Alveolar Proteinosis

Alveolar proteinosis is a rare lung disease where proteins, fats, and other substances build up inside the tiny air sacs of the lungs, making it hard to breathe and blocking oxygen from reaching the blood.

Table of contents

• What is alveolar proteinosis?
• Types of alveolar proteinosis
• Who gets this disease?
• What causes alveolar proteinosis?
• Symptoms
• How is it diagnosed?
• Treatment options
• Outlook and prognosis

What is alveolar proteinosis?

Pulmonary alveolar proteinosis (PAP) is a rare lung disease that occurs when a fatty substance called surfactant accumulates abnormally in the air sacs of the lungs^[1]. Surfactant is a natural substance that normally coats the inside of the alveoli (the tiny air sacs where oxygen enters the blood) to help keep them open^[1].

In healthy lungs, special cleaning cells called alveolar macrophages remove old surfactant regularly so it doesn’t build up^[1]. However, in people with PAP, this cleaning process doesn’t work properly. The surfactant accumulates and clogs the alveoli, preventing oxygen from passing through to the blood as it should^[1].

The disease was first described in 1958 and understanding of its causes has improved dramatically since then^[2]. Initially, doctors thought PAP was caused by overproduction of surfactant, but now it is understood that all forms of PAP result from decreased clearance of surfactant rather than increased production^[2].

PAP is rare, affecting between 3 and 40 people per million worldwide^[1]. In recent studies, the prevalence has been estimated at approximately 6 to 7 per million in the general population^[6][13].

Types of alveolar proteinosis

There are three main pathways that lead to the development of PAP, each with different underlying causes^[2]:

Autoimmune pulmonary alveolar proteinosis is by far the most common form, accounting for about 90% of all adult cases^[1][2]. In this type, the immune system mistakenly produces antibodies against a protein called granulocyte-macrophage colony-stimulating factor (GM-CSF)^[2]. GM-CSF is essential for the development and function of alveolar macrophages, the cells that clean surfactant from the lungs. When these antibodies block GM-CSF, the macrophages cannot work properly, and surfactant accumulates^[2].

Secondary pulmonary alveolar proteinosis develops when another disease or exposure to toxins affects the function of cells in the alveoli^[1]. This form lacks the anti-GM-CSF antibodies found in autoimmune PAP^[2]. It can be caused by blood cancers such as myelodysplastic syndrome or chronic myelogenous leukemia, immune deficiency diseases, lung infections, or exposure to certain dusts and chemicals including nickel, silica, aluminum, titanium, and cellulose^[2][4][7]. In one analysis, about 34% of secondary PAP cases were associated with myelodysplastic syndrome^[2].

Congenital pulmonary alveolar proteinosis is the least common form and results from genetic mutations that affect either GM-CSF receptor proteins or surfactant proteins^[2]. This form may be present at birth or appear at various ages throughout life. Children can inherit the disease from their biological parents^[1].

Who gets this disease?

Autoimmune and secondary PAP typically affect people between the ages of 30 and 60^[1][7]. These two types appear to be more common in males^[1], though some recent studies suggest no significant gender difference^[13].

Smoking and exposure to certain dusts or chemicals increase the risk of developing PAP^[1]. While there is a high prevalence of smoking among PAP patients, no definite causal link has been established between cigarette smoke and autoimmune PAP^[2].

Congenital PAP is most common in children under the age of 10, but it may start to appear at any age^[1].

What causes alveolar proteinosis?

The fundamental problem in all forms of PAP is that surfactant is not being cleared properly from the alveoli. The thin walls of the alveoli naturally have an oily layer of surfactant that helps them stay open so oxygen can pass through into the blood^[1].

In PAP, the alveolar macrophages don’t receive the signal they need to clean the alveolar walls. As a result, surfactant builds up and blocks the alveoli, preventing oxygen from passing through to the blood^[1].

The specific cause depends on the type of PAP. In autoimmune PAP, antibodies against GM-CSF prevent proper development and function of alveolar macrophages^[2]. In secondary PAP, various diseases reduce the number of functioning macrophages^[2]. In congenital PAP, genetic mutations directly affect surfactant or macrophage function^[2].

Symptoms

Shortness of breath, called dyspnea, is the most common symptom of PAP^[1][7]. Most people with the disease have difficulty breathing while exercising, though some also have breathing problems at rest^[1].

The symptoms of PAP tend to develop slowly and worsen as the disease progresses^[5]. The disease has an insidious onset and can progress to severe respiratory failure in some cases^[13]. However, some people with PAP may have very mild disease and not experience any symptoms at all^[4][5]. In such cases, the condition may only be detected incidentally during medical evaluations^[4].

Other symptoms of PAP include^[1][5]:

• Chest pain or discomfort
• Cough, sometimes with blood or phlegm
• Cyanosis (bluish coloring of the skin and fingernails due to low oxygen)
• Fatigue
• Fever
• Lung infections
• Clubbed fingers (enlarged fingertips)
• Weight loss
• Lightheadedness

Patients are often initially misdiagnosed as having asthma or recurrent pneumonias^[5]. People with PAP are more vulnerable to lung infections, including nocardiosis, Mycobacterium avium-intracellulare infection, and fungal infections^[4].

How is it diagnosed?

A healthcare provider will perform a physical exam and listen to the lungs if PAP is suspected^[1][5]. During the exam, abnormal breathing sounds may be detected, though inspiratory crackles are rare because the alveoli are fluid-filled^[7].

The provider will ask questions about personal and family medical history, as well as lifestyle. Patients should inform their provider if they smoke or have had exposure to dust, chemicals, or other toxins^[1].

PAP is usually first suspected when a chest X-ray is taken for nonspecific respiratory symptoms^[7]. The chest X-ray typically shows bilateral mid- and lower-lung field opacities in a butterfly distribution with normal hila^[7].

Tests that may be used to diagnose PAP include^[1][5][7]:

• Blood tests to check blood oxygen levels
• Testing for the GM-CSF antibody (to confirm autoimmune PAP)
• Pulmonary function tests to measure how well the lungs are working
• Chest X-ray, which may show areas resembling pneumonia
• High-resolution CT scan, which may show ground-glass opacification, thickened structures, and a characteristic “crazy-paving” pattern
• Bronchoalveolar lavage (lung washing through a scope), which is the key diagnostic test
• Lung biopsy in cases where other tests are not definitive

Bronchoalveolar lavage is typically done to confirm the diagnosis^[7]. The lavage fluid appears milky or opaque and shows specific characteristics under the microscope^[7][13]. In autoimmune PAP, the fluid can be tested for anti-GM-CSF antibodies^[5].

Genetic testing may be performed if congenital PAP is suspected. Results usually take several weeks, and sometimes testing of parents is also needed^[5].

If a patient is very sick or diagnosis cannot be made through other means, a thoracoscopic or open lung biopsy may be necessary^[5][7]. The biopsy shows surfactant protein filling the alveoli and may help identify the underlying cause^[5].

Treatment options

There is no cure for pulmonary alveolar proteinosis at this time^[5]. However, regular treatments can help patients breathe better and relieve symptoms. Treatment depends on the type of PAP, the severity of symptoms, the presence of infections, and the degree of physiological impairment^[12].

PAP can spontaneously clear on its own in a small number of people^[5][4]. Some patients have stable symptoms and may not require immediate treatment^[4]. Patients with very mild disease may not need any intervention^[11].

Whole lung lavage (WLL) has been the main treatment for PAP since 1963 and remains the standard of care^[11][12]. This procedure involves washing the lungs with sterile saline (salt water) to remove the abnormal buildup of surfactant material^[11].

The procedure is performed in an operating room under general anesthesia, treating one lung at a time^[11]. The anesthesiologist inserts a special double-barreled breathing tube that allows the left and right lungs to be isolated from each other. One lung is used for ventilation with oxygen while the other is washed with large volumes of saline, sometimes 30 to 40 liters^[11]. The procedure may take several hours until the fluid comes out clear^[11].

After whole lung lavage, patients typically don’t feel better immediately, probably due to anesthesia effects and remaining saline. However, most notice significant improvement about 24 hours after the procedure^[11]. A second lavage for the other lung may be performed during the same hospital stay or scheduled for a later date^[11].

Granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy can be helpful, particularly for autoimmune PAP^[12][13]. GM-CSF can be administered by injection under the skin or through inhalation^[12]. This medication helps the body clear extra surfactant by increasing the activity of alveolar macrophages^[11]. In various studies, response rates have ranged from 43% to 92%, with an average response rate of about 59%^[12].

For patients who do not respond adequately to whole lung lavage or GM-CSF therapy, other options may be considered, including^[12]:

• Rituximab, a medication that targets immune cells producing harmful antibodies
• Plasmapheresis, a procedure that removes antibodies from the bloodstream
• Lung transplantation in severe, refractory cases

In secondary PAP, treating the underlying cause is essential^[12].

Supportive care is important for all patients with PAP^[5][13]. This includes:

• Oxygen therapy at home for patients with low blood oxygen levels
• Vaccination against flu, pneumonia, and COVID-19 to prevent infections
• Avoiding smoking
• Monitoring for lung infections

Patients should contact their healthcare provider if they develop sudden or worsening shortness of breath, chest pain, or other concerning symptoms^[5].

Outlook and prognosis

The course of PAP is unpredictable and varies widely between individuals^[4]. Some patients experience spontaneous remission, while others have stable symptoms^[4]. With proper treatment, the five-year survival rate is approximately 80%^[7].

PAP can cause life-threatening respiratory failure in severe cases^[1][5]. Without treatment, severe PAP can sometimes lead to respiratory failure or death^[1][5]. Death may also occur due to progression of any underlying associated disease or secondary infections^[4].

With the right treatment from an experienced pulmonary medicine doctor (a healthcare provider specializing in lung diseases), PAP is manageable^[1][5]. Healthcare providers can also advise patients on healthy lifestyle changes that can improve quality of life^[1].

Getting care from an experienced specialist is important for optimal management of this rare condition^[1]. Recent advances in understanding the genetic and autoimmune mechanisms underlying PAP have provided newer diagnostic and treatment options^[13].