© 2003 American Thoracic Society
Systemic effects of inhaled corticosteroidsTo the Editor:We were very interested in the paper by Martin and colleagues (1) comparing the systemic effects of six inhaled corticosteroid preparations. We too have been interested in developing techniques to enable the beneficial and adverse effects of different inhaled corticosteroids to be compared. Furthermore, we have been trying to explain what appeared to us to be an anomaly in the literature, namely that in healthy subjects or subjects with mild asthma short-term treatment with fluticasone propionate appeared to cause more suppression of the hypothalamic-pituitary-adrenal (HPA) axis than equivalent doses of budesonide, whereas in subjects with more severe asthma the differences between fluticasone propionate and budesonide are much smaller. To explore these differences further we compared the systemic effects of fluticasone propionate and budesonide given by their respective dry powder inhaler (DPI) in normal and subjects with asthma (2) and found that fluticasone propionate 1,500 µg/day had a greater effect on the HPA axis in healthy subjects than in subjects with asthma. This was not the case for budesonide, however. A further single dose study looking at plasma concentrations of the two drugs confirms that, after receiving the same dose, plasma fluticasone concentrations are higher in normal subjects compared with subjects with moderately severe asthma, whereas the budesonide plasma concentrations are almost identical in the two groups (3). Our findings with fluticasone are in keeping with the findings by Brutsche and colleagues (4), who gave fluticasone by MDI. They are also in keeping with the study by Weiner and colleagues (5), who showed a strong correlation between the systemic activity of fluticasone and FEV1 in subjects with asthma. The implication of these findings is that comparative studies in one group of subjects cannot be extrapolated to another group since the effects of individual inhaled corticosteroids may or may not vary with lung function. Since the subjects studied by Martin and colleagues had relatively mild asthma, we would anticipate that the effects of fluticasone might be greater than would be expected in patients with more severe asthma. While this may have occurred with fluticasone by MDI, the changes with fluticasone by DPI were smaller than those seen with the other drugs. It is noteworthy that in two recent reports of acute adrenal insufficiency due to inhaled corticosteroids all the children were taking fluticasone (6, 7). The one adult who developed acute adrenal suppression while taking fluticasone by DPI had a high peak flow (500–700 L/min), supporting our hypothesis that adrenal suppression with high doses of fluticasone is more likely to occur in patients with good lung function (7).
Nottingham City Hospital Nottingham, United Kingdom REFERENCES
From the Authors:The available literature and our results suggest that differences in cortisol suppression can occur based on the individual steroid, dose administered, delivery device, and perhaps the patient's pulmonary function. We evaluated six inhaled corticosteroid delivery device combinations with regard to cortisol suppression (1). Our asthmatic study population FEV1 ranged from 45–120% predicted. One important difference between our study and most other cortisol suppression studies was the fact that subjects were steroid naïve for greater than 1 year. All inhaled steroids demonstrated significant dose response relationships for cortisol suppression, except fluticasone dry powder inhaler. Comparisons of fluticasone metered dose inhaler and dry powder inhaler are mentioned by Harrison and Tattersfield, so we can comment on some of their observations.We limited the fluticasone doses up to 800 mcg per day and this could represent a major difference from other studies. The studies by Todd and colleague (2) and Drake and colleagues (3) suggested that doses greater than 1,000 mcg per day carry a greater risk for cortisol suppression and systemic effects. However, the case reports by Drake and colleagues do not specify the formulation of fluticasone, and the majority of the cases by Todd and colleagues appear to use the metered dose inhaler formulation. The report by Weiner and colleagues (4) demonstrated an exceptionally strong correlation (R2 = 0.865) between FEV1% predicted and cortisol suppression with a single dose of fluticasone dry powder inhaler (500 mcg). We performed a similar analysis with our data and found no significant relationships. What is important in regard to the use of inhaled steroids is the beneficial–systemic effect ratio. In another Asthma Clinical Research Network study (5), we found that low dose fluticasone metered dose inhaler and medium dose beclomethasone metered dose inhaler were sufficient to obtain maximal improvement in FEV1 and increase in methacholine PC20. As the dose was increased, no further increase in efficacy was obtained while cortisol suppression increased. Thus, the therapeutic ratio decreases as the dose is increased beyond maximal effect. Most studies suggest inhaled steroid doses should be limited to low–medium range unless higher doses are clinically indicated. If high doses are necessary, then the formulation that results in the lowest level of cortisol suppression should be used. Additional studies are needed to develop the therapeutic ratio of all inhaled steroids. Hopefully, it will be possible to improve inhaled steroid structure or delivery systems to provide maximal efficacy with minimal systemic effect, even with high dose therapy, regardless of asthma severity.
Asthma Clinical Research Network Denver, Colorado REFERENCES
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