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Pulmonary Alveolar Proteinosis (PAP)What is PAP? Pulmonary Alveolar Proteinosis (PAP) is a rare syndrome that is characterized by excessive accumulation of surfactant lipids and proteins in the lungs, which impairs absorption of oxygen from the air and causes a feeling of breathlessness. What Are Some Important Facts About PAP?
Do I Have this Disease? (Symptoms) Common Findings:
Less Common Findings:
How Is PAP Diagnosed? A diagnosis of PAP can be established in most patients by a combination of a typical history of symptoms, radiographic abnormalities, hypoxemia, and analysis of fluid and/or biopsies recovered from the lung by a procedure called bronchoscopy. This procedure involves passage of the bronchoscope (a flexible tube) through the nose or mouth into the airways of the lung. A computed tomography (CT) scan of the chest is typically performed and has a characteristic appearance (see below). Although surgical lung biopsy can be used to confirm the diagnosis and exclude other causes, it is usually not necessary in most patients. A blood test is now available to identify people who have the common idiopathic form of PAP (see below).
A chest x-ray of a person with PAP reveals the presence of the excess surfactant in the lungs. The accumulated surfactant has a white "fluffy" appearance that is best seen in between and overlying the ribs.
A CT scan of the chest of a person with PAP reveals the presence of patchy ground glass opacities and septal thickening in a geographic distribution, commonly referred to as crazy paving. What Is The Natural History Of PAP? Presentation Idiopathic PAP usually begins insidiously and goes unnoticed until enough surfactant has accumulated in the lungs to cause a feeling of breathlessness. The chest x-ray (below) is frequently out of proportion compared to the severity of the patient's symptoms. Cough is the next most common finding. Sometimes, the x-ray, cough and breathlessness are interpreted as suggesting the presence of pneumonia. However, antibiotic therapy fails to the improve symptoms. This can lead to a delay in obtaining a correct diagnosis. Disease Progression The clinical course in PAP is variable and ranges from spontaneous remission of symptoms to progressive deterioration and death. Many individuals continue to have symptoms and require treatment by whole lung lavage. The overall 5-year survival is approximately 95% with treatment and about 85% in without. Secondary Infections Review of the world literature suggests that approximately 18% of PAP patients present with or will develop some type of infection. Infections are frequently caused by microbes that cause infections in people with an underlying immune abnormality (so called opportunistic organisms). Infections can occur in the lungs, but frequently occur outside the lungs. The recent experience of doctors treating PAP patients suggests that the rate of secondary infections in PAP patients may be much less than 18 percent. What Is Surfactant And What Does It Do? Surfactant is comprised of about 90% lipids (fat molecules) and 10% proteins. It is produced by cells that line the lung surface and functions to help keep the tiny air sacs (alveoli) from collapsing with each breath. Premature babies develop lung disease because their lungs don't make sufficient amounts of surfactant. In PAP, the opposite is true; excess surfactant occupies so much of the space within alveoli that not enough room is left for air to enter. There are four types of surfactant proteins that serve important roles in lung function and lung host defense.
A very high-magnification picture (electron micrograph) of the material recovered by this procedure reveals the typical lamellar (layered) appearance of surfactant. Excess surfactant can be removed from the lungs of PAP patients by a therapeutic procedure know as whole lung lavage. What Causes PAP? Surfactant produced in the lungs is normally either recycled by lung cells or destroyed (catabolized) by alveolar macrophages in the lungs. GM-CSF is required to stimulate surfactant catabolism and other functions in these cells. In PAP, very high levels of antibodies against GM-CSF are present in the blood and lungs and completely neutralize the activity of GM-CSF. Without GM-CSF-stimulation, alveolar macrophages are unable to catabolize surfactant. Consequently, surfactant accumulates progressively leading to impaired oxygen absorption in the lungs and symptoms. PAP also develops in mice that are genetically deficient in GM-CSF and studies with such mice have vastly improved our understanding of the disease. Detection of Anti-GM-CSF Antibodies High levels of anti-GM-CSF autoantibodies can be detected by a reliable test that can performed on either blood (serum) or lung lavage fluid. The test has a sensitivity and specificity that approaches 100% however, it is not yet widely available. For further information, please see the contact information for the Central RLDC Laboratory NEED LINK HERE TO THE LAB TEST.
GM-CSF is the target of an attack by the body's immune system that is believed to cause the disease in most people who develop PAP (below). The GM-CSF molecule is composed of two identical protein subunits (shown in red and blue); one region of GM-CSF is particularly prone to autoimmune antibody attack (shown in yellow). How is PAP Treated?
A Brief History of PAP Research Highlights Although described in 1958, the first important clue about the pathogenesis of PAP came in 1994 with the serendipitous discovery that PAP develops in genetically modified mice that are deficient in expression of the cytokine growth factor granulocyte-macrophage colony stimulating factor (GM-CSF) or its receptor. In the subsequent three years, reports demonstrated that PAP in mice was caused by a defect in surfactant catabolism by alveolar macrophages, and could be corrected by GM-CSF protein or gene therapy, or genetic reconstitution of pulmonary GM-CSF expression in GM-CSF deficient mice or by transplantation of normal bone marrow in GM-CSF receptor deficient mice. In 1999, a defect in lung host defense was reported in GM-CSF deficient mice. By 2001, this defect was found to be associated with a number of immune function abnormalities in alveolar macrophages, which were arrested at an early stage of maturation due to reduced expression of the transcription factor, PU.1. The abnormalities included defects in cell adhesion, surfactant lipid and protein catabolism, cell surface receptor expression, integrin expression, phagocytosis, microbial killing, toll receptor signaling, abnormal cytoskeletal organization and others. In 2004, GM-CSF was found to regulate neutrophil trafficking and chemotaxis in mice. In 2005, list of neutrophil defects in GMCSF deficient mice has expanded to include abnormalities in cell adhesion, phagocytosis, oxidative burst, microbial killing and cell survival. In 1995, only one year after the discovery of PAP in GM-CSF deficient mice, GM-CSF administration was used to treat one PAP in Australia and was associated with clinical improvement. Subsequently, several studies evaluating the use of GM-CSF therapy in PAP were initiated; currently, GM-CSF treatment studies are ongoing in Japan and the United States. To date, no defects have been positively identified in the genes encoding either GMCSF or its receptor. In 1999, an important leap in our understanding of the pathogenesis of human idiopathic PAP occurred when high levels of neutralizing anti-GM-CSF autoantibodies were found in the serum and lungs of these patients. In 2001, GM-CSF was found in the serum and blood of PAP patients; however, anti-GM-CSF autoantibodies were found to completely eliminate GM-CSF bioactivity in PAP patients. High levels of these autoantibodies were specifically associated with idiopathic PAP and have high diagnostic utility with a sensitivity and specificity approaching 100 percent. In 2003, the Rare Lung Disease Consortium (RLDC) was formed in order facilitate clinical research on PAP and other lung diseases with funding from the National Institutes of Health. In the same year, RLDC investigators reported that many of the defects found in alveolar macrophages from PAP mice were also present in alveolar macrophages from human PAP patients. These included the defect in PU.1 expression, cell adhesion, phagocytosis, TLR-4 signaling and others. In 2004, the clinical observation of an unexpectedly high frequency (~10%) of opportunistic and other infections in PAP patients led RLDC investigators to hypothesize that a defect exists in neutrophil function in PAP patients. Recent unpublished results that were discussed at the RLDC 2005 meeting show that neutrophils from PAP patients have a number of defects including impaired cell adhesion, phagocytosis, oxidative burst, microbial killing and cell survival. Other studies to be shown at the meeting will describe the important roles played by other transcription factors including the interferon consensus sequence binding protein (ICSBP) and the peroxisome proliferator-activated receptor gamma (PPAR g) in macrophage function in PAP. Contact Registry for PAP | Find a Trial | PAP Brochure | PAP Advocacy Groups | Back to RLDC Disease Menu |
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