© 2003 American Thoracic Society
Montelukast for Respiratory Syncytial Virus BronchiolitisSignificant Effect or Provocative Findings?
a National Jewish Medical and Research Center University of Colorado Health Sciences Center Denver, Colorado Respiratory syncytial virus (RSV) is associated with significant morbidity in young children. ß-Adrenergic agonists and corticosteroids, whether inhaled or oral, have little to offer on the acute course of illness (1). After a lower respiratory tract infection caused by RSV, infants and children appear to have recurrent wheezing and lower respiratory tract disease for up to 11 years (2). The benefit of antiviral or antiinflammatory therapy for a lower respiratory infection caused by RSV on short- and long-term respiratory outcome is debatable (3). There does not appear to be a significant benefit of antiviral therapy during the course of illness on long-term (1–6 years) lower respiratory outcomes (3). Studies with nebulized glucocorticoids suggest that therapy for acute illness and daily therapy for up to 2 months potentially show a longer lasting impact on respiratory outcomes (4–6). A preliminary study (7) demonstrated that prevention of lower respiratory infection caused by RSV in infants with chronic lung disease by a high-titered immunogloblin resulted in significantly improved respiratory outcomes at 5–7 years. Studies show that cysteinyl leukotrienes produced by both bronchial epithelial cells (8) and macrophages (9) are increased in the wheezing disease induced by RSV (10, 11). The advent of cysteinyl leukotriene receptor agonists and leukotriene synthesis inhibitors makes them attractive candidates for reducing the short- and long-term respiratory morbidity after a lower respiratory infection caused by RSV. In this issue of AJRCCM (pp. 379–383), Bisgaard (12) presents interesting observations on the effect of montelukast on short-term respiratory symptoms after RSV bronchiolitis. Infants and children receiving montelukast within 7 days of symptom onset and continued for 28 days were free of symptoms on 22% of the days and nights compared with 4% for the infants who received placebo. This effect, primarily on cough, was not apparent until 2 weeks. The times of onset for additional therapy and for a recurrent exacerbation were delayed in the montelukast group as compared with the placebo group. The results, however, are at best provocative and raise questions for further research. The study population had a median age of 9 months and included children of up to 36 months. It is not clear whether the demonstrated effect occurred equally in the younger infant and the older child. Because they studied children as old as 36 months of age, the entire effect could have been in older children; this subgroup might have had RSV in either of the two previous seasons, and at the time of this study, they might have had the post-RSV reactive airways disease (2) that responds to montelukast. It is interesting that the two study groups had similar levels of nasal cysteinyl leukotrienes with a slight reduction after treatment and recovery from the acute illness. It has been shown both in tissue culture (6) and weanling rats (13) that the effect of RSV on 5-lipoxygenase gene expression is transient. It is maximal by 3 days, reduced by 5 days, and completely resolved by 30 days. This time course suggests that leukotriene production/release rapidly returns to baseline after the early phase of viral infection. One reason that a significant difference between treatment groups was not observed at 2 months after enrollment may have been either that treatment was not started early enough in the illness or that cysteinyl leukotrienes are not elevated at 2 and 3 months after the illness. Perhaps this population had high cysteinyl leukotrienes during the course of illness, and the selected dose was effective only at lower levels during the recovery phase. It would have been useful to associate the responders and nonresponders to the levels of cysteinyl leukotrienes. This observation raises the question of whether montelukast at a higher dose or an inhibitor of leukotriene synthesis would be more effective. The dose–response relationship for young children with an acute illness secondary to viral infection is unknown. The study highlights the prolonged duration of morbidity associated with RSV bronchiolitis. The major symptom, however, was cough. It would have been useful to compare the symptom scores for the two treatment arms over the course of illness. It does not appear that montelukast had a significant effect on the early course of the disease, although there was a pattern for less supplementary steroid therapy. In addition, the time for a recurrent exacerbation was delayed and less frequent, although not statistically different. They suggest that a sample size of 300 could test the outcome of significant exacerbations. Perhaps the next step is to assess the effect in a younger population, including a sample size sufficient to evaluate the outcome of significant exacerbations. The questions derived from this study include the following: Should treatment be started at the onset of illness? Should the duration of treatment be 28 days or, based on corticosteroid studies, 2 months? Would continuous treatment in patients at risk for recurrent illness attenuate respiratory symptoms over the RSV season? Would additive therapy, such as a short course of inhaled or oral steroids, with montelukast provide more significant effects? Would the effect seen only in the 1st month after a respiratory infection caused by RSV be extended to more long-term outcomes if the study included (1) infants with first time respiratory infection caused by RSV, (2) early treatment of lower respiratory infection (even mild), (3) higher doses, or (4) longer therapy? These preliminary observations will catch the attention of clinicians seeking treatment for these patients. Some caution, however, is needed. First, the drug in the available chewable tablet is approved for use only in children 2 years of age and older. A new formulation will be released that will be suitable for administration and approved down to 1 year of age. The profile for this approval is largely based on safety and pharmacokinetic evaluation. Second, the primary benefits are related to cough reduction in the later course of the illness. More information is needed to determine whether there is indeed a reduction of more disconcerting features associated with the acute onset of illness. In addition, safety and efficacy studies are needed in the younger age group where the incidence is the highest. It would also be useful to see whether this treatment can alter the natural history of persistent asthma that has been associated with RSV. To date, there is no indication that any of our treatments, including inhaled corticosteroids, can prevent the onset of asthma or alter the course of illness except during the administration of the medication. Nevertheless, the investigators must be congratulated on making this interesting observation that will resurrect interest in developing more effective treatment strategies for RSV-associated bronchiolitis and its sequelae. REFERENCES
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