Is children's asthma made worse by inhalers?

“Genetic tests could pave way to ‘personalised’ asthma drugs” the Guardian has reported, before warning that current treatments may make symptoms worse. The newspaper goes on to say that, “screening could help GPs tailor drugs to children as study confirms variations in response to asthma medications”.

This headline is based on a small, proof-of-concept study that compared the effectiveness of standard treatment to an alternative asthma medication among children with poorly controlled asthma who were known to have a specific genetic variant (arginine-16 genotype).

If children’s asthma symptoms fail to respond to the standard treatment (such as a reliever inhaler), their doctor will usually step up their treatment to additional, more powerful options.

Children with more troublesome asthma are usually treated with a combination of a steroid inhaler and a medication called salmeterol. However, concern has been expressed that salmeterol may be ineffective in many children, or even make their symptoms worse.

Based on previous studies, the researchers thought that children with the arginine-16 genotype would respond better to a different medication called montelukast.

The study found that montelukast was more effective at managing asthma in this group of children. Whether this study will ultimately lead to a change in asthma treatment guidelines, ushering in personalised asthma treatment based on genetic variation remains to be seen.

Larger clinical trials and cost effectiveness studies are likely to be needed before deciding whether to alter treatment and introduce routine genetic screening for asthma as the accuracy (and cost) of the testing itself will need to be considered.

Where did the story come from?

The study was carried out by researchers from Brighton and Sussex Medical School, NHS Tayside, and the University of Dundee.

The research was funded by Merck, the pharmaceutical company that manufactures montelukast – though they had no involvement in how the research was conducted or the results were assessed.

The study was published in the peer-reviewed journal Clinical Science.

Interestingly, the research was covered in two distinct ways by the media.

The Guardian and the BBC took a glass-half full approach by focusing on the success of montelukast as a treatment in a subset of patients, and the potential for genetic testing to improve asthma treatment. While the Daily Mail and The Daily Telegraph took a glass-half empty approach, primarily focusing on the failure of standard therapy (salmeterol), and how such treatment may actually make the condition worse (a conclusion actually based on another study).

What kind of research was this?

This was a pragmatic randomised controlled trial that compared the effectiveness of one asthma treatment (montelukast) to standard treatment (salmeterol) among children with a particular genetic variant (arginine-16 genotype).

Previous research has shown that in highly controlled clinical trials, salmeterol is a more effective treatment than montelukast for children with poorly controlled asthma.

However, researchers report that in real life conditions, there is variability in how an individual child responds to treatment, with many children still experiencing symptoms, despite treatment.

Previous research also suggests that children with the arginine-16 genotype are less likely to respond to salmeterol treatment, and may miss more days of school due to asthma than similar children who are treated with inhaled steroids only (possibly suggesting that salmeterol may actually be making symptoms worse) .

The researchers enrolled children with poorly controlled asthma who had the arginine-16 genotype in order to determine whether they would respond better to montelukast.

This trial was designed to gather evidence in support of the idea that a different treatment regimen, tailored to patients based on their genetic makeup, may be more effective at controlling asthma symptoms among a specific subgroup of asthmatic children.

As a proof-of-concept study, the small sample size is appropriate. However, further research involving more children will be needed before drawing any firm conclusions about the effectiveness of montelukast in this group.

What did the research involve?

The researchers screened 154 children with the target genetic variation for inclusion in the trial. Of these 154 children, 52 (34%) did not meet the inclusion criteria, 40 children (26%) declined to participate, and 62 (40%) agreed to participate.

The children were split into two groups:

the first group received a combined treatment of inhaled fluticasone (a type of steroid inhaler) and salmeterol for one year (standard treatment)
the second group received the same inhaled fluticasone as well as montelukast for one year

At the beginning of the study, the children were tested for lung function, and were given an asthma symptom diary in which to write down regular medication use, rescue inhaler use, and any asthma symptoms.

The researchers followed-up with the children and their parents every three months over the course of the year, collecting information from the diaries, and assessing lung function.

They noted any side effects that the children had experienced over the previous months.

The researchers were interested in the long-term effectiveness of montelukast compared to that of salmeterol. Their primary outcome was the number of school days missed. Secondary outcomes included:

asthma exacerbation scores (defined as the number of school absences, requirements for a course of oral steroid use, or asthma-related hospitalisations)
use of an inhaled bronchodilator to relieve symptoms (scored as 0 for no use, 1 for occasional use [more than once a week, but not daily], 2 for daily use, and 3 for excessive use [multiple daily doses for symptom control])
daily asthma symptoms (cough, wheeze, breathlessness in the morning and night)
lung function (measured as Functional Expiratory Volume over 1 second, FEV1)
overall quality of life

What were the basic results?

The researchers found that children receiving montelukast missed significantly fewer days of school over the course of the year than the group receiving salmeterol (difference: 0.40, 95% confidence interval CI 0.07 to 0.87, p=0.005).

In terms of secondary outcomes, the researchers found that:

the montelukast group experienced significantly fewer asthma exacerbations compared to the salmeterol group (difference: 0.39, 95% CI 0.20 to 0.99, p=0.049)
salbutamol (a reliever inhaler) use was lower in the montelukast group vs. the salmeterol group (difference: 0.47, 95% CI 0.16 to 0.79, p<0.0001)
daily use of a reliever did not change significantly over the course of the year in the salmeterol group (32% at beginning of the study, 38% at 3 months, 32% at 6 months, 38% at 9 months, and 35% at 12 months)
there was a significant reduction in daily use in the montelukast group, however (36% at the beginning of the study, 18% at 3 months, 14% at 6 months, 11% at 9 months, 18% at 12 months)
quality of life scores improved significantly more over the course of the year in the montelukast group compared to the salmeterol group (p=0.003)
all asthma symptom scores were significantly better in the montelukast group compared to the salmeterol group (p≤0.004 for all symptom comparisons)
there was no significant difference in lung function (FEV1) between the two groups (mean difference: 5.46%, 95% CI -1.43% to 12.35%)

How did the researchers interpret the results?

The researchers concluded that asthmatic children with a specific genetic variation “appear to fare better on montelukast than salmeterol” when the treatment is added to inhaled corticosteroid as a second line therapy.

Conclusion

This proof-of-concept trial suggests that montelukast offers a more effective treatment option than salmeterol in a group of children with poorly controlled asthma and a specific genetic variation.

The researchers concluded that “adding montelukast to inhaled fluticasone significantly reduced school absences, improved asthma symptoms and quality-of-life, while reducing inhaled reliever use” compared to salmeterol. They also say that “the relative benefits of montelukast in comparison to salmeterol became evident within the first three months and persisted throughout the whole year.” They suggest that their trial “raises the question as to whether prior gene testing could be used to tailor appropriate” control treatments, allowing asthma therapies to move towards a personalised medicine approach.

While this may be promising news for children who experience continuing asthma symptoms despite ongoing treatment, there are limitations to the study to bear in mind, including:

This was a relatively small study (62 patients); the researchers report that this size offers sufficient power to detect a meaningful difference in school absences over one year. No power calculation was reported, however, for the secondary outcomes. While this may be an appropriate study size for proof-of-concept research, larger studies would likely be needed before changing treatment guidelines.
The results of this study are only relevant to children with poorly controlled asthma who also have a particular genetic variation, and should not be generalised to children on the basis of asthma control only. Whether widespread genetic testing of asthmatic children is feasible or cost-effective remains to be seen.
A relatively low percentage (61%) of children who met the inclusion criteria agreed to participate. It is unclear based on the information provided in the paper whether those who agreed to participate differed in meaningful ways from those who declined participation. As such, caution should be exercised before generalising these findings to the wider population of asthmatic children with this genetic variation.

This useful study provides some evidence that montelukast is more effective than salmeterol at reducing the number of school days missed in a specific subgroup of asthmatic children.

However, at this point it is not sufficiently broad to conclude that routine genetic testing should be introduced in order to personalise treatment regimens, as suggested by the media.

It will be interesting to see whether larger trials support the findings of this proof-of-concept study, and whether cost effectiveness studies support the use of a personalised medicine approach to treating childhood asthma.