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University of Saskatchewan, Saskatoon, Saskatchewan, Canada
Correspondence to: Donald W. Cockroft, MD, FCCP, University of Saskatchewan, Division of Respiratory Medicine, 103 Hospital Dr, Ellis Hall, Saskatoon, SK, Canada S7N 0W0
To The Editor:
We read with great interest the report by Giannini et al (March 1999)1 suggesting that regular use of inhaled beclomethasone dipropionate (BDP) might partially inhibit the development of tolerance to the bronchoprotective effect of salmeterol against allergen challenge. In 12 atopic asthmatic subjects, they initially confirm their previous observation2 that 7 days of salmeterol therapy, 50 µg bid, results in almost complete loss of the bronchoprotective effect of a single dose of salmeterol against allergen-induced early asthmatic response (EAR). Subjects then were entered into a double-blind parallel trial in which all subjects received BDP, 500 µg bid, for a week accompanied by either placebo or salmeterol, 50 µg bid. In the six subjects receiving salmeterol and BDP, the EAR at 1 week was improved compared to that after 1 week of salmeterol adminstration alone. The authors suggest that this was the result of BDP reducing the tolerance to salmeterol rather than a direct effect of BDP on baseline (ie, without salmeterol therapy) EAR. Their conclusions are based on the failure of BDP alone to significantly alter the EAR in the other six subjects; two references are cited in support of this conclusion.3 4
In contrast to their claims, several investigators have shown that a
week of inhaled corticosteroid therapy, often at substantially lower
doses than BDP, 500 µg bid, inhibits the allergen-induced EAR by
50%, which is equivalent to more than or equal to a doubling of a
provocative concentration of allergen causing a 20% fall in
FEV1.5
6
7
A careful look at the two
studies cited by Giannini et al3
4
shows that the first
involved a single dose of BDP,3
which is well recognized
to have no influence on the EAR, and the second4
documented a 30% reduction in EAR evaluated by peak expiratory flow
rate after 1 week of treatment with budesonide. There is marked
interindividual variability in the effect of inhaled corticosteroids on
allergen-induced EAR as documented by Burge et al5
and
seen in the course of our own studies6
7
; this supports
the superiority of the cross-over design for this type of study. In
summary, since most studies demonstrate that a week of inhaled
corticosteroid therapy produces similar improvement in the EARs of
patients as that demonstrated by Giannini et al1
in six
subjects receiving BDP plus salmeterol, the conclusion that BDP
partially reverses the tolerance produced by the regular use of
salmeterol must be accepted with caution and requires confirmation by a
study with a cross-over design.
References
Ospedale di Cisanello, Pisa, Italy
Correspondence to: Daniele Giannini, MD, U.O. Fisiopatologia Respiratoria, Ospedale di Cisanello, Via Paradisa 2, 56100 Pisa, Italy
To the Editor:
The observations about our report (March 1999)1 are important and appropriate, and they particularly highlight the difficulty in finding the best design for this type of study. Actually, several studies have demonstrated that regular treatment with inhaled corticosteriods can reduce early asthmatic response (EAR) to allergens.2 3 4 5 All these studies considered patients with both EARs and late asthmatic responses (LARs) to allergens,2 3 4 and in some studies the LAR was stopped immediately after the EAR by short-term treatment with corticosteroids.5 In all these studies, a large variability in the ability of corticosteroids to protect individual patients experiencing EARs was observed. In contrast to the subjects in these studies, those in our study had mild cases of asthma that did not require regular treatment and who did not experience LAR during the screening baseline allergen challenge. No studies evaluated the effect of inhaled corticosteroids on EAR in this particular subpopulation of patients.
Our study was a double-blind placebo-controlled trial: the subjects were randomized to receive beclomethasone dipropionate (BDP) accompanied by placebo or salmeterol. After receiving BDP plus placebo, subjects showed a response to the allergen challenge similar to that observed during the screening provocative test, in terms of changes in FEV1 level at each time point of the EAR. The unequivocal positive response of the subjects to the allergen, in terms of area under curve and maximal percentage change in FEV1, after receiving BDP plus placebo, showed that the partial protection against EAR observed in the group treated with salmeterol plus BDP was not due to treatment with inhaled corticosteroid alone.
Our study investigated a very select population of patients: those with mild forms of asthma who had never been regularly treated before the trial and who had positive EARs to the allergen. To determine the effect of different therapies against allergen challenge, it is mandatory to have subjects who have not been treated before. Our study population permitted evaluation of the baseline response to the protective effect of the study drug and the change obtained after regular treatment with it. A study with a cross-over design would not permit treatment of patients during the two randomized sequences of treatment, for the same time period as in our study. These limitations of the cross-over design are not present when regularly treated subjects are considered.
In conclusion, even considering the limitations we have suggested, the absolute absence of protection against EAR in the control group and the validity of the parallel-groups design make our study results reliable.
References
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