Waiting to Inhale

Kenia de Marco has lived most of her life in constant fear of the tightening of the throat that precedes an attack of asthma. She's been getting them since she was 8, but the worst year was 1997, when she was 17. On four separate occasions, she was taken away in an ambulance and hospitalized for a week. Her doctors could never say with any certainty what was causing her affliction. Was it the stress of her father's recent death? Or mold and dust mites at home? As a precaution, they had de Marco remove all curtains and carpeting from her home--even her teddy bear. De Marco still won't travel anywhere without an emergency drug that dilates the bronchial passages. Like many asthmatics, she's well-practiced in the tricky art of emptying her lungs completely of air and breathing in deeply through the inhaler.

De Marco has plenty of company in Brazil. More than 17 million asthma sufferers now account for 16 percent of hospital admissions and 2,000 deaths a year, according to the Health Ministry. In January, the government kicked off a plan to train 20,000 doctors and 20,000 nurses in diagnosis and treatment. "We believe we can spend far less money by treating the condition with drugs before the person develops an acute attack that requires hospitalization," says Dr. Jorge Solla, a Health Ministry official. Similar sentiments are being echoed throughout the world, as each year's batch of statistics show asthma to be on the rise.

The medical profession has long sought to carry the notion of prevention even further and to come up with a cure for the disease. But it has been hampered by a poor understanding of asthma's underlying causes. For decades the condition has been seen as a series of sporadic attacks, punctuated by long periods in which normal breathing was possible. So far doctors have been able to treat only asthma's symptoms--breathlessness, wheezing and a tight chest. Recently, though, scientists have made several breakthroughs in their understanding of its root causes.

Recent studies have confirmed what scientists have suspected for years: that asthma is an immune-system reaction to dust, pollution and other allergens in the environment, which trigger spasms and tightening of the airways in some people who also have a genetic predisposition. Now they're zeroing in on that genetic vulnerability. The new thinking is that asthma isn't simply a matter of having the wrong genes. Instead, at some point in early childhood, or possibly in the womb, an event takes place that turns a person into a lifetime asthmatic. Scientists think the fetus or infant is somehow exposed to a critical dose of pollutants that causes the immune system to overreact, permanently narrowing the airways and making them more sensitive to irritants. It might be possible to inoculate children against the condition before this even occurs, preventing asthma entirely.

Scientists are also finding that there may be distinct forms of asthma that call for vastly different treatment strategies. Researchers at Cincinnati Children's Hospital Medical Center have recently identified gene clusters active in people who suffer from acute asthma, which doesn't respond to medication, but not in those with a more stable form of the disease. Researchers are now trying to pinpoint the precise biochemical pathways in this process, with the goal of coming up with drugs that interrupt them.

A treatment breakthrough would come at a welcome time. Asthma is a growing global problem, particularly for those living in big, polluted metropolises like New Delhi and Mexico City. A report last year from the Global Initiative for Asthma, an alliance of health-care professionals, found that 300 million people suffer from asthma. The percentage of the world's population living in urban areas is expected to jump from 45 to 59 percent in 20 years, which could add 100 million more asthma sufferers by 2025.

Inhaled corticosteroids have been successful in preventing asthma symptoms and suppressing inflammation, but they don't fundamentally improve a patient's lungs--even when an attack subsides, airways remain restricted. Problems also arise when patients go off the steroids because they're feeling fine. Despite having been hospitalized several times, Michal Gassner, a 17-year-old girl from Jerusalem, has decided not to take medication between episodes--she "just wants to get on with her life," says mom Aya Gassner. Asthma is the most common chronic childhood disease, the No. 1 cause of school days missed, and the third-ranking cause of hospitalization for children under 14.

The most popular explanation for asthma, the "hygiene hypothesis," suggests that the immune systems of children living in superclean environments, with little exposure to infection, turn against their own bodies, overreacting to harmless substances. In a normal immune-system reaction, white blood cells produce antibodies that attack the pathogens. When a harmless substance triggers an asthmatic's immune-system, it reacts by producing histamines, which cause tiny passages called bronchioles to contract. The hygiene hypothesis is not airtight. In Brazil, the highest incidence of asthma occurs in the poorest cities. Doctors think that residents may have so much exposure to viruses and fungi in untreated water, sewage and air pollution that their immune systems are overwhelmed.

New research exploring exactly how the immune system reacts to triggers may lead to a vaccine. Researchers at the University of San Diego in California recently completed a three-month study in which they had mice inhale an allergen that caused a buildup of mucus and collagen, and the inflamed, scarred airways typical of human asthma sufferers. Treating these mice with short, synthetic DNA molecules that affect the immune response to allergens halted, and helped reverse, the buildup of scarring. The animals' bodies recognized the synthetic DNA as a foreign substance and forced a normal immune response that doesn't entail the production of histamines. The DNA "fools the immune system into not eliciting an allergic response," says researcher David H. Broide. Tests on asthmatics are planned. Similar types of synthetic DNA were found in a study last June to be an effective treatment for people suffering from an allergy to ragweed, an asthma trigger.

Some researchers argue for a fundamental rethinking of asthma. Whereas doctors used to focus on treating inflammation, assuming that in between attacks the airways returned to normal, increasingly, they're focused on what happens to the airways in between attacks. In 1992, a team led by Jean Bousquet at the University of Montpellier I in France found evidence that in asthmatics the airway walls are permanently scarred and thickened, increasing the severity and likelihood of attacks. "Asthma is now seen as a chronic wound to the airways," says Stephen Holgate of the University of Southampton. He thinks examining ongoing damage to the epithelium--the lining of the lung--is key to developing a preventive treatment. "When the epithelium is damaged, rather than healing properly a set of molecules are released which make the airways remodel, a bit like a chronic-scar situation."

Genetic research is helping to pinpoint why this happens in some people and not others. Scientists at the University of Southampton, Oscient Pharmaceuticals and Schering-Plough have identified a gene, called ADAM33, that may play a part in the striking remodeling of the airways that is seen in asthmatics. ADAM33 acts to accelerate the production of smooth-muscle cells in the bronchial passages, causing them to become inflamed and hypersensitive. The muscle lining gets twitchier and more sensitive and is more likely to overreact to allergens like cigarette smoke and pollution, going into spasm and constricting. Dr. Tim Keith, chief scientific officer at Genizon BioSciences, who was also involved with the study, thinks it may be possible to inhibit ADAM33 with drugs.

While the science is being worked out, health officials are turning to educating asthmatics on how to trigger-proof their homes, removing moldy rugs and curtains, and take other steps to cope. The hope is that new research will make such efforts superfluous, enabling folks like de Marco to live free of the fear of losing their breath.

With Mike Kepp in Rio de Janeiro, Joanna Chen in Tel Aviv, Avrham Karshmer in Los Angeles, Sarah Schafer in Beijing and Tracy McNicoll in Paris