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A double dose is not enough
The management of asthma consists of the regular use of anti-inflammatory medications and an action plan for worsening of symptoms or an asthma exacerbation. Guidelines for the treatment of asthma have recommended doubling the dose of maintenance inhaled corticosteroids for deteriorations in asthma control that are not responding to β agonist rescue treatment in the usual manner.1,2 Although this approach has been advocated, evidence to support its effectiveness has been largely wanting.
In this issue of Thorax FitzGerald and colleagues3 and members of the Canadian Asthma Exacerbation Study Group evaluated this approach. They identified 290 patients with well characterised asthma, all of whom had a history of at least one previous asthma exacerbation—defined as an increase in symptoms and the need for a change in medication not more than 12 months and not less than 1 month before the start of the run in period. During the run in period all subjects were maintained on their usual dose of inhaled corticosteroids. Subjects were then either assigned to maintenance treatment and received their usual dose of budesonide (100, 200, or 400 μg twice daily) plus a placebo inhaler to be used twice a day with an exacerbation, or were on the same doses of inhaled corticosteroid plus an inhaler containing active inhaled corticosteroid which therefore doubled their maintenance dose of inhaled corticosteroids during the exacerbation. An asthma exacerbation was defined as a combination of two of the following six criteria:
fall in peak flow to less than 80% baseline value;
bronchodilator use more than four times a day;
night time waking;
increase in asthma symptom scores;
inability to go to school or work for two consecutive days;
unscheduled visit to a physician during the study period.
The major outcome was the proportion of patients who failed to regain control after developing symptoms of an impending exacerbation of asthma, as judged by the need for treatment with oral corticosteroids or an unscheduled visit to a physician after 14 days of treatment.
Of the recruited subjects, 52 in the maintenance treatment group and 46 of those assigned to the double dose of inhaled corticosteroid had an asthma exacerbation. Treatment failure was equivalent in both study groups, and the major component of treatment failure was asthma instability: 23% were unstable on maintenance treatment after the appropriate observation period compared with 13% in the doubling dose group. The difference between the two treatment approaches did not achieve statistical significance. Other outcomes were also similar between the two groups. The authors therefore concluded that doubling the dose of inhaled corticosteroids was not effective in the management of impending asthma exacerbations.
Their findings are similar to and support those recently published by Harrison and colleagues4 who monitored morning peak flows and asthma symptoms for up to 12 months in 390 patients with asthma. When peak flow values and symptoms began to deteriorate, an active inhaled corticosteroid or placebo was added to the maintenance treatment for 14 days. The primary outcome (number of individuals starting oral prednisolone) did not differ between the treatment groups. The reasons for starting prednisolone were a 40% fall in peak flow, advice from a general practitioner, or a subjective deterioration in asthma control.
These two studies thus provide evidence that early or impending exacerbations of asthma are not always effectively treated by doubling the dose of inhaled corticosteroids. What explanations do we have for these observations? As pointed out by FitzGerald et al,3 there are a number of reasons why doubling the dose of inhaled corticosteroids may have been ineffective: (1) some studies have indicated that four times a day administration may be more effective than twice a day dosing as used in these two studies;5 (2) the onset of action with inhaled corticosteroids may be slower than with systemic corticosteroids; (3) airflow limitation may impair drug delivery; and (4) the dosage increase may have been insufficient.
It is, however, more likely that other factors play a role in this failure to achieve a beneficial response to an increased amount of inhaled corticosteroids. Reddel and colleagues6 compared differences between asthma exacerbations and poor asthma control and showed that unstable asthma could be controlled with the initiation of inhaled corticosteroids. With exacerbations maintenance inhaled corticosteroid therapy was not sufficient to regain and maintain control, and the reversal of airflow obstruction to β agonists was also diminished. They speculated that the loss of asthma control with exacerbations was caused by respiratory infections and that increased asthma under these circumstances may be very different from the physiological abnormalities seen with unstable asthma which could occur from chronic exposure to aeroallergens or other environmental stimuli.
As shown by Johnston and colleagues,7 the major cause (80%) of asthma exacerbations is viral upper respiratory infections. With viral respiratory infections the inflammatory response is more likely to be neutrophilic than eosinophilic,8 with the latter marker usually predicting a response to inhaled corticosteroids.9 Previous attempts to treat acute asthma exacerbations caused by respiratory infection with inhaled corticosteroids have not always been successful.10,11 The use of inhaled corticosteroids, even in large doses, may not, therefore, be sufficient to control asthma exacerbations under these circumstances in some patients.
Questions remain as to how best to prevent asthma exacerbations. Studies indicate that the addition of maintenance treatment with a long acting inhaled β agonist to inhaled corticosteroids is more effective in reducing rates of asthma exacerbations than identical doses of inhaled corticosteroids alone.12,13 Whether the addition of long acting β agonists at the onset of symptoms that foreshadow asthma exacerbations would be more effective than larger doses of inhaled corticosteroids has yet to be ascertained. Moreover, Bisgaard14 has recently indicated that the leukotriene receptor antagonist montelukast may be effective in hastening the recovery from airway changes associated with bronchiolitis induced by respiratory syncytial virus (RSV) in young children. Whether this approach is effective in attenuating the development of significant lower respiratory tract involvement at the onset of symptoms with RSV or other viruses has yet to be established.
How do we translate the recent observations by FitzGerald et al3 and Harrison et al4 into current and future asthma care? Firstly, for most asthma exacerbations a doubling of the inhaled corticosteroid does not appear to be sufficient and perhaps a more rapid initiation of a prednisone burst is the most appropriate step. Secondly, the prevention of asthma exacerbations needs to be a primary target of treatment and inhaled corticosteroids15 or the combination of inhaled corticosteroids and long acting β agonist maintenance treatment;12,13 both approaches may be underused. Moreover, although combination therapy is effective in preventing asthma exacerbations, a significant proportion of these individuals still suffer worsening of asthma on this treatment regimen.12,13 Finally, and perhaps most importantly, insights into the mechanisms by which respiratory infections provoke asthma will probably give us better direction for controlling this important and underserved outcome of asthma.