Affiliations: University of Saskatchewan, Saskatoon, Saskatchewan, Canada ,
Ospedale di Cisanello, Pisa, Italy
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)1suggesting 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 observation2that 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.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
FEV1.5–7 A careful look at the two
studies cited by Giannini et al3–4 shows that the first
involved a single dose of BDP,3which 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 al5and
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.
The observations about our report (March
1999)1are 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.2–5 All these
studies considered patients with both EARs and late asthmatic responses
(LARs) to allergens,2–4 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
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.
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