Pulmonary Alveolar Proteinosis, PAP (NORD)

Pulmonary alveolar proteinosis, also called PAP, is a rare syndrome characterized by progressive accumulation of surfactant in the alveoli.

Alveoli are the tiny air sacs in the lungs where gas exchange occurs. Surfactant is a substance produced by alveolar cells that reduces the surface tension in the alveoli and prevents them from collapsing.

In PAP, there’s so much surfactant that it blocks air from entering the alveoli, making breathing more difficult and causing other respiratory issues.Disorders of surfactant production can be divided into primary, secondary, and congenital PAP.

Primary PAP is characterized by reduced function of the granulocyte-macrophage colony-stimulating factor, also called GM-CSF.

GM-CSF stimulates alveolar macrophages to remove excess surfactant from alveoli. When less GM-CSF is present, surfactant builds up in the alveoli.

Primary PAP can be categorized further as autoimmune or hereditary. In autoimmune PAP, the body creates a protein that attacks GM-CSF and blocks the stimulation of alveolar macrophages.

In hereditary PAP, individuals are born with genetic changes that destroy alveolar macrophage proteins, preventing GM-CSF from stimulating the macrophages.

Secondary PAP can be caused by any underlying condition, such as myelodysplastic syndrome, that reduces the number of working alveolar macrophages, or by breathing in high levels of environmental toxins such as silica and talc.

Congenital PAP occurs in individuals with inherited changes in genes that cause the production of abnormal surfactant. These genes include ABCA3, NKX2.1, SFTPB, and SFTPC, but there are likely other genes yet to be discovered.

The abnormal surfactant not only leads to excess surfactant in the alveoli, but other effects that cause reduced lung function or respiratory failure.Although most types of PAP can present at any age, hereditary PAP usually presents in children between ages 1 and 10 years.

The most common symptom of hereditary, autoimmune, and secondary PAP is dyspnea, or difficulty breathing, which may occur only with exertion at first, but in severely affected patients, it can also be present at rest.

Other symptoms include cyanosis, or bluish discoloration of fingertips; hemoptysis, or coughing up blood; chest pain; and systemic manifestations like generalized fatigue and weight loss.

As the disease progresses, individuals may experience life-threatening respiratory failure. In congenital PAP, the clinical presentation depends primarily on the genetic variants or mutations that are present.

In severely affected patients, it can present with respiratory failure shortly after birth, whereas patients with less severe forms may have symptoms that do not appear until late infancy or childhood.

Signs and symptoms may include difficulty breathing, failure to thrive, or systemic symptoms like fever. The disease may progress over time to respiratory failure depending on the gene involved.

Diagnosis of PAP begins with an assessment of the individual’s clinical signs and symptoms followed by chest X-ray or computed tomography, or CT, to support the diagnosis.

A pattern of extensive white patches with overlying angular lines, or ‘crazy paving’, is characteristic of PAP. Examining lung fluids or tissue collected during specialized procedures like bronchoscopy or surgery, can also confirm a PAP diagnosis.

Blood tests can confirm whether there are increased levels of the protein that attacks GM-CSF, indicating autoimmune PAP, and genetic testing can be used to look for genetic changes that may result in hereditary or congenital PAP.

Treatment for PAP depends upon the type and severity. In mildly affected patients, the disease typically resolves on its own.

When therapy is needed, the first-line treatment is whole lung lavage which uses saline to remove excess surfactant. The procedure can be repeated as needed until the lungs are clear.

In patients with secondary PAP, management also involves treatment of the underlying disorder and avoiding exposure to environmental toxins.

Congenital PAP treatment is typically supportive though lung transplantation can be successful. For those diagnosed with hereditary or congenital PAP, genetic counseling is recommended to help families understand their risk factors.As a quick recap, PAP is a rare syndrome caused by accumulation of surfactant in alveoli which makes breathing difficult and causes other respiratory issues.

Depending on the cause, PAP can be categorized as primary, including the autoimmune and hereditary subtypes; secondary; or congenital.

Symptoms and progression of PAP vary according to the type and severity. Clinical presentation may include dyspnea, cyanosis, hemoptysis, chest pain, and systemic manifestations like fever, generalized fatigue and weight loss.

In severely affected patients, the disease may progress to life-threatening respiratory failure. Diagnosis involves a thorough clinical examination, chest x-ray and CT, and laboratory and genetic testing.

Treatment can include whole lung lavage, supportive care, or lung transplantation. Genetic counseling is recommended for individuals and families with hereditary and congenital PAP.

Genetic counseling is recommended for individuals and families with hereditary