematologic malignancy. It is also important to perform an infectious work-up to rule out infection in appropriate patients.

Patients with suspected hereditary PAP should have their serum level of GM-CSF and STAT5-Phosphorylation Index tested, which are elevated and reduced respectively. These tests are available at specialty laboratories along with genetic testing.

What imaging studies will be helpful in making or excluding the diagnosis of Pulmonary alveolar proteinosis (PAP)?

CXR will generally show symmetric opacities in the mid to lower lung fields bilaterally, often described as a “bat wing” distribution.

High-resolution chest CT often shows ground-glass opacities with interlobular septal thickening in polygonal shapes, described as “crazy-paving”; however, crazy-paving is not specific for PAP.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of Pulmonary alveolar proteinosis (PAP)?

Pulmonary function testing should be performed, but findings are not specific for this diagnosis. Forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) are generally within normal limits although some patients may show decreased FVC, consistent with restrictive physiology. The diffusion capacity of the lung for carbon monoxide (DLCO) is commonly reduced and correlates with disease severity.

What diagnostic procedures will be helpful in making or excluding the diagnosis of Pulmonary alveolar proteinosis (PAP)?

Flexible bronchoscopy with bronchoalveolar lavage (BAL) and possible transbronchial lung biopsy (TBLB) are helpful for the diagnosis of PAP. BAL fluid is notable for a thick, milky appearance.

Surgical lung biopsy is performed in ~10-20% of patients due to non-diagnostic findings on CT and bronchoscopy. In the majority of cases, however, the BAL fluid analysis, along with the measurement of serum GM-CSF auto-antibodies, essentially negates the need for surgical biopsies in patients with suspected PAP.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of Pulmonary alveolar proteinosis (PAP)?

Cytology of BAL fluid will show periodic acid-schiff (PAS) and oil red O stain positive large foamy macrophages.

Pathology from lung biopsies will show preserved alveoli containing amorphic, eosinophilic, PAS-positive material along with foamy alveolar macrophages. There is typically minimal inflammation or fibrosis.

Genetic studies are essential, especially when evaluating a patient with suspected PAP due to a surfactant production disorder or hereditary PAP. There are a number of mutations tested (CSF2RA, CSF2RB, SFTPB, SFTPC, ABCA3 among others).

If you decide the patient has Pulmonary alveolar proteinosis (PAP), how should the patient be managed?

The treatment of choice for PAP is whole lung lavage (WLL). This involves placing a double lumen endotracheal tube under general anesthesia to ventilate one lung while filling and emptying the other lung with warm normal saline to remove surfactant.

Other therapy modalities shown to reduce anti-GM-CSF levels and improve lung function include exogenous GM-CSF given subcutaneously or aerosolized, rituximab, and plasmapheresis. Although these newer approaches have shown promising results, further studies need to be performed to assess their efficacy and safety profiles in patients with PAP. Corticosteroids have not been shown to be effective for autoimmune PAP and may actually worsen disease severity. Patients treated with corticosteroids are also at higher risk for infections.

For cases of secondary PAP, treatment is dependent on the underlying disease.

Treatment for surfactant production diseases is mainly supportive care; however, lung transplantation has been shown to be effective in some patients.

All patients should be counseled to stop smoking and receive their annual age-appropriate vaccinations, including influenza and pneumococcal vaccinations.

What is the prognosis for patients managed in the recommended ways?

Five-year survival in PAP is ~85% without therapy and ~94% with WLL. The majority of deaths are related to respiratory failure and a minority caused by uncontrolled infections.

Autoimmune PAP generally follows one of three patterns: 1. spontaneous improvement (5-7%); 2. persistent, unremitting symptoms; 3. progressive deterioration with respiratory failure.

The development of parenchymal fibrosis on HRCT is associated with a poorer prognosis.

Secondary PAP has a poorer prognosis than autoimmune PAP, and its clinical course is strongly affected by that of the underlying disease.

What other considerations exist for patients with Pulmonary alveolar proteinosis (PAP)?

Infants with severe unexplained lung disease or children with diffuse disease involving the entire lung parenchyma on CT scan should be tested for inborn errors of surfactant metabolism.

Patients with PAP are more susceptible to opportunistic infections with organisms such as Nocardia, Aspergillus, mycobacteria, and fungi due to dysfunction of neutrophils and macrophages.

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