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NORD is very grateful to Christopher Towe, MD and Bruce Trapnell, MS, MD, Cincinnati Children's Hospital Medical Center, for assistance in the preparation of this report.
The lung is composed of millions of tiny air sacs (alveoli) with very thin walls that allow oxygen in the air we breathe to pass through into the blood. Surfactant is a natural substance consisting of fat (mostly phospholipids) and a small amount of protein made in alveoli. Normally, a thin layer of surfactant present on the surface of alveoli helps them stay open. This allows air to come in and out as we breathe. Once used, surfactant is removed (cleared) from alveoli by cells called alveolar macrophages. This helps prevent surfactant from building up too much. Alveolar macrophages require a protein called granulocyte/macrophage-colony stimulating factor (GM-CSF) to maintain a normal surfactant level in alveoli (a process called surfactant homeostasis).
Pulmonary alveolar proteinosis (PAP) is a syndrome, a set of symptoms and signs and not just a single disease, in which surfactant slowly builds up in alveoli. This blocks air from entering alveoli and oxygen from passing through into the blood, which results in a feeling of breathlessness (dyspnea). Research has greatly improved our understanding of the diseases that cause PAP and how to identify (diagnose) and treat them. Diseases that cause PAP can occur in men, women, and children of all ages, ethnic backgrounds, and geographic locations. Disease severity varies from mild to severe and depends on which disease is present. Thus, it is important to know which disease is causing PAP in order to determine the best therapy and expected treatment response. Diseases that cause PAP can be grouped into three categories: primary PAP, secondary PAP, and congenital PAP (more accurately called disorders of surfactant production).
In autoimmune PAP, a feeling of breathlessness (dyspnea) is the most common symptom. Most patients develop dyspnea very slowly over time typically noticing it only with activity at first and eventually also at rest. As the disease gets worse from the buildup of surfactant, the fingertips can become bluish in color (cyanosis) due to a low level of oxygen in the blood. Cough is the next most common symptom. This can be a dry cough or a productive cough that produces whitish phlegm (sputum). Coughing up phlegm with streaks of blood (hemoptysis), with or without fever, usually indicates that infection is also present. Rounding of the fingernails and swelling of the finger tips (clubbing) is not a sign of autoimmune PAP. Fatigue, weight loss, chest pain, or a general feeling of ill health (malaise) can also occur. Infrequently, secondary infections can occur within or outside the lungs. The disease activity over time (natural history) can vary with some patients experiencing life-threatening respiratory failure while about 5 – 7 percent undergo spontaneous improvement. About thirty percent of patients do not have any symptoms and the disease is discovered accidentally (incidental).
In hereditary PAP, the presentation is similar to that of autoimmune PAP except that it usually develops in children between the ages of 1 and 10 years of age. The natural history is also similar to that of autoimmune PAP except that spontaneous improvement has not been reported.
In secondary PAP, the presentation is similar to that of primary PAP but occurs in individuals with another underlying disease (or toxic exposure) known to cause PAP. The natural history typically follows the clinical course of the underlying disease.
In congenital PAP, the presentation depends on which genetic mutation is present. It can vary from respiratory failure at birth to slow development of lung scaring (fibrosis) in children, adolescents, or adults. Symptoms can include rapid breathing (tachypnea), difficulty gaining weight, and fever. This is usually an indication that infection is present. The natural history, although poorly studied, may involve worsening of disease over time and progression to respiratory failure at various ages, depending on the specific gene involved and mutation present.
Primary PAP is caused by reduced GM-CSF stimulation of alveolar macrophages, which reduces their ability to remove surfactant from alveoli and results in surfactant build up and breathlessness. Since GM-CSF is also necessary to help alveolar macrophages (and white blood cells) kill and remove bacteria and viruses, loss of GM-CSF stimulation can also result in secondary infections. Primary PAP includes two diseases: autoimmune PAP and hereditary PAP.
In autoimmune PAP, the body’s immune cells (B cells) begin making a protein (GM-CSF autoantibody) that attacks GM-CSF and blocks its ability to stimulate alveolar macrophages. While it is known how GM-CSF autoantibodies cause disease (pathogenesis), it is not known what causes the disease to start (etiology). However, PAP occurs more commonly in smokers suggesting cigarette smoke is a ‘trigger’ for the disease.
In hereditary PAP, individuals are born with genetic mutations that destroy the function of proteins (receptors) on alveolar macrophage that interact with GM-CSF. The loss of GM-CSF receptor function blocks the ability of GM-CSF to stimulate alveolar macrophages. Hereditary PAP is a recessive genetic disorder determined by inheritance of traits from each parent. Here, the trait (specific characteristic) is abnormal GM-CSF receptor function caused by the presence of a specific gene mutation. Recessive genetic disorders occur when an individual inherits a mutant gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25% with each pregnancy.
In secondary PAP, an underlying disease or clinical condition causes a reduction in the number (or function) of alveolar macrophages, which in turn results in the buildup of surfactant in alveoli and breathlessness. Many diseases or toxic substance exposures are associated with secondary PAP. Examples include myelodysplasia (most common), HIV infection, chemotherapy and inhalation of dusts (silica, titanium, aluminum, others).
In congenital PAP, individuals are born with genetic mutations that disrupt the production of normal surfactant. These include genes coding for surfactant protein B (SFTPB), surfactant protein C (SFTPC), a protein involved in lung development (NKX2.1), a protein needed for inclusion of surfactant lipids (ABCA3), and probably other undiscovered genes. These mutations lead to production of abnormal surfactant. This buildup in the alveoli results in PAP, but also has more important harmful effects including alveolar collapse, alveolar scarring and distortion (interstitial fibrosis) that can result in reduced lung function or respiratory failure. Some forms of congenital PAP are caused by recessive genetic mutations (see above) while others are caused by dominant genetic mutations in which only one of the inherited genes is abnormal and the other is normal.
While the frequency of diseases causing PAP in the general population (prevalence) is not well studied, it is thought that autoimmune PAP accounts for 85 - 90 % of all cases. Hereditary PAP, secondary PAP, and congenital PAP each account for roughly 5%. Autoimmune PAP occurs in 6-7 people per million individuals in the general population. It most commonly presents in adults of 30 - 40 years of age, but can occur in children as young as three years old. It is more common in men, presumably because more men smoke. Hereditary PAP usually present in children less than ten years old, but can present in adults as old as 35 years. The presentation of secondary PAP is linked to the development of another disease capable of causing PAP. The presentation of congenital PAP is variable ranging from respiratory failure at the time of birth (mutations in SFTPB, ABCA3, or NKX2.1 gene mutations), or slow development of interstitial lung disease in children, adolescents, or adults (SFTBC, ABCA3 gene mutations)
Symptoms of the following disorders can be similar to those of PAP. Comparisons may be useful for a differential diagnosis.
Sarcoidosis is a multisystem disorder characterized by the abnormal formation of inflammatory masses or nodules (granulomas) consisting of certain granular white blood cells (modified macrophages or epithelioid cells) in certain organs of the body. The granulomas formed are thought to alter the normal structure of, and potentially the normal functions of, the affected organ(s). This causes symptoms associated with the particular body system(s) in question. Such granuloma formation most commonly affects the lungs in individuals with sarcoidosis. However, in many cases the upper respiratory system, lymph nodes, skin, and/or eyes may be involved. The range and severity of symptoms associated with sarcoidosis vary greatly, depending upon the specific organ(s) involved and the degree of the involvement. In some cases, the symptoms may begin suddenly (acute), can be severe, and subside in a relatively short period of time (self-limited). Acute sarcoidosis is often characterized by fatigue, fever, generalized muscle aches, difficulty breathing (dyspnea), joint pain, swollen glands, skin eruptions, eye irregularities, and/or other symptoms. In the sub-acute form, affected individuals may experience no symptoms (asymptomatic) even with organ involvement. In the chronic form of sarcoidosis, symptoms may appear slowly and subtly and may persist or reoccur over a long time span. Initial symptoms of the chronic form of the disorder may include difficulty breathing (dyspnea), dry cough, limited airflow, and other respiratory abnormalities. Symptoms associated with other organ involvement may develop later. (For more information on this disorder, choose “sarcoidosis” as your search term in the Rare Disease Database.)
Pneumonia is an acute infection of the alveolar spaces and/or the interstitial tissue of the lung. A whole lobe or only a part of a lobe can be involved. The pneumonia may be caused by different bacteria, viruses, fungi, or protozoa. Pneumonia is often preceded by an upper respiratory infection. Symptoms usually start suddenly, with a shaking chill, sharp pain in the affected side of the chest, a cough, a high fever, and/or a headache. Breathing is difficult and painful.
Idiopathic pulmonary fibrosis is an inflammatory lung disorder characterized by abnormal formation of fibrous tissue (fibrosis) between tiny air sacs (alveoli) or ducts in the lungs. Coughing and rapid, shallow breathing occur with moderate exercise. The skin may appear slightly bluish in color (cyanotic) due to lack of circulating oxygen. Complications such as infection, emphysema, or heart problems may develop. The exact cause of idiopathic pulmonary fibrosis is unknown. (For more information on this disorder, choose "idiopathic pulmonary fibrosis" as your search term in the Rare Disease Database.)
Acute respiratory distress syndrome (ARDS) is a type of severe, acute lung dysfunction affecting all or most of both lungs. It occurs as a result of illness or injury. Although it is sometimes called adult respiratory distress syndrome, it can also affect children. Major symptoms may include breathing difficulties (dyspnea), rapid breathing (tachypnea), excessively deep and rapid breathing (hyperventilation) and insufficient levels of oxygen in the circulating blood (hypoxemia). ARDS may develop in conjunction with widespread infection in the body (sepsis). It can also result from pneumonia, trauma, shock, severe burns, aspiration of food into the lung, multiple blood transfusions, and inhalation of toxic fumes. It usually develops within 24 to 48 hours after the original illness or injury and is considered a medical emergency. ARDS may progress to involvement of other organs. (For more information on this disorder, choose "acute respiratory distress" as your search term in the Rare Disease Database.)
Pulmonary alveolar proteinosis (PAP) may be suspected based upon the history (breathlessness of very slow onset) and physical examination (occasionally, crackles heard by listening with a stethoscope, and rarely, cyanosis). Routine blood tests are usually normal. A diagnosis of PAP is typically supported by results from a chest x-ray or computed tomography (CT scan), which typically reveal extensive white patches within the lungs (ground glass opacity) with superimposed angular lines (reticular densities). This pattern is known as ‘crazy paving’ and is characteristic, but not diagnostic, of PAP.
Specialized procedures such as bronchoscopy or surgery can be used to obtain lung washings (bronchoalveolar lavage fluid (BAL)) or lung tissue (biopsy) that can be examined to demonstrate PAP is present. Importantly, however, neither of these approaches can determine which disease is present and the cause of PAP.
Autoimmune PAP can be identified by very sensitive and specific blood tests that identify the presence or absence of an increased level of GM-CSF autoantibody. Such tests are currently available as clinical research tests but efforts are underway to introduce them into routine clinical practice. Hereditary PAP can be identified by a series of blood tests that are similarly being developed for introduction into routine clinical practice. Finally, the genetic risk factors for hereditary PAP and congenital PAP can be identified by genetic testing.
Therapy of PAP varies depending upon what disease is present, disease severity, and the age of the patient. In autoimmune PAP, about one third of patients do not have symptoms and 5 - 7 percent improve spontaneously. Of those needing therapy, whole lung lavage (WLL) is the current standard therapy. WLL is a procedure done with the patient asleep in which excess surfactant is ‘washed’ out of one lung with salt water (saline) while the other is hooked to a breathing machine supplying pure oxygen. In some patients, WLL is needed only once while in others it is needed repeatedly on average every year or so. For some, it can be required as frequently as every month. Most patients with autoimmune PAP respond very well to WLL. Hereditary PAP is also treated by WLL and most patients respond well to therapy. In secondary PAP, removal and avoidance of the causative agent (e.g., silica dust exposure) or successful treatment of the underlying disorder may improve symptoms. Treatment of congenital PAP is generally supportive. However, lung transplantation has been successfully used in infants with congenital PAP caused by surfactant protein B deficiency. Genetic counseling may be beneficial for families of individuals with the congenital form of PAP.
Recent studies now strongly suggest that GM-CSF administration is effective in treating autoimmune PAP. In particular, reports indicate that up to 95% of patients may respond to inhaled GM-CSF therapy. However, further studies are needed (and underway) to determine the safety and most appropriate dosing and administration of inhaled GM-CSF in these patients. GM-CSF is generally considered not useful as therapy of secondary PAP and congenital PAP and its use may be problematic in these patients.
Another experimental treatment approach is the use of rituximab, which has been tested in a few patients with autoimmune PAP (and other autoimmune diseases). In this approach, rituximab is used to kill B-cells that produce GM-CSF autoantibodies. Insufficient evidence is available about this approach to comment on its potential effectiveness or safety at this time.
Finally, a physical procedure to remove GM-CSF autoantibodies from the blood (plasmapheresis) while retaining the blood cells has been tested in very few people with autoimmune PAP. While safe, insufficient evidence is available to comment on the potential effectiveness of this approach in PAP.
Lung transplantation has been used but the disease may recur in the transplanted lungs. This approach is recommended only when other approaches have failed, for example, in patients who develop significant lung fibrosis.
Information on current clinical trials is posted on the Internet at www.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:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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University of South Florida, Pediatrics Epidemiology Center
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Tampa, FL 33612
Phone #: 813-396-9501
800 #: 866-533-9104
e-mail: RareDiseasesNetwork.org, RDCRN.org
Home page: http://rarediseasesnetwork.epi.usf.edu/registry/
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Huddleston CB, et al., Lung transplantation in children. Ann Surg. 2002;236:270-6.
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McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:265120; Last Update: 12/05/2011. Available at http://omim.org/entry/265120 Accessed September 10, 2014.
Report last updated: 2014/09/10 00:00:00 GMT+0