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Communications to the Editor |

Duration of Steroid Therapy Determines Dose-Response Effect FREE TO VIEW

Brian J. Lipworth, MD
Author and Funding Information

Affiliations: University of Dundee Dundee, Scotland,  National Jewish Medical Center Denver, CO

Correspondence to: Brian J. Lipworth, MD, Professor of Allergy and Pulmonology, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland DD1 9SY; e-mail: b.j.lipworth@dundee.ac.uk



Chest. 2002;121(1):306-307. doi:10.1378/chest.121.1.306
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Published online

To the Editor:

The conclusion of Silkoff et al, in a recent issue of CHEST (April 2001),1that exhaled nitric oxide (NO) is superior to methacholine challenge in separating doses of inhaled steroid, does not stand up to close scrutiny, as the response is dependent on the duration of treatment, especially for methacholine challenge. In study A, the duration was only 1 week for each dose level, which would be sufficient to show a maximum effect on NO but not on bronchial hyperresponsiveness. For example, Vathenen et al2showed, with budesonide, 800 μg bid, that the improvement in histamine hyperresponsiveness was 1.3 vs 2.4 doubling doses after 3 weeks and 6 weeks, respectively. Kerrebijn et al3found a plateau in response to budesonide, 200 μg tid, after 3 months, while Van Essen-Zandvliet et al4 observed progressive improvement in bronchial hyperresponsiveness over a 20-month period of follow-up with budesonide, 200 μg tid. In other words, it is likely that the effect of the last dose after 4 weeks could be due to a carry-over effect from the previous two doses. Inspection of the data shows a clear numerical trend of a dose-response effect on the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20), even though there was no significant dose separation. It was evident that the variability in PC20 was considerable, due to a small sample size (n = 12), which is likely to have contributed to the inability to show a significant dose separation for this variable. For effects on NO, there was overlap of the confidence intervals comparing 100 μg vs 800 μg, as was the case for 100 μg vs 400μ g. Thus, with a larger sample size, it is likely that they would have observed better dose separation with methacholine than NO. This is supported by other dose- ranging studies, with a longer period of dosing at each dose. Data (n = 26) from Wilson and Lipworth,5 where doses of budesonide were administered for 3 weeks each (400, 800, and 1,600 μg/d) have shown clear evidence of a significant improvement for dose response in both methacholine and adenosine monophosphate challenge, with the maximal effect seen at 1,600 μg, in contrast to dosing with NO, where a plateau was seen at> 400 μg. These are similar to results reported by Jatakanon et al,6 where effects of dosing with budesonide for 4 weeks exhibited a plateau at 400 μg/d on NO, but at 1,600 μg/d on methacholine hyperresponsiveness. Thus, the results of Silkoff et al1 should be interpreted in the light of other data, where treatment has been administered for longer periods, and where methacholine challenge has been shown to be superior to NO, in order to evaluate dose-response effects of inhaled steroids.

References

Silkoff, PE, McClean, P, Spino, M, et al (2001) Dose-response relationships and reproducibility of the fall in exhaled nitric oxide after inhaled beclomethasone dipropionate therapy in asthma patients.Chest119,1322-1328. [PubMed] [CrossRef]
 
Vathenen, AS, Knox, AJ, Wisniewski, A, et al Time course of change in bronchial reactivity with an inhaled corticosteroid in asthma.Am Rev Respir Dis1991;143,1317-1321. [PubMed]
 
Kerrebijn, KF, Van Essen-Zandvliet, EEM, Neijens, HJ Effect of long-term treatment with inhaled corticosteroids and β-agonists on the bronchial responsiveness in children with asthma.J Allergy Clin Immunol1987;79,653-659. [PubMed]
 
Van Essen-Zandvliet, EEM, Hughes, M, Waalkens, H, et al Effects of 22 months of treatment with inhaled corticosteroids and or β2-agonists on lung function, airway responsiveness. and symptoms in children with asthma.Am Rev Respir Dis1992;146,547-554. [PubMed]
 
Wilson, AM, Lipworth, BJ Dose-response evaluation of the therapeutic index for inhaled budesonide in patients with mild to moderate asthma.Am J Med2000;108,269-275. [PubMed]
 
Jatakanon, A, Kharitinov, S, Barnes, PJ Effect of different doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma.Thorax1999;54,108-114. [PubMed]
 
To the Editor:

We welcome the comments of Dr. Lipworth regarding the comparison between exhaled nitric oxide (NO) and methacholine reactivity in separating doses of inhaled steroid. Our study looked at the short-term effects of administering doses, increased weekly, of inhaled beclomethasone on exhaled NO and PC20 methacholine, in a small number of asthmatic subjects.

First, there are important differences in the time courses of response of these two measures of asthma outcome. Exhaled NO is a rapidly responding marker, as seen in a previous study of ours where the maximal fall of NO after 1,000 μg inhaled beclomethasone was complete after only one week.1 This was the basis for selecting periods of 1 week for each dose level in this study. Thus, it is difficult to compare exhaled NO with PC20 methacholine, where the maximal response takes several months.

Second, we agree that, with dose intervals of 1 week, there may have been carry-over effects from the previous dose. We mentioned this in the “Discussion” section.

Third, it is true that, in all subjects combined, the exhaled NO response plateaus at 400 μg, while in the publications referred to by Dr. Lipworth, PC20 methacholine plateaus at 1,600μ g. However, because the potential for a parameter to change depends on its absolute value, exhaled NO plateaus at > 800 μg/d in those subjects with very high baseline exhaled NO, as shown in Figure 1 of our manuscript. Our study is limited, however, by a small number of subjects.

A dose-response relationship for an asthma outcome measure could lead to the ability to tailor the dose of inhaled steroids. Because exhaled NO reacts rapidly, this could be performed in a short period, whereas with PC20 methacholine, several months might be necessary.

Before closing the chapter comparing dose responses between exhaled NO and PC20, there is a need to perform further studies of inhaled steroid dose-response in a larger number of subjects, looking at exhaled NO and PC20 methacholine over longer periods of time, while controlling for baseline values as covariates.

References
Silkoff, PE, McClean, PA, Slutsky, AS, et al Exhaled nitric oxide and bronchial reactivity during and after inhaled beclomethasone in mild asthma.J Asthma1998;35,473-479. [PubMed] [CrossRef]
 

Figures

Tables

References

Silkoff, PE, McClean, P, Spino, M, et al (2001) Dose-response relationships and reproducibility of the fall in exhaled nitric oxide after inhaled beclomethasone dipropionate therapy in asthma patients.Chest119,1322-1328. [PubMed] [CrossRef]
 
Vathenen, AS, Knox, AJ, Wisniewski, A, et al Time course of change in bronchial reactivity with an inhaled corticosteroid in asthma.Am Rev Respir Dis1991;143,1317-1321. [PubMed]
 
Kerrebijn, KF, Van Essen-Zandvliet, EEM, Neijens, HJ Effect of long-term treatment with inhaled corticosteroids and β-agonists on the bronchial responsiveness in children with asthma.J Allergy Clin Immunol1987;79,653-659. [PubMed]
 
Van Essen-Zandvliet, EEM, Hughes, M, Waalkens, H, et al Effects of 22 months of treatment with inhaled corticosteroids and or β2-agonists on lung function, airway responsiveness. and symptoms in children with asthma.Am Rev Respir Dis1992;146,547-554. [PubMed]
 
Wilson, AM, Lipworth, BJ Dose-response evaluation of the therapeutic index for inhaled budesonide in patients with mild to moderate asthma.Am J Med2000;108,269-275. [PubMed]
 
Jatakanon, A, Kharitinov, S, Barnes, PJ Effect of different doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma.Thorax1999;54,108-114. [PubMed]
 
Silkoff, PE, McClean, PA, Slutsky, AS, et al Exhaled nitric oxide and bronchial reactivity during and after inhaled beclomethasone in mild asthma.J Asthma1998;35,473-479. [PubMed] [CrossRef]
 
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