New Hypotheses Emerge to Explain Epidemic
Why does Aaron have asthma? Now 8 years old, the young Hispanic Philadelphian has struggled to manage the disease since infancy. Aaron’s asthma stabilized as he grew older, but his wheeze sent him to the emergency room and kept him out of school many times.
In the past, epidemiologists would look at Aaron’s chart and note he was a minority child (statistically at risk) living in an urban environment (a documented risk factor). He may have been exposed to dust mites or cockroach allergens as an infant. Aaron’s disease was probably linked to lung irritants he breathed. A paternal aunt and a cousin also suffer from asthma, suggesting a familial link.
Today, the epidemiologists who pointed to household allergens as the villains behind the asthma epidemic are reconsidering their previous explanations. They are developing new and radical hypotheses, and they realize there could be an element of truth in each one. Asthma may have many causes, depending on the environment and the genetic makeup of the patient. Not only that, asthma may have more than one face.
“It’s not like cystic fibrosis, caused by one genetic risk,” explains Pierre Ernst, MD, MSc, a professor of medicine in the division of clinical epidemiology at Royal Victoria Hospital in Montreal, Canada. “It could be caused by multiple genes and multiple environmental exposures. It may not be one disease. There may be several ways to become an asthmatic.”
Stephen Redd, MD, chief of the air pollution and respiratory health branch at the Centers for Disease Control and Prevention in Atlanta, echoed Dr. Ernst’s suggestion, noting that asthma may represent “multiple diseases” and may differ depending on the age the symptoms appeared.
“With the tools currently available, it’s hard to pick out,” he says.
By expanding their view of asthma and its causes, epidemiologists have created a larger theater to explore. The cause or causes of asthma seem more illusive.
“We have a lot to do because we haven’t figured out what’s happening,” Dr. Ernst observes.
In the meantime, asthma specialists are refining their hypotheses to explain the global increase in the prevalence and severity of asthma. Some of these explanations grew from inconsistencies identified in previous theories.
Epidemiologists like Thomas Platts-Mills, MD, a professor of medicine at the University of Virginia in Charlottesville, try to match the increase in asthma with change in public health policy or lifestyle. He points to children’s developmental differences during the past 40 years.
To place this hypothesis in context, peer into the 1960s family home and see Johnny and Jill charge through the back door in the late afternoon, their school satchels flying from their shoulders. Mother greets them with a glass of milk and a peanut butter sandwich or juice and an apple. The children gobble their snack and change their clothes. They’re soon in a neighborhood yard with their friends, tossing balls or climbing trees.
Fast-forward to the 1990s. Jason and Juliet unlock the back door because Mother is not home from work yet. They dump their heavy backpacks on the floor and open the refrigerator, helping themselves to cans of soda. The children pick up a bag of potato chips or box of cookies and collapse on the couch, switching on the TV with the remote control. There they stay, often until bedtime, squeezing in homework between commercials. Some children settle in front of a computer, surfing the Internet or testing their mettle with a video game.
“A fantastic change in lifestyle,” exclaims Dr. Platts-Mills, a leading voice in the epidemiology of the asthma epidemic. He finds himself favoring the change from activity and exercise to sedentary activities such as watching television as a possible explanation. He also believes the rise in obesity may play a role.
Stretching the lungs through exercise activities “decreases resistance,” he explains during a telephone interview with ADVANCE. “People say asthma is an inflammatory disease, but I think you can inflame your lungs with allergy and provided you run about normally, it won’t matter.”
While Dr. Ernst acknowledges lack of exercise may contribute to the increase in asthma and obesity is certainly a risk factor, he says, “It can’t be the only factor.”
Dr. Redd also found merits in the hypothesis but notes, “It’s not a rock-solid ‘A causes B hypothesis,’ but there is increasing evidence of that association.”
British epidemiologists in search of asthma’s cause recently proposed what has been dubbed as “the hygiene hypothesis,” a theory suggesting that improved cleanliness in homes may have altered the development of children’s immune response. The theory suggests children from clean homes and small families are no longer exposed to antigens that once stimulated their immune systems in a protective path.
Dr. Redd explains that the hypothesis grew from the notion that “something used to protect people that doesn’t anymore.” He suggests “a cell-mediated response” sends the immune system in a different direction.
The hypothesis proposes that allergic people switched from a Th1 response to a Th2 response because they did not gain exposure to common antigens, Dr. Platts-Mills explains. But because the increase in asthma incidence and severity is universal, reflecting many different lifestyles and environments, he says, “It is awfully unlikely to be due to a simple shift in immune response.”
A similar theory linking exposures or lack of them to the increase in asthma has been applied to animal dander, especially cat dander. In the past, asthma specialists frowned at feline companions sharing living quarters, especially the bedroom. They now realize that exposure to cat dander can be protective for children who are not allergic to cats. Dr. Platts-Mills explains the mechanisms, noting that exposure to cat allergens in non-allergic children generates IGG and IGG4 antibodies, a process he describes as “a modified Th2 response.”
Dr. Ernst and his colleagues discovered some interesting trends when they compared farm children and city children in Canada. Defining asthma as wheeze within the past 12 months and a bronchospastic reaction to methacholine, they found a 5.1 percent incidence of asthma in farm children and a 9.3 percent incidence in non-farm children. Farm children had more siblings, and they had more exposure to animals, although the animals were less likely to live in the house with them.
The data “suggested a significant protective effect of being raised on a farm, both for asthma and atopy,” Dr. Ernst told an audience gathered in Toronto for the 96th International Conference sponsored by the American Thoracic Society last year. Dr. Ernst and Dr. Platts-Mills both spoke during a penetrating session centered on the topic “Childhood Asthma: Is Change in Lifestyle the Key?”
Dr. Ernst also reported a risk linked to socioeconomic status in a study that compared respiratory symptoms, demographics and home exposures of 1,111 elementary school children. They found children from the least advantaged homes were more likely to suffer from exercise-induced bronchospasm, night cough and cough with mucus.1
“Our results suggest that unidentified environmental factors contribute to the excess asthma morbidity in poor children,” the group concluded.
Geographical differences may be another component in the global picture, as epidemiologists identify different allergens as risk factors in different countries. In New Zealand, dust mites appear to be a problem; in Arizona the disease could be linked to the mold Alternaria, while domestic animals like cats and dogs have been identified as risk factors in New Mexico. Cockroach allergen was once thought to be harmful for children in the South Bronx, although this was not a new feature in these impoverished urban neighborhoods.
“Quite clearly the increase in allergens has occurred in countries where completely different allergens are involved,” Dr. Platts-Mills told his Toronto audience. Even then, he added, “An increase in allergens is not enough to explain what is going on.”
Communities where asthma is rare, such as the Inuit who live in Northern Quebec, also point to a geographic ingredient. Dr. Ernst and a colleague found a surprisingly low incidence of asthma among the Inuit children, in spite of the obvious risk factors.2
Japan also has a lower incidence of asthma, and epidemiologists have considered diet as a possible explanation.
Research from Australia has demonstrated a protective role for fatty fish such as salmon.
The quest to identify the causes of asthma is still far from being achieved, but epidemiologists have uncovered a few definite links. Maternal smoking during pregnancy has been identified as a risk factor for asthma, for example. Dr. Ernst would take the smoking risk one step further, saying, “No one should smoke in the house.”
As asthma specialists ask new questions and introduce provocative possibilities regarding asthma’s causes and mechanisms, they’re driven by a sense of urgency.
“We are not looking at a little bit of wheezing in a few children who previously we had not talked about,” Dr. Platts-Mills said in Toronto. “We are talking about a disease that puts people in the hospital…and also kills people.”
Dr. Redd notes that the annual death toll from asthma hovers around 5,500 per year.
“The work that is going on is really important,” he says.
1. Ernst P, Demissie K, Joseph L, Locker U. Socioeconomic status and indicators of asthma in children. Am J Respir Crit Care Med. Aug 1995;152:570-5.
2. Hemmelgarn B, Ernst P. Airway function among Inuit school children in far northern Quebec. Am J Respir Crit Care Med. 1997;156:1870-5.
Francie Scott is senior editor of ADVANCE.