Affiliations: Aberdeen Royal Infirmary, Aberdeen, Scotland, UK,
Ipswich Hospital, Ipswich, UK
Correspondence to: Graeme P. Currie, MD, Department of Respiratory Medicine, Chest Clinic C, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, AB25 2ZN, Scotland, UK; e-mail: firstname.lastname@example.org
The recent study by Perng et al in CHEST (May 2004)1 provides valuable insight into the comparative effects of therapy with zafirlukast (20 mg bid) plus low-dose budesonide (400 μg/d) vs high-dose budesonide alone (1,200 μg/d) in terms of airway hyperresponsiveness to methacholine and inflammatory biomarkers.
Attenuating airway hyperresponsiveness to methacholine is only tenuously linked to antiinflammatory activity and tends to be a function of airway caliber.2Indeed, both randomized treatments conferred improvements in lung function, suggesting that the observed reduction in airway hyperresponsiveness may have been in part due to a greater airway diameter. In contrast, the use of an indirect stimulus such as adenosine monophosphate, which causes the release of proinflammatory mediators, would have provided greater insight into the antiinflammatory effects of leukotriene receptor antagonists and inhaled corticosteroids. For example, the shift in adenosine monophosphate threshold is closely correlated to the degree of sputum eosinophilia and has been shown to be a more sensitive indicator of allergic airway inflammation than methacholine.3–4
It would have been of interest if the authors had measured the time taken to recover following bronchial challenge, as it is likely that a further useful effect of leukotriene antagonism in asthma would have demonstrated. Previous data5–6 have shown that montelukast (another leukotriene receptor antagonist) quickens the time taken to recover following bronchial challenge compared to placebo. This in turn suggests that cysteinyl leukotrienes are important mediators in sustaining the bronchoconstrictor response. Indeed, the “real-life” implication of this was observed in a randomized controlled study that evaluated 194 patients admitted to the hospital with acute asthma.7 It was demonstrated that therapy with IV montelukast, in addition to standard therapy, conferred a more rapid recovery in FEV1 over a 2-h period compared to therapy with placebo.
In conclusion, this study serves as an important reminder of the beneficial effects of administering leukotriene receptor antagonists as add-on therapy to inhaled corticosteroids in terms of the integral components of the asthmatic inflammatory process. However, assessing shifts in airway hyperresponsiveness with an indirect bronchoconstrictor stimulus such as adenosine monophosphate would have provided a more robust surrogate marker of antiinflammatory activity than the use of a direct agent such as methacholine.
Dr. Currie has received funding from Merck, Sharp and Dohme (the manufacturer of montelukast) to attend postgraduate international educational meetings.
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