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The benefits of maintenance therapy with inhaled corticosteroids have been convincingly established in patients with moderate and severe asthma disease, but only recently have studies assessed the potential benefits for children with mild disease. In this issue of Archives of Disease in Childhood, Turpeinen and colleagues report the findings of such a study.1 Their results confirmed that continuous treatment with inhaled corticosteroids is associated with significantly better asthma control than with treatment with disodium cromoglycate or intermittent treatment with inhaled corticosteroids. However, better asthma control was achieved at the expense of some reduction in annual growth. These findings corroborate the results of earlier, differently designed, much larger and longer studies on around 3000 children with mild asthma.2–4 So, there is good evidence that optimal or near optimal asthma control can be achieved in most children with mild asthma with inhaled corticosteroids. Furthermore, inhaled corticosteroids are clinically more effective and improve outcomes to a greater extent than any other asthma drug available for maintenance treatment in patients with mild, persistent asthma.2 5–7
However, the adverse effect on annual growth rates reported in the study of Turpeinen and colleagues and some other studies raises the question of whether it is justified to always aim for optimal near optimal asthma control even if the price could be an adverse effect on growth velocity. Should we accept a few more asthma exacerbations and a somewhat poorer daily asthma control and ensure a normal growth rate for these children? Unfortunately this cannot be answered in any way that fulfills the criteria for evidence-based decision making. However, the literature does provide data that may help answer these questions.
When interpreting the findings from controlled clinical studies and implementing them in daily clinical practice it is worth remembering the quote of Albert Einstein: “What counts cannot always be measured and what can be measured does not always count”. Large clinical trials often base their conclusions on efficacy and safety outcomes, which are standardized and easy to measure such as daily peak expiratory flow rates, lung functions measured at the clinic, growth rates and bone mineral density. However, the question is what is the clinical relevance of small, but statistically significant, differences in these outcomes? In patients with mild asthma, lung-function measurements are poor predictors of the risk of having an asthma exacerbation. Moreover, their correlation to clinical measures such as quality of life, impairment during physical activities, daily symptoms or more comprehensive scores of daily asthma control is poor or non-existing. Similarly, the change in growth rate during one to two years of treatment is a poor predictor of long-term growth or attained adult height,8 and bone mineral density is a surrogate marker of the risk of having a fracture.9 Therefore, interpreting the clinical importance of a statistically significant difference between treatments in some of these outcomes in a 1–2 year study is not straightforward. There is definitely room for disagreements. In contrast, exacerbations are dramatic events that are considered important to patients and expensive for society. Therefore, any reduction in this outcome is normally worthwhile and clinically relevant.
Mild asthma is not as trivial a disease as the name implies, and owing to its frequent occurrence (70–80% of the asthma population is estimated to suffer from mild disease10) mild asthma contributes substantially to the asthma morbidity in the society:
Exacerbations are common. In clinical studies 30–50% of the placebo-treated children received one or more courses of prednisolone during the first year of study.2 4
Patients with mild asthma account for the majority of acute asthma hospitalisations and emergency-room visits and contribute substantially to the (rare) occurrence of asthma deaths.11 12
Inhaled corticosteroid treatment consistently reduces the need for prednisolone, emergency-room visits and hospitalisations in children with mild asthma by around 50% in most studies.2–4 Considering that some of these events are rather rare in children with mild asthma, an impressive percentage reduction may not necessarily be the best basis for assessing the clinical relevance. Therefore, the number of patients that need to be treated for one year with inhaled corticosteroids to prevent one incidence as compared with the comparator is more appropriate. On the basis of the literature, two to three patients are needed to prevent a prednisolone course, 25 to prevent an unscheduled visit and around 50 to prevent an emergency-room visit or a hospitalisation.2 4 In the study of Turpeinen and colleagues, the number needed to be treated to prevent an exacerbation seemed to be around two and around 10 for preventing an exacerbation severe enough to be withdrawn from the study. These numbers are all within a range that is normally considered acceptable for justifying an intervention. From a societal perspective, continuous treatment with inhaled corticosteroids was found to be cost-effective (cost-saving) in children with mild asthma in the only study that evaluated the health–economy of the intervention.13
Perspective on the paper by Turpeinen et al (see p 654)
While it is generally agreed that reductions in exacerbations, emergency-room visits and hospitalisations are clinically important to the patients, their parents and society, less is known about the level of changes needed in other outcomes for an intervention to be assessed as clinically worthwhile. Ability to participate in sports and other physical activities or the quality of life of the patients may matter even more to patients, but these outcomes are rarely measured in clinical trials owing to the lack of accurate measuring tools or the requirement for more sophisticated, time-consuming procedures. In the various studies, inhaled corticosteroid increased the number of symptom-free days by 3–4 days per month in children with mild asthma. Most people believe that this in itself justifies the treatment, but others disagree. The number of symptom-free days correlates with the quality of life,14 but whether the magnitude of the change in symptom-free days is enough to result in a clinically relevant improvement in quality of life is not known. Statistically significant improvements in quality of life have been reported in some trials, and the magnitude of the increases has normally been around the level considered clinically important.
Do these benefits balance or outweigh the risks of adverse effects of the treatment? To answer this some issues must first be considered:
The doses of inhaled corticosteroid needed to obtain the clinical benefits
Dose–response studies in children demonstrate marked clinical improvements at 100–200 μg of inhaled corticosteroid per day, and no study has demonstrated any benefits of increasing the daily dose beyond 200 μg in groups of patients with mild asthma.15 Moreover, low daily doses control more clinical outcomes to a greater extent than any other asthma drug used for maintenance therapy. Therefore, the relevant question is whether treatment with 200 μg per day is associated with any clinically important adverse effects.
Risk of adverse effects of effective doses and long term-consequences
Six out of seven studies comparing low-dose ICS (100–200 μg/day) with placebo or non-steroidal therapy found that inhaled corticosteroids had no adverse effect on growth over 1–2 years, and one found a significant effect.7 In contrast, studies of higher doses such as the study by Turpeinen and colleagues reported some degree of growth impairment. The long-term clinical relevance of this growth retardation is debated because results from studies of 1–3 years’ duration do not seem to predict long-term growth or effects on attained adult height.8 This is probably because these children are likely to grow for longer than their peers and therefore eventually end up at a normal adult height, but at a somewhat later age. However, they may be 1–2 cm shorter than their peers for some years on their way to adult height.
No studies have reported any increased risk of fractures in children taking inhaled corticosteroids, and no controlled studies have found any adverse effects on bone mineral density following long-term treatment with daily doses <400 μg.9
So, do the benefits of continuous treatment with inhaled corticosteroids in children with mild asthma outweigh the risks? Virtually all local and international guidelines think so, and they recommend continuous treatment with inhaled corticosteroids as the preferred treatment option in children with mild asthma. The main arguments are that daily doses of 200 μg are clinically safe, clinically more effective than any other asthma treatment available, as cheap as or cheaper than other treatment alternatives, including no treatment, and that the beneficial effects are considered clinically relevant. Finally, both physicians and patients often under-estimate the asthma severity and the daily morbidity associated with the disease. Consequently many patients are under-treated.16 It is hoped that the level of under-treatment can be reduced by using the most effective treatment in all candidates for continuous treatment. However, it must be remembered the mild asthma population is heterogeneous. Only a proportion will need the treatment for many years, and some will only need it during a certain season of the year. Unfortunately, we cannot predict which of these categories a patient belongs to. Therefore, regular follow-up is required in patients with mild disease. Otherwise we may go from under-treatment to over-treatment of this group of patients.
Competing interests: SP has served on advisory boards for GlaxoSmithKline AstraZeneca and Nycomed, and has received honoraria for educational activities organized by these three companies. His institution has received funding for research from AstraZeneca, GlaxoSmithKline, Merck and Nycomed.