LETTERS TO THE EDITOR Sodium cromoglycate in childhood asthma

The review of placebo controlled trials of sodium cromoglycate (SCG) in childhood asthma by Tasche et al concludes that “there is insuYcient evidence that SCG has a beneficial eVect as maintenance treatment in children with asthma”. We do not believe this conclusion is justified. The principal criteria for assessing the eYcacy of inhaled SCG are the mean diVerences in the eVect on the symptoms of cough and wheeze between SCG and placebo across all trials included in the review. The 95% confidence intervals for these diVerences are 0.12 to 0.27 for cough and 0.11 to 0.26 for wheeze. As the diVerences are in favour of SCG and the confidence intervals do not include zero, the only conclusion that can be drawn is that there is strong statistical evidence for a beneficial eVect of SCG in children with asthma—the reverse conclusion to that presented. The review identified 24 randomised controlled trials and is claimed to include “all published randomised, placebo controlled trials”. Two published trials are not included (those by Berman et al and Mikawa et al) and the trial by Silverman et al, which is included, does not meet the author’s criteria. Both excluded trials, which involved 472 children, reported statistically significant differences in favour of SCG compared with placebo. The study by Silverman et al compared the combination of inhaled SCG and isoprenaline with isoprenaline alone and did not include a placebo comparison. The authors have calculated a tolerance distribution for study eVects and we believe it is this distribution which has been fundamentally misinterpreted. They provide a tolerance interval for the results of future studies based on the between study variation seen. The fact that this interval contains zero does not mean that there is no evidence of a diVerence between treatments, as the authors imply, but that not all future studies can be predicted to give a diVerence numerically in favour of SCG. The tolerance interval quoted suggests that perhaps 90% of future trials will have an outcome in favour of SCG, a really positive finding. This is, of course, entirely consistent with the data from studies used in the review which indicates that, although some studies are directionally in favour of placebo, the vast majority are in favour of SCG. The fact that a few of the studies are in favour of placebo is not surprising since the authors reject the null hypothesis of homogeneity. In the comment section of the paper the authors state that older studies were more likely to produce a positive eVect of SCG treatment. Inhaled SCG was originally developed as a capsule containing 20 mg of dry powder of SCG to be inhaled four times a day using a special inhalation device, the Spinhaler, and its eYcacy was established in trials involving children aged 5–17 years. Twelve trials included in this review use this dose and inhaler system, of which 11 are described as positive and one as positive/equal. All were published between 1968 and 1980. Examination of the mean diVerences for severity scores shows that, in all 12 trials, the 95% confidence intervals do not include zero and inhaled SCG is therefore statistically (p<0.05) significantly better than placebo. The remaining 12 studies were published between 1980 and 1997. All used diVerent inhalation systems, dosage schedules and, in some cases, a diVerent diagnosis from the earlier trials. In nine trials the drug was delivered as a nebulised solution at a dosing schedule of 20 mg 3–4 times daily, two used a 5 mg metered dose inhaler (MDI), and one used a 1 mg MDI. The age range of the children in these trials was from 0 to 6 years, with many under 1 year of age. Of the nine trials which used a nebuliser solution, four were in children with asthma, two in children with wheezy bronchitis, and one each in children with persistent wheezing, recurrent wheezing, and preterm babies with respiratory symptoms. Four were classed as positive (0–6 years), one as equal/positive (0–2 years), and four as equal (0–4 years). The MDI formulations were introduced 10–15 years after the original capsule formulation. The one trial using the 1 mg MDI conducted in children aged 4–13 years was classed as positive/equal. Of the two trials which used the 5 mg MDI, one was conducted in patients for whom the drug is not indicated—recurrent respiratory symptoms in preterm babies at a dose of 5 mg three times daily using a coVee cup as a spacer— and the other was conducted by the authors of this paper in a general practice setting in children aged 1–4 years and it has already been pointed out that the delivery system used may not have provided an adequate dose. 6 They also used less than the recommended dose (three times a day rather than four) and an incorrect dosing method (two puVs into the spacer for one inhalation). In view of the major flaws in this trial it is diYcult to understand how it scored highest in the methodological assessment of the trials. One can only conclude that the outcome of this one trial has influenced the conclusion drawn by the authors and they have chosen to ignore the 16 positive and the three positive/equal trials of the 24 they reviewed. This more detailed examination of the sequencing of the trials does show that the main trials that clearly demonstrate the eYcacy of the drug in childhood asthma were conducted in children over the age of 5 years with the drug delivered as a dry powder using the Spinhaler at a dose of 20 mg four times a day. They were published before 1980. The trials published after 1980 were conducted mainly in children aged less than 5 years using either nebulised solution or metered dose aerosols. As the authors rightly state, “diagnosis and measurement of asthma in young children is diYcult”. It is therefore not surprising that in these later trials it has proved more diYcult to demonstrate consistently the eYcacy of SCG. It appears that the authors’ conclusions of lack of beneficial eVect are based mainly on their own trial and trials conducted in younger age groups using nebuliser solution. While it is possible that the drug is less eVective in the younger age groups, it is more likely that the apparent lesser eVect in these children is related to the diYculties of diagnosis, assessment, and drug delivery. The authors identified 251 articles in their Medline search but only 18 met their inclusion criteria. Many of the excluded articles are supportive of the use of SCG in childhood asthma. They also refer to a number of other review articles but ignore the fact that these were all positive towards the drug, preferring their own conclusions. Finally, the authors further conclude that they doubt whether the eVect seen is of clinical relevance but also point out that mean symptom scores in childhood asthma studies are generally low due to dilution by symptom-free days. In these circumstances the estimated size of eVect may well have clinical relevance. The analysis as presented provides very strong evidence of statistically significant benefits in favour of SCG for the key symptoms of cough and wheeze; this would be strengthened further by the inclusion of all published studies and further still if only those studies which identified a clear asthmatic population were included. Despite the fact that we consider this review to have major flaws, we believe that the results have been misinterpreted, that it does show clearly and significantly that inhaled SCG is of benefit in childhood asthma, and it cannot be used to draw the conclusion of the authors.