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Ninewells Hospital and Medical School Dundee, Scotland
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: b.j.lipworth{at}dundee.ac.uk
To the Editor:
I read with interest the recent articles in CHEST (August 2000) by Nathan et al1 and 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 cosyntropin stimulation.
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 dose.3
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 study4 in 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 excretion.
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.
References
Colorado Springs, CO Hartford, CT
Correspondence to: Robert A. Nathan, MD, FCCP, Asthma and Allergy Associates, P.C., 2709 North Tejon St, Colorado Springs, CO 80907-6231
To the Editor:
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 cortisol results.
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. Lipworth.5 6
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,10 which 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 12 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 15 16 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.
References
This article has been cited by other articles:
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  M. E. Purucker, C. J. Rosebraugh, F. Zhou, and R. J. Meyer Inhaled Fluticasone Propionate by Diskus in the Treatment of Asthma: A Comparison of the Efficacy of the Same Nominal Dose Given Either Once or Twice a Day Chest, October 1, 2003; 124(4): 1584 - 1593. [Abstract] [Full Text] [PDF]
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F. Caballero-Fonseca, M. Sanchez-Borges, and G. R.G. Todd Adrenal Suppression Related to Inhaled Corticosteroids Revisited Chest, September 1, 2002; 122(3): 1103 - 1104. [Full Text] [PDF]
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