Safety of intranasal steroids

Correspondence Safety of intranasal steroids To the Editor: The recent article by Wilson et al (J Allergy Clin Immunol 1998; 101 :470-4) rather startled me, and I was concerned that the hitherto good safety record of intranasal steroids might have come into question. The authors fail to take into account, or discuss, the large body of contrary evidence that exists in the literature. The "headline" finding that intranasal steroids reduce urinary cortisol levels by between 21 % and 43% is misleading because this is an inappropriate method with which to assess this sort of effect. In fact the autJ}ors' own findings with creatinine-corrected cortisol levels and low-dose adrenocorticotropic hormone challenge rather confirm the safety of intranasal steroids. It is curious that an apparently more sensitive method of assessment (creatinine-corrected data) has in fact shown no statistical differences, whereas the uncorrected and more variable data did achieve significance. The authors cite 2 published references to add weight to their contention. The article by Knutsson et all was flawed in its design in that it did not include a placebo group. The changes that were observed are consistent not with a systemic effect of nasal steroids but with changes over time. The study by Foresi et al 2 also does not provide support for a systemic effect of steroids as speculated. The effects attributed to fluticasone propionate (FP) are consistent with an effect of a topical steroid, having a topical anti-inflammatory effect and subsequently diminishing the signal to the bone marrow,3 which indirectly diminishes the level of circulating eosinophils. The topic of systemic effects of inhaled steroids has been the subject of study in the past by the authors and their colleagues. By using their data on FP and that of others, it is possible to calculate the approximate plasma levels of fluticasone that would be required (as it is a sine qua non that to influence plasma cortisol levels an appropriate concentration of an exogenous steroid must be present in the plasma) to cause a fall of approximately 50% in plasma cortisollevels. The approximate 24-hour area under the curve of FP to achieve a mean fall of 50% in plasma cortisol levels is 3200 pg·h/mL. The highest blood level that has been reported after intranasal dosing is 68 pg·h/mL.4 The level after 500 /lg FP twice daily in the lung is approximately 1000 pg·h/mL, and this is approximately the level in volunteers at which one sees the threshold of a change in plasma cortisol levels. It appears that even to detect the threshold of change in plasma cortisol levels after intranasal dosing, approximately 50 times the therapeutic dose of FP would have to be given as a single dose. To achieve the approximately 50% reduction in cortisol levels reported by the authors, the whole contents of 12 bottles would have to be administered as a single dose! I am concerned that other readers of this journal might, like me, take this data at its face value initially, and I would urge caution and care in the interpretation of it. I remain convinced of the safety of the intranasal corticosteroids when used at recommended dosages. Claus Bachert, MD, PhD ENT Department University a/Ghent De Pintelaan 185 B-9000 Ghent Belgium REFERENCES 1. Knutsson PU. Stierna P, Marcus C, Carlstedt-Duke J, Carlstrom K. Bronnegard M. Effects of intranasal glucocorticoids on endogenous glucocorticoid peripheral and central function. J Endocrinol 1995:144:301-10.

2. Foresi A. Pelucchi A, Gherson G, Mastropasqua B. Chiapparino A, Testi R. Once daily intranasal fluticasone propionate (200 ~g) reduces nasal symptoms and inflammation but also attenuates the increase in bronchial responsiveness during the pollen season in allergic rhinitis. J Allergy Clin Immunol I 996;9R:274-82. 3. Wood LJ, Inman MD, Dcnburg JA, OByrne PM. Allergen challenge increases cell traffic between bone marrow and lung. Am J Respir Cell Mol BioI 1998;18:759-67. 4. Daley-Yates P, McAllister T. Systemic bioavailability of fluticasone propionate administered as nasal drops and aqueous nasal spray formulations. Allergy 1998;53(SuppI43):412.

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Reply To the Editor: In response to the letter of Dr Bachert. we wish to make the following points. In our article (J Allergy Clin Immunol 1998;101:470-4) we showed the same overall trend for suppression of overnight urinary cortisol excretion as for creatinine-corrected urinary cortisol excretion. For the latter, compared with the randomized placebo value, intranasal fluticasone propionate produced 17% suppression as compared with 4% suppression for triamcinolone acetonide and 17% for beclomethasone dipropionate, although this was not significant. It is incorrect to say that the creatinine-corrected cortisol secretion is the more sensitive method because by definition it comprises the combined variance of 2 separate endpoints. The magnitude of mean suppression of uncorrected overnight urinary cortisol with fluticasone compared with the randomized placebo (43% difference) was more than 2-fold greater than the mean difference between the nonrandomized placebo and the randomized placebo (18% difference). It was also evident that the 95% confidence interval for the mean difference between fluticasone versus the randomized placebo excluded zero (95% CI, 1% to 67%), although there was a considerable degree of intraindividual variability in response, as indicated in Fig I of our paper. We used Bonferroni multiple-range testing set at 95% confidence limits, which is a robust statistical comparison, as well as obviating multiple pairwise comparisons, Also, as we stated in the statistical analysis section of our paper, the study was powered to detect a 20% difference in uncorrected overnight urinary cortisol as the primary endpoint. We therefore feel entirely justified in making our conclusions regarding the significant suppression of overnight urinary cortisol excretion with intranasal fluticasone 200 /lg/day. In contrast we found no detectable effect on the cortisol response to stimulation with low-dose (0,5 /lg) cosyntropin. This is not surprising because it would be expected to take a more prolonged period of treatment with exogenous corticosteroid to produce any detectable degree of impaired adrenocortical reserve as a consequence of attenuated secretion of corticotropin-releasing hormone and corticotropin hormone from the hypothalamus and pituitary gland, respectively. This emphasizes the point that cosyntropin stimulation is not an appropriate test to evaluate the systemic bioactivity of exogenous corticosteroids administered in the short term. The study of Foresi et all showed that there was significant suppression of peripheral blood eosinophil count (a 38% fall) but no associated effect on serum eosinophilic cationic protein (a 17% rise). This dissociation in eosinophilic response would be more in keeping with an effect caused by the systemic bioavailability of intranasal fluticasone rather than its topical anti-inflammatory

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