Mapping the landscape of Asthma

Anyone who visited East Germany prior to the fall of the Berlin Wall in 1989 remembers a heavy pall of gray and yellow smoke that hung over much of the landscape. The widespread burning of soft coal for heat and energy and the lack of pollution controls for motor vehicle exhaust and heavy industry made for some of the worst air pollution and general environmental quality in the world. An ecological nightmare, it was also a disaster for the lungs of East Germans, who suffered extremely high rates of respiratory problems like emphysema and bronchitis. Public health officials, who were already contending with the skyrocketing increase in asthma rates throughout Western Europe, feared a veritable tidal wave of patients arriving from the East with severe asthma problems when the wall came down. They were in for a shock.

Airborne pollutants like coal dust, auto exhaust and chemical emissions from industrial smokestacks are among the most potent triggers of the chronic coughing, mucous production, wheezing and dangerously constricted airways that typify asthma. According to most standard theories about its causes, chronic, high-level exposure to pollutants, dust and other environmental stimuli should increase the likelihood that a person will develop the disease and suffer frequent attacks. That and the generally limited health care system and medications available in East Germany appeared to create fertile ground for an asthma problem of monumental proportions. Yet just the opposite proved true. While East Germans did have very high levels of other respiratory infections, they were afflicted with dramatically lower rates of asthma than their Western brethren. Much of the medical community was baffled.

Some scientists, including many at Yale, now believe they have a plausible explanation for why this happened. These researchers suspect that improved hygiene and pollution control, immunization, antibiotics and early diagnosis and treatment of diseases may have paradoxically made Western Europeans and Americans more prone to developing asthma. Our immune systems, they contend, evolved to deal with a pathogen-filled world. With fewer pathogens around to defend against, powerful immune responses have instead focused on otherwise benign inhaled allergens, setting off a cascade of changes to lung tissue resulting in asthma. While the theory remains controversial, epidemiologists have found additional anecdotal evidence in other population groups around the world to support it, and Yale researchers have recently discovered molecular evidence to back it up.

That research is part of a concerted effort at Yale to tackle the disease. The designation by the National Heart, Lung and Blood Institute of the National Institutes of Health (NHLBI, NIH) in January 1997 of Yale as one of the nation’s seven Specialized Centers of Research (SCOR) for the study of asthma underscored the strength of the work being done by the researchers. If their efforts to parse out the genetic and molecular pathways that lead to asthma ultimately bear fruit, they—along with their clinical colleagues applying these basic science concepts to health care practices—will raise hopes of finding new means to prevent and even halt the chronic and sometimes fatal disease.

An epidemic of wheezing

There is an enormous need for improved understanding of asthma and for better diagnostic tools, prevention methods and treatments. While some have insisted that the rise in asthma rates reflects improved recognition of the disease by clinicians and better reporting by the health care industry, there is little evidence that this can account for the across-the-board size of the increase. Jack Elias, M.D., a professor of medicine at Yale and chief of the section of pulmonary and critical care medicine is head of the asthma SCOR. He says, “In the 1970s, asthma was actually getting less common. Then something happened. We’ve seen a documented increase, a doubling of its prevalence and severity.” According to the U.S. Centers for Disease Control and Prevention (CDC) statistics, asthma rates have risen enormously by all measures. There were about 6.8 million cases of asthma in 1980. That number rose to more than 15 million in 1998, encompassing about 5 percent of the population.

The highest proportion of cases is seen among children ages 5 to 14. According to the NHLBI, somewhere between 5 and 6 million children suffer from asthma, making it the most prevalent chronic childhood disease. It causes more missed school days—well over 10 million annually—than any other chronic disease. It is also among the top three causes of hospital admission in the country for all age groups and the leading cause for children. The annual cost of treating asthma jumped from around $6 billion in 1990 to more than $10.2 billion by 1997. The severity of asthma attacks has increased alarmingly as well. In the 1970s, death from asthma was uncommon. Unrelieved asthma suffocated somewhere between 5,000 and 7,000 people last year.

Although high asthma rates now affect all segments of American society, it has reached epidemic proportions among inner-city minorities. For instance, in Connecticut non-whites make up only 13 percent of the total population but account for nearly 50 percent of all asthma hospitalizations. The death rate among non-whites from asthma is three times higher than that for whites.

It is only in the past decade that researchers have begun to gain a clearer understanding of the disease. Asthma is a chronic disease characterized clinically by recurring episodes of spasms, or muscle contractions, of the bronchial tubes, constricting and closing off airways. Pathologically, the tissue of an asthmatic’s airways is constantly raw and inflamed, leading to frequent coughing and wheezing. Those inflamed airways are hyper-responsive to a wide variety of stimuli. In the large majority of cases, asthma attacks result from viral infection. In many others, asthma is worsened by allergic-type reactions to allergens, or triggers, like pollen, foods, dust mites, mold, animal dander and feathers. (Most often, these asthmatics have other types of allergic reactions as well, such as rashes and food allergies.) Once asthma becomes chronic, the triggers that can set off an attack embrace more and more environmental stimuli and can include colds and other upper-respiratory-tract infections, cigarette smoke, heavy exercise and even rapid swings in weather conditions.

For reasons that aren’t entirely understood, the seriousness of asthma can range widely. Low-level asthma problems can be limited to occasional wheezing and shortness of breath. (Moreover, children will sometimes “outgrow” their asthma, like other allergies.) During a full-blown asthma attack, however, the airways undergo a condition similar to what takes place in nasal passages during a bad cold: The walls of the airways produce excess mucus, become swollen and further inflamed, and their muscles spasm and contract. An attack may be brief or can last several days or more. Lack of early treatment of asthma can have grave consequences down the line, because the damage can accumulate until the airways lose their ability to recover from the spasms. Delaying treatment of a severe attack can have deadly consequences because the inflamed airways may not respond to medications.

Historically, inhalers—bronchodilators—that relax the muscles of the airways and open them up were the main weapon in treating asthma. By 1990, investigators had identified the condition that causes asthma: chronic inflammation of the airways. Controlling that inflammation is now recognized as the key to preventing asthma attacks and reducing their severity. While bronchodilators are used for symptomatic relief, the only medications with proven effectiveness in controlling airway inflammation are corticosteroids. Generally the steroids are inhaled or, in severe cases, taken in pill form.

There has been a huge rise in the use of steroids as a result of the increase in asthma and improved understanding of the etiology of the disease. Many pediatricians and pulmonary specialists now recommend that very young children, even infants, receive steroids at the first signs of asthma to prevent the inflammation from becoming chronic. However, the use of steroids, especially by children, is controversial because of their immune-system-suppressing side effects and because, at very high doses, they have the potential to thwart growth. Robert Biondi, M.D., assistant clinical professor of pediatrics and co-director of the pediatric allergy and asthma clinic of the Yale-New Haven Hospital Primary Care Center, says, “Like any medication, you pay a price. The benefits in this case definitely outweigh the side effects. Studies show that many adults who develop chronic pulmonary disease had untreated asthma as kids. Moreover, persistent inflammation remodels the airways—they get stiff. Eventually, they don’t budge with bronchodilators.” Ramsay Fuleihan, associate research scientist in pediatrics and clinic co-director, says, “Early treatment, medical management and patient education are absolutely vital for preventing lifelong problems.”

Searching for a cause

There are many theories about the causes behind the huge increase in asthma rates. Most are environmental and none is proven. Speaking at an American Medical Association briefing last year, Dr. Stephen Redd of the CDC expressed the general bafflement of the medical community: “The genetic makeup of the population couldn’t have changed enough to see the increases in asthma that are being seen in many developed countries. So there’s got to be some kind of environmental exposure, but exactly what that is really isn’t known.” Environment-related theories include population concentration in urban centers, more energy-efficient, airtight homes that don’t recirculate fresh air and more sedentary lifestyles, especially among inner-city children, all resulting in higher exposure to dust mites, cockroach droppings, air pollution, animal dander, cigarette smoke and other common allergens. “No one answer seems to explain everything,” says Yale pulmonary medicine chief Dr. Elias. “It may end up that a lot of little things are going on that add together to increase the rate.”

Researchers face a complex puzzle that doesn’t fit neatly into any single discipline. Laboratory scientists and clinicians from a half dozen separate departments at Yale are looking at the full disease phenomenon, from the genetic and cellular cascade that results in chronic airway inflammation to the environmental and genetic factors that may combine to trigger the disease to new clinical interventions aimed at preventing the disease from developing and, when it does, reducing the current great demand for hospital treatment of asthma attacks.

A major breakthrough in the understanding of the molecular mechanism behind the disease came through the work of basic scientists, including some at Yale. When it occurred, no one even realized the work they were doing had anything to do with asthma. In the mid-1980s, Kim Bottomly, Ph.D., professor of immunobiology and investigator in the Howard Hughes Medical Institute, showed that one of the basic components of the immune system, the CD4+ T lymphocyte cells, differentiate when activated into two different effector cell lines. She found that the two types of effector T cells have distinctly separate immune functions. Shortly after her finding, Tim Mosmann, Ph.D., an immunobiologist at the University of Rochester, made an epochal discovery: he found that the two types of effector T cells secreted unique panels of small molecules called cytokines that accounted for their distinct functions. The two types of lymphocytes were designated Th1 and Th2.

The Th1 and Th2 lymphocytes use a variety of mechanisms to rid the body of pathogens such as viruses and parasites. Th1 cells secrete cytokines that induce cells containing disease-causing microbes to kill them, clearing the body of pathogens that live inside cells. Th2 cells deal with pathogens that are too large to be engulfed by cells or replicate themselves outside of body cells, such as worms. Th2 cells induce the production of a variety of small molecules that bind to the pathogen and facilitate clearing it from the body.

An overarching evolutionary economy seems to govern the immune system. Researchers speculate that the immune response to the continuous presence of pathogens is normally kept in balance by Th1 and Th2 cells working in a dynamic system that reciprocally regulates each other’s activities. The body needs to have enough of both kinds of cells and not too many of either one. “It’s important,” says Dr. Bottomly, “that the immune system make the right kind of response to a pathogen. Mostly it does because we’re all alive in a world filled with germs and parasites.” Sometimes, though, the immune response goes haywire and it attacks the body’s own cells. Many diseases that plague humans, including rheumatoid arthritis, diabetes and possibly multiple sclerosis, are autoimmune disorders that are now believed to be caused by an inappropriate Th1 response.

Researchers suspect that other categories of disease may be caused by overactive Th2 cells, including allergic disorders. One unrealized side effect of successful immunization programs and the widespread use of antibiotics to eradicate childhood diseases may be that the lack of childhood infections leads to a reduction in Th1 cell responses. The pathogens that induce their activation simply aren’t there anymore. While the health benefits of immunization and antibiotics have been beyond calculation, the consequences for the body in some cases are not entirely positive. “The lack of Th1 immunity allows Th2 activity to go unchecked,” says Dr. Bottomly. “In a world without the worms and other large parasites Th2 cells evolved to respond to, they’re left to become activated by the benign environmental substances present in chronic, low-dose amounts.” One extremely common source of low-dose environmental substances is air breathed through the nose. The “immune distraction” or “immune deviation” model of asthma holds that asthma results from a chronically exaggerated response to pollen, dust mites and other allergens in the absence of infectious diseases leading to Th1 immunity and in the absence of worms leading to Th2 immunity.

Retrospective studies of populations such as those that lived behind the wall in East Germany have lent support to the theory. Other studies have found that children in Japan who responded strongly to a skin test indicating that they had been exposed to tuberculosis are less likely to suffer from asthma or other allergic diseases. Similarly, in a study of Italian soldiers, those who tested positive for antibodies to hepatitis A virus—a sign of more childhood infections in general—had significantly fewer allergies.

Armed with promising new directions for the study of molecular mechanisms for asthma, in the early 1990s Dr. Elias set out to expand research in the field at Yale. The first challenge he encountered, however, wasn’t scientific at all. Instead, he needed to convince his colleagues to devote valuable time and resources to understanding the disease.

Building the asthma team

He faced an uphill struggle. At the time, Yale had very little presence in the study of asthma. “Yale has a great tradition in biology and immunology,” says Dr. Elias, “but lacks much of a tradition in the asthma and allergy fields.” He wanted to bring that great tradition to bear on a new and pressing problem. “I literally went door to door.” His enthusiasm for the possibilities opening up in the field drew a strong response and soon about 75 scientists from all over campus, including the departments of pathology, public health, occupational medicine, immunobiology, pediatrics, the Boyer Center for Molecular Medicine and his own pulmonary medicine section, were looking into the disease. The Yale Asthma Working Group, as the loose confederation of researchers was designated, has now been gathering once a month for more than five years. At first, the educators needed an education. “We spent the first years having clinicians teach basic scientists what asthma was and the basic scientists explaining to the clinicians what could be happening at the cellular and molecular level,” recalls Dr. Elias.

The efforts to build an organization paid off handsomely. With Dr. Elias as principal investigator, the asthma working group achieved a major coup when it was awarded a five-year, $10.2 million grant in January 1997 from the NHLBI to support multidisciplinary research. That prestigious award established Yale as one of only seven Specialized Centers of Research (SCOR) focusing on asthma in the country. The SCOR group has since added more than a half dozen other substantial federal grants as it pursues its general goal of ferreting out the molecular causes of asthma and moving those basic science discoveries rapidly to clinical testing. “The vision in creating this group has been an outstanding success,” says Anuradha Ray, Ph.D., who, along with her husband Prabir Ray, Ph.D., both associate professors of pulmonary medicine, studies the genetics underlying asthma. “Jack has shown that with the right vision, you can do tremendous things. Now, the goal is landmark observations.”

From basic science to clinical care, the landmarks have started to pile up.

One of the biggest challenges to understanding asthma has been the lack of an adequate animal model to study the development of the disease. Dr. Elias has been working closely with Dr. Bottomly and Richard Flavell, Ph.D., chair of the Section of Immunobiology and investigator in the Howard Hughes Medical Institute, to create transgenic mice. They have succeeded spectacularly over the past year. “It’s so exciting how powerful this is,” says Dr. Elias. “We’re the only people in the world who have put a human asthma gene in a mouse lung and turned it on and off, even in utero. This mouse is as close as we’ve come to human asthma. It allows us to study asthma in neonates and the adult mouse, and to see the difference in how the disease affects each.” With this new mouse model, researchers can go back to study how the gene is produced in humans on the one hand and how to block its production in the mouse on the other. Eventually, the asthma team hopes to figure out how to modulate the genetic activity—to prevent asthma in humans from occurring or possibly to develop a cure.

To that end, Dr. Anuradha Ray’s studies in mouse models of asthma have recently identified the transcription factors that explain how Th2 gene expression results in the cascade of signals that bring eosinophils, a type of white blood cell, into the lungs. When compared with normal lungs, asthmatic lungs have hugely higher numbers of eosinophils. Once in the airways, eosinophils release a group of proteins that injure tissues, causing the inflammation that makes the airways of asthmatics so hypersensitive. Working with colleagues at Yale and at McGill University in Montreal, Dr. Anuradha Ray is now looking for ways to target the early genetic expression leading to the proliferation of eosinophils with medications. “It would be like steroids,” she says, “but steroids affect many other things. We would hope that this would have more specific action and fewer side effects.”

Breathing easier

While the study of animal models provides excellent clues about the nature of the disease in humans, only clinical study can provide a true understanding. Other members of the SCOR group have been attempting to take the knowledge learned in the laboratory and bring it to clinical research. “There’s a great marriage between M.D.s and Ph.D.s,” says Dr. Ray. Clinicians have been studying industrial workers who contracted asthma as adults as a result of exposure to workplace chemicals to examine the disease process. (See Isolating asthma.) Epidemiologists are looking closely at how home environment might affect the development of the disease in children. (See Collecting dust for science.)

Efforts to understand and improve treatment of asthma are taking place in many different disciplines. For instance, researchers in the section of pediatric respiratory medicine are studying the effects of hypoxia (low oxygen in the blood)—a common consequence of an asthma attack—on brain function in the young as well as how the muscles of respiration respond to the increased work of breathing imposed by acute and chronic airway obstruction.

Physicians from the section have also come together with primary care physicians in the community as the Pediatric Asthma Care Team (PACT) to coordinate care for children with severe asthma. According to Alia Bazzy-Asaad, M.D., an associate professor of pediatrics who is co-director of PACT along with Gabriel Haddad, M.D., chief of the section of respiratory medicine, the Department of Pediatrics now treats more than 500 children each year, making it the single largest patient group in the department. “Patients often get seen in many different places,” she says. “We get everyone around the table and ask how we can do this in a coordinated way.” PACT members are also developing innovative programs to reach out to the minority community to reduce epidemic asthma rates. (See Speaking the language of asthma.)

These many different approaches to asthma raise hopes that the skyrocketing increase can be slowed. At the same time, the very recent breakthroughs in understanding the biological basis of the disease have created guarded optimism that prevention and perhaps a cure may one day be possible. The researchers still have a long way to go before they can get a handle on the disease. “We’re making headway in understanding the disease mechanism,” says Dr. Bottomly, “but we don’t know much about interfering with it.”

They recognize just how important it is to figure that out. “For some people,” says Dr. Elias, “asthma dictates everything about their everyday life. It can be a life-threatening event every time they get a cold or walk into a room filled with animal hair or sleep in a dusty bed.” For the first time since asthma rates began their upward climb, though, there’s hope that one day asthma sufferers may no longer need to worry about losing their breath.