Treating Asthma, or Is Simple Too Simple?

Johan C. Kips, M.D.

Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium

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The clinical benefit of adding long-acting inhaled ₂-agonists as maintenance treatment to inhaled glucocorticoids (ICS) has been well established in moderate to severe persistent asthma. The OPTIMA study, reported by Dr. O'Byrne and colleagues in the current issue of the Journal (pp. 1392-1397), expands this concept to patients with milder disease (1). They evaluated the effect of adding formoterol to a low dose of budesonide over 1 yr in 1,970 mild asthmatics with a mean baseline FEV₁ above 85% of predicted, taking no or a small dose of ICS. The results are worth highlighting. First, this study convincingly demonstrates the important benefit of a low dose of budesonide (100 µg twice daily) over placebo in the patient group not receiving ICS at entry into the study. The second observation is that in mild asthmatics treated with ICS, a twofold difference in budesonide dose (100 versus 200 µg twice daily) had no clinically noticeable effect, whereas adding a low dose of formoterol clearly had.

What messages does this study leave us with? First, the current observations further add to the known effects of low doses of ICS on other important outcome measures such as hospital admissions and mortality (2, 3). Combined with the increasing proof of safety of ICS at low doses (4, 5), this report provides a strong plea for the introduction of low doses of ICS, even in patients who are perceived to have very mild disease. A second, more disputable, interpretation of the results could be that the introduction of devices that combine both compounds in a single inhaler will simplify asthma treatment even further than now anticipated. Although adding formoterol to budesonide in the ICS-free group did not produce a further decrease in the exacerbation rate, it did improve baseline FEV₁ without influencing reported adverse events. One of the major goals of asthma treatment is to maintain lung function within (near) normal limits. Therefore, it could be argued that, apart from the extra cost involved, there is no good reason for not combining long-acting ₂-agonists with low doses of ICS from the start of treatment. At the same time, the study indicates that this combination is also beneficial for mild asthmatics that had been seen to require a small dose of ICS. Hence, the same mono-inhaler would fit all patient categories, achieving increased control over monotherapy with ICS, and at the same time permit a decrease in the dose given to patients at the more severe end of the spectrum. Before accepting this concept, a few questions, however, seem worthwhile addressing.

One particular issue is to link the current clinical observations to a better insight into the underlying pathophysiologic mechanisms. An important, potentially dangerous feature of asthma is the occurrence of exacerbations. A salient feature that emerges from this study of mild asthmatics is the unexpected high frequency of severe exacerbations, 75% of which were identified by the need for oral steroids. This is in broad agreement with other studies in adults or in children with mild asthma (4, 6) and is strikingly similar to data obtained in patients with mild to moderate persistent asthma (7). These observations would seem to dissociate the mechanisms that cause exacerbations from those that underlie other clinical criteria of asthma severity such as symptoms or baseline lung function. The pathophysiology of exacerbations remains to be fully explored, but it is tempting to speculate that it may in large part result from bouts of acute inflammation superimposed on existing structural alterations. The extent of airway remodeling in asthmatic airways appears to be largely independent of duration or severity of the disease (8, 9). This could explain why patients, despite differences in asthma severity, have a similar propensity to develop exacerbations in response to an acute inflammatory event.

A key finding in the OPTIMA trial is that a low dose of budesonide significantly reduces the exacerbation frequency. Low doses of steroids are unlikely to influence remodeling but are known to reduce markers of acute inflammation, which could account for the observed effect (10). Whether formoterol given in conjunction with steroids reduces the exacerbation frequency merely through functional antagonism at the smooth muscle level or by exerting any antiinflammatory effects in its own right, and whether these effects are any different from other long-acting ₂-agonists remains unknown.

Another interesting observation is that whereas in the OPTIMA study, a twofold higher maintenance dose of budesonide (200 µg twice daily) does not influence the exacerbation rate, it has been shown in mild to moderate asthma that a fourfold higher dose (400 µg twice daily) clearly does (7). It is within this latter dose range that ICS have been shown to influence airway remodeling in conjunction with a reduction in the number of exacerbations (11). It could therefore be hypothesized that whereas a low dose of ICS influences the exacerbation rate by an effect on the acute component of airway inflammation, a substantially higher dose could have an additional effect by influencing remodeling or its progression. To what extent this is influenced by concomitant treatment with long-acting ₂-agonists again needs to be further evaluated. It has been shown that sputum eosinophil counts are not different in patients treated for 1 yr with the combination of formoterol plus budesonide 100 µg twice daily versus budesonide 400 µg twice daily (12). That study, however, did not include markers of airway remodeling. Concern exists that the clinical benefit of adding long-acting ₂-agonists could result in underdosing of steroids. The consequences of this possibility on airway morphology and its functional implications remain to be established. Only then will we know what is really the lowest effective dose of ICS that can be included in combination regimens.

In conclusion, the OPTIMA study clearly supports using the combination of long-acting ₂-agonists with a low dose of ICS in patients with mild persistent asthma. At the same time, the study raises a number of interesting questions. Unless these are resolved, it would seem that instituting this combination in all asthma patients, as simple an option as it might seem, is probably too simple.

	References

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