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Rebuttal from Dr. Boushey

University of California at San Francisco, San Francisco, California

For patients minimally troubled by symptoms of a disease, the rationale for prescribing regular treatment must be that it reduces the risk of impairment in the future, whether from episodic or permanent interference with full enjoyment of life. How do the studies cited by Dr. O'Byrne—the "OPTIMA" and "START" trials (1, 2)—bear on this rationale? The "START" study enrolled only patients with asthma of recent onset. And neither study restricted enrollment to patients with "mild persistent asthma" as defined by the NIH or GINA Guidelines. Both included patients with a postbronchodilator FEV₁ greater than or equal to 80% predicted. So patients with a low baseline FEV₁ were enrolled, so long as they had a large bronchodilator response, which may itself be a marker of heightened risk of exacerbations (3). This may account for the exacerbation rates being so much higher than the authors expected (1). As for the finding of the START study that compared with placebo, prolonged treatment with budesonide increased postbronchodilator FEV₁ after 1 and 3 years, it is too bad the investigators did not make this measurement after brief "open label" treatment with budesonide. The drug increases airway caliber, possibly because of its vasoconstrictor activity (4, 5), and even a single dose, let alone a few days of treatment, might have erased entirely the difference in postbronchodilator FEV₁.

Dr. O'Byrne actually seems actually to agree with the implications of the IMPACT study (6) in suggesting that a therapeutic trial of an ICS should be given to patients with mild persistent asthma, so that they can decide whether the benefit from its use is worth taking the medication daily. This restates a conclusion of the IMPACT study, that for patients with asthma of this low severity, the decision can be based on the value the patient assigns to the improvement in symptoms associated with ICS use.

But what about controlling airway inflammation? O'Byrne recently wrote that "periodic fluctuations in symptoms and airway inflammation are characteristic of asthma, which means that treatment requirements... can vary over time," so that a treatment strategy providing additional antiinflammatory therapy when symptoms appear might be an effective approach to controlling the disease (7). A better statement of the rationale for the IMPACT study would be hard to find.

REFERENCES

1. O'Byrne PM, Barnes PJ, Rodriguez-Roisin R, Runnerstrom E, Sandstrom T, Svensson K, Tattersfield A. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392–1397.[Abstract/Free Full Text]
2. Pauwels RA, Pedersen S, Busse WW, Tan WC, Chen YZ, Ohlsson SV, Ullman A, Lamm CJ, O'Byrne PM. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071–1076.[CrossRef][Medline]
3. Ulrik CS, Frederiksen J. Mortality and fatal risk factors in 1075 outpatients treated for asthma. Chest 1995;108:10–15.[Abstract/Free Full Text]
4. Ellul-Micallef R, Hansson E, Johansson SA. Budesonide: a new corticosteroid in bronchial asthma. Eur J Respir Dis 1980;61:167–173.[Medline]
5. Engel T, Dirksen A, Heinig JH, Nielsen NH, Weeke B, Johansson SA. Single-dose inhaled budesonide in subjects with chronic asthma. Allergy 1991;46:547–553.[Medline]
6. Boushey HA, Sorkness CA, King TS, Sullivan SD, Fahy JV, Lazarus SC, Chinchilli VM, Craig TJ, Dimango EA, Deykin A, et al. Daily versus as-needed corticosteroids for mild persistent asthma. N Engl J Med 2005;352:1519–1528.[Abstract/Free Full Text]
7. O'Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y, Ekstrom T, Bateman ED. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005;171:129–136.[Abstract/Free Full Text]

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