Montelukast for Viral Respiratory Infection-induced Exacerbations of Asthma/From the Authors

To the Editor.

The publication of the PREvention of Viral Induced Asthma (PREVIA) study by Dr. Bisgaard and colleagues indicates that it was designed to investigate the role of montelukast in the prevention of viral respiratory-induced asthma exacerbations in children 2-5 years of age (1). However, during this 12-month-long study, only an average of 2.3 asthma exacerbations occurred with the placebo regimen. This compares with an average of more than 6 episodes over 6 months, with each lasting an average of more than 8 days, in the study by Doull and coworkers (Reference 6 in the article by Bisgaard and colleagues) (2), and an average of 2.5 episodes lasting an average of 8 days in the 4-month-long study by Wilson and coworkers (Reference 7 in the article by Bisgaard and colleagues) (3), both of which found no difference between inhaled corticosteroids and placebo in preventing viral respiratory infection-induced asthma exacerbations. The small decrease in exacerbations observed by Bisgaard and coworkers, from an average of 2.3 to 1.6 over the course of a year, was not accompanied by any significant decrease in the need for courses of oral corticosteroids. In fact, the magnitude of effect was on the order of that seen in a previous study of montelukast in children of the same age with reportedly persistent asthma (Reference 15 in the article by Bisgaard and colleagues) (4). In contrast to the claim that the patients in the PREVlA study exclusively had intermittent respiratory symptoms due to viral respiratory infection, a baseline frequency of asthma symptoms more than twice weekly was present in 17% of the patients. Moreover, more than 30% of those patients had a history of atopic dermatitis, allergic rhinitis, and evidence for specific IgE to an inhalant allergen as shown by a positive RAST test, characteristics associated with a greater likelihood of persistent asthma (5). This study would have been cleaner if patients with specific IgE to inhalant allergens had been excluded, with inclusion criteria limited to those who had a history of being completely free of symptoms for extended periods between apparent viral respiratory infections. As currently designed, the data of the PREVIA study do not support the hypothesis that viral respiratory infection-induced asthma exacerbations will be prevented with montelukast.

Conflict of Interest Statement: M.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

MILES WEINBERGER

University of Iowa

Iowa City, Iowa

References

1. Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, Menten J, Tozzi CA, Polos P. Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma. Am J Respir Crit Care Med 2005;171:315-322.

2. Doull IF, Lampe FC, Smith S, Schreiber J, Freezer NJ, Holgate ST. Effect of inhaled corlicosteroids on episodes of wheezing associated with viral infection in school age children: randomized double blind placebo controlled trial. BMJ 1997;315:858-862.

3. Wilson N, Sloper K, Silverman M. Effect of continuous treatment with topical corticosteroid on episodic viral wheeze in preschool children. Arch Dis Child 1995;72:317-320.

4. Knorr B, Franchi LM, Bisgaard H, Vermeulen JH, LeSouef P, Santanello N, Michele TM, Reiss TF, Nguyen HH, Bratton DL. Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics 2001;108:E48.

5. Castro-Rodriguez JA, Holberg CF, Wright AL, Martinez F. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med 2000;162:1403-1406.

From the Authors:

We would like to thank Dr. Weinberger for identifying some aspects of the PREVIA study that may need further clarification. The first issue raised concerns about the fact that there was no change in the treatment course of oral corticosteroids. As mentioned in the article, the protocol for worsening asthma standardized the use of oral corticosteroids for predefined periods of time even if symptoms resolved earlier. Therefore, no conclusions can be drawn on the use of oral corticosteroids from this study (1).

The second issue raised relates to whether the patients really had intermittent asthma. As detailed in the article, the majority of patients probably had intermittent asthma rather than mild persistent asthma. Although patients could have had symptoms for up to 4 days during the 2 weeks of the run-in period, the severity of symptoms had to be very low (i.e., no symptoms > 1.0 out of an average daily score of 4 for the daytime symptom questions, 0-5 range). Because patients had to be asymptomatic in a typical week in the 3 months before the run-in period and also could not use ß-agonists between episodes, they all had a history of being free of symptoms for extended periods of time. In addition, as part of the study design, no preventive therapy could be used, except for montelukast (or placebo), during the 12-month trial. The genuinely intermittent nature of the patient population is illustrated in Figure 2 of the article, which shows a mean severity score of 0.4 of 20 during the month before and after the first episode. We may add a word of caution on overinterpreting asthma categories since patients often move in and out of such categories over time; yet, to the extent possible, we are confident that the study population predominantly represents intermittent asthma.

Dr. Weinberger highlights that our study population had fewer exacerbations compared with those in the studies of Doull and coworkers and Wilson and coworkers (see References 2 and 3 of Dr. Weinberger's letter.) The most obvious explanations would include different seasonal viral load, different populations, different exposures to viruses, different age groups, and more severe underlying asthma in the former two trials. For example, the study by Doull and associates was conducted in the United Kingdom during the winter (virus) season (September to March) to cover the maximum wheezing episodes. Our study was conducted on five continents over 12 months, including summer periods. We studied preschool children 2-5 years of age, whereas those studied by Doull and colleagues were 7-9 years of age. It is hardly justified to expect similar exacerbation rates under such different circumstances.

Finally, Dr. Weinberger suggests that the study would have been cleaner had we excluded children with risk factors for persistent asthma. However, the treatment effect was found to be independent of such risk factors, showing that risk factors for persistent asthma should not be confused with factors predicting response to treatment.

Our study therefore convincingly documents a treatment effect of montelukast in preschool children with intermittent asthma typically driven by viral infections.

Conflict of Interest Statement: H. B. has, within the last 3 years, received honoraria for lectures and attendance at pediatric advisory boards for Aerocrine, Altana, AstraZeneca, GlaxoSmithKline (GSK), and Merck and holds no stock options in the pharmaceutical industry in the respiratory field, and owns a world patent for an inhaler device but received no royalty; and the COPSAC clinical research unit has in the last 3 years received research grants from the following industry partners in increasing order: Aerocrine, Merck, GSK, and AstraZeneca.

HANS BISGAARD

Copenhagen University Hospital, Gentofte

Copenhagen, Denmark

References

1. Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, Menten J, Tozzi CA, Polos P. Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma. Am J Respir Crit Care Med 2005;171:315-322.

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