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Hamilton, ON, Canada
Dr. Parameswaran is Assistant Professor of Medicine, McMaster University, Firestone Institute for Respiratory Health, St. Joseph’s Healthcare.
Correspondence to: Krishnan Parameswaran, MD, PhD, FCCP, McMaster University, Firestone Institute for Respiratory Health, St. Joseph’s Healthcare, Hamilton, ON, L8N 4A6 Canada; e-mail: parames{at}mcmaster.ca
Treatment with inhaled antiinflammatory drugs and inhaled bronchodilators is the mainstay of treatment of asthma. Traditionally, inhaled corticosteroids have been considered to be the most effective treatment for the inflammatory component of asthma, and ß2-agonists have been considered as the most effective bronchodilator. The demonstration that the combination of an inhaled corticosteroid with a long-acting ß2-agonist, on average, improved measures of airflow better than higher doses of inhaled corticosteroids alone123 prompted national and international guidelines to recommend therapy with a combination of the two drugs when asthma is inadequately controlled with a moderate dose of inhaled corticosteroids.4
Two combinations of medications are currently available for clinical use: fluticasone combined with salmeterol; and budesonide combined with formoterol. Formoterol, in addition to providing sustained bronchodilation, has a rapid onset of action that enables it to be used as a reliever medication.5 This pharmacologic property, in theory, enables the combination of budesonide and formoterol to be used as a maintenance and reliever medication. This has now been tested in three randomized clinical trials, including the report by Rabe et al6 in this issue of CHEST (see page 246).78 Rabe and colleagues6 report the results of a comparison of the following two treatment strategies: a combination of budesonide (160 µg) and formoterol (9 µg) in a single inhaler used once daily as maintenance therapy and up to eight additional puffs of the combination as required; and a higher dose of budesonide (320 µg) once daily and additional therapy with terbutaline as required. Over a period of 6 months in this multicenter parallel-group study, the combination strategy significantly improved morning peak expiratory flow (primary outcome) and reduced the risk of severe exacerbations by 54% compared to maintenance therapy with a higher dose of corticosteroids alone (number-needed-to-treat to prevent one severe exacerbation, 3.5). This was achieved with a mean less cumulative inhaled budesonide dose of 80 µg. This is consistent with the results of two previous studies,78 which examined the efficacy of this treatment strategy over a period of 1 year in patients with more severe asthma. The study by O’Byrne and colleagues8 further demonstrated that the combination therapy received during an exacerbation, compared to therapy with a short-acting bronchodilator alone, improved the resolution of the exacerbation.
The relevance of these observations is that it enables the simplification of the treatment of asthma for both patients and prescribers, while effectively improving clinically relevant asthma outcomes such as decreasing asthma exacerbations and improving symptoms and airflow obstruction. However, before it becomes widely endorsed as the most effective clinical strategy to prevent and treat asthma exacerbations, there are a number of issues to be considered. First, one needs to recognize the heterogeneity of airway inflammation associated with a loss of asthma control and exacerbations. A patient with an exacerbation associated with eosinophilic bronchitis almost always responds to therapy with an inhaled corticosteroid alone.9 A long-acting ß2-agonist is not necessary. Despite ex vivo data,10 there is no convincing clinical evidence that a long-acting ß2-agonist potentiates the antiinflammatory effect of a steroid.11 A patient with an exacerbation that is associated with neutrophilic bronchitis (usually due to a viral or a bacterial infection) usually does not respond to increased doses of corticosteroids.12 There is currently no effective therapy for this phenotype of exacerbation because this has not been investigated. A ß2-agonist (rapid or long-acting) may simply provide symptom relief while the exacerbation resolves spontaneously. Since more than half of exacerbations may be noneosinophilic (usually neutrophilic),13 the efficacy may be wrongly attributed to the combination treatment. This can only be resolved if the effect of an antiinflammatory therapy is evaluated using direct measurements of airway inflammation, such as sputum cell counts.14 Further, in the same patient, the nature of inflammation may vary with each exacerbation depending on the cause of the exacerbation.15 Second, the regular and excessive use of ß2-agonists is not without side effects.16 It is, therefore, prudent not to recommend them for all patients with asthma until it is possible to identify the responders and nonresponders, and the patients who are likely to be adversely affected with excessive use of ß2-agonists. Also, it is necessary to identify whether it is the corticosteroid or the long-acting ß2-agonist in the combination that can be credited with the clinical efficacy.
Asthma is a heterogeneous disease. Various components of the disease such as airflow limitation, airway hyperresponsiveness, and airway inflammation of different types and causes, in different combinations, may contribute to symptoms. Individualized therapy is thus necessary for optimal disease management. Currently, sputum cell counts are only used for clinical practice in a few academic centers. Thus, this "tailored" therapy may seem impractical. However, the measurements are practical, and when they become properly remunerated and automated, they will become more widely available and utilized. Before a single therapy is recommended by all guidelines for all patients, it is important to consider the individual variability in the nature of airway inflammation and therapeutic responses. We may even need to consider separate guidelines for specialists and general practitioners.
Footnotes
This research was supported by a Canadian Institutes of Health Research Clinician-Scientist Award.
References
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