What is Pulmonary Alveolar Proteinosis (PAP) Syndrome?
Pulmonary Alveolar Proteinosis (PAP) is a not a single disease – it is a rare syndrome or condition that can occur in several different diseases. The syndrome is caused by the build up of surfactant in the lungs that makes breathing difficult.
Normally, surfactant is present as a very thin layer on the lung surface. It helps keep the millions of tiny air sacs (alveoli) stay open as we breath. The thin layer of surfactant is maintained by balanced production and destruction inside alveoli.
Alveolar macrophages are special cells inside alveoli that remove excess surfactant from alveoli. This helps keep the surfactant layer thin and useful. Macrophages require stimulation by a protein called GM-CSF in order to function correctly and remove surfactant.
PAP occurs when something happens that disturbs the balance of surfactant production and removal. When this occurs, surfactant builds up inside the alveoli over time. Eventually, the alveoli fill up completely with surfactant leaving no room for the air we breath to enter. The result is that oxygen can’t get into the blood as easily, which causes a feeling of breathlessness.
What causes PAP?
The different diseases in which PAP occur can be divided into three groups: Primary PAP, Secondary PAP, and Disorders of surfactant Metabolism.
Primary PAP occurs when something prevents GM-CSF from stimulating alveolar macrophages. This reduces their ability to remove excess surfactant and causes PAP. There are two diseases in this group autoimmune PAP and hereditary PAP.
Autoimmune PAP (aPAP) is a disease that develops when a person’s immune system begins making proteins that attack GM-CSF. These proteins are called GM-CSF autoantibodies and large amounts of them prevent GM-CSF from helping alveolar macrophages remove excess surfactant. This results in surfactant accumulation and the development of PAP. Autoimmune PAP occurs mostly in adults but can occur in young children.
Hereditary PAP (hPAP) is a genetic disease that causes GM-CSF to not be recognized by alveolar macrophages. This prevents GM-CSF from helping alveolar macrophages remove excess surfactant. This results in surfactant accumulation and the development of PAP. Normally, GM-CSF is recognized by proteins on the surface of alveolar macrophages (and other cells) called GM-CSF receptors. Similar to the way a key fits into and turns a lock to open it, GM-CSF fits into these surface proteins and ‘opens’ or, rather, activates them. This causes alveolar macrophages to be able to remove excess surfactant. In hPAP, mutations occur in the genes that serve as blueprints for making GM-CSF receptors. The result is that when the blueprint containing ‘bad’ instructions is used, the GM-CSF receptors are abnormal and don’t recognize GM-CSF. Some mutations are so severe that the GM-CSF receptors aren’t even made. Hereditary PAP occurs mostly in children but can occur in adults.
Secondary PAP (sPAP) occurs when something reduces either the number of alveolar macrophages or reduces their ability to function to remove surfactant.
In either case, there are less alveolar macrophages inside alveoli to remove excess surfactant. This results in surfactant accumulation and the development of PAP. Secondary PAP can occur in diseases that affect the formation of blood cells. It can also occur after breathing in toxic dusts. Secondary PAP is more common in adults but can occur in children.
Disorders of surfactant production (DSP) are genetic diseases that cause abnormalities in proteins needed to make surfactant. This results in the production of abnormal surfactant. The disease that occurs depends on which gene is affected and exactly what mutation is present. Some mutations result in death in the first hour of life and some slowly scar the lungs over time and appear in children, adolescents, or adults.
What are the symptoms of PAP?
PAP usually causes a feeling of breathlessness (a feeling of being unable to breathe easily) that starts slowly and gets worse over time. Doctors refer to this as “progressive dyspnea of insidious onset”. Some patients develop a dry cough. Less commonly – in less than 5% of people with PAP, a frothy, whitish phlegm may accompany the cough. Rarely blood-streaked phlegm, chest pain, and fever may also be present, which indicate that infection is probably also present.
How is PAP diagnosed?
Evaluation of a person's symptoms and clinical tests cannot identify what disease is causing PAP. Chest x-rays reveal the presence of whitish, fluffy shadows throughout the lungs. Chest CT scans reveal areas of increased whitish shadows next to areas of normal appearing lung. Chest x-rays and CT scans can suggest but not prove that PAP syndrome is present. This is because other diseases can have a similar appearance. A lung biopsy can determine if PAP syndrome is present but can not identify which disease is causing PAP in any patient.
Blood tests identify the disease in most patients with PAP. Detection of GM-CSF autoantibodies in the blood is used to identify aPAP. Detection of genetic mutations in genes for GM-CSF receptors is used to identify hPAP. Secondary PAP is diagnosed on the history and clinical findings. Detection of genetic mutations in genes needed to make surfactant is used to identify DSP.
How common is PAP?
Current estimates suggest that 40,000 - 50,000 PAP patients exist worldwide.
What is the natural history of PAP?
Symptoms may improve spontaneously in a small percentage of patients. More commonly, symptoms persist for long periods of time or progress more rapidly.
What is the treatment for PAP?
The most common treatment for PAP is whole lung lavage, a procedure used to ‘wash’ surfactant out of the lung. This therapy is useful in aPAP, hPAP, and some types of sPAP but is not useful in DSP.
Several potential treatments for PAP are in development and testing. Inhaled GM-CSF is an interesting and promising approach for aPAP. Pulmonary macrophage transplantation is a potential therapy that is in development for hPAP.