US asthma specialist Prof. Fernando Martinez says a cure is still some way off.
By JUDY SIEGEL-ITZKOVICHasthma 298.88(photo credit: American Academy of Asthma, Allergy & Immunology)
Generations of parents have tried to sanitize their children's environment to protect them from disease, while antibiotics introduced nearly seven decades ago helped overcome many pathogens once they were infected. But it seems they did too good a job - at least when it comes to preventing asthma, which has become much more prevalent because of "too-clean" surroundings, overuse of antibiotics and environmental pollution. About 10 percent of adults and 15% of children in Western countries suffer from this potentially fatal disorder.
There is also a genetic component to asthma, an as-yet incurable condition which causes the airways to tighten, preventing air from reaching the lungs. It tends to run in families - and two years ago, a pair of genes on chromosome #5 was discovered at Sweden's Karolinska Institute that seem to have strong links to asthma. However, experts say there are many more unknown genes responsible, but of all the latest drugs, none are based on genetic discoveries.
Most of the prescription drugs used by asthmatics are aimed either at suppression of the immune system or suppression of inflammation, says Prof. Fernando Martinez, a leading expert. The Chilean-born physician and researcher, who has since 1996 been director of the Arizona Respiratory Center, visited Israel recently to address a Dead Sea medical conference sponsored by the Israel Lung and Allergy Societies.
MARTINEZ WAS inspired to research this disease by a personal connection.
"My mother had severe asthma," he confided to The Jerusalem Post during his first visit to Israel. "This was one of the reasons I went into it. I remember that she took nebulizers but they didn't help much, and she used to scream at night when she couldn't breathe. I saw her suffering. This remains ingrained in my mind. Fortunately, I didn't inherit asthma from her."
His wife, a special education teacher who was also born in Chile, doesn't have it, nor do their three adult children.
Martinez, who received medical degrees from the University of Chile and the University of Rome and specialized in pediatrics and pulmonology, heads the leading respiratory research institution in the US. It was opened in 1971 as a small, specialized respiratory sciences research effort at the University of Arizona's College of Medicine, but has grown into an internationally renowned, comprehensive center of excellence combining high-caliber clinical care for patients, research and teaching. The center has taken a multidisciplinary collaborative approach, with physician specialists, epidemiologists, immunologists, pharmacologists, molecular and cellular biologists and population geneticists in integrated teams.
ASTHMA AND other chronic obstructive pulmonary diseases are the fifth leading cause of death in the US; more than 15 million Americans are affected. Sufferers used to flock to Arizona for its clean air, as their Israeli counterparts went to Arad, but today even living in such places - with their plant life and even some pollution - is no guarantee against asthma attacks.
Martinez, a member of the US National Institutes of Health Special Emphasis Panel on Asthma and an advisor to the Food and Drug Administration, has conducted extensive research on the causes and manifestations of childhood asthma, immune system development and genetic epidemiology. In 1997, he helped develop national guidelines for the diagnosis and management of asthma, and is now an active participant in developing the new version.
Mice are usually a good model for the study of human diseases, but not asthma. "Rodents can't get real asthma. Horses," he added, "have something similar to asthma, but they are huge animals, and it's not easy to do research on them. While animal studies have helped, this is a peculiarly human disease. In the end, we have to conduct studies on humans, and be careful about the ethical problems."
The latest randomized, double-blind, controlled study he was involved in - published last month in the New England Journal of Medicine (NEJM), had clinically important conclusions that also proved disappointing.
"For two years, we gave inhaled steroids to 280 children aged two to three who had a very high risk of developing asthma because of parental disease and had just started showing symptoms - such as wheezing, coughing and chest tightness. We thought it would prevent the disease from developing. But it didn't work, except to relieve the symptoms. It did this well, but we found that as soon as the children stopped taking the drug, the condition came back. We had hoped that if inhaled steroids are given at an early stage it might prevent or delay the onset of the disease. But the immune system mechanisms persist," he explained. "This was a big disappointment for me."
In the meantime, there are other drugs, such as Merck's Singulair (generically known as montelukast sodium) - chewable or oral tablets that "alleviate symptoms, although less than corticosteroids." But the drug, which was approved by the FDA eight years ago and can be taken by children as young as six months, "doesn't change the natural course of asthma," he says.
Inhaled corticosteroids have side effects, in that they can decrease a child's growth rate by an average of one centimeter, and in adults, inhaled corticosteroids can cause osteoporosis. However, Martinez noted, "children taking them eventually catch up. We don't know how long they can take inhaled drugs safely, or identify when patients should stop taking it. It's more trial and error. But one of most interesting developments in academia and the pharmaceutical industry is that they are looking for biomarkers to identify people at high risk of continued asthma symptoms and have to go on taking medications. Fortunately, some children grow out of the disease, so doctors can gradually decrease dosage. Since these drugs are taken for years, it's important not to give them to people who no longer need them."
THE ARIZONA expert said he's strongly against smoking, but the latest data have not shown a connection between asthma and tobacco smoke. However, he stressed, once someone has asthma, exposure to cigarette smoke clearly makes the condition worse. "We abuse our environment. Air pollution, especially particulate matter from cars, is a very important factor, but there is also ozone. And some people can suddenly get asthma at 50, and nobody knows why
There is a strong association between wheezing and airway obstruction in young children and their development of asthma, he continued. "We don't know exactly what triggers the disease, but we think it is the immune system. There seems to be a window of opportunity between birth and four years when children exposed to less-sterile conditions, such as those raised on farms or with pets have a lower risk of developing asthma. Apparently the immune system, which is stimulated by viruses and bacteria, learns to defend itself from the environment," Martinez suggested. But later exposure to mold, dust mites, cockroaches, cats and dogs can actually trigger asthma attacks. Yet there are no dust mites in Arizona, and children there still get asthma. "There has to be a balance; the immune system should not be stimulated too much."
WAYS TO prevent the disease must be found, he said, "but you can't keep children in a bubble." There could eventually be a vaccine to stimulate the maturation of the immune system without endangering the child, he said. "It would be exposure to allergens that help the immune system learn it has to cope with, like giving children vaccines made out of attenuated viruses. But there must be no negative consequences, so this is not an easy task. I see a lot of very bright researchers working on attenuated bacteria, but it's hard to do because it involves young children."
Although he had never been to Israel, he is a good friend of Hadassah pediatric pulmonology expert Prof. Simon Godfrey, who invited him to speak at the Dead Sea conference. Martinez says there is some "very good research here in the field of asthma. It's a small country, but it's amazing how significant Israeli scientific interest is. There are many working here to develop new technologies."
In the future, he concluded, genetics will allow researchers to identify people who need specific medicines for preventing and treating asthma. "In the past, we tried to find one medicine for everybody, but increasingly we will move into customization, identifying genetic and phenotypic factors and treating each individual differently."
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