What causes asthma?
Beyond allergens, other culpritsviruses
By bringing together clinical and laboratory expertise from different fields, were hoping to get a clearer understanding of asthma development.
MICHAEL J. HOLTZMAN, MD
Because RSV in particular is known to increase the risk
of asthma later in life, Holtzman and Castro have joined together to examine
THE BELIEF THAT ALLERGIES CAUSE ASTHMA is commonly held, both by asthma sufferers and the specialists who treat them. But according to Mario Castro, MD, MPH, associate professor of medicine, about 20 percent of his asthma patients do not have allergies.
Theres plenty of allergy without asthma, and plenty of asthma without allergy, concurs Michael J. Holtzman, MD, the Selma and Herman Seldin Professor of Medicine and professor of cell biology and physiology.
Its easy to explain things away by saying that the allergic response is complex and not fully understood, says Holtzman, but I personally think theres something missing from the equation.
The missing link, Holtzman and Castro believe, is a virus. Each year, an estimated 125,000 infants in America are diagnosed with respiratory syncytial virus (RSV), the most common respiratory illness in infants and children. About 40 percent of those later develop asthma, approximately four times the rate seen in the general population.
Holtzman, Castro and their School of Medicine colleagues have proposed a new model of asthma that incorporates their findings into existing allergy theory: They believe that both allergens and viruses are capable of making a person with the right genetic predisposition susceptible to asthma. As a result, some people with allergies may not develop asthma, thanks to good genes, while others who develop asthma will not have allergies, because their disease is rooted in a virus like RSV.
I think the reason diseases like asthma are so common is that they can result from multiple factors, Holtzman says. By bringing together clinical and laboratory expertise from different fields, were hoping to get a clearer understanding of asthma development.
While there are drugs available to alleviate some of the symptoms of asthma, such as tightness in the chest and shortness of breath, researchers still are trying to understand the precise underlying mechanism that causes the disease in order to develop more effective treatments.
Asthma is characterized by inflammation of the airways that connect the nose to the lungs. Two main factors make it difficult for people with asthma to breathe: Excessive amounts of mucus-producing cells, called goblet cells, accumulate in the airways, and the muscles around the airways tighten and spasm.
Drugs such as steroids help combat inflammation and mucus production, and another class of drugs called bronchodilators aids in relaxing tightened muscles. But neither effectively fixes the problem. Steroids do prevent asthma exacerbations.
To develop better therapies, scientists first must find the root cause of chronic inflammation in asthma. The most commonly accused culprit is an immune response triggered by allergies combined with the right genetic milieu.
People with allergies are overly sensitive to particular substances. Just as the immune system is activated during a cold or virus, people with allergies experience an acute immune response when they encounter an allergen.
Immune cells flood to and deal with the offending particle and send messages back to their home base, where an army of new cells is mobilized and trained to patrol the body thereafter for signs of similar foreign substances. When the individual later encounters the allergen, trained immune cells spring into action and produce chemicals that cause the symptoms of asthma.
Based on the assumption that asthma results from an allergic response, investigators have been trying to interfere with immunoglobulin E (IgE), the protein largely responsible for activating the immune system during an allergy attack. Thus far, drugs that eliminate IgE have failed to solve the asthma predicament.
If the allergic-response theory is correct, anti-IgE drugs should in theory wipe out the allergic response and cure asthma, says Holtzman. But after almost a decade of research with these drugs, its pretty clear that they dont even work as well as the anti-inflammatory steroid treatments already available.
However, says Holtzman, anti-IgE drugs may very well work
for a subset of asthma sufferers. But without separating asthma patients
whose disease is largely dependent on the allergic response from those
whose asthma also may result from other factors such as an anti-viral
reaction, it may be impossible to discern the drugs true effectiveness
Because RSV in particular is known to increase the risk of asthma later in life, Holtzman and Castro have joined together to examine the role of RSV on immune response and respiratory illness in mice and humans.
Castros research team is following 206 babies admitted to St. Louis Childrens Hospital with RSV. The trial, called RSV Bronchiolitis in Early Life (RBEL), recently received five additional years of funding from the National Heart Lung and Blood Institute.
Were trying to determine whether children with RSV have a higher risk of developing airway obstruction and asthma, Castro explains. Its too early to say anything conclusive, but what weve found so far has been quite surprising.
Unlike many chronic diseases, Caucasian children appear more likely to develop respiratory problems after RSV than children of other races. Also, the amount of allergens infants are exposed to does not seem to correlate with the risk of asthma.
Our ultimate goal with this project is to develop an asthma predictive index based on babies immune cells and genetic background, says Castro. Only then will we be able to intervene and prevent children from developing the disease.
In the laboratory, Holtzman has been putting RSV to the test in animal models. In the July 2002 issue of the Journal of Clinical Investigation, his team reported that mice infected with a mouse version of RSV end up with asthma-like conditions.
Mice in the study immediately responded to infection. Moreover, the airways of the lung remained extremely sensitive, or hyperreactive, for more than a year, and the airway lining became overpopulated with goblet cells, similar to human asthma patients. Even when the initial, acute airway response was prevented, the long- term changes and symptoms of asthma still appeared.
Mice that were exposed to a common experimental allergen, called ovalbumin, also developed inflam-mation of the airways, but recovered within months.
This type of single, viral infection is generally thought to cause problems for a couple of weeks, but not to result in lifelong alterations, says Holtzman. Our findings suggest that a virus early in infancy or childhood may create a hit-and-run effect in which this brief infection causes permanent changes in the bodys anti-viral system.
The teams research also implicates another suspect: genes. When the same virus was given to a different strain of mice, the animals only developed a short-term, acute infection, not long-term asthma. Investigators now are breeding the susceptible and resistant strains of mice and have used genetic techniques to isolate potential susceptibility genes and are testing for the role of these genes in causing asthma in humans.
Interestingly, it appears that some of the same genes overexpressed in the viral model of asthma also are overexpressed in response to allergens. In other words, viral and allergen responses may represent two separate routes along the same genetic and clinical problem. The question is not whether immune cells flood the respiratory tract and cause inflammation, but why.