Scientists probe for asthma risk factors

Maternal diet, vaccinations may play a role

It’s an epidemic, experts say, that doesn’t make sense. Asthma, already a huge public health problem affecting 12 million people, has risen dramatically in the last two decades. But environmental factors traditionally thought to have the biggest impact on the disease are better. Air pollution, for example, is much less of a problem than it was 30 years ago, and cigarette smoking by women of childbearing age hasn’t increased. So why did 58% more children under 18 and 34% of the population at large get asthma from 1983 to 1993? And why does the number of asthma cases continue to rise at least 5% each year?

That is exactly the question that a small but growing group of scientists is beginning to research. Sparked by a 1995 study1 from the University of Arizona in Tucson that suggested a predisposition to asthma among certain infants, researchers are searching for clues to the epidemic that may appear as early as in the womb. This year, a $9.6 million grant program from the Bethesda, MD-based National Heart, Lung, and Blood Institute (NHLBI) will encourage more study on the topic. The NHLBI plans to award six or seven four-year grants in September for studies focusing on women of childbearing age, infants, and young children.

"We want to make sure there are at least six people looking at this issue right away," says Virginia Taggart, MPH, health scientist administrator for the NHLBI. "We want scientists to delve into the early reasons that cause asthma to develop. Once we can understand what starts the process, we can see what opportunities exist to stop it."

Several clues but still a mystery

The University of Arizona study led the NHLBI to hold two workshops in the last two years with a small group of experts to discuss where the most promising research lies and what specific questions need to be answered. The consensus among the scientists was that clues are coming out, but big gaps still exist, Taggart says.

"The main message we heard from them was that asthma must be developing earlier in life than we thought previously," she says, "and that risk factors could probably be traced back to the fetal environment rather than just the first years of life."

Specific research questions suggested by the experts and proposed to the grant applicants include:

• Is there a "pre-asthma" state in which exposures bring about asthma in genetically predisposed infants?

• What is the influence of passive smoking and indoor air pollutants?

• What is the effect of diet on programming the immune response and onset of asthma? Does the mother’s diet have an affect on the fetus’ immune system development?

• What is the role of early life Th1 vs. Th2 responses in the onset of asthma? Does the placenta influence the balance between Th1 and Th2 responses in the developing fetus? Are there factors in the amniotic fluid that influence the development of antigen-presenting cells in the lung?

Changes in risk factors fuel epidemic

Scott Weiss, MD, professor of medicine at Harvard Medical School and director of respiratory and environmental epidemiology at the Channing Laboratory of Brigham and Women’s Hospital, is one researcher looking for connections between environmental risk factors and genetics in the onset of asthma. He says the research is critical not only because asthma is increasing dramatically but also because it’s the biggest cause of hospitalization among children and increases the long-term risk for adult chronic obstructive pulmonary disease.

"We presume it’s not changes in genetics but changes in environmental risk factors that have fueled this epidemic," Weiss says. "It’s unlikely that genes would have changed over such a short time span of 20 or 25 years."

About 70% of all asthma cases are diagnosed by age 5, Weiss says, so it makes sense to zero in on what happens to the immune system early in life. Few conclusions have been reached, but scientists think several factors may be impacting immune system development that weren’t a problem 30 years ago.

"We think antibiotic use, vaccination practices, diet, and bacterial, viral, and parasitic infections influence immune system development," Weiss says. "We think these are the areas to concentrate on, and we want to determine whether they’re acting in a protective way or becoming risk factors for asthma. If we can understand that, we can modify the impact through vaccines or exposure to certain types of infections."

For example, Weiss says, some viral and bacterial infections can actually improve the immune system’s response to allergens and perhaps decrease the likelihood that asthma will develop. Studies have shown that having the measles early in life or having the ability to respond to tuberculosis (as demonstrated by skin test response) is associated with decreased asthma and allergy. Since children now receive a vaccine against measles, and tuberculosis is rare, that opportunity to stimulate protective immune system responses is weaker than in the past. The increasing use of antibiotics may also contribute.

Influence of mother-fetus interaction

Another critically important area is the interaction between the mother and the developing fetus, Weiss says. Maternal immunity is transferred to the fetus, so the mother’s exposures potentially influence the fetus’ immune system development.

Weiss is studying maternal diet, investigating the effects of anti-oxidant vitamins such as A, E, and C that are known to impact the immune system. He’s also looking at essential fatty acids, which have been shown to be protective for other conditions such as coronary disease. The change in Americans’ diet over the past couple of decades, including more consumption of processed foods and less of fresh fruits and vegetables, could be a factor in the rise of asthma, Weiss says.

[For more information on fetal and maternal risk factors for asthma, contact: Virginia Taggart, MPH, health scientist administrator, National Heart, Lung and Blood Institute, 6701 Rockledge Drive, Suite 10018, Bethesda, MD 20892-7952. Telephone: (301) 435-0202. Scott Weiss, MD, professor of medicine at Harvard Medical School. Telephone: (617) 525-2278.]

Reference

1. Martinez, Fernando D, et al. Asthma and wheezing in the first six years of life. N Engl J Med 1995; 332:133-8.