Pulmonary Alveolar Proteinosis, commonly known by the acronym PAP, is a rare lung disease characterized by the build-up of grainy material in the alveoli (air sacs) of the lungs. This grainy material is composed mainly of phospholipid (a fat-like substance) and protein. Phospholipid and protein are the key components of lung surfactant, an important substance that coats the alveoli to prevent lung collapse and which promotes oxygen absorption by the lungs.
In normal lungs, specialized immune cells called alveolar macrophages swallow and remove inhaled particles and excess surfactant from the alveoli. In the most common form of PAP, it has been suggested that the alveolar macrophages do not function properly and consequently cannot break-down and remove the material they swallow. They become inefficient at clearing material from the lungs.
In PAP patients, the accumulation of excess surfactant material in the alveoli makes it increasingly difficult for the lungs to absorb oxygen from inhaled air. This leads to breathing difficulties such as shortness of breath and cough. Respiratory failure may occur in severe cases. In addition to breathing problems, many PAP patients acquire secondary infections, frequently caused by opportunistic pathogens. Interestingly, some patients with the disorder exhibit no symptoms.
PAP may progress in severity, remain stable, or spontaneously clear. The lower and rear lung regions are most commonly affected. Occasionally only the front segments of the lungs may be involved.
Three forms of PAP are currently recognized: congenital, secondary, and acquired. The congenital disease is most frequently diagnosed in infants and is considered a genetic disorder that has been linked to mutations in a gene encoding for a type of surfactant protein. In a limited number of cases it has been linked to a defect in a growth factor receptor.
Secondary PAP is diagnosed in individuals who may exhibit a primary disease that causes the alveolar macrophages to malfunction or reduces the number of alveolar macrophages in the lungs.
Acquired PAP (also known as idiopathic PAP) is the most common form of PAP, accounting for 90% of all cases. It is considered to be an autoimmune disease in which an individual produces antibodies that target an important growth factor for destruction by the immune system.
What causes PAP? 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.
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 administration). 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. Where can I find detailed information (published medical literature) about PAP?
Click here to find published papers about PAP (Coming Soon)
Glossary in Important Terms Click here to see the glossary.
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.
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.
Clinical Trials How can I help in the development of new therapies for PAP? You can help by learning about and participating in the ongoing research studies to develop new diagnostic methods and therapy for PAP. The Rare Lung Diseases Consortium (RLDC) is a group of clinical research centers and patient organizations (the Rare Lung Disease Foundation Consortium) who are collaborating together to speed the pace of PAP research and development.
Choosing to participate in a clinical trial is an important personal decision. It is often helpful to talk to a physician, family members, or friends about deciding to participate a clinical trial. The following frequently asked questions provide a basic introduction to clinical trials. Clinical trials currently recruiting research participants are listed at the bottom of this page.
What is a clinical trial? A clinical trial (also called clinical research) is a research study using human volunteers designed to determine the safety and effectiveness of a drug, biologic (such as a vaccine), device (such as prosthesis) or other treatment or behavioral intervention. Carefully conducted clinical trials are the fastest and safest way to find treatments that work in people and methods to improve health. Interventional trials determine whether experimental treatments or new ways of using known therapies are safe and effective under controlled environments. Observational trials address health issues in large groups of people or populations in natural settings.
Why participate in a clinical trial? Participants in clinical trials can play a more active role in their own health care, gain access to new research treatments before they are widely available, and help others by contributing to medical research.
Who can participate in a clinical trial? All clinical trials have guidelines about who can participate. The factors that allow someone to participate in a clinical trial are called "inclusion criteria" and those that disallow someone from participating are called "exclusion criteria." Using inclusion and exclusion criteria is an important principle of medical research that helps to produce reliable results. These criteria are based on such factors as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions.
Before joining a clinical trial, a participant must qualify for the study. Some research studies seek participants with illnesses or conditions to be studied in the clinical trial, while others need healthy participants. It is important to note that inclusion and exclusion criteria are not used to reject people personally. Instead, the criteria are used to identify appropriate participants and keep them safe. The criteria help ensure that researchers will be able to answer the questions they plan to study.
What happens during a clinical trial? The clinical trial process depends on the kind of trial being conducted. The clinical trial team includes doctors and nurses as well other health care professionals. They check the health of the participant at the beginning of the trial, give specific instructions for participating in the trial, monitor the participant carefully during the trial, and stay in touch after the trial is completed. Some clinical trials involve more tests and doctor visits than the participant would normally have for an illness or condition. For all types of trials, the participant works with a research team.
Clinical trial participation is most successful when the protocol is carefully followed, including frequent contact with the research staff. The protocol is a study plan on which all clinical trials are based. The plan is carefully designed to safeguard the health of the participants as well as answer specific research questions.
A protocol describes what types of people may participate in the trial; the length of the study; and if applicable, the schedule of tests, procedures, medications, and dosages. Participants in an interventional (treatment) clinical trial are seen regularly by the research staff to monitor their health and to determine the safety and effectiveness of their treatment. Whereas, there are other types of research trials that involve interviews, questionnaires, or surveys instead of interventional treatment.
What is informed consent? Informed consent is the process of learning the key facts about a clinical trial before deciding whether to participate. It is also a continuing process throughout the study to provide information for participants. To help someone decide whether to participate, the doctors and nurses involved in the trial explain the details of the study. If the participant's native language is not English, translation assistance can be provided. Then the research team provides an informed consent document that includes details about the study, such as its purpose, duration, required procedures, and key contacts. Risks and potential benefits are explained in the informed consent document. The participant then decides whether to sign the document. Informed consent is not a contract, and the participant may withdraw from the trial at any time. If a participant is a non-English speaking person, federal guidelines require a version of the consent form be provided in a language the participant can understand. What is a protocol? A protocol is a study plan on which all clinical trials are based. The plan is carefully designed to safeguard the health of the participants as well as answer specific research questions. A protocol describes what types of people may participate in the trial; the schedule of tests, procedures, medications, and dosages; and the length of the study. While in a clinical trial, participants following a protocol are seen regularly by the research staff to monitor their health and to determine the safety and effectiveness of their treatment.
What is a placebo? A placebo is an inactive pill, liquid, or powder that has no treatment value. In clinical trials, experimental treatments are often compared with placebos to assess the experimental treatment's effectiveness. In some studies, the participants in the control group will receive a placebo instead of an active drug or experimental treatment. What is a control or control group? A control is the standard by which experimental observations are evaluated. In many clinical trials, one group of patients will be given an experimental drug or treatment, while the control group is given either a standard treatment for the illness or a placebo.
Do I get to choose which group (experimental or control) to participate in? No, each person who agrees to participate in a clinical trial that compares an experimental medicine or device with a standard treatment or placebo is randomly assigned (that is by chance) to one or the other group. In general, the participant and the research team do not know the group assignment until after the study is completed.
What difference does it make if I know (or the research team knows) that I am in the experimental or control/placebo group? Knowledge of this information may influence a participant’s or study team’s reporting of how things are going in the study. For example, if the participant and/or study team knows that the participant is in the experimental group, an adverse event such as a skin rash might be reported as being “likely” related to the experimental medicine, instead of “possibly related”. Or the participant might report adverse events more frequently than if he/she was unaware of the group assignment. However, if the participant and/or study team knows that the participant is in the control/placebo group, the skin rash would be reported as “unrelated” and more importantly, the participant in this group might report worsening of his/her illness or condition, when there has been no change.
What does “single-blind” or “double-blind” mean? “Blinding” is a procedure in which one or more persons in the research trial are kept unaware of the treatment assignment(s). Single-blind usually means that the research participant is not told of the treatment assignment. Double-blind usually means that the research participant, investigator, study coordinator/nurse, study sponsor, and in some cases the data analyst are kept unaware of the treatment assignment. The purpose of a “blinded” study design is to remove the unintentional bias that can affect the interpretation of the research information that is collected, if the treatment assignment is known.
What are the benefits and risks of participating in a clinical trial?
Benefits: Well-designed and well-executed clinical trials provide the best approach for eligible participants to:
Play an active role in their health care decisions.
Gain access to new research treatments before they are widely available.
Obtain expert medical care at leading health care facilities during the trial.
Help others by contributing to medical research.
Risks: Clinical trials entail risks, which may include:
There may be unacceptable worsening of the illness or condition if the participant is randomly assigned to a control group and/or receives a placebo.
There may be unpleasant, serious or even life-threatening side effects to experimental treatment.
The experimental treatment may not be effective for the participant.
The protocol may require more of their time and attention than would a non-protocol treatment, including trips to the study site, more treatments, hospital stays or complex dosage requirements.
What happens if my illness or condition gets worse while participating in a trial? A participant has the right to withdraw his/her participation in a clinical trial at any time for any reason including unacceptable worsening of his/her illness or condition regardless of whether or not it is related to the study. It is important for the participant to read the consent form carefully to understand what the consequences (if any) are for early withdrawal from the study.
Is an “adverse event” the same as a “side effect”? No, these two terms do not have the same meaning. An adverse event (or experience) describes an unfavorable event or experience that occurs after a participant begins the research study. The event or experience may be reported by the research participant (such as “I was feeling dizzy all day”) or observed by the researcher (such as an abnormal lab test result). The occurrence of an unfavorable experience or event does not necessarily mean that it is associated with (or caused by) the experimental drug, device or treatment. Generally, an adverse event/experience is considered a “side effect” when it occurs much more frequently in participants who are in the experimental group than in the control group and there isn’t a reasonable explanation for the occurrence of the event.
What should people consider before participating in a trial? People should know as much as possible about the clinical trial and feel comfortable asking the members of the health care team questions about it, the care expected while in a trial, and the cost of the trial. The following questions might be helpful for the participant to discuss with the health care team. Some answers should be addressed in the informed consent document.
What is the purpose of the study?
Who is going to be in the study?
Why do researchers believe the experimental treatment being tested may be effective? Has it been tested before?
What kinds of tests and experimental treatments are involved?
How do the possible risks, side effects, and benefits in the study compare with my current treatment?
How might this trial affect my daily life? How long will the trial last?
If I am assigned to a control or placebo group, will I be given a chance to receive the experimental drug/device/treatment later on?
Will hospitalization be required?
Who will pay for the experimental treatment?
Will I be reimbursed for other expenses?
What type of long-term follow up care is part of this study?
How will I know that the experimental treatment is working?
Will results of the trials be provided to me?
Who will be in charge of my care?
What if I change my mind about participating in the study?
Where do the ideas for trials come from? Ideas for clinical trials usually come from researchers. After researchers test new therapies or procedures in the laboratory and in animal studies, the experimental treatments with the most promising laboratory results are moved into clinical trials. During a trial, more and more information is gained about an experimental treatment, its risks and how well it may or may not work.
What are the phases of clinical trials? PHASE I TRIALS: These studies include the initial introduction of new drugs usually in healthy human volunteers to determine how the human body metabolizes the drug and what the associated side effects are with increasing doses. Generally, less than 100 volunteers participate in this type of study.
PHASE II TRIALS: These are controlled clinical studies conducted to evaluate the effectiveness of a drug or device for a particular symptom or symptoms in patients with the disease or condition under study and to determine the common adverse effects and risks. These types of studies generally involve no more than several hundred participants.
PHASE III TRIALS: These are larger controlled and uncontrolled studies conducted after preliminary evidence suggests effectiveness of an investigational drug or device. These studies generally involve several hundred to thousands of participants to gather additional information about effectiveness and safety and adequate basis for physician labeling.
PHASE IV TRIALS: These studies are commonly referred to as “post-marketing” studies because they are generally conducted concurrent or after marketing approval to obtain additional information about risks, benefits, and optimal use of a drug or device. These studies could include, but would not be limited to, studying different doses of a drug that were not done during Phase II trials, or use of a drug/device in other patient populations.
For More Information One of the 20 institutes at the U.S. National Institutes of Health (NIH) is the U.S. National Library of Medicine (NLM). The NLM developed a website that provides regularly updated information about clinical research in human volunteers -- www.clinicaltrials.gov, where you will find additional links to other medical research resources, such as:
Access to all clinical trials
A glossary of terms related to clinical trials
MedlinePlus – an access to medical journals and latest health news
Genetics Home Reference – a guide to understanding genetic conditions
Additional Support www.everydaywarriors.com is an online gathering place that offers support and information for kids, teens, and adults who battle chronic illness or who have a disability. This site has different sections for adults, teens and kids including articles, columns, fiction, games, humor and more. There are also separate sections for parents and caregivers.
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