© 2004 American Thoracic Society
Montelukast in Respiratory Syncytial Virus PostbronchiolitisTo the Editor:We read with interest Bisgaard's (1) randomized trial of montelukast in respiratory syncytial virus (RSV) postbronchiolitis. Although the author's conclusion was that "cys-LT [cysteinyl-leukotrienes] antagonist treatment reduces lung symptoms subsequent to RSV bronchiolitis," a more skeptical judgment may be formed on the basis of the following points. The median duration of illness in ambulatory children younger than 2 years diagnosed with bronchiolitis is 12 days, and 9% are still symptomatic at 4 weeks (2). Postbronchiolitis reactive airways disease, which may account for an important subgroup of children with asthma, refers to recurrent wheezing once bronchiolitis has resolved (3). The early therapy for the first 4 weeks, as well as the significant outcome differences during the treatment period, contrast with the author's conclusion of "clinical improvement of RSV postbronchiolitis RAD [reactive airway disease]." The author does not clearly define the chronology of the symptoms to be resolved. Moreover, the study population, with a wide age range (3–36 months), may have included children with RSV in either of the two previous seasons (4). Eligible patients had moderate to severe symptoms requiring hospital admission. In this context, the low proportion (29%) of patients requiring supplemental oxygen suggests a more benign clinical course, likely confirmed by a mean composite symptom score of the placebo group less than 1. Patients with a more severe course of RSV bronchiolitis are at greater risk for recurrent wheezing (5), and it is likely that this sample is less representative of the target population of those interventions aimed to prevent postbronchiolitis reactive airway disease. Despite the declared intention-to-treat analysis of data and a clear participant flow, those who did not return the diary for the treatment period (11% of those randomized) were not considered. We missed a sensitivity analysis, which if done may have significantly changed the results and, consequently, the conclusion. Moreover, the author states that the days with missing values were excluded from analysis, but at the same time it can be interpreted from Figure 2 (see Reference 1) that they were considered to be symptomatic days. No data on the number of days with missing values are provided. The assessment instrument used (6), originally validated in children with asthma aged 2 to 5 years on regular therapy, seems inappropriate due to the younger age of the study population and the likely inferior competence of their caregivers to assess respiratory symptomatology. Although we are aware that these limitations can be in part overcome with adequate training of parents, it should have been described if done.
University Hospital La Fe Valencia, Spain FOOTNOTES Conflict of Interest Statement: J.A.L-A., I.C-A., and V.R-G. do not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
From the Authors: Regrettably, we fail to understand the points raised by Dr. López-Andreu and colleagues regarding the severity of patients in our trial (1). Clearly, our patients were more severe than patients seen in outpatient clinics. Likewise, our patients did not belong to the most severe category of respiratory syncytial virus (RSV) bronchiolitis. Our study population was clearly detailed in our article as patients hospitalized with RSV-bronchiolitis in pediatric hospitals. We made no statements regarding any other group of patients other than those included in the analysis. We fail to understand why Dr. López-Andreu and colleagues would claim that the primary outcome (22% versus 4% symptom-free days) contrasts with our conclusion of a clinical improvement of RSV postbronchiolitis. The argument that some of the children included in the study may have had previous RSV infections is obviously correct. However, the issue seems irrelevant for the treatment effect documented. Because some diaries were not returned, no efficacy data were available for these patients. Although patients on placebo may be less likely to return the diaries, a comparison between montelukast and placebo groups for return was not statistically significant (p = 0.09). Moreover, the median score was used, which is much less sensitive to individual results, particularly given a 4% versus 22% difference for symptom-free days and nights. In all descriptive and test statistics, days with missing diary cards are excluded (see METHODS in Reference 1). The percentage of symptom-free days (see the tables in Reference 1) are expressed as a percentage of the days that were symptom-free divided by the total number of days with complete diary card (maximum 28 days). In Figure 2 of our article (see Reference 1), missing days are necessarily imputed because a continuous cumulative number of symptom-free days were calculated each day—expressed as a percentage of elapsed days. The conservative approach used for the figure is to assume that the missing days are symptomatic. There is no discrepancy between these presentations in the tables and in Figure 2 of our article (1). The number of days with missing symptom score is consistent between treatment groups with a median number of 0 days with missed diary cards in both treatment arms, and associated quartiles are 0 to 1 for each treatment. The Pediatric Asthma Caregiver Diary was successfully validated for both reliability and construct validity within this age group using this study and a manuscript is currently in preparation. In addition, the caregivers in this study were given considerable instruction and follow-up on use of the diary.
National Jewish Medical and Research Center Denver, Colorado FOOTNOTES Conflict of Interest Statement: H.B. has within the last 3 years received honoraria for lectures and attendance at pediatric advisory boards for Aerocrine, AstraZeneca, GlaxoSmithKline, Hoffman-La-Roche, Merck, Novartis, and Yamanouchi. H.B. holds no stock options in the pharmaceutical industry in the respiratory field. H.B. owns a world patent for an inhaler device but receives no royalty. The COPSAC clinical research unit has in the last 3 years received research grants from the following industry partners in increasing order: Aerocrine, Merck, GlaxoSmithKline, and AstraZeneca. REFERENCES
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