Asthma: The Breathtaking Disease
In the last 20 years, asthma rates have soared to epidemic levels. School researchers are investigating the food we eat, the air we breathe, and the way our bodies work for clues to better asthma treatment and prevention.
All her life, Elauna Griffin had struggled against the disease. There were many times when she could not make it to school, many anxious trips to the emergency room. There were pills that made her heart race, and inhaled drugs that left her feeling giddy and light-headed. Sometimes she would pass out, and wake up hours later in a doctor's care, her worried parents by her side. Hospitalizations—often weeks at a time—were an annual event, most frequently in the springtime when the weather began to change.
Like others with her condition, she learned not to push, to conserve her strength. Athletics were out. Unabashedly gregarious, she took to theater instead, where she displayed a natural talent. But when she was offered a generous scholarship to New York University, her parents demurred. It was too far, they said, we could never get to you in an emergency. Reluctantly, she agreed to attend nearby Howard University in Washington, D.C., where she studied drama and dreamed of becoming an actress.
"She was scrappy," says her mother, Dale Griffin, manager of visitor services at Baltimore's Walters Art Museum. "She never let it get the best of her." "Daddy," she would tell her father, "I can't just stop living." In later years, she began keeping a gratitude journal, every page beginning exactly as the one before it: "I can breathe," she would write, "I'm alive." In March of 2001, just 11 days after her 28th birthday, Elauna was performing in a professional production of Pearl Cleage's "Blues for an Alabama Sky" at Baltimore's Everyman Theatre, playing a naïvely optimistic social worker. In fine health at the morning cast call, she started having difficulty breathing during the matinee performance, several times resorting to her albuterol inhaler while offstage. After the show, her condition suddenly worsened. She asked for an ambulance and then collapsed. She never regained consciousness. "For months after her funeral," recalls her father, Alonzo Griffin, an insurance executive, "people would come up to me and they'd all say the same thing: 'I'm so sorry. I had no idea you could die from asthma.'"
It is the disease that failed to sound an alarm—a disease that today afflicts more than 15 million people in the United States, about a third of whom are children. Starting in about 1980, the number of asthma cases in the United States and around the world began increasing steadily. According to the U.S. Centers for Disease Control and Prevention, between 1980 and 1994, the number of people with asthma in America rose by 75 percent. Among children under 4, asthma exploded, increasing by 160 percent, and the number of asthma-related hospitalizations increased by 20 percent. Perhaps most alarming of all, as new drugs and better treatment for asthma became available, the number of deaths from the disease did not decline but instead continued to increase—defying the trend of declining rates of death from most other diseases and conditions, including such stubborn opponents as heart disease and even cancer.
Yet even though the trends were unmistakable, surprisingly little was done to raise an alarm. For a time, it was supposed that heightened awareness and better reporting were creating an artificial increase—a statistical aberration—and that rates would soon level off. Only recently have researchers and public health officials, prompted in part by work done at the School and other divisions at Hopkins, declared the obvious: America is in the grip of an epidemic of asthma. In the United States today, no chronic disease is increasing faster than asthma. More than two decades into the epidemic, very little is known about what causes asthma or how it may be prevented. And still the numbers continue to rise.
Faced with such a troubling increase, "you need to initiate an appropriate public health response," says Lynn Goldman , professor of Environmental Health Sciences, who was lead author for an influential 2000 report on asthma.
"There is relatively little research under way identifying the causal factors," says Goldman. "We know genetics is a part of it, but our genes aren't shifting rapidly over a 15-year period. It's something in the environment, but we don't know what it is. We need to know in order to bring the rates back to a reasonable baseline—something close to the 1970s rates. This should be our goal."
The 2000 report, which grew out of the School's Pew Environmental Health Commission, was an unusually blunt document titled Attack Asthma: Why America Needs a Public Health Defense System to Battle Environmental Threats . The report cited the 1999 Health and Human Services budget, finding that less than 9 percent of the planned $125 million expenditures on asthma research was to be spent on prevention, and less than 1 percent on the core public health activity of asthma tracking. Most of the money was to be spent on improving asthma treatment rather than preventing it from occurring in the first place.
It is the disease that failed to sound an alarm—a disease that today afflicts more than 15 million people in the United States, about a third of whom are children. Starting in about 1980, the number of asthma cases in the United States and around the world began increasing steadily. According to the U.S. Centers for Disease Control and Prevention, between 1980 and 1994, the number of people with asthma in America rose by 75 percent. Among children under 4, asthma exploded, increasing by 160 percent, and the number of asthma-related hospitalizations increased by 20 percent. Perhaps most alarming of all, as new drugs and better treatment for asthma became available, the number of deaths from the disease did not decline but instead continued to increase—defying the trend of declining rates of death from most other diseases and conditions, including such stubborn opponents as heart disease and even cancer.
Yet even though the trends were unmistakable, surprisingly little was done to raise an alarm. For a time, it was supposed that heightened awareness and better reporting were creating an artificial increase—a statistical aberration—and that rates would soon level off. Only recently have researchers and public health officials, prompted in part by work done at the School and other divisions at Hopkins, declared the obvious: America is in the grip of an epidemic of asthma. In the United States today, no chronic disease is increasing faster than asthma. More than two decades into the epidemic, very little is known about what causes asthma or how it may be prevented. And still the numbers continue to rise.
Faced with such a troubling increase, "you need to initiate an appropriate public health response," says Lynn Goldman , professor of Environmental Health Sciences, who was lead author for an influential 2000 report on asthma.
"There is relatively little research under way identifying the causal factors," says Goldman. "We know genetics is a part of it, but our genes aren't shifting rapidly over a 15-year period. It's something in the environment, but we don't know what it is. We need to know in order to bring the rates back to a reasonable baseline—something close to the 1970s rates. This should be our goal."
The 2000 report, which grew out of the School's Pew Environmental Health Commission, was an unusually blunt document titled Attack Asthma: Why America Needs a Public Health Defense System to Battle Environmental Threats . The report cited the 1999 Health and Human Services budget, finding that less than 9 percent of the planned $125 million expenditures on asthma research was to be spent on prevention, and less than 1 percent on the core public health activity of asthma tracking. Most of the money was to be spent on improving asthma treatment rather than preventing it from occurring in the first place.
"We were very critical of what we found," says Goldman, MD, MPH '81, MS. "Our public health infrastructure was in such terrible shape. Congress isn't going to fix something it doesn't believe is broken. We had to show the system was broken." Attack Asthma did just that, warning "we are passive witnesses to an unfolding public health catastrophe."
Following on the heels of Attack Asthma came a second important report in July 2001: Short of Breath: Our Lack of Response to the Growing Asthma Epidemic and the Need for Nationwide Tracking. This report was released by The Trust for America's Health , a non-governmental organization created a year ago to build upon the work performed by the Pew Environmental Health Commission. Short of Breath proposed a three-year, $255 million program of beefing up state and local health departments to better track and monitor the asthma epidemic. Together, the two reports attracted considerable attention, both in the media and in Congress.
"Asthma rates are increasing for everyone. It's an equal opportunity disease," notes Shelley Hearne, DrPH, executive director of the Trust for America's Health and a visiting scholar in Health Policy and Management. Although African Americans, Hispanics, and the poor suffer higher rates of asthma than the general population, no amount of education, income, or social status can guarantee protection.
Finding out what causes asthma attacks—particularly the severe attacks that most often result in emergency room visits and hospitalizations—clearly has enormous public health implications. In Maryland, asthma is the most diagnosed pediatric illness, and the number one cause of pediatric emergency room visits. It is also the number one reason why kids miss school. But perhaps most significant, recent research indicates that children don't actually "outgrow" asthma as was once thought; the condition merely becomes quiescent, and very often serious symptoms can reappear later in life. Peyton Eggleston, MD, director of Hopkins' Center for Childhood Asthma in the Urban Environment, says the implications of this new understanding are important: "If we can prevent asthma in kids, then we'll end up with healthier adults." But the problem is, how? No one, at present, can say.
Imagine trying to breathe in all your air through a pinched straw. That is how many asthma sufferers describe an acute attack. Medical literature describes asthma as an obstructive lung disease brought on by a heightened reaction of the airways to various stimuli, yet even today, the exact mechanism of an asthma attack is not understood. Muscles in the airways can constrict, causing a feeling of tightness, or the lining of the airways can become inflamed and swollen, resulting in wheezing and shortness of breath. In extreme cases, like that of Elauna Griffin, airway muscles constrict, trapping air deep inside the lungs where it is rapidly depleted of oxygen. The asthma sufferer can take only brief, shallow breaths insufficient to provide enough oxygen for the body and, unless the muscles are relaxed and fresh air brought into the lungs, can suffocate.
The number of variables involved in developing asthma and in the onset of an attack has suggested to some researchers that asthma may not be just one disease. "I think of asthma as more like saying someone has cancer. There are all these different diseases we call cancer, but it's really not just one disease," says Allison Fryer , PhD, associate professor in Environmental Health Sciences, who is investigating the role that the parasympathetic nervous system may play in asthma. "What is becoming clear is that there are different kinds of asthma. There is exercise-induced asthma. There is cold, dry air asthma that affects people doing winter athletics like skiing. Those same individuals can get in an indoor heated pool, where the air is very warm and moist, and they won't have any symptoms at all."
Different asthmas point to the possibility of different causes for the diseases and, probably, different routes of prevention. At the School, researchers are investigating numerous pieces of this complex puzzle.
the pesticide link
In her lab on the eighth floor of the Wolfe Street Building, Pam Lein , PhD, has been investigating the role of pesticides in the epidemic. A specialist in how environmental compounds affect nerve functions, Lein, an assistant professor in Environmental Health Sciences, is one of a team that has found evidence that certain pesticides may increase airway hyper-reactivity, thereby initiating or aggravating an asthma attack. "What this means is if you administer a stimulus that normally causes constriction of the airway, when these pesticides are present you get a much greater reaction," Lein says. "This suggests that the pesticide somehow alters the nerve function controlling the smooth muscle lining the airway. It contracts, and restrains airflow, which is a hallmark feature of asthma."
Lein says that many people misunderstand the implications of her research, assuming that pesticide exposure is largely an issue unique to agricultural workers. Not so, she says: "The general public is exposed to pesticides through a number of means. One common source of exposure is the food we eat. [In addition], household pesticides used to control roaches and other insects have been detected as residue on toys and also as dust particulates, so there are alternate routes for possible exposure." Exposure in humans is measured through testing urine samples for the metabolites of pesticides. These tests have shown, Lein says, "measurable exposure to pesticides across a wide swath of socio-economic profiles," suggesting that a pesticide-related increase in asthma would be felt across all segments of the population.
There is other evidence that pollutants (like pesticides) could be at least partly to blame for the growing asthma epidemic. Consider: During the 1996 Summer Olympic Games in Atlanta, city officials instituted draconian bans on automobile use in the downtown area to prevent gridlock. A 24-hour-a-day public transportation system was put in place, and an additional 1,000 buses were brought on line. According to a study published last year in the Journal of the American Medical Association , the resultant 28 percent drop in ozone concentrations during the Olympic Games was associated with a significant decline in asthma events, including a 41 percent drop in Medicaid emergency care and hospitalizations, and a 44 percent decline in asthma-related emergency care, urgent care, and hospitalizations. One immediate way to decrease the burden of asthma, the article concludes, is to decrease ozone and particulate matter concentrations from automobile emissions.
are nerves involved?
There was a time when Allison Fryer would receive skeptical responses to her grant applications. "Why are you doing this?" she'd be asked. "The nerves are not important in asthma attacks." But Fryer, an investigator into human physiology, thought that perhaps they were. As a doctoral student, she'd looked at why the common class of blood pressure medications known as beta blockers tended to cause bronchorestriction in asthmatics. At that time, the idea that the nervous system was somehow responsible for asthma attacks had been largely discounted. But using animal models, Fryer discovered that one of the neuromuscular blocking drugs she was testing caused a 10-fold greater constriction of the lungs when the nerves were stimulated. Armed with this insight, she abandoned beta blockers and went looking for—and found—specific nerve receptors on the parasympathetic nerves controlling the smooth muscles in the respiratory system.
It has been known for more than 80 years that nerves can communicate in the body by releasing a substance called acetylcholine, which is stored in vesicles at the nerve endings. Acetylcholine acts as a transmitter that can, depending on the location, decrease cardiac contraction, increase digestive contractions, or stimulate a number of other bodily functions. These changes occur when the presence of acetylcholine is detected by specific receptors, which are protein molecules in surface membranes of cells that serve to receive the message transmitted by acetylcholine from the nerve. Fryer discovered a specific subtype of receptor at the nerve endings—now known as the M2 receptor—that hadn't previously been observed in the lung's parasympathetic nervous system.
"If you cough after inhaling an irritant, that reaction is all mediated through the parasympathetic nervous system," explains Fryer. Parasympathetic nerve fibers release acetylcholine to stimulate smooth muscle contraction, the underlying physiological response in a cough or an asthma attack. But what is the purpose of the M2 receptor, wondered Fryer, and does it perhaps play a role in asthma?
Increasingly, it appears that it does. Fryer and her colleagues at the School are leading several investigations into an exciting new avenue of asthma research that may result in new classes of drugs for treatment and control of the disease, as well as a more complete understanding of how an asthma attack can turn fatal.
"Our research shows that when working properly, the M2 receptor functions to inhibit the release of additional acetylcholine, [acting] as a brake on the process," she says. But if the function of the M2 receptor is blocked or turned off, additional acetylcholine can be released, greatly increasing the severity of the asthma attack. Fryer's experiments with neuromuscular blocking drugs while working on her dissertation indicated the drugs were doing just that.
The M2 receptor may help explain how asthma attacks can become severe enough to cause fatalities. Fryer and colleagues have shown that eosinophils, the inflammatory cells long known to infiltrate the airways in an asthma attack, also surround the airway nerves in patients with asthma. Post-mortem biopsies of asthma fatalities have shown the parasympathetic nerves literally surrounded by eosinophils. Fryer believes a protein released by the eosinophils (called major basic protein) blocks the M2 receptor, effectively "turning off the brakes" on an asthma attack, leading to airway hyper-responsiveness and, in extreme cases, death.
"Our research is the first to show there are M2 receptors on the parasympathetic nerves and that eosinophils are interacting with them in a way that can greatly increase the severity of an asthma attack," says Fryer. Scientists may use this insight to find ways to block eosinophils from surrounding the airway nerves or counter their release of the major basic protein and thus preserve the M2 receptors' ability to rein in smooth muscle contraction during an asthma attack.
is asthma an allergy?
To a man with a hammer, it is said, every problem looks like a nail. So allergist Peyton Eggleston may be forgiven for having a strong inclination to see a close association between asthma and allergy. "It's a relationship that is not completely understood at this time," says Eggleston, a Pediatrics professor with a joint appointment in Environmental Health Sciences. "But the pathology of asthma shows that eosinophils are the inflammatory cells in play during an asthma attack. This is different from the inflammation that results, say, from a burn, in which neutrophils are the inflammatory cells"—but the same eosinophils are found in the red and swollen tissues typical of an acute allergic reaction. So, says Eggleston, "the pathology suggests a link."Over the years, research conducted at the childhood asthma center that Eggleston directs, and at other centers, has shown that allergens like cockroach saliva and dust mite fecal particles can make asthma attacks more severe. More recently, Eggleston and his team have been conducting intervention studies to ascertain if the removal of allergens can improve asthma. "We're still in the proof stage of this," he says of his conviction that allergies play a key role in asthma. "Of the people who take care of [asthma] patients, about half believe allergies are important. We still haven't sold everyone. There is still a significant question and a need for research to keep testing the hypothesis and come up with a consistent answer."
Part of the challenge is the nature of the intervention research required. "Compliance is a real issue in these studies," Eggleston notes. "It takes a lot of effort on the families' parts." He points, as example, to two studies currently under way at the Center. To reduce exposure to allergens (including cockroaches and dust mites), fairly exacting standards of cleanliness must be consistently maintained, with few or no lapses. Cats and dogs and other allergen sources must be banished from the house, and researchers must pay frequent visits to make sure the rules are being obeyed. "It's hard to convince people it's worth their time and effort," Eggleston says. Nonetheless, he believes research at Hopkins and elsewhere is close to showing that controlling allergens could be key to reducing asthma attacks. "I think it will be shown in another five years," he says, "I am absolutely positive the link exists. But of course, I'm biased. Everywhere I look I see allergy."
common cold as culprit
It has been known for some time that environmental factors can exacerbate asthma—provoking attacks in some asthmatics, or increasing the severity of those attacks. Most researchers also believe that environmental factors play an important role in initiating the onset of asthma. But whether these factors are one and the same is uncertain. "It is very important to differentiate between two issues here: First, there is the issue of the cause and development of the disease; second, there is the question of what factors make the disease worse," explains William Spannhake , PhD, professor and associate chair of Environmental Health Sciences.The term "environmental factors" is itself potentially misleading, since it can mean any irritant, natural or man-made, that can cause or contribute to airway constriction in asthmatics. It can be pesticides, as in Pam Lein's research, or the ozone, particulate matter, and other pollutants found in the smog during the Atlanta study. It can be secondhand cigarette smoke, or naturally occurring allergens such as those associated with pets, pollen, mold, dust mites, and cockroaches. In recent years, considerable attention has been given to "bad air" in tightly sealed modern buildings and homes that endlessly recirculate allergens and other contaminants through forced air heating and cooling systems.
But of all environmental factors, the most common and troublesome are arguably also the most natural and unavoidable—the viruses and other pathogens that move continually through human populations. For children in particular, colds and other common respiratory infections can be some of the most potent asthma triggers. "We know virus infections—even the common cold—in many asthmatics will lead to the exacerbation of symptoms," says Spannhake. "But the mechanism of how this happens is not totally clear." Rhinoviruses such as those responsible for the common cold have been shown to attack the epithelial cells lining the respiratory tract and provoke an inflammatory response, in much the same way that oxidant air pollutants such as ozone and nitrogen dioxide do. Spannhake's research attempts to discover if viruses and oxidant pollutants somehow work together to increase the frequency and severity of asthmatic attacks.
the hygiene hypothesis
The genetic component of asthma is thought to be a key element in understanding the disease. An asthma attack is often described as an allergic response by the lungs, and not surprisingly, asthma tends to run in families along with other kinds of allergic disorders. Asthma, it is commonly said, is a disease in which genetics loads the gun, but environment pulls the trigger. Yet a purely genetic basis for the explosive growth in new asthma cases—the suggestion that humans have simply bred more asthmatics since 1980—would defy current thinking about how changes in gene pools take place. "This is not an issue of genetics," declares Franklin Adkinson, MD, professor of Clinical Immunology at the medical school with a joint appointment in Environmental Health Sciences. "We are not breeding more asthma. This idea has never been taken seriously by scientists." Nor, he says, is it likely that increases in dust mite, cockroach, or domestic animal allergens could be sufficient to explain the scale or consistency of the increase in asthma prevalence.
One recent, intriguing theory is the so-called "hygiene hypothesis," which suggests asthma may be an outgrowth of normal human immunologic response run amok. "The hygiene hypothesis suggests that the immune system drifts naturally toward allergy unless it is pushed away from allergy at birth by having infection to fight," says Adkinson, Baltimore director of the Childhood Asthma Management Program , the largest and longest study conducted on children with asthma. "As we have become cleaner, as we have used increasing numbers of antibiotics and vaccines, the immune system has begun to drift back toward allergic reaction."
Certain observations support this theory. For instance, early day care participation seems to protect against asthma, as does exposure in the home to cats and dogs, or farm life. Babies born into these environments tend to have less asthma, it is thought, because they are exposed to sources of bacterial DNA that serve to push the immune system away from allergies. "It also suggests that if we want to do something about the asthma epidemic we are going to have to do something very early in life—even in vitro," Adkinson says. "This is one of the most exciting asthma theories out there right now."
Exciting, perhaps, but also difficult to confirm and even more problematic to overcome. The implications of the hygiene hypothesis are hard to miss. Are we to give up antibiotics and vaccinations? Not any time soon, if that is what is required. "There are a lot of new experiments under way to try to reorient the immune system, but it's hard to do this research," says Adkinson of less extreme dietary and lifestyle measures under study. "How do you convince an asthmatic mother-to-be that there is maybe a 1 in 4 chance her child will get asthma and this potential therapy might lessen the odds? It's going to be hard to really get this done."
In the best of all possible worlds, researchers would find new drugs or therapies aimed not at treatment but prevention. Yet one of the biggest obstacles researchers face in the quest to prevent asthma is a lack of hard data. "To begin to deal with an epidemic, you've got to know where your numbers are," says Shelley Hearne of Trust for America's Health. "Right now, we estimate asthma rates by extrapolating from drug sales or telephone surveys. Essentially, we're working in the dark. As a public health practitioner, I can't tell you for certain how many children in Baltimore suffer from asthma. Without this information, we are hamstrung from putting in place the most effective prevention strategies."
Both the Attack Asthma and Short of Breath reports made strong cases for a national surveillance and tracking system that would monitor asthma and other chronic diseases. Ironically, 9/11 has helped convince legislators that public health surveillance is a national priority. "The public health system needs to have its finger on the pulse at a very local level—this is how you get information collected fastest, and disseminate information most effectively. And that's how you minimize risk and terror," says Environmental Health Sciences' Lynn Goldman. "We've got the health tracking legislation introduced with a real chance of moving forward. The CDC is establishing uniform data standards, which are an essential component of this effort. There are pilot studies under way, and a whole confluence of events give me a tremendous amount of hope that we are learning to put in place the systems that we need to monitor, track, and begin to address asthma and other pressing public health issues."
Will there be a real commitment of the resources needed to understand and eventually reduce the growing incidence of asthma? Many would argue we don't have a choice. Asthma's estimated yearly cost to society is $11 billion and growing rapidly. By the year 2020, the overall cost to society for the projected 29 million Americans with asthma will run to $18 billion.
Like many researchers, Lynn Goldman is unequivocal: "This kind of investment pays off many times over. It's worth it. It's worth it."