Send letter to journal:
Re: Inhaled corticosteroids and adrenal insufficiency

Dear Editor

The editorial by Russell [1] suggests that when high dose inhaled steroids are being considered the use of fluticasone diproprionate should be avoided, on the basis of this survey.[2] Clinical studies rather than a questionnaire based survey should form the basis for such advice. Such studies show no increased risk of hypothalamic pituitary axis (HPA) suppression with fluticasone propionate when compared with other inhaled steroids.

The recent publication by the CSM "Current Problems in Pharmacovigilance"[3] on inhaled steroids and adrenal suppression in children emphasises that all inhaled steroids may cause side effects. As such, cases of adrenal suppression are dose-related class effects, associated with all inhaled steroids. Focussing on one inhaled steroid may lead to children being switched inappropriately from one inhaled steroid to another rather than highlighting the potential problems associated with the prescribing of out of licence doses of drugs in children.[3]

The paper states that a considerable proportion of the patients are likely to have been over-treated with inhaled steroids.[2] With reference to children it should be noted that all (rather than a considerable proportion) of the children reported in the paper were treated with doses of fluticasone between 500-2000 mcg daily, which are up five times greater than the maximum recommended dose.

In a published correspondence entitled "The side effects of high-dose fluticasone propionate in children", Dr Todd highlighted that a survey of specialist paediatric centres in the UK showed that when high doses of inhaled corticosteroids (>1000mcg daily) were thought necessary, nearly all choose fluticasone propionate.[4] This may explain the preponderance of cases on fluticasone propionate in the article.

It is worth noting that reported cases of adrenal suppression are not restricted to fluticasone diproprionate alone. Of eight cases reported by Patel in 2001, three were receiving budesonide 400mcg/day, one beclometasone 600mcg/day and the remainder Flixotide at doses of 500mcg/day and above.[5]

Individuals have differing sensitivities to inhaled corticosteroids. It can be difficult to establish the cause of adrenal suppression through survey methods, such studies are inadequate to determine safety. Idiosyncratic responses to inhaled corticosteroids may occur even at licensed doses.[2]

The authors state that the low response rate (24%) means that the results are likely to underestimate the true scale of the problem. This would appear to be an unsupported and probably unfounded assertion. It cannot be assumed that the incidence in the centres that did not respond would be the same as in those that did. As adrenal crisis is an unusual event, the presence of such an event is more likely to be remembered by clinicians and reported in response to a specific request, than cases where such events did not occur.

Linda Pearce
Respiratory Nurse Consultant

Dr David Mabin
Consultant Paediatrician
West Suffolk Hospital

References

(1) Russell G. Inhaled corticosteroids and adrenal insufficiency Arch Dis Child 2002; 87:455-456.

(2) Todd GRG, Acerini CL, Ross-Russell R, Zahra S, Warner JT, McCance D. Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Arch Dis Child 2002; 87: 457-461.

(3) Committee on the Safety of Medicines. Inhaled corticosteroids and adrenal suppression in children. Current Problems in Pharmacovigilance 2002; 28: 7.

(4) Todd GRG. Side effects of high dose fluticasone propionate in children. Eur Respir J 1999; 13: 707-709.

(5) Patel L, Wales JK, Kilbirige MA, Massarano AA, Couriel JM, Clayton PE. Symptomatic adrenal insufficiency during inhaled corticosteroid treatment. Arch Dis Child 2001; 85: 330-334.

Statements of conflict of interest
Linda Pearce:
I have received fees for delivering lectures, hospitality at scientific meetings and/or payments for participation in clinical trials or other asthma-related research from Astra-Zeneca, Boehringer Ingelheim, 3M Health Care, Glaxo SmithKline, MSD, Novartis, Schering Plough, Trinity Pharmaceuticals.

David Mabin:
I have received fees for providing professional advice and delivering lectures as well as hospitality at, and sponsorship to attend, scientific meetings and/or payments (sometimes in kind, for example educational materiel and textbooks) to me personally and my discretionary funds for participation in clinical trials or other asthma, allergic rhinitis and atopic dermatitis-related research from Astra-Zeneca, GSK, Schering Plough, UCB Pharma and MSD.

Send letter to journal:
Re: Response to Pearce and Mabin

Dear Editor

I have been disappointed by the lack of response to the paper by Todd et al. [1] and to my accompanying editorial,[2] and I am indebted to Pearce and Mabin for opening what I hope will be an interesting discussion, although I must take issue with much of what they say. Their opening comment to the effect that clinical studies rather than a questionnaire-based survey should form the basis for advice on drug selection does not bear close examination. Had we relied upon clinical studies, we would still be using Opren?, or for that matter thalidomide. Surveys, yellow cards and the like are vital in providing early warning of unforeseen side-effects. As Pearce and Mabin say, many clinical studies have shown no increased risk of hypothalamic pituitary axis suppression with fluticasone propionate when compared with other inhaled steroids. On the basis of such studies, the apparent toxicity of fluticasone at high doses was indeed unforeseen, and was only likely to have been detected by the previously published reports and by surveys such as that of Todd et al. As Pearce and Mabin also emphasise, individuals have differing sensitivities to inhaled corticosteroids. It is because of this that clinical studies, involving the relatively small numbers of patients dictated by economics and patient co-operation, are inadequate to identify the occasional hypersensitive individual, or to determine risk in the population at large.

It is not in dispute that adrenal suppression is a dose-related class effect, and has been reported with all inhaled corticosteroids, but this does not explain the extraordinarily high proportion of reported cases associated with the use of fluticasone. The results of the questionnaire survey indicating that fluticasone is favoured by British paediatric respirologists for high-dose therapy might go some way towards explaining this proportion, but does not explain why acute adrenal failure was so rare when the only drugs available for high-dose therapy were Becloforte? or standard strength budesonide.

Moreover, there are pharmacological reasons to direct the finger of suspicion at fluticasone. Based on a literature review, Pedersen and O?Byrne[3] concluded that on a ?g basis fluticasone had three times the systemic potency of budesonide, whereas it is generally believed to have only twice the therapeutic activity. Clark et al.[4] also compared fluticasone and budesonide on a ?g basis, and found in asthmatic children that fluticasone produced greater adrenal suppression than budesonide. Examination of their figures suggests that the difference in favour of budesonide was apparent when the 800 ?g and even the 1250 ?g doses of budesonide was compared with 400 ?g fluticasone. Although the literature on fluticasone is voluminous and capable of several interpretations, there is a very real possibility that fluticasone has greater bioactivity at higher doses than the alternative inhaled corticosteroids.

Todd et al. have provided us with numerators but no denominators. I can see no reason for suggesting that these numerators represent anything other than an underestimate, as I am sure I am not the only clinician to have put Dr Todd?s questionnaire aside for completion during the sort of quiet time that never quite seems to occur in paediatrics. What we need now is denominators in the form of the numbers of prescriptions issued for high-dose therapy with each of the three corticosteroids licensed in the UK for inhaled use. Given the volume of prescribing data collected routinely by the Ministry of Health, it might be possible to get some approximation of the comparative risk of adrenal suppression on each of these drugs when used in high dosage. No more than an approximation will be possible, because of the marked differences in systemic bioavailability between metered dose inhalers with and without spacers, and dry powder inhalers,[5] together with variable pulmonary absorption depending upon age and the state of the airways. Until then, I for one will remain wary of prescribing any sort of high dose inhaled corticosteroids to children, but will be particularly wary of fluticasone.

References

(1) Todd GRG, Acerini CL, Ross-Russell R, Zahra S, Warner JT, McCance D. Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Arch Dis Child 2002; 87: 457-461.

(2) Russell G. Inhaled corticosteroids and adrenal insufficiency Arch Dis Child 2002; 87:455-456.

(3) Pedersen S, O?Byrne P. A comparison of the efficacy abd safety of inhaled corticosteroids in asthma. Allergy 1997;52 (Suppl 39):1-34.

(4) Clark DJ, Clark RA, Lipworth BJ. Adrenal suppression with inhaled budesonide and fluticasone propionate given by large volume spacer to asthmatic children. Thorax 1996;51:941-3.

(5) Martin RJ, Szefler SJ, Chinchilli VM, et al. Systemic effect comparisons of six inhaled corticosteroid preparations. Am J Respir Crit Care Med 2002;1.

Statement of conflict of interest
I have received fees for delivering lectures, hospitality at scientific meetings and/or payments to my discretionary funds for participation in clinical trials or other asthma-related research from Astra-Zeneca, Fisons Pharmaceuticals, GSK and MSD.

Send letter to journal:
Re: Moderately high doses stilll need to be considered for very young children

Dear Editor

In relation to the question of adrenal suppression when using higher doses of inhaled corticosteroid, I believe there is an aspect of dose selection which has not been mentioned by previous authors.

There is limited data on the question of intra-pulmonary drug deposition in children under 3 years but the studies that have been publised seem to indicate that around 1-2% of the drug released into the spacer reaches the airways,[1] compared to 15-17% in an adult using the same device. Based on this figure, it seems reasonable to prescribe similar doses to very young children and adults alike.

I note that none of the cases of adrenal impairment have been reported in children under 3 years of age; most of them are significantly older. This could be partly because higher doses are not being used in this age group, but might also be confirmation that a smaller fraction of the drug reaches the airways in this age group.

I would argue that there are good reasons to use higher doses, at least initially, when treating very young children. The diagnosis of asthma is exceptionally difficult here, and if a "trial of treatment" is inneffective, one wishes to be reasonably confident that the reason for the negative response was not related to an inadequate dose. A negative response allows the clinician to withdraw ineffective steroid treatment in those infants who may well not have asthma at all. If there is an excellent response the dose of steroid should be stepped down to the minimum required to control symptoms.

Finally, for clarity, the doses I am referring to are budesonide / beclomethasone 800 mcg/day or fluticasone 500 mcg/day.

Reference

(1) A Tal, H Golan, N Grauer, et al. Deposition pattern of radiolabelled salbutamol inhaled from a meterd-dose inhaler by mans of a spacer with mask in young children with airway obstruction. J Pediatr 1996; 128:479-84.

Send letter to journal:
Re: High dose fluticasone and adrenal suppression

Dear Editor

Following the editorial by Russell [1] recommending a short synacthen test for asthmatics receiving fluticasone in a daily dose of 1000 mcg or above, we undertook a computer search of our records of asthmatic patients.

Asthmatics have approximately 4000 consultations per year with our team. We identified 190 children taking inhaled fluticasone either alone or in combination with salmeterol. Of these 21 were on daily doses of 1000 mcg or over and one was on a dose of 500 mcg daily having previously been on 1000 mcg for 8 months. Two had taken oral prednisolone within the last month and were not investigated because of possible adrenal suppression due to the oral steroid. Of the remainder, 13 were female and 6 were male. Their ages ranged from 7.79 years to 18.54 years (mean 13.0 years). Only one patient was on concomitant intranasal fluticasone. Twelve were using Diskus dry powder inhalers, five a metered dose inhaler with a spacer (volumatic) and one a metered dose inhaler alone. A short synacthen test was performed on all 19 patients and was normal in all as judged by a rise of 200 nmol or a peak of 500 nmol.[2]

One of the authors has cared for asthmatic patients since the introduction of inhaled steroids in the early 1970s and has seen only one asthmatic patient suffer an Addisonian crisis. The crisis followed acute cessation of long continued oral prednisolone. While the recent reports of adrenal suppression in asthmatics on high dose inhaled corticosteroids indicate that this serious side effect must be kept in mind when caring for such patients, our experience is that it is not a common occurrence. Further information regarding the prevalence and risk factors for this complication would be of benefit to clinicians and might rapidly be obtained by using the British Paediatric Surveillance Unit's ‘Orange Card’ reporting system.

Yours sincerely,

References

(1) Russell G. Inhaled corticosteroids and adrenal insufficiency. Arch Dis Child 2002;87:455-6.

(2) Todd GRG Acerini CL Ross-Russell R, et al. Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Arch Dis Child 2002;87:457-61.