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University of Dundee Dundee, Scotland
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{at}dundee.ac.uk
To the Editor:
The conclusion of Silkoff et al, in a recent issue of CHEST (April 2001),1 that 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 al2 showed, 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 al3 found 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 400 µg. 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
National Jewish Medical Center Denver, CO
Correspondence to: Philip E. Silkoff, MBBS, University of Colorado, National Jewish Medical Center, 1400 Jackson St, Denver, CO 80206; e-mail: silkoffp{at}njc.org 
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 1,600 µg. 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
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