Dear Editor

We thank Dr Lee for his interest in our reports.[1,2] However, he appears to confuse the terms “treatment failure� and “non-responder�. “Treatment failure,� as defined in the original report for our study,[1] referred to a clinical outcome (a composite endpoint of hospitalization, need for excluded medication, or need for prolonged acute asthma treatment in the emergency setting). In contrast, “non-responders� generally refers to a subset of patients who fail to surpass a defined threshold of response. As we have commented previously using chronic asthma as an example, simplistic “responder/non-responder� analyses often fail to account for clinically important aspects of disease variability and the impact of treatment intervention.[3] Moreover, in our initial report of intravenous montelukast in acute asthma,[1] a systematic analysis of baseline variables did not identify any factor which predicted response to intravenous montelukast, in terms of either FEV1 or treatment failures, with the exception of baseline FEV1.

The present report [2] addressed the relationship between FEV1 and cysteinyl leukotriene production, as measured by LTE4 excretion. A similar analysis of treatment failures and LTE4 levels is complicated by the fact that unlike baseline FEV1 which was measured before administration of study drug, treatment failures tended to be reduced by intravenous montelukast.[1] Nevertheless, 27/201 patients (15 (11.1%) in the montelukast group and 12 (18.2%) in the placebo group) met one or more of the criteria for treatment failure during the study. Of these, 20 patients had LTE4 data for analyses. Compared to patients who did not meet the criteria for treatment failures and who had LTE4 data available (n=161), LTE4 levels were numerically higher at baseline in the treatment failure group, although this did not reach statistical significance (see Table 1). Were Dr Lee’s hypothesis correct, LTE4 levels should have been lower amongst treatment failures. Accordingly, the data suggest that rather than serving as a useful predictor of clinical outcome, elevated LTE4 levels are more likely a marker of worsened acute asthma severity, consist with our analyses of LTE4 levels and FEV1.[2] Taken together, the data provide a strong biological rationale for the observed benefit of antileukotriene therapy in acute asthma.[1]

Table 1 LTE4 levels (pg/mg creatinine) during Acute Period By Clinical Outcome

 

Clinical Outcome	N	Mean 1	95% Confidence Interval
Treatment Failure	20	121.6	(91.5;161.6)
No Treatment Failure	161	111.6	(100.0; 128.5)

1 Geometric Mean

References

1. Camargo CA, Smithline HA, Malice M-P, et al. A randomized controlled trial of intravenous montelukast in acute asthma. Am J Respir Crit Care Med 2003;167:528-37.

2. Green SA, Malice M-P, Tanaka W, Tozzi CA, et al.Increase in urinary leukotriene LTE4 levels in acute asthma: correlation with airflow limitation. Thorax 2004;59:100-4.

3. Zhang J, Yu C, Holgate ST, Reiss TF. Variability and lack of predictive ability of asthma and endpoints in clinical trials. Eur Resp J 2002; 20:1102-1109.

Dear Editor

I read with interest the recent article by Green et al. [1] showing that in acute asthma, activation of leukotriene pathways correlated with the degree of airflow obstruction, and a reduction in leukotriene levels was associated with resolution of asthma exacerbation.

However, no analysis was performed on patients categorised as being in the treatment failure group, which was reported to be as high as 10% of patients receiving intravenous montelukast.[2]

The importance of this analysis can not be understated as not everyone with asthma respond to antileukotriene therapy[3,4] and non- responders have been reported to be as high as 50% in chronic asthma.[5]

It would have been interesting to observe urinary leukotriene LTE4 levels in the treatment failure group as it has been shown that cysteinyl leukotriene release from leukocytes of responders were higher than non- responders, which in turn correlated with response to antileukotriene therapy.[5]

References

1. Green SA, Malice M-P, Tanaka W, Tozzi CA, et al.Increase in urinary leukotriene LTE4 levels in acute asthma: correlation with airflow limitation. Thorax 2004;59:100-4.

2. Camargo CA, Smithline HA, Malice M-P, et al. A randomized controlled trial of intravenous montelukast in acute asthma. Am J Respir Crit Care Med 2003;167:528-37.

3. Wenzel SE. Antileukotriene drugs in the management of asthma. JAMA 1998;280:2068-9.

4. Drazen JM, Israel E, O’Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. N Engl J Med 1999;340:197-206.

5. Terashima T, Amakawa K, Matsumaru A, et al. Correlation between cysteinyl leukotriene release from leukocytes and clinical response to a leukotriene inhibitor. Chest 2002;122:1566-70.