Inhaled β2-agonists and allergen-induced airway responses

Cockcroft, D.W.; Bhagat, R.; Kalra, S.; Swystun, V.A.

« Previous Next »The Journal of Allergy and Clinical Immunology
Volume 96, Issue 6 , Pages 1013-1014, December 1995

Inhaled β2-agonists and allergen-induced airway responses

Division of Respiratory Medicine, Royal University Hospital, University of Saskatchewan, Saskatoon, SK, S7N OW8, Canada

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To the Editor:

We were interested to read Dr. McFadden's opinions on β ₂-agonist therapy (Rostrum,J ALLERGY CLIN IMMUNOL 1995;95:641-51). Our opinions differ in several areas. We wish, however, to point out an error in McFadden's reanalysis of our data regarding salbutamol-induced increase in the allergen-induced early asthmatic response.¹ Dr. McFadden states that reanalysis of untransformed allergen PC ₂₀ data fails to show any significant effects between salbutamol and placebo.

Our investigation was designed to look for reduced functional antagonism of salbutamol versus allergen and was modeled after the study of O'Connor et al.,² substituting allergen as a mast cell stimulus that was more clinically relevant than adenosine monophosphate. We found an unexpected increase in airway response to allergen, almost double, after 2-week treatment with inhaled salbutamol, 200 μg four times daily, compared with placebo.¹ The untransformed and log-transformed data for the 11 subjects with complete data are shown in Table I. After the 2-week salbutamol treatment, 10 of 11 subjects showed increased airway response to allergen; the change in allergen PC ₂₀ was 50% or greater in five. PC ₂₀ values are not normally distributed; therefore, it is not appropriate to use parametric statistics on untransformed data. However, contrary to McFadden's claim, the calculations still show significance for untransformed data (p = 0.027), as well as for the log-transformed data (p = 0.0012) (Table I). Nonparametric tests might be more appropriate to use to analyze these data; we used several nonparametric tests and these all showed significance (p values ranged from 0.007 to 0.04).

TABLE I. Allergen PC ₂₀ after 2-week treatments with salbutamol and placebo

	Allergen PC ₂₀ (PNU/ml)			Log allergen PC ₂₀
Subject No.	Placebo		Salbutamol	Placebo		Salbutamol
1	1479		675	3.17		2.83
2	1264		1041	3.10		3.02
3	70		34	1.85		1.53
4	1188		868	3.07		2.94
5	3495		3846	3.54		3.59
6	312		148	2.49		2.17
7	79		38	1.90		1.58
8	625		130	2.80		2.11
9	391		130	2.59		2.11
10	364		244	2.56		2.39
11	1146		718	3.06		2.86
Mean difference		231			0.27
SD		296			0.20
Paired t test		2.59			4.49
p Value		0.027			0.0012

PNU, Protein nitrogen units.

Two subsequent studies have confirmed this finding in largely different subjects.³, ⁴ Two independent labs have shown that this effect extends to the more clinically relevant late asthmatic response.⁵, ⁶ Similar findings regarding salbutamol and exercise-induced bronchospasm have been observed.⁷

Inhaled allergens are the most important inflammatory stimuli in the pathogenesis of asthma. Enhanced allergen-induced airway responses,¹, ³, ⁴, ⁵, ⁶ and possibly enhanced allergen-induced airway inflammation⁶ after regular use of inhaled β ₂-agonists, are almost certainly highly clinically relevant. We believe that this significant effect of regularly used inhaled β ₂-agonists should not be ignored.

1/8/66385

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References

Cockcroft DW, McParland CP, Britto SA, Swystun VA, Rutherford BC. Regular inhaled salbutamol and airway responsiveness to allergen. Lancet. 1993;342:833–837

O'Connor BJ, Aikman SL, Barnes PJ. Tolerance to the nonbronchodilator effects of inhaled β ₂-agonists in asthma. N Engl J Med. 1992;327:1204–1208

Cockcroft DW, Swystun VA, Bhagat R. Interaction of inhaled β ₂ agonist and inhaled corticosteroid on airway responsiveness to allergen and methacholine. Am J Respir Crit Care Med. 1995; (in press)
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Bhagat R, Swystun VA, Cockcroft DW. Salbutamol-induced increased airway responsiveness to allergen and reduced protection vs methacholine: dose-response [Abstract]. J ALLERGY CLIN IMMUNOL. 1995;95:387
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Cockcroft DW, O'Byrne PM, Swystun VA, Bhagat R. Regular use of inhaled albuterol and the allergen-induced late asthmatic response. J ALLERGY CLIN IMMUNOL. 1995;96:44–49

Gauvreau GM, Watson RM, Jordana M, Cockcroft D, O'Byrne PM. The effect of regular inhaled salbutamol on allergen-induced airway responses and inflammatory cells in blood and induced sputum [Abstract]. Am J Respir Crit Care Med. 1995;151:A39
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Inman MD, O'Byrne PM. The effect of regular inhaled salbutamol treatment for 1 week on exercise-induced bronchoconstriction [Abstract]. Clin Invest Med. 1995; (in press)
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