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Communications to the Editor |

Salmeterol, Inhaled Corticosteroids, and Tolerance to Allergen Bronchoprotection Salmeterol, Inhaled Corticosteroids, and Tolerance to Allergen Bronchoprotection FREE TO VIEW

Donald W. Cockcroft, MD, FCCP; Beth E. Davis, BSc; Veronica A. Swystun, BSc
Author and Funding Information

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



Chest. 1999;116(5):1497-1498. doi:10.1378/chest.116.5.1497
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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 FEV1.57 A careful look at the two studies cited by Giannini et al34 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 studies67; 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.

Giannini, D, Bacci, E, Dente, FL, et al (1999) Inhaled beclomethasone dipropionate reverts tolerance to the protective effect of salmeterol on allergen challenge.Chest115,629-634. [PubMed] [CrossRef]
 
Giannini, D, Carletti, A, Dente, FL, et al Tolerance to the protective effect of salmeterol on allergen challenges.Chest1996;110,1452-457. [PubMed]
 
Pizzichini, MMM, Kidney, JC, Wong, BJO, et al Effect of salmeterol compared with beclomethasone on allergen- induced asthmatic and inflammatory responses.Eur Respir J1996;9,449-455. [PubMed]
 
Dahl, R, Johansson, S-A Importance of duration of treatment with inhaled budesonide on the immediate and late bronchial reaction.Eur J Respir Dis1982;63(suppl 122),167-175
 
Burge, PS, Efthimiou, J, Turner-Warwick, M, et al Double-blind trials of inhaled beclomethasone dipropionate and fluocortin butyl ester in allergen-induced immediate and late reactions.Clin Allergy1982;12,523-531. [PubMed]
 
Cockcroft, DW, Swystun, VA, Bhagat, R Interaction of inhaled β2agonist and inhaled corticosteroid on airway responsiveness to allergen and methacholine.Am J Respir Crit Care Med1995;152,1485-1489. [PubMed]
 
Swystun, VA, Bhagat, R, Kalra, S, et al Comparison of 3 different doses of budesonide and placebo on the early asthmatic response to inhaled allergen.J Allergy Clin Immunol1998;102,363-367. [PubMed]
 

Salmeterol, Inhaled Corticosteroids, and Tolerance to Allergen Bronchoprotection

To the Editor:

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.25 All these studies considered patients with both EARs and late asthmatic responses (LARs) to allergens,24 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
Giannini, D, Bacci, E, Dente, FL, et al Inhaled beclomethasone dipropionate reverts tolerance to the protective effect of salmeterol on allergen challenge.Chest1999;115,629-634. [PubMed] [CrossRef]
 
Dahl, R, Johansson, S-A Importance of duration of treatment with inhaled budesonide on the immediate and late bronchial reaction.Eur J Respir Dis1982;6(Suppl 122),167-175
 
Burge, PS, Efthimiou, J, Turner-Warwick, M, et al Double-blind trials of inhaled beclomethasone dipropionate and fluocortin butyl ester in allergen-induced immediate and late reactions.Clin Allergy1982;12,523-531. [PubMed]
 
Cockcroft, DW, Swystun, VA, Bhagat, R Interaction of inhaled beta2-agonist and inhaled corticosteroid on airway responsiveness to allergen and methacholine.Am J Respir Crit Care Med1995;152,1485-1489. [PubMed]
 
Swystun, VA, Bhagat, R, Kalra, S, et al Comparison of 3 different doses of budesonide and placebo on the early asthmatic response to inhaled allergen.J Allergy Clin Immunol1998;102,363-367. [PubMed]
 

Figures

Tables

References

Giannini, D, Bacci, E, Dente, FL, et al (1999) Inhaled beclomethasone dipropionate reverts tolerance to the protective effect of salmeterol on allergen challenge.Chest115,629-634. [PubMed] [CrossRef]
 
Giannini, D, Carletti, A, Dente, FL, et al Tolerance to the protective effect of salmeterol on allergen challenges.Chest1996;110,1452-457. [PubMed]
 
Pizzichini, MMM, Kidney, JC, Wong, BJO, et al Effect of salmeterol compared with beclomethasone on allergen- induced asthmatic and inflammatory responses.Eur Respir J1996;9,449-455. [PubMed]
 
Dahl, R, Johansson, S-A Importance of duration of treatment with inhaled budesonide on the immediate and late bronchial reaction.Eur J Respir Dis1982;63(suppl 122),167-175
 
Burge, PS, Efthimiou, J, Turner-Warwick, M, et al Double-blind trials of inhaled beclomethasone dipropionate and fluocortin butyl ester in allergen-induced immediate and late reactions.Clin Allergy1982;12,523-531. [PubMed]
 
Cockcroft, DW, Swystun, VA, Bhagat, R Interaction of inhaled β2agonist and inhaled corticosteroid on airway responsiveness to allergen and methacholine.Am J Respir Crit Care Med1995;152,1485-1489. [PubMed]
 
Swystun, VA, Bhagat, R, Kalra, S, et al Comparison of 3 different doses of budesonide and placebo on the early asthmatic response to inhaled allergen.J Allergy Clin Immunol1998;102,363-367. [PubMed]
 
Giannini, D, Bacci, E, Dente, FL, et al Inhaled beclomethasone dipropionate reverts tolerance to the protective effect of salmeterol on allergen challenge.Chest1999;115,629-634. [PubMed] [CrossRef]
 
Dahl, R, Johansson, S-A Importance of duration of treatment with inhaled budesonide on the immediate and late bronchial reaction.Eur J Respir Dis1982;6(Suppl 122),167-175
 
Burge, PS, Efthimiou, J, Turner-Warwick, M, et al Double-blind trials of inhaled beclomethasone dipropionate and fluocortin butyl ester in allergen-induced immediate and late reactions.Clin Allergy1982;12,523-531. [PubMed]
 
Cockcroft, DW, Swystun, VA, Bhagat, R Interaction of inhaled beta2-agonist and inhaled corticosteroid on airway responsiveness to allergen and methacholine.Am J Respir Crit Care Med1995;152,1485-1489. [PubMed]
 
Swystun, VA, Bhagat, R, Kalra, S, et al Comparison of 3 different doses of budesonide and placebo on the early asthmatic response to inhaled allergen.J Allergy Clin Immunol1998;102,363-367. [PubMed]
 
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