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Stanford Report, January 19, 2000

Researchers pool data to answer questions about rare lung disease


Becoming sick can seem doubly unfair if you have a rare disease. Falling ill is already a misfortune, but to make matters worse, the rarity of the disease often thwarts scientific investigation that could lead to a treatment or cure.

Hoping to overcome the limitation of small numbers, Stanford has joined with five other research centers to pool data on the rare lung disease lymphangioleiomyomatosis (LAM). The goal of the LAM registry, which began operating about two years ago, is to bring together enough information to answer questions about the origin, course and cause of LAM, including the role played by genes.

Each center will collect a standard set of data on as many LAM patients as possible and monitor their health for five years. Each year, patients will be given chest X-rays, lung function tests, exercise tests to measure lung capacity and to check for shortness of breath, and a questionnaire to measure how the disease is affecting their quality of life. All of this information, along with samples of lung tissue and blood, will be sent to a central databank at the Cleveland Clinic in Ohio, where it will be available to other researchers in the project. The National Heart, Lung and Blood Institute, a branch of the National Institutes of Health, is providing the funding.

Stanford was chosen as one of the six sites because Thomas Raffin, MD, professor and chief of the division of pulmonary and critical care medicine, is one of the few LAM experts in the world.

LAM is a relentless and often fatal disease that ravages the lungs of young and middle-aged women. In normal lungs, a sheath of smooth muscle cells surrounds the airways and, by contracting or relaxing, regulates air flow to match the body's need for oxygen. But in LAM patients, over years the smooth muscle cells begin to multiply uncontrollably. Bundles of cells can narrow the airways and block blood and lymph vessels, causing difficulty breathing, internal bleeding and fluid buildup. Proliferating muscle can pinch off the small air sacs known as alveoli, which can then form air-filled cysts. Cysts near the surface of the lungs -- known as blebs -- can rupture and cause a partial or complete collapse of the lung. Although LAM involves out-of-control cell replication and shows some similarities to the skin cancer malignant melanoma, the disease is not considered a form of cancer, Raffin said.

For LAM patients, whose first symptom is usually shortness of breath during exercise, treatment usually does not stop the progression of the disease. Most patients develop severe breathing difficulties within 10 years of diagnosis, and less than 50 percent survive more than 20 years. Since the disease occurs almost exclusively in women of child-bearing age, scientists naturally suspected the hormone estrogen was somehow involved. However, chemical treatment to block estrogen and even removal of the ovaries do not seem to slow the disease, Raffin and colleagues reported in a 1990 study published in the New England Journal of Medicine. Lung transplants can extend life for a number of years but create other problems, such as the risk of rejection and infection.

As with so much else about LAM, the cause remains mysterious. Genes undoubtedly play a role, Raffin said, but further research is hampered not only by the rarity of patients, but also by the lack of an animal model of the disease that could be studied in the laboratory. Besides humans, only bottlenose dolphins have been reported to get LAM, Raffin noted.

In the two years since the registry opened, 129 patients have enrolled, said Susan Jacobs, RN, who coordinates clinical trials in pulmonary and critical care medicine. That may not seem impressive in these days of massive, multicenter trials until you consider that only 500 or so Americans have LAM. So the registry has enrolled approximately 25 percent of the LAM patients in the country, and it will continue accepting new patients through 2001.

With the information in the LAM registry, scientists will be able to better understand how the disease damages the lungs and to undertake longitudinal studies of LAM's progression. Researchers will also be able to evaluate the success of treatments, identify likely complications, and determine how long patients survive with the disease. Blood samples should speed the hunt for genes that contribute to the disease.

Future LAM patients could also benefit, Jacobs said, because a better understanding of how the disease begins and progresses could help scientists develop a more precise definition of LAM that would improve diagnosis. Today, almost four years typically elapse between initial symptoms and diagnosis. SR