February 2000
CHICAGO - Disturbances in the immune responses of some children may alter their lung growth and predispose them to bronchial hyperresponsiveness and asthma, according to preliminary data from a children's respiratory study conducted by Fernando D. Martinez, MD, and colleagues at the University of Arizona, Tucson. These changes are developmental and begin in the first years of life.
"There's no doubt that if we're going to be able to develop a strategy of primary and secondary prevention of asthma, we will have to somehow intervene in the very first years of life," said Martinez at the 1999 American College of Asthma, Allergy and Immunology Annual Meeting here. "Because it is then that the first cases of asthma develop."
But determining which children will develop asthma and which children won't is complicated, Martinez said. One factor is that different forms of recurrent airway obstruction coexist during the first years of life. In particular, a large proportion of children wheeze because of respiratory tract infections. Many of these children do not have any other risk factors associated with chronic asthma.
It is a common belief that an essential risk factor for developing asthma is previous lower respiratory illness, specifically respiratory syncytial virus (RSV), accompanied by wheeze during the first few years of life. But according to Martinez, "RSV by itself is not a factor that determines increased asthma risk in the long term."
Those children in the study who developed an RSV infection within the first years of life were three times more likely to wheeze at age 6 than those who did not develop an RSV infection. "But what is interesting," Martinez said, "is that after you correct for everything else - genetic background, family history, smoking, for all possible factors except RSV - what you see is a clear and unmistakable downward trend up to the age of 13, when children who had RSV are not any more at risk of having mild wheezing episodes."
Also, "children who had RSV were more likely to have recurrent wheezing at the age of 6, but this risk tended to decrease significantly with age," he said.
Although the researchers found that developing RSV in early life did not solely determine the risk of developing asthma, they did find that RSV was related to a child's level of lung function. "At the age of 11, children who had RSV and other respiratory viruses during early life still had very low levels of lung function," said Martinez. "What RSV is doing is probably flagging children who have an alteration of their airway tunnel, which determines lower levels of lung function in early life. And in doing so, increases the risk of wheezing when they have a lower respiratory tract illness."
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The study also revealed that children who will outgrow their symptoms usually begin life with a lower level of lung function.
"So, there is a group of children ... who wheeze probably because their lungs are small," Martinez said. "But the children who are going to be the most likely asthmatics start life with a level of lung function which is not significantly different from that of their peers. For [children likely to develop asthma], the low level of lung function is not the main risk factor to start with. The low level of lung function is something that they acquire," he said.
Also, "the children who started wheezing in early life because they had low lung function show a trend to improve, which is quite reassuring," said Martinez. "And the main risk factor is having a mother who smoked during pregnancy. My opinion is that if we allow these children to stop being exposed to the carcinogens and other factors present in smoke, probably they are going to get better with age."
The children who began life with low lung function still had low lung function at the age of 6, but were no longer wheezing. "But it is the group of children who started wheezing in the first years of life, and who are still wheezing at 6, who show a level of lung function which is ... lower than what they had at birth," said Martinez. They have a progressive loss of lung function with age, which is approximately a 10% total loss of function by age 11.
The researchers found that as the influence of RSV on wheeze risk decreased, the influence of allergy on wheeze increased.
"[For] practically every child who was wheezing at age 11, his skin was positive to local allergens," said Martinez. "And this influence increased significantly with age to the point that around the ages of 11 to 13, the allergic background of the individual was one of the most important risk factors for persistent wheezing."
The study showed that most children who eventually develop chronic and severe asthma are sensitized to the aeroallergens prevalent around them. However, it is unlikely that becoming sensitized to any specific aeroallergen is the sole cause of asthma since children worldwide become sensitized to different aeroallergens.
According to Martinez, there appears to be a basic disturbance in the immune system of asthmatics that allows them to become sensitized to different asthma-related allergens. This disturbance is related to an imbalance between the two main poles of immune responses, the Th-1 and Th-2 responses.
"Infants who will go on to become sensitized to asthma-related allergens have a delayed development of the Th-1-like responses during early life in such a way that the normal balance between these two forms of immune responses is only established in them later in life," Martinez said.
Asthmatic children tend to react against local aeroallergens and other antigens with a Th-2-type response. This allows a "window of opportunity" for early allergic sensitization to develop. However, not all children who become sensitized to aeroallergens early in life become asthmatic, since there is also the element of an abnormal pattern of lung development that occurs in asthmatics.
Martinez said that this pattern is not well understood, but suggested that early development of immunoglobulin E-mediated response in the lungs, triggered by the Th-2-like response, predisposes children to abnormal development, or remodeling of the lungs, which could be a major risk factor for asthma and bronchial hyperresponsiveness.
It is also likely that asthmatics have an increased susceptibility to the immune mediators and growth factors that are produced in the lungs, said Martinez. "It is thus likely that asthma may be the final combination of, on the one hand, a delayed development of the normal and balanced Th-1/Th-2 responses, and on the other hand, the presence of an inherited or acquired susceptibility to the immune mediators that are released during the abnormal immune responses present in asthma in early life."
For more information:
- Martinez FD. Evolution of asthma through childhood. Presented at the 1999 American College of Asthma, Allergy and Immunology Annual Meeting. Nov. 12-17, 1999. Chicago.
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