FREQUENTLY ASKED QUESTIONS ABOUT PAP

What are the different types of PAP?
PAP is known to occur in three different clinical forms; primary (also called idiopathic or occasionally acquired), secondary and congenital forms.  Primary PAP is associated with high levels of antibodies that recognize and neutralize an essential blood protein called GM-CSF (granulocyte-macrophage colony-stimulating factor).   Secondary PAP occurs as a consequence of another clinical condition that reduces either the numbers or function of alveolar macrophages.  Congenital PAP is a less-well characterized collection of specific lung diseases that are due to genetic defects in the genes responsible for production of normal surfactant.

What causes PAP to occur in the first place?
PAP is a condition in which surfactant, a normal milky substance lining the lungs, accumulates to abnormally high levels and results in a feeling of breathlessness.  There are several different clinical forms or types of PAP; primary (also called idiopathic or occasionally acquired), secondary and congenital forms.  Primary PAP is associated with high levels of antibodies that recognize and neutralize an essential blood protein called GM-CSF (granulocyte-macrophage colony-stimulating factor).   Secondary PAP occurs as a consequence of another clinical condition that reduces either the numbers or function of alveolar macrophages.  Congenital PAP is a less-well characterized collection of specific lung diseases that are due to genetic defects in the genes responsible for production of normal surfactant.

What are the Symptoms of PAP?
Primary PAP usually starts without notice and then gradually gets worse until a feeling of breathlessness (dyspnea) becomes apparent and progresses.  Some patients also have cough and / or may produce small amounts of whitish phlegm (sputum).  Fever can be present if infection is also present.  Rarely, an affected individual may cough up blood (hemoptysis) or have chest pain, especially if lung infection is also present.

How is PAP diagnosed?
PAP can be suspected on the basis of clinical symptoms (dyspnea) and the results of a chest x-ray and/or chest CT scan.  The chest x-ray in PAP typically reveals the presence of whitish, fluffy shadows scattered throughout both lungs (referred by doctors as a diffuse, bilateral alveolar filling or ground glass pattern).  The chest CT scan in PAP typically reveals a pattern commonly referred to as "crazy paving", which consists of areas of increased whitish shadows (ground glass opacities) adjacent to areas of normal appearing lung (a geographic distribution) scattered throughout the lungs that is superimposed on thick white lines (septal wall thickening).

Notwithstanding clinical suspicion, PAP is still diagnoses by directly observing the abnormal appearance of a sample of the abnormal lung tissue (lung biopsy).  A lung biopsy can be obtained during bronchoscopy (called a transbronchial biopsy) or by the surgeon (an open lung biopsy).

A new technique, referred to as the "anti-GM-CSF antibody titer" determination, is currently being used in clinical research studies to identify individuals with primary PAP. High levels of anti-GM-CSF antibodies are present in individuals with primary PAP, but not secondary PAP, congenital PAP, other lung diseases or normal, healthy individuals.  The anti-GM-CSF antibody titer test is currently in a period of testing to determine how well it predicts the presence of primary PAP in individuals suspected of having the disorder.  Investigators hope that current studies will establish this test as a simple and very useful tool that can be used to diagnose primary PAP in the future.

What is GM-CSF and how is it related to primary PAP?
GM-CSF is a cytokine required to stimulate certain lung cells (alveolar macrophages) to destroy (catabolize) surfactant. The ability of GM-CSF to stimulate alveolar macrophages to destroy surfactant results in removal (clearance) of surfactant from the lungs. In fact, GM-CSF is required to stimulate the ability of alveolar macrophages to remove excess surfactant.  Antibodies that recognize GM-CSF and are capable of neutralizing its function (neutralizing anti-GM-CSF autoantibodies) effectively eliminate the function of GM-CSF bound by the antibody.  This, in turn, prevents GM-CSF from activating surfactant destroying pathways in alveolar macrophages and thus blocks their ability to remove excess surfactant, which then accumulates abnormally.

What is the natural history of PAP?
PAP can follow one of three different pathways over time. In the first group, patients have an improvement in their symptoms either spontaneously or after one or more whole lung lavages. In the second group, the symptoms continue without spontaneous improvement or worsening. In the third group, the clinical symptoms progressively decline.

What are the treatment options for PAP?
Whole lung lavage is the most commonly used treatment for primary PAP and is currently considered to be "standard therapy".

In addition standard therapy, several new "experimental" approaches for the treatment of PAP are currently under evaluation in clinical research studies. One form involves GM-CSF administration, either by injection under the skin (subcutaneous administration) or by breathing in a fine mist of saline that contains GM-CSF (aerosol administraion). Another involves a procedure known as plasmapheresis in which antibodies are removed from the blood stream.  Another therapy involved treatment to reduce the number of antibody-secreting blood cells (B lymphocytes).

What is a lung lavage?
Whole lung lavage is a procedure in which the patient is placed under general anesthesia, a double-lumen endotracheal tube (a special "Y" shaped plastic breathing tube) is positioned with one end of the "Y" in each lung and the other end protruding out from the windpipe (trachea) and mouth. This allows air to be moved into and out of one lung using a ventilator (mechanical breathing machine) while saline (salt water solution)is flowed into and drained out of the other lung to "wash out" the excess surfactant. Approximately 15 to 50 liters of saline is used to wash each lung. After completing the lavage of the firs lung, the second lung is washed. In most, but not all centers, there is a period of one or more days between lung lavages to allow the patient to recover.

How common is PAP?
PAP is a rare disorder. The number of people affected by PAP has been estimated to be about 3.7 per million individuals.

How will having PAP affect my lifestyle?
PAP affects the lungs by causing surfactant to accumulate to abnormally, thus reducing the ability of the lung to transfer oxygen from the air into the blood.  This has the effect of making an individual with moderate or severe PAP feel "breathless" or "short of breath".  The reduced uptake of oxygen into the bloodstream is worse at times of increased exercise. This causes an awareness of "exercise-induced breathlessness".  The net effect of this limitation is that people with PAP may have more trouble with mild or strenuous activities. This is what doctors refer to as exercise limitation. 

Sometimes, PAP patients need oxygen therapy.  This usually involves the use of a portable oxygen tank and a plastic tube that rests over the ears and drapes under the nose and across the upper lip projecting oxygen into the nose.   Breathing in a higher concentration of oxygen in each breath helps because the lung surface is exposed to gas with a higher percentage of and this results in more oxygen transferred into the bloodstream for each breath taken. 

The current standard of care for treating PAP is whole lung lavage.  Published medical literature reports that this procedure is needed every 15 months, on average, by those that require it.  The procedure is performed in the hospital, so patients need to be admitted to the hospital periodically.

Glossary
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