Last updated:
4/9/2026
Years published: 2026
NORD gratefully acknowledges Ali Ataya, MD, ATSF, Associate Professor of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, Gainesville, for assistance in the preparation of this report.
Summary
Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare lung disorder. It is characterized by the abnormal accumulation of surfactant within the tiny air sacs (alveoli) of the lungs. Surfactant is a naturally occurring mixture of certain fats (phospholipids), cholesterol, and proteins, produced by specialized cells in the tiny air sacs (alveoli) in the lungs. 1, 2 Alveoli have very thin walls that allow oxygen to pass through the lungs and into the bloodstream while also allowing carbon dioxide to pass from the bloodstream into the alveoli. Surfactant helps the walls of the alveoli to open and allow for the passage of oxygen and carbon dioxide. Once surfactant is used, it is removed from the alveoli by specialized immune cells called alveolar macrophages. 1 This process helps to prevent surfactant from building up within the lungs. In individuals with aPAP, these macrophage cells cannot efficiently remove surfactant, so the material builds in the lungs, causing a variety of symptoms. 3, 4
Introduction
There are different forms of pulmonary alveolar proteinosis including genetic forms and forms that occur secondary to another disorder or condition. aPAP accounts for 90% of cases of pulmonary alveolar proteinosis. 5, 6
Some people with aPAP may not have any noticeable symptoms (asymptomatic).7 Often, the disorder develops slowly over many years. The symptoms that do develop can vary among affected individuals.5 Usually, the first symptom is shortness of breath (dyspnea) with activity (exertional dyspnea) that may slowly progress to shortness of breath even at rest. Affected individuals may be unable to exercise to the level they are used to (decreased exercise capacity).6
Some individuals have a chronic dry cough that does not effectively clear mucus from the lungs, known as a nonproductive cough. At times, they may also report coughing up small amounts of white material or mucus (surfactant). Additional symptoms can include: 5, 8
People with aPAP are at an increased risk of secondary (opportunistic) infections 9 because the disorder impairs the immune system’s ability to respond effectively. Fever and coughing blood (hemoptysis) are uncommon in aPAP and usually suggest the presence of a secondary infection. When infections occur, they tend to be more frequent and may be more severe. The most frequently reported opportunistic infections in aPAP include infections caused by Nocardia species, Cryptococcus species, and mycobacteria. 1, 2, 9 Nocardia is a bacterium that can cause infections that most commonly affect the lungs and may spread to the brain, and in some cases to the skin and other organs. Cryptococcus is a genus of fungi that causes serious, sometimes fatal, infections (cryptococcosis).
In some affected individuals, aPAP can potentially progress into a disorder called pulmonary fibrosis. Pulmonary fibrosis is a condition characterized by scarring of the lungs, making it difficult for the lungs to function properly. The scarring cannot be repaired or reversed. The development of pulmonary fibrosis, while rare in aPAP, is a potentially life-threatening complication. It remains unclear why certain people with aPAP develop pulmonary fibrosis.
The course of aPAP differs from one person to another. In some people, the disease gradually worsens, leading to declining lung function and eventually causing, in severe cases, life-threatening respiratory failure. 2, 8, 10 In others, it may remain stable over time. In rare cases, the condition can resolve on its own (spontaneous resolution).3, 11
aPAP is an autoimmune disorder. Autoimmune disorders occur when the body’s natural defenses, such as antibodies and lymphocytes, mistakenly attack healthy tissue instead of protecting against infection. aPAP is characterized by the presence of specific autoantibodies. Antibodies are proteins produced by the immune system that normally help fight infection, but in individuals with aPAP, these antibodies target the body’s own healthy tissue (autoantibodies).
A signaling or ‘messenger’ molecule called granulocyte macrophage-colony stimulating factor (GM-CSF) plays a major role in the development of aPAP.9, 11 GM-CSF is a growth factor, a protein that is important for the proper development and function of certain cells.10, 12 GM-CSF is necessary to stimulate certain cells known as alveolar macrophages to mature and function properly. Alveolar macrophages are immune cells that help to maintain normal surfactant levels in the lungs. This process, called surfactant homeostasis, requires GM-CSF to stimulate alveolar macrophages to remove excess surfactant.11
People with aPAP produce autoantibodies against GM-CSF. These antibodies neutralize GM-CSF activity, which prevents the normal maturation and activation of alveolar macrophages. 5 In people with aPAP, alveolar macrophages are abnormally large and foamy, and unable to function properly. Therefore these macrophages do not clear surfactant from the lungs efficiently, allowing the surfactant to build up and inhibit proper lung function including adequate gas exchange.8, 10, 11, 13
GM-CSF is also important for the maturation and function of white blood cells called neutrophils.8 Neutrophils play an essential role in fighting bacterial infections by surrounding and destroying invading bacteria, a process called phagocytosis. Impaired GM-CSF activity likely helps explain why people with aPAP have a higher risk of developing infections.8
The proportion of the population that has aPAP (prevalence) is unknown, and estimates vary from 4-40 per million. 3, 8, 9 aPAP often occurs between the 20s and 40s (third and fifth decades) of life. 8 However, the disorder has been reported to occur in children as young as three, and adults as old as 90, but it is extremely rare in children.14
The symptoms of aPAP are not specific to the disorder,5 which can make diagnosis more challenging. 8 A diagnosis may be suspected based upon the identification of characteristic symptoms, a physical examination, a detailed patient and family history, and a thorough clinical evaluation including specific tests. Certain sounds called crackles may be present and heard on a stethoscope in approximately 50% of individuals.7 A pulmonary function test can be performed to determine how well the lungs are working.
Affected individuals will test positive for the presence of autoantibodies against GM-CSF in the blood1,7,15 A simple, noninvasive blood test called aPAP ClearPath ™ can detect the presence of these autoantibodies in the blood2 and can distinguish aPAP from other forms of pulmonary alveolar proteinosis. This test is nearly 100% accurate for diagnosing aPAP.2
High levels of GM-CSF autoantibodies are associated with an increased risk of opportunistic infections, such as infections caused by Nocardia and Cryptococcus species. 9
Respiratory fluid can be obtained through a procedure called a bronchoalveolar lavage or BAL. During this procedure, a specialized breathing tube is used to ventilate one lung while the other is washed with saline solution, often while the chest is percussed (shaken) to help loosen debris, after which the fluid is drained. 7 This fluid is collected and then the camera tube is removed, allowing the cells to be studied to identify abnormal surfactant build up in the lungs. BAL can also help detect slow-growing organisms, sometimes before symptoms of infection appear. 9
Imaging tests play a role in obtaining a diagnosis.11 A computed tomography (CAT) scan can reveal a characteristic pattern of disease, which will appear as hazy or gray areas on the scan and may be referred to as ground-glass opacities, and may show up in a specific pattern called a “crazy-paving pattern”. 2, 5 However, this characteristic finding is not specific to aPAP and can be associated with other conditions affecting the lungs.
In the past, diagnosis of aPAP required an open-lung biopsy, in which a small piece of lung tissue was surgically removed for examination. However, this is no longer necessary for most individuals due to the availability of the ClearPath blood test. Biopsy should be reserved only for rare cases with complex presentations. 5, 8
A pulmonary biopsy cannot differentiate the different forms of PAP.
Treatment
It is recommended that people with aPAP receive care at medical centers with experience in treating this disorder.11 Treatment can include lifestyle modifications, general measures including preventative vaccinations, and specific therapies to treat aPAP.11
Lifestyle modifications include having affected individuals stop smoking and avoid personal or occupational exposure to airborne pollutants such as dust.1 In some individuals, quitting smoking or avoiding environmental pollutants may help improve symptoms of the disorder. Asymptomatic people may only require surveillance.11
Whole lung lavage (WLL) remains a widely accepted therapy for aPAP. WLL is mainly used for severe cases, including individuals experiencing respiratory failure. Such procedures should be performed at a specialty center, with an experienced team of medical professionals. 3, 11 This procedure is performed under anesthesia. During this procedure, a small, flexible tube called a bronchoscope is inserted into one of the lungs through the mouth. The physician will deliver oxygen from a machine to the other lung. The affected individual wears a vest around the chest that vibrates, loosening the surfactant that is clogging the alveoli. The lung is then flushed with a saltwater (saline) solution to remove the surfactant. 2,16 The procedure is repeated in the other lung shortly afterward, or sometimes a few days later. Whole lung lavage does not correct the underlying issue in aPAP and some people do not fully improve with this treatment. 5, 6 Additionally, although many people show improvement, the procedure often must be repeated as surfactant will build up in the lungs again. 2, 16 Whole lung lavage is less effective in children than in adults. 14
Vaccinations are recommended against several conditions that affect the lungs, including influenza, pneumococcus, and severe acute respiratory syndrome. Many individuals can have a near-normal lifespan with proper management. 2, 11
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ . All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
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For information about clinical trials sponsored by private sources, contact:
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For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Inhaled GM-CSF is a drug treatment that affected individuals can administer at home.3 This medication is delivered as a nebulizer and potentially can reverse the abnormalities of alveolar macrophages due to autoantibodies blocking the action of GM-CSF. A phase III clinical trial of an inhaled drug called molgramostim led to a greater increase in pulmonary gas transfer.6 Other inhaled GM-CSF medications such as sargramostin are also being studied for treatment of aPAP. Studies have shown some benefit of this therapy for individuals with aPAP.6, 16 Some studies have involved using whole lung lavage followed by inhaled GM-CSF therapy showing effectiveness of this approach.3
Further studies are necessary to determine the long-term safety and effectiveness of these medications for the treatment of individuals with aPAP. The European Respiratory Society (ERS) guidelines suggest inhaled GM-CSF as a treatment option for autoimmune PAP, alongside whole lung lavage. 4 Inhaled GM-CSF may eventually become a standard initial therapy for this disorder. 1,11
Rituximab has been used to treat affected individuals after other therapies such as whole lung lavage have already been attempted.10-12 Rituximab is classified as a monoclonal antibody or biologic therapy (medications that act like antibodies but are artificially created in a lab). Rituximab has not been studied extensively for aPAP but is well-tolerated by individuals with other conditions. 4, 11 Individual case reports and small studies have shown differing results for rituximab as a treatment for aPAP.10-12
Plasmapheresis, or plasma exchange, has been used to remove the autoantibodies that inhibit the GM-CSF. 4,11 In this process, blood is removed by a machine from the affected individual, blood cells are separated from plasma, the patient’s plasma is replaced with healthy plasma, and the blood is then returned to the patient by the machine. Plasmapheresis is generally reserved for individuals who had multiple whole lung lavages, and who haven’t responded to additional therapy with inhaled GM-CSF and rituximab.11 A major drawback of plasmapheresis is that the procedure must be repeated frequently because of high levels of autoantibodies in the blood. 8
Medications such as pioglitazone and statins have been studied as a potential therapy for individuals with aPAP. 2, 17 These medications help alveolar macrophages recover some of their function and clear surfactant from the lungs. Initial small studies have shown some promise for these medications. 2, 17 More research is necessary to determine the long-term safety and effectiveness of these therapies as a potential treatment for aPAP.
Some individuals may be treated with a lung transplant, particularly individuals where lung disease has worsened despite undergoing additional therapies (refractory disease), or where the lungs no longer function (end-stage disease fibrosis).4,11 However, aPAP may develop in the new lungs and require treatment as well.8
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Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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