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Pulmonary alveolar proteinosis (PAP)

Introduction

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by the accumulation of protein and lipid material, called surfactant, within the lung air sacs or alveoli. This disease generally manifests itself in a younger population, mainly in the 20-40 age group. The disease is frustrating to those it impairs since they are usually otherwise healthy individuals. This booklet is designed to serve as a resource for individuals that have been diagnosed with the disease, or their relatives and friends. Please see the contact information section at the end of this booklet for further information on individuals that will assist you in dealing with the lung disease known as PAP.

An overview of PAP

Although the actual number of patients with PAP is not known, it is considered a "rare" or "orphan" disease by researchers. PAP likely afflicts less than 10,000 in the U.S. Because of the rarity of this lung disease, it is difficult to obtain reliable information for patients and it also poses challenges for medical advances. Patients with PAP may complain of shortness of breath, cough, or chest discomfort. This condition is diagnosed by doctors by a variety of tests including chest x-rays, breathing tests, and lung biopsy. PAP is sometimes inactive (little or no symptoms) and at other times is active (increased symptoms) and even life threatening.

What is it?

Pulmonary alveolar proteinosis (PAP) is a rare disease of the lung. In PAP, the alveoli (air sacs in the lungs) become flooded with more surfactant than normal. The alveoli absorb oxygen from the air into the blood. To do this, the alveoli are lined by a special liquid called surfactant. Surfactant is made up of proteins, lipids and other chemicals, and serves to keep airsacs open to capture oxygen so that the blood can transport it from the lung to the rest of the body. The exact reason why there is excess accumulation of surfactant is unknown. Most investigators suspect that a decreased clearance of surfactant from the air spaces by alveolar macrophages is the underlying pathology behind this disease. PAP decreases the ability of the alveoli to absorb oxygen and can cause a variety of lung symptoms

Who gets PAP?

Although the exact incidence and prevalence of PAP are unknown, it is likely that the published literature underestimates the lung disease's prevalence. PAP has been reported in different parts of the world including Europe, Japan, Australia and Latin America. It affects men far more frequently than women. Although most cases of PAP occur as an unknown or "idiopathic" entity, it has been rarely reported with certain occupational exposures (i.e. silica, spray painting) or other medical conditions. A variety of PAP can be seen in the lung of infants, but the adult variety is discussed here.

How is it diagnosed?

Diagnosis can be established with a typical history of symptoms (i.e. breathlessness, cough, and activity intolerance), x-ray abnormalities, and low oxygen levels along with milky-appearing lavage fluid on bronchoscopy and suggestive transbronchial biopsies. However, open surgical lung biopsy is often performed to confirm a diagnosis and exclude secondary causes. Currently, blood tests for the initial diagnosis of PAP are being studied. Appropriate clinical history, radiographic and physiologic findings, and confirmatory findings on bronchoscopy with bronchoalveolar lavage and/or open lung biopsy will establish a diagnosis of primary PAP.

Why have a bronchoscopic exam? What are brushings, washings, and biopsies?

A bronchoscopy involves passing a narrow, flexible instrument through the mouth or nose into the airways. This procedure is useful in the diagnosis and treatment of pulmonary diseases, involves little hazard, and is not painful. In brushings, a soft sterile brush resembling a pipe cleaner is inserted through a tube in the scope and gently wipes lung tissue or a lesion. When the brush is withdrawn, cells adhere to it and are taken to the laboratory for study. Washings and alveolar lavage involve a small amount of salt solution introduced into the lung, then suctioned out. Cells that have floated back out with the solution are analyzed. When a biopsy is needed, a device is passed through the bronchoscope and a small sample of lung tissue is obtained with relatively little discomfort for microscopic examination. Full instructions are given before a bronchoscopy, and any additional lung questions you have will be answered.

Initial presentation and symptoms of PAP

Patients with PAP may present with progressive cough and shortness of breath or be asymptomatic despite abnormal chest x-rays. PAP usually does not involve other parts of the body. Chest x-ray findings in PAP are quite variable although diffuse alveolar filling is typical.

Progression of PAP symptoms

The clinical course of PAP is quite variable. Progressive cough and shortness of breath are generally initial symptoms and in some patients are the only symptoms that are visible. When these symptoms are further evaluated, the abnormal chest x-ray is usually the next finding, and the one that prompts further evaluation. A bronchoscopy or open lung biopsy is the means to definitively diagnose PAP. Whole lung lavage, as mentioned in the treatment section, is the only standard treatment for PAP patients. After the lavage process is complete, some patients recover and require no further treatment, whereas other patients require periodic treatment with whole lung lavage. Although prospective data regarding spontaneous resolution are not available, a recent literature review indicated that, among 303 published cases, spontaneous resolution resulted in normalization of the chest x-ray in only 8% of the cases and arterial oxygenation in 2% of the cases.

What is the most up-to-date understanding of the cause of PAP?

Five years ago, it was noted that mice developed an illness very similar to PAP when they were depleted of a normally occurring chemical (GM-CSF) in the blood. This observation linked GM-CSF as being vital for normal lung health (i.e. free of PAP). Studies in PAP patients unexpectedly found an abnormal antibody (a protein) that specifically ties up GM-CSF leading to a state of GM-CSF deficiency. Finally, studies from several research groups noted that giving GM-CSF to PAP patients resulted in improvement of the lung disease in some patients (about half to two thirds). These observations support the idea that PAP may somehow be related to an abnormality or deficiency of GM-CSF.

Treatment of PAP

Whole Lung Lavage

A variety of treatments, including corticosteroids, have been attempted in the past and have been largely unsuccessful. Sequential whole lung lavage is the current standard treatment for PAP and the only treatment which has been clearly shown to improve symptoms and oxygenation in patients with this disease. A whole lung lavage procedure requires general anesthesia and intubation with a specific endotracheal tube, which allows ventilation of one lung while the other lung is repeatedly filled with saline and drained to clean out the material from the air spaces. The lavage is repeated in the other lung during the same day under anesthesia or repeated on a later date depending on the experience and approach taken by the doctors. The whole lung lavage procedure typically takes 2-5 hours to complete. Oxygen may be used as an adjunctive therapy for PAP patients during times when arterial oxygen levels fall. PAP patients may find the periodic need for oxygen during exertion.

Experimental Treatment through Clinical Trials

Several approaches are being studied by researchers around the world. One is to administer the normally occurring chemical called GM-CSF, either as a daily shot or as a breathing treatment, for 6-12 months. Another approach is to lower the blood level of GM-CSF antibody through other methods. Patients with newly diagnosed PAP or established disease may be considered for a clinical trial if they present with mild-to-moderate disease that may tolerate therapy on an outpatient basis over several months without the "need" for whole lung lavage. Typically, these patients have less disabling symptoms, gas exchange is less severely impaired (room air arterial oxygen level greater than 55, and the radiographic abnormalities are less severe. Severe exacerbation of PAP is usually defined as requiring in-patient care and more urgent therapy with unilateral or bilateral whole lung lavage. Patients with severe PAP may be treated with whole lung lavage and be subsequently considered for a clinical trial. If a patient has a history of more than 2 lavages in the prior four months, he/she may be eligible for participation in a clinical trial after a lavage for severe PAP exacerbation.

Frequently Asked Questions

How long does it take for PAP symptoms to show up?

PAP patients become symptomatic at all different ages. Most patients with PAP are between the ages of 20-40, although this may vary. Basically, this is a lung disease that shows up in a fairly young population.

Will my PAP get better?

While it is impossible to predict whether your PAP will get better or worse, patients report they feel better when they avoid certain activities such as cigarette smoking; or are free of respiratory infections or “colds”. Your physician will advise you on a lifestyle that is the most conducive to good health. Do not hesitate to confer with your health care provider on the best options for you.

Is there any medicine I can take to improve my breathing?

Your physician will evaluate your breathing and decide if any medications can help you. Generally, there are no medications that can be used to treat the shortness of breath associated with PAP, but if there is another disease in addition to your PAP that causes your shortness of breath, your physician may recommend treating that condition with medication. A bronchodilator may be beneficial if there is an asthmatic component to your lung disease. Your physician will test you via pulmonary function tests to see the exact extent of your disease. In addition to your symptoms, the test results will be the guide to the type of treatment that is prescribed for you. Weight also plays an important factor in maintaining good health. Make sure your weight is in the normal range for your height. Your health care provider can let you know the best way for you to maintain your weight or the best weight loss program available to meet your particular lifestyle.

How did I get PAP (no one in my family has lung disease)?

The exact mechanism that determines whether or not a patient will get PAP has not yet been proven. It appears that PAP is not a hereditary disease so there does not have to be anyone in the family with that disease in order for a patient to contract it. Researchers are working diligently on obtaining the cause(s) for PAP. Your physician can tell you about the latest research findings in this area.

Should I get a flu shot?

It is generally recommended that patients with chronic respiratory illness such as PAP get a flu shot each year, since the flu shot can reduce the frequency and severity of common influenza. Talk to your physician specifically about a flu shot. Remember that another way to decrease your chance of getting an infection is to wash hands thoroughly with soap and water. In addition, avoidance of people who are sick also helps to reduce the spread of infection.

How will smoking affect my PAP?

There is a positive correlation between the effect of smoke on the lungs and the worsening of PAP symptoms. If you are smoking, it is recommended that you quit as soon as possible. If you need help with quitting, talk to your doctor about the best way to break the habit!

Is there a cure for PAP?

No, there is no known cure for PAP but whole lung lavage is the standard treatment for this disease. In addition to whole lung lavage, there may be clinical trials available to help control your disease. Your physician will be able to advise you on research trials that would be appropriate for you. Although these trials will be considered experimental, they do provide an opportunity to get the latest approaches to disease improvement and medical advancement. Look for these trials at centers that specialize in PAP.

Where do I get evaluated for clinical trials?

The Pulmonary Medicine Department at the Cleveland Clinic, as one of the leading PAP referral centers in the US, has clinical trials available in the area of pulmonary alveolar proteinosis. Over 60 patients with PAP are currently under consultation by Cleveland Clinic physicians. An evaluation for PAP can be arranged by contacting this department at 216-444-2901 and requesting an appointment. An initial telephone consultation can be followed by an outpatient appointment for review of records, chest x-rays and prior biopsy material.

If I am coming to Cleveland Clinic, what should I bring with me?

In order to help the physician and PAP coordinator get an accurate picture of your lung disease, please bring the following with you from any previous doctor or hospital visits: chart notes, actual pathology / biopsy slides, chest x-rays, and CAT scans. Please note that you may need to request these in writing ahead of time from your physician’s office.

Contact information for clinical trials

For further information on clinical trials for PAP, please contact:

The Cleveland Clinic Foundation

Department of Pulmonary & Critical Care Medicine
9500 Euclid Avenue, Desk A90
Cleveland, Ohio 44195

PAP Research Coordinator

216.444.6508
or toll-free 800.223.2273 x 46508


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