Affiliations: Ninewells Hospital and Medical School
Colorado Springs, CO
Correspondence to: Brian J. Lipworth, MD, Asthma and Allergy Research Group, Department of Clinical Pharmacology & Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee DDI 95Y, Scotland; e-mail: firstname.lastname@example.org
To the Editor:
I read with interest the recent articles in CHEST
(August 2000) by Nathan et al1and ZuWallack et
al,2 who reported on the efficacy and safety of the
fluticasone propionate multidose dry-powder Diskus inhaler (Glaxo
Wellcome; Research Triangle Park, NC) in patients with moderate asthma.
Both studies1–2 concluded that fluticasone propionate in
doses up to 500 μg/d exhibited no significant systemic effects
compared with placebo on “morning” plasma cortisol before and after
These conclusions however ought to be interpretated with extreme
caution because of the sensitivity of the end points that were measured
in both studies. The exact timing for measurement of morning and
stimulated plasma cortisol is not given in either study, which is
crucial because of the known insensitivity of a spot morning cortisol
value within a variable sample window (eg, 8 am
to 10 am), as is commonly the case in these type of
multicenter studies.3 Moreover, the 250-μg dose of
cosyntropin is well recognized to represent a supraphysiologic dose and
is much less sensitive than, for example, a physiologic 1-μg
Consequently, one must assume that these types of studies are set up in
order not to detect significant systemic adverse effects using
insensitive end points. This is in contrast to a previous
study4in asthmatic patients where fluticasone propionate
dry powder in a dose of 500 μg/d produced significant suppression
(p < 0.01) of 24-h urinary cortisol excretion amounting to a 33%
reduction, along with a 70% reduction (p < 0.01) in peripheral
blood lymphocyte glucocorticoid messenger RNA levels—both consistent
with a significant degree of detectable systemic bioactivity. In
another study,5 also in asthmatic patients, fluticasone
produced a 40% suppression of overnight urinary cortisol/creatinine
It is therefore important to appreciate the appropriate use of
sensitive tests of hypothalmic-pituitary-adrenal–axis suppression when
evaluating exaggerated claims of no detectable systemic effects with
inhaled corticosteroid therapy.
We thank Dr. Lipworth for his interest in our
articles,1–2 although we note that his comments and
queries are very similar to those he has made regarding earlier
publications,3–4 and we believe that these queries were
comprehensively answered.5–6 We thank you for the
opportunity to provide the following response.
With regard to Dr. Lipworth’s comments on morning cortisol values,
blood samples were collected for these measurements in a narrow time
window, between 8 am and 10 am. The safety
conclusions stated in our articles were based mainly on the stimulated
The 250-μg cosyntropin test was the preferred test for assessing
hypothalamic-pituitary-adrenal (HPA)-axis function at the time this
study was planned. This point was previously addressed.5–6
We do not disagree that there is now more evidence that a lower dose of
cosyntropin is more sensitive; however, the clinical relevance of small
effects detectable with a more sensitive test has not yet been
validated. In addition, a previous study7 has demonstrated
that the 250-μg cosyntropin test is sensitive enough to differentiate
between two inhaled corticosteroids and oral prednisone, which has
well-defined clinical side effects; this point has been discussed
previously by Dr. Li in his response to Dr. Lipworth.6
In our studies,1–2 blood samples were collected 30
to 60 min after injections of cosyntropin. These poststimulation
cortisol measurements indicated that there were no clinically
relevant differences between the fluticasone propionate (FP) dosage
groups and placebo in response to cosyntropin. These results are
similar to those reported by Li et al,7 who measured both
peak plasma cortisol levels and 8-h cortisol area under curve (AUC)
values. Li et al5 found that both peak plasma and 8-h AUC
cortisol data were sensitive measures of HPA-axis function, since both
measures detected differences between the inhaled corticosteroids (FP
at 88 μg or 220 μg bid and triamcinolone acetonide at 200 μg qid
or 400 μg bid) and between the inhaled corticosteroids and oral
prednisone (10 mg qd). However, no differences were noted between the
two FP dosage groups with regard to poststimulation AUC or peak plasma
data. These results support the safety of inhaled corticosteroids at
recommended dosages and are consistent with current asthma treatment
guidelines, which emphasize the benefit of using inhaled steroids,
rather than oral steroids, as the anti-inflammatory treatment of choice
for maintenance therapy in asthma. This point has been reinforced
several times before in correspondence with Dr.
Regarding the data on human lymphocyte messenger RNA (mRNA)
mentioned by Dr. Lipworth,9 we find this data interesting
but would question the relevance at this point in time. For example,
while it is accepted that growth may be a more sensitive maker of
corticosteroid exposure than HPA-axis function in children, it is not
known at this time whether mRNA data may be extrapolated to clinically
relevant effects. While more markers that may prove useful in the
future are being explored, bone mineral density is relevant and
clinically meaningful. A 2-year study in asthmatics looking at the
effect of FP on bone mineral density failed to reveal any major safety
concerns.8 With regard to Dr. Lipworth’s reference to his
own work,10which showed a 40% suppression of overnight
urinary cortisol/creatinine excretion, this parameter is an indirect
measurement that is dissimilar from that used by other workers
and does not appear to be highly predictive of corticosteroid systemic
exposure.11–13 Furthermore, the conclusions drawn from
these results are divergent from, and disagree with, conclusions drawn
from a large body of clinical data.7–8,14–17
In summary, the primary objective of the two studies1–2 in
question was to compare the efficacy of various FP dosage
regimens, with the end goal of determining the lowest dosage of FP
required for the treatment of persistent asthma. We believe that the
results of these studies support the efficacy and safety of FP and
agree with current National Institutes of Health guidelines, which
recommend the use of inhaled corticosteroids as first-line treatment
for persistent asthma.
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