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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

7th International Congress on Pediatric Pulmonology

Montreal, Quebec / July 8-11, 2006

Exercise-induced Asthma

According to Dr. Soo-Jong Hong, Department of Pediatrics, Asan Medical Center, College of Medicine, Ulsan University, Seoul, Korea, “Asthma triggered by activity is very common in children and about 80% of my young patients with asthma experience exercise-induced asthma [EIA].”

The mechanism behind the pathogenesis of EIA in children remains to be elucidated, Dr. Hong told delegates. However, it has been established that leukotriene receptor antagonists (LTRAs) can inhibit the severity of EIA in children (Carraro et al. J Allergy Clin Immunol 2005;115(4):764-70). Dr. Hong and colleagues have published data showing that the LTRA montelukast has a protective role in exercise-induced bronchoconstriction and that it may offer prolonged protection lasting up to two months (Kim et al. Pediatr Pulmonol 2005;39(2):162-6, Li et al. J Allergy Clin Immunol 2006;117(1):119-26).

Researchers noted that patients’ responsiveness to treatment was highly variable, which prompted them to perform genetic studies. They found that the leukotriene C4 synthase A444C gene may be associated with severity of EIA in Korean children. “Of the inflammatory mediators that are predominant in asthma triggered by activity in children, I think leukotrienes are the most important ones,” Dr. Hong indicated. “Leukotrienes are ten thousand times more potent than histamines. Our research also suggests that eosinophils might be involved in the origin of asthma.”

Physicians need to educate their patients about how to better manage asthma, he suggested. Patient information messages should include the fact that it is important for children to warm up slowly before performing vigorous exercise and that certain sports, such as swimming, might be better than others, such as ice-skating. Pharmacotherapy should involve giving daily controller medication in a stepwise way, with the first step being albuterol, or another quick-acting beta2-adrenergic agonist.

Viral-triggered Asthma

As reported by Dr. Hans Bisgaard, Professor of Pediatrics, Copenhagen University Hospital, Denmark, in addition to EIA, asthma triggered by the common cold occurs frequently in children. An early study reported that viruses account for 80% of asthma episodes in schoolchildren (Johnston et al. BMJ 1995;310(6989):1225-9).

Another study by Lemanske and colleagues demonstrated that viruses could be identified in 66% of children who had severe wheezing symptoms. By far the most common virus in symptomatic asthma was rhinovirus. There was also a high percentage of respiratory syncytial virus, followed by corona virus, then other viruses.

Similar findings were observed when Dr. Bisgaard and colleagues studied 1700 “wheezy episodes” in 411 infants of asthmatic mothers (N Engl J Med 2006;354(19):1998-2005). “The majority of wheezy kids have virus infection,” he noted.

This research has important clinical implications. For decades, allergen provocation was the model that was studied in animals. It is now known that from studies of preschool children, virus challenge is a key element of asthma, Dr. Bisgaard reported.

A study of 294 infants who received budesonide or placebo at the very first instance of three consecutive days of wheeze reported no benefit in giving intermittent steroid. “We cannot treat these patients. The good news is we have a very clear negative with no short-term or long-term benefits,” Dr. Bisgaard stated. There are other data that indicate steroids have little effect on episodic viral-triggered asthma.

In a study of 217 asthmatic children aged one to five, findings indicated that treatment with prednisolone 20 mg (vs. placebo) did not appear to exert a clear benefit (Oommen et al. Lancet 2003;362(9394):1433-8).

On the other hand, there is evidence of benefits from LTRA treatment. The PREVIA (Preventing Episodic Viral-Induced Asthma) study showed reductions in asthma exacerbations following one year of LTRA treatment in children (Bisgaard et al. Am J Respir Crit Care Med 2005;171(4):315-22). This large double-blind study looked at 522 patients aged two to five with a history of intermittent asthma and demonstrated a 31.9% decrease in the exacerbation rate. “The good news is it works; [however,] it is not a magic bullet, since it leaves two-thirds unchecked. But it is the only treatment that is evidence-based,” Dr. Bisgaard indicated.

In a pilot study, Dr. Malcolm Sears, Professor of Medicine, McMaster University and Research Director, Firestone Institute for Respiratory Health, St. Joseph’s Healthcare, Hamilton, Ontario, and colleagues examined children aged two to five with physician-diagnosed asthma who received an LTRA 4 mg and in children over five years of age who received 5 mg. They found significantly fewer days of worsening asthma symptoms among the children who received an LTRA compared with those who received placebo (130 days vs. 200 days, P<0.05). A larger follow-up study is under review for publication.

Dr. Bisgaard concluded that the reason why physicians see a significant response is likely because leukotriene is one of many mediators in the inflammatory cascade.

Long-acting Beta-agonists in Children

As discussed by Dr. Fernando Martinez, Director, Arizona Respiratory Center, and Professor of Pediatrics, University of Arizona, Tucson, there are very few data supporting the use of long-acting beta-agonists (LABAs) in children with asthma. “Most data for LABAs, as for most medicines used for the treatment of many childhood conditions, are extrapolations of what has been found in older children and in adults [patients over age 12],” he explained. “The idea is that these manifestations of recurrent airway obstruction in children are of a similar etiology and basis as those of adults, which is not always true. In spite of that complete lack of data, therapy with LABAs is abundantly used in childhood. We need to address the issue of how they should be used in children.”

A recent article questioned the practice of basing guidelines for asthma treatment in children on extrapolation from studies in adults (Bisgaard H, Szefler S. Lancet 2006;367(9507):286-8). The authors noted that in Denmark between 2000 and 2004, the use of fluticasone and salmeterol has steadily increased, to the point where in 2004, more children used this combination than fluticasone alone, despite a lack of evidence to support this treatment in children.

Dr. Martinez went on to discuss inherent design flaws in a UK and US trial on salmeterol. The UK’s Salmeterol Nationwide Surveillance study was a 16-week, 2:1 randomization trial in which about 16,000 patients were randomized to salmeterol and about 8000 patients were randomized to salbuterol. Approximately 80% of the study participants were taking inhaled corticosteroids (ICS) concomitantly. The incidence of asthma-related death was numerically but not statistically greater with the addition of salmeterol vs. albuterol to usual asthma therapy (12 vs. two deaths). The study was not sufficiently powered to detect statistical significance; 60,000 patients would have been needed to show significant outcome.

The SMART (Salmeterol Multicenter Asthma Research Trial) in the US was designed the same way, i.e. adding salmeterol or placebo to the therapy the participants were already receiving. This created a problem towards the end of the trial, since by then, almost all potential new study patients were taking LABAs and did not qualify. The study was designed to examine 30,000 patients taking salmeterol vs. 30,000 taking placebo, but only slightly more than 26,000 patients were enrolled. The study was underpowered and, according to Dr. Martinez, treatment should have been administered in the way physicians usually use salmeterol, i.e. in combination with ICS in every patient. The rate of ICS use was 47%. There was an increased risk for fatal asthma events compared with placebo (13 vs. three deaths) which led to early discontinuation. Rates of death were higher among African Americans, but relative risks were similar among Caucasians and African Americans.

Summary

“Children are very different from adults with respect to asthma treatment,” summarized Dr. Bisgaard. “You see asthma in one in 20 adults, one in 10 schoolchildren and one in five preschool children. It is a totally different disease, affecting many more preschoolers, many children and fewer adults, so one cannot compare adults and children.”

Dr. Martinez stressed that in addition to being different from adults, each young asthma patient is unique. “In the end, different children respond differently. The best treatment will very much depend on the child we have in front of us and sometimes we have to try different medicines until we find the best treatment.”

Questions and Answers

The following section is based on discussions during the scientific sessions with Dr. Soo-Jong Hong, Department of Pediatrics, Asan Medical Center, College of Medicine, Ulsan University, Seoul, Korea; Dr. Hans Bisgaard, Professor of Pediatrics, Copenhagen University Hospital, Denmark; Dr. Fernando Martinez, Director, Arizona Respiratory Center, and Professor of Pediatrics, University of Arizona, Tucson; and Dr. Malcolm Sears, Professor of Medicine, McMaster University, and Research Director, Firestone Institute for Respiratory Health, St. Joseph’s Healthcare, Hamilton, Ontario.

Q: What was the main finding of your study on montelukast treatment in EIA in children?

Dr. Hong: Montelukast had an immediate and prolonged effect. We do not yet know what the mechanism is, but we saw the same protective effect two months later.

Q: How are these results relevant for physicians who treat children?

Dr. Hong: These are important issues. Prevention of EIA is very difficult in children because the situation is [unpredictable]. Compliance is a very important issue. By giving montelukast to my patients, I can control some of the aspects of EIA.

Q: How are the results of the PREVIA study relevant to physicians who treat children?

Dr. Bisgaard: The PREVIA study showed reductions in asthma exacerbations in children following one year of treatment with leukotriene blockers. The results are relevant in the sense that they offer the only evidence-based treatment that we have for viral-triggered episodes in children.

Q: What should pediatric guidelines be recommending with respect to the prevention of asthma exacerbations triggered by the common cold?

Dr. Bisgaard: For the segment of patients who have intermittent asthma, the only evidence-based treatment is the leukotriene blockers. Therefore, that should be in the guidelines.

Q: What data are there to support the use of LABAs in children?

Dr. Martinez: That is one of the issues. There are very little data. Specific studies for LABAs in children will need to be done.

Q: What do you think pediatric asthma guidelines should say about LABAs?

Dr. Martinez: They should say we do not have the data to recommend anything based on evidence studies applicable directly to children. So once again, we have to [treat young children] based on data obtained in older children and adults. Based on that information and based on the quality of the first-line therapies that we have, I think it is a second-line therapy.

Q: What is the “September peak?”

Dr. Sears: In the northern hemisphere, there is an enormous three- or fourfold increase in the frequency that children present at hospital emergency departments with asthma at approximately two or three weeks after children go back to school in the fall. This phenomenon, known as the “September peak,” occurs every year and in every country we have looked for it. It is very consistently related to school return and is largely associated with rhinovirus infection.

Q: What do you think pediatric asthma guidelines should say about prevention of asthma exacerbations caused by the common cold?

Dr. Sears: We have seen data showing that ICS are not very effective in exacerbations related to the common cold. We have heard criticisms of that, saying that the patients had such mild symptoms, you would not have seen an effect. We have certainly seen data showing that montelukast reduces the impact of cold-associated wheezing. The data are in Dr. Bisgaard’s study, where they gave montelukast for a year... and in our study, where we gave it for a month during the high-risk, back-to-school period. I think the evidence is accumulating that there is benefit. Taking a tablet once a day is much easier than taking inhaled steroids, and we know that inhaled steroid use, in the best of cases, is about one-third of what is prescribed. Taking tablets is still not perfect, but it is easier.