Clinical adverse effects of inhaledcorticosteroids: results of a questionnaire surveyof asthma specialistsWilliam W Storms, MD and Charity Theen

Background: Inhaled corticosteroids are recognized as the mainstay of prophy-lactic anti-inflammatory therapy in patients with persistent asthma. In large multi-clinic trials, the clinical adverse event profiles have been not significantly differentthan patients treated with placebo or other medications; however, in small studiesevaluating very sensitive in vitro measurements of the hypothalamic pituitaryadrenal axis there have been adverse laboratory events noted with moderate andhigh doses of inhaled steroids.Objective: To survey asthma specialists in North America with regard to their

personal clinical experience of adverse events with the use of inhaled corticoste-roids.Methods: Two hundred thirteen physicians specializing in the treatment of

asthma responded to questionnaires asking their experiences with specific adverseclinical events that have the potential to occur after the use of inhaled corticosteroids(see appendix A for questionnaire).Results: There was a 67% response rate for the questionnaire. Eighty percent of

the respondents were allergists/immunologists and 20% were pulmonologists. Theaverage length of time they had been in practice was 16 years. In general, sideeffects from inhaled steroids were seen very infrequently in the hands of thesephysicians in spite of the fact that they were primarily secondary or tertiary referralphysicians for the treatment of asthma. The local oropharyngeal adverse events wereseen 48% of the time on an occasional basis but only 3% of the time on a frequentbasis. When spacers were used the oropharyngeal symptoms were reduced signif-icantly. Skin changes such as bruising or thin skin were seen frequently 6% of thetime and occasionally 24% of the time only. In general, these skin changes werefound in elderly or middle-aged individuals. Weight gain was very unusually seen,as were adverse effects on bone (osteoporosis, fractures, growth problems, etc.).Hypothalamic pituitary axis abnormalities were seen quite infrequently and primar-ily in patients who had also received oral corticosteroids.Conclusions: This study shows that inhaled corticosteroids are generally safe in

the treatment of asthma and are rarely associated with systemic side effects, asdetected in routine clinical practice.

Ann Allergy Asthma Immunol 1998;80:391–4.

INTRODUCTIONInhaled corticosteroids have been usedin the treatment of asthma for almost20 years. They were originally pre-scribed for use in patients who re-quired oral corticosteroids for control

of asthma, but their clinical use ex-panded to prophylactic treatment in pa-tients who had chronic persistentasthma and usage in this manner hasbeen shown to result in reduced fre-quency of emergency room visits, hos-pitalizations, oral steroid bursts, andother parameters indicating severeasthma. In recent years multiple in-haled corticosteroid products have ap-peared on the market, and there havebeen a number of studies evaluating

the potential side effects of the variousdrugs.1–15 In the large multiclinic trials,which have been used for regulatoryapproval of these compounds, side ef-fects have infrequently been notedwith their use. Some patients have hadlocal side effects in the oropharynxincluding dysphonia, candidiasis, andhoarseness. Some patients have hadmorning serum cortisol readings lessthan the normal range but clinical ad-verse consequences of these loweredserum cortisols have not been identi-fied. There have been many recentstudies with small groups of patients inwhich very sensitive tests of the hypo-thalamic pituitary adrenal axis (HPAaxis) have been performed showingthat inhaled corticosteroids may sup-press HPA function.4,6,9,10 The questionis whether or not these clinical labora-tory changes are reflected in true clin-ical adverse events. Concerns about in-haled corticosteroids have also beenraised in regard to potential problemswith cataracts, glaucoma, and growthin children. The current study was un-dertaken in order to attempt to shedsome light on this issue.

STUDY DESIGNA questionnaire (Appendix A) was de-signed that identified potential adverseclinical events which had been de-scribed as possibly associated with in-haled corticosteroids. These includedoropharyngeal events, bone changes,skin changes, eye changes, HPA axisabnormalities, short stature in children,and weight gain. The questionnairewas mailed to asthma specialists inNorth America and each physician wasasked to record the frequency withwhich he/she had observed these ad-verse events in his/her clinical experi-

Asthma & Allergy Associates, PC, ColoradoSprings, Colorado.Received for publication January 6, 1998.Accepted for publication in revised form Feb-

ruary 26, 1998.

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ence. The names of 320 asthma spe-cialists were chosen from themembership directories of the Ameri-can Thoracic Society, American Col-lege of Chest Physicians, AmericanCollege of Allergy, Asthma & Immu-nology, and the American Academy ofAllergy, Asthma & Immunology byone of the authors (W.S.) based on hisknowledge of the fact that the physi-cians to whom the questionnaires weresent met the criteria of having a clini-cal practice (whether or not theyworked at an academic center) andhaving had at least 10 years of experi-ence in treating patients with asthma.The physicians who were questionedincluded adult and pediatric allergists/pulmonologists and adult and pediatricpulmonologists. The questionnaire didnot request specific information on theage of patients treated by individualphysicians. The one page question-naire was sent back by mail or fax tothe authors and the data was then sum-marized and analyzed.

RESULTSTwo hundred thirteen physicians re-turned the questionnaire for a responserate of 67%. Of these, 80% were aller-gists/immunologists and 20% werepulmonologists. The 213 physiciansreported that they had been in practicefor an average of 16 years each; thiscomputed to a total experience of3,408 physician-years for the data col-lected from the questionnaires.

The results are described in Table 1.In general, side effects were seen“rarely” and “occasionally.” Oropha-ryngeal adverse events were seen oc-casionally in 48% of physician’s prac-tices and seen frequently in 3%. Thequestionnaire asked whether or notspacers were beneficial for these oro-pharyngeal symptoms and two-thirdsof the physicians indicated that spacersresolved these local side effects.Skin changes, such as bruising or

thin skin, were noted frequently in 6%of practices, occasionally in 24% ofpractices, and rarely or never in 70%.The respondents were asked to breakthis down by age groups: 55% of theseskin changes were found in elderly in-dividuals, 33% in middle-aged, andless than 10% in children.Weight gain was seen occasionally

in 8% and never or rarely in 91%.Questions regarding bone metabo-

lism, growth, and HPA axis functionwere included on the questionnaire totry to obtain information from thosephysicians who might include those intheir evaluations, knowing full wellthat this would probably be reservedfor the academic asthma specialists intertiary referral settings. The frequencyof measurement of these tests was notquantitated in any manner, but thesequestions were included to try to gainsome extra information from thosephysicians who measured these param-eters. Adverse effects on bone werenot seen frequently. There were 1% of

physicians who saw osteoporosis orfractures occasionally, and 3% saw ab-normal bone markers occasionally.The strong majority either never sawthese changes or saw them very rarely.Some physicians who responded to thequestionnaire indicated that these sideeffects were actually attributed to oralsteroids since most of these patientshad received oral steroids in the past.This was probably due to the fact thatthe physicians responding to the ques-tionnaire tended to be asthma special-ists who were seeing patients primarilyon a referral basis; in many cases theywere in tertiary referral centers forasthma.Changes in the HPA were seen quite

infrequently. In those practices inwhich some of these changes werenoted, the patients had also been onoral steroids.Cataracts were not seen frequently

or occasionally but only rarely.

DISCUSSIONInhaled corticosteroids have been usedfor the treatment of asthma for almost20 years. Studies of sensitive markersof the HPA and of bone metabolismhave shown that inhaled corticoste-roids may adversely effect these pa-rameters, indicating definite systemicactivity. These recent findings have ledsome authors to conclude that inhaledsteroids might have dangerous clinicalside effects. In some cases, these clin-ical laboratory adverse events havebeen used by pharmaceutical compa-nies to try to make their product lookbetter than the competitors. The endresult of these “steroid wars” may leadto an underutilization of inhaled ste-roids in the American market, and the1997 Expert Panel II Report on asthmarecommends increased usage of in-haled steroids, especially in newly di-agnosed asthma.Concerns have been raised regard-

ing possible effects of inhaled steroidson growth in children and their possi-ble association with cataracts and glau-coma.7,8,9,11–13 The current study wasdesigned in order to shed some light onthe true issue of clinical adverse eventsfrom inhaled steroids since most of the

Table 1. Percent of Physicians Responding to Frequency of Side Effects in Each IndividualCategory

Occasional Frequent Never Rare Occasional Frequent

Local side effectsOropharyngeal symptoms 1% 48% 48% 3%

Skin changes (bruising/thin skin) 36% 34% 24% 6%Weight gain 50% 41% 8% 1%Bone metabolism

Osteoporosis or fractures 89% 10% 1% 0%Short stature in children 83% 15% 1% 1%Abnormal bone markers 82% 14% 3% 1%

Hypothalamic pituitary axis changesReduced/serum urine cortisol 71% 20% 8% 1%Blunted ACTH stimulation 76% 18% 5% 1%Hypoadrenalism 86% 11% 2% 1%

Cataracts 75% 24% 1% 0%

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data that was being published ad-dressed laboratory adverse events. Theresponse rate from the physicians in-volved in this study was excellent andwe appreciate the fact that the respond-ing physicians took the time out oftheir busy practices to fill out the ques-tionnaire and return it. There was nocompensation for this whatsoever.The results clearly show that oro-

pharyngeal side effects are occasion-ally seen but in most situations theseside effects can be resolved by using aspacer.Systemic side effects from inhaled

steroids are either never seen or rarely

seen in most physician practices. Inthose cases in which they are seenthere usually is some other extenuatingcircumstance: (1) elderly patients onhigh dose steroids may have bruisingof the skin; (2) some children mayshow weight gain but in most instancesthey also had received oral steroids inthe past; or (3) osteoporosis and frac-tures have been seen in some patientswho were also on oral steroids.The percentage of physician re-

sponses who were treating pediatric ascompared with adult asthma patientswas not identified; therefore the resultsmay reflect some bias towards either

pediatric or adult patients and associ-ated adverse events.

CONCLUSIONThe results of this study show thatinhaled corticosteroids are generallysafe in the treatment of asthma and arerarely associated with systemic side ef-fects as detected in routine clinicalpractice, even in the hands of physi-cians who see more severe asthma pa-tients.ACKNOWLEDGEMENTSThe efficient and knowledgeable assis-tance of Kay Bailey was invaluable forthe preparation of this manuscript.

APPENDIX A

QUESTIONNAIRE ON THE USE OF INHALED CORTICOSTEROIDS IN PATIENTS WITH ASTHMA

These questions relate only to patients with asthma and only to patients you have seen yourself.

1. How many years have you been in practice? years.2. Have you seen the clinical complications (adverse effects) listed below from inhaled corticosteroids?

A. Oral/pharyngeal symptoms: Never Rare Occasional FrequentHoarseness, sore throat of candida of

the throatDid a spacer resolve the problem?

Yes No Were these patientsalso on oral steroids?

Yes NoB. Osteoporosis or fractures:C. Skin changes (bruising/thin skin):

If yes, check age groups:childadultelderly

D. Weight Gain:If yes, check age groups:

childadultelderly

E. Short stature in children:F. Cataracts:G. Lab abnormalities:

1. Reduced serum/urine cortisol2. Blunted ACTH stimulation3. Abnormal bone markers

H. Hypoadrenalism:

Name DateYour specialty: Allergy/Immunology Pulmonary disease Other ( )Please mail or Fax to William W. Storms, M.D. Fax 719-630-3658

VOLUME 80, MAY, 1998 393

REFERENCES1. Johnson M. Pharmacodynamics andpharmacokinetics of inhaled glucocor-ticoids. J Allergy Clin Immunol 1996;97:169–76.

2. Hanania NA, Chapman KR, Kesten S.Adverse effects of inhaled corticoste-roids. Am J Medicine 1995;98:196–208.

3. Padfield PL, Teelucksingh S. Inhaledcorticosteroids: the endocrinologist’sview. Eur Respir Rev 1993;3(15):494–500.

4. Grove A, Allam C, McFarlane LC. Acomparison of the systemic bioactivityof inhaled budesonide and fluticasonepropionate in normal subjects. Br JClin Pharm 1994;38:527–32.

5. Dogterom P, Oosterhuis B, Ebels JT,Jonkman JHG. Inhaled fluticasonepropionate induces greater cortisolsuppression compared to budesonide.A dose response study using pressur-ized metered dose inhalers (PMDI’s)[Abstract]. Eur Resp J 1995;8(Suppl19):303s.

6. Clark DJ, Grove A, Cargill RI. Com-parative adrenal suppression with in-haled budesonide and fluticasone pro-pionate in adult asthmatic patients.Thorax 1996;51:262–6.

7. Wolthers OD, Pedersen S. Short termgrowth during treatment with inhaledfluticasone propionate and be-clomethasone dipropionate. Arch DisChild 1993;68(5):673–6.

8. Price JF. Asthma, growth and inhaledcorticosteroids. Respir Med 1993;87(Suppl A):23–6.

9. Lipworth BJ. Airway and systemic ef-fects of inhaled corticosteroids asthma:dose response relationship. PulmonaryPharmacology 1996;9:19–27.

10. Clark DJ, Lipworth BJ. Adrenal sup-pression with chronic dosing of fluti-casone propionate compared withbudesonide in adult asthmatic patients.Thorax 1997;52:55–8.

11. Agertoft L, Pedersen S, et al. Short-term knemometry and urine cortisolexcretion in children treated with flu-ticasone propionate and budesonide: adose response study. Eur Respir J1997;10:1507–12.

12. Kamada AK, et al. Issues in the use ofinhaled glucocorticoids. Am J RespirCrit Care Med 1996;153:1739–48.

13. Garbe E, et al. Inhaled and nasal glu-cocorticoids and the risks of ocularhypertension or open-angle glaucoma.JAMA 1997;277:722–7.

14. Wolthers OD, et al. Knemometry,urine cortisol excretion, and measuresof the insulin-like growth factor axisand collagen turnover in childrentreated with inhaled glucocorticoste-roids. Pediatr Res 1997;41:44–50.

15. Grove A, et al. Effects of short-termexposure to high-dose inhaled cortico-steroids on novel markers of bone me-tabolism. Eur J Clin Pharmacol 1996;50:275–7.

16. Corren J, Rachelefsky G, Hochhaus G,et al. A five-way parallel randomizedstudy to compare the safety profile ofbeclomethasone dipropionate (BDP),budesonide (BUD), flunisolide (FLU),fluticasone propionate (FP), and triam-cinolone acetonide (TA) in healthymale volunteers [Abstract]. Chest1996;110(4):83S.

17. Guidelines for the diagnosis and man-agement of asthma. NIH 97-4051,1997.

Request for reprints should be addressed to:William W Storms, MD2709 N Tejon StColorado Springs, CO 80907email: Sneezedoc@aol.com

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