Years published: 1988, 1989, 1993, 1997, 2004, 2014, 2017, 2023
NORD gratefully acknowledges 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 an oily substance comprising phospholipids, lesser amounts of cholesterol and proteins and is made in alveoli. It is present as a thin layer on the surface of alveolar walls and helps them stay open allowing 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 signaling or ‘messenger’ molecule called granulocyte/macrophage-colony stimulating factor (GM-CSF) to stimulate alveolar macrophages to function properly and maintain a normal surfactant level in alveoli. This process, called surfactant homeostasis, requires GM-CSF to stimulate alveolar macrophages to remove excess surfactant normally.
Pulmonary alveolar proteinosis (PAP) is a syndrome, a set of symptoms and signs – not a single disease, in which surfactant in alveoli builds up slowly. 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 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 fingertips (clubbing) is not a sign of autoimmune PAP. Fatigue, weight loss, chest pain or a general feeling of ill health (malaise) can also occur. Less commonly, secondary infections can occur in or outside the lungs. The disease activity over time (natural history) varies among patients with some experiencing life-threatening respiratory failure while others having a ‘smoldering’ or slowly progressing course and others (about 5-7 percent) may undergo spontaneous improvement. At any given time, about thirty percent of patients may not have any symptoms and the disease is discovered accidentally (incidental).
Hereditary PAP is caused by harmful gene variants (mutations) that disrupt the structure of GM-CSF receptors (proteins) on alveolar macrophages, which normally bind GM-CSF and function in an ‘ignition switch’ and ‘car key’ allowing GM-CSF to stimulate these cells. The gene mutations prevent GM-CSF receptors from functioning normally and thus block the effects of GM-CSF on surfactant removal by alveolar macrophages. The clinical presentation of hereditary PAP is similar to that of autoimmune PAP except that it usually develops in children between the ages of 1 and 10 years of age but occasionally occurs in adolescents and older adults. 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 clinical 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. Fever is usually an indication that infection is present. The natural history may involve worsening of disease over time and progression to respiratory failure at various ages, depending on the specific gene involved and which mutations are 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 harmful gene variants (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. The abnormal GM-CSF receptor function is caused by the presence of two harmful gene variants.
Recessive genetic disorders occur when an individual inherits a harmful gene variant from each parent. If an individual inherits one normal gene and one harmful gene variant 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 harmful gene variant 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 is 25%. The risk is the same for males and females.
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, medications or toxic substance exposures are associated with secondary PAP. Examples include, but are not limited to, myelodysplasia (most common), HIV infection, systemic juvenile idiopathic arthritis, chemotherapy, immune suppression medications such as sirolimus, and inhalation of dusts (silica, titanium, aluminum, others).
In congenital PAP, individuals are born with harmful gene variants that disrupt the production of normal surfactant. These include variants in 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 most likely other undiscovered genes. These harmful gene variants 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 alveolar distortion (interstitial fibrosis) that can result in reduced lung function or respiratory failure. Some forms of congenital PAP are inherited in a recessive pattern (see above) while others follow a dominant pattern where only one of the genes is harmful 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 presents 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 (associated with harmful variants in SFTPB, ABCA3 or NKX2.1 genes) or slow development of interstitial lung disease in children, adolescents or adults (associated with harmful variants in SFTPC or ABCA3 genes).
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. 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 for 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 and children with congenital PAP caused by genetic mutations that disrupt the production of normal surfactant.
Genetic counseling is recommended for families of individuals with the hereditary or congenital forms 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 formulation, 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:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
For information about diagnostic testing for PAP in clinical practice or clinical research, contact the Translational Pulmonary Science Center Laboratory at Cincinnati Children’s Hospital Medical Center:
Phone: (844) 843-8772
Email: [email protected]
Physicians: To order testing to diagnose autoimmune PAP, contact Cincinnati Children’s Diagnostic Immunology Laboratory: https://www.cincinnatichildrens.org/service/c/cancer-blood/hcp/clinical-laboratories/diagnostic-lab/assay
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