dysphoniacaused of a characteristic

Thorax 1983;38:813-821

Dysphonia caused by inhaled steroids: recognition ofa characteristic laryngeal abnormalityALAN J WILLIAMS, MS BAGHAT, DE STABLEFORTH, RM CAYTON, PM SHENOI,CRAIG SKINNER

From the Departments of Thoracic Medicine and ENT Surgery, East Birmingham Hospital, Birmingham

ABSTRACr Nine of 14 asthmatic patients who presented with persistent dysphonia while takinginhaled corticosteroids had a bilateral adductor vocal cord deformity with bowing of the cords onphonation. This causes the dysphonia and usually occurs without candidiasis. It was seen withbeclomethasone dipropionate (in both pressurised aerosol and dry powder preparations),betamethasone valerate, and budesonide. It was related to the dose and potency of inhaledsteroid and may represent a local steroid myopathy. It was reversed when the inhaled steroid wasstopped, although resolution sometimes took weeks. Laryngeal candidiasis may have contributedto the vocal cord abnormality in two of these nine patients. Of the five patients without vocal corddeformity, laryngeal candidiasis was the sole cause of dysphonia in three. In the remaining twodysphonia was thought to be psychogenic. The vocal cord deformity may exist subclinically. Ofnine patients who started to take aerosol steroid and who were examined monthly for one year,

three developed vocal cord deformity but only one had persistent dysphonia. Vocal abuse did notappear to contribute to dysphonia.

Inhaled steroids have an important and wellestablished role in the treatment of chronicasthma.'-6 Troublesome side effects includecandidiasis, sore throat, and dysphonia. These com-plications occur with all inhaled steroids '-'1 and areprobably dose related.48 11 15 The incidence of theseside effects is uncertain. The reported incidence ofcandidiasis ranges from zero'6-'9 to 91 %2° and thatof sore throat and dysphonia from zero to55%48 I1 21 of patients receiving inhaled steroids. Itis not clear whether candidiasis is the sole cause ofsore throat and dysphonia as there is no predictableassociation between these symptoms andcandidiasis. Moreover, confusion arises owing todifferent diagnostic criteria for candidiasis; incom-plete ear, nose, and throat examination in mostreported studies; and failure to distinguish betweenthe symptoms of sore throat and dysphonia. The twopresent studies were undertaken to clarify theseproblems; they included detailed analysis of voicerecordings, a detailed history with formal assess-ment of vocal abuse, and both indirect and direct(fibreoptic) laryngoscopy.

Address for reprint requests: Dr AJ Williams, East BirminghamHospital, Birmingham B9 5ST.

Accepted 26 July 1983

Patients and methods

STUDY 1The first study included all patients who presentedto the ENT and thoracic medicine departments withsevere and persistent dysphonia while receivinginhaled steroids for asthma. A careful history ofdysphonia was recorded, with particular reference tothe onset and its relation to the start of treatmentwith inhaled steroids. The type and total daily doseof inhaled and oral treatment were noted and thepatient's inhaler technique was scrutinised andgraded " efficient" or " inefficient." "Efficiency" wasrecorded if the following criteria were fulfilled: (1)mixture of the aerosol contents by shaking; (2)depression of the actuator shortly after the start of adeep inspiration, followed by (3) breath holding forat least four seconds.

In each patient an independent assessment ofdysphonia was made by two speech therapists afteran interview and analysis of the patient's voicerecordings. Specific inquiry was made about smok-ing, shouting, coughing, loud voice, noise duringwork, family deafness, and excessive throat clearing.The patient was considered to have vocal abuse ifthree or more of these factors were present. Thesame criteria for vocal abuse were applied to a

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random sample of people attending a hospital out-patient department. The severity of dysphonia wasscored for each patient on a scale of 0-4, zero denot-ing normal phonation and 4 the most severedysphonia short of aphonia.

In all cases an examination of the pharynx andlarynx was undertaken. Naked eye appearanceswere documented and a throat swab was taken formycological study. The presence of fungus wasrecorded if colonies were grown in Sabouraud'smedium after culture for 24-48 hours. The larynxwas examined by standard mirror (indirect) laryngo-scopy supplemented by direct fibreoptic examina-tion, the latter after the application of localanaesthetic (25% cocaine paste) to the nasal fossaeand lignocaine spray to the oropharynx and post-nasal space. Care was taken that no anaesthetic wasapplied to the larynx. The appearances and move-ments of the vocal cords were documented andphotographs taken during deep inspiration (abduc-tion) and phonation (adduction).

Fig 1 Laryngoscopic appearances during phonation: (a)showing the bilateral adductor vocal cord abnormality;(b) showing normal appearance (full adduction).

Williams, Baghat, Stableforth, Cayton, Shenoi, Skinner

In all patients the effects of discontinuing inhaledsteroid were assessed, the laryngeal appearancesand dysphonia being recorded at intervals of two tofour weeks. During this follow up period beta agon-ist inhaler treatment was continued, with anincreased dose in some cases and the addition ofinhaled ipratropium bromide in others. The mod-ified medication was intended to maintain control ofthe asthma and also served to replace and match thetotal quantity of propellant in the discontinuedsteroid inhaler.

STUDY 2Patients with chronic asthma of sufficient severity towarrant treatment with inhaled steroids werestudied before or within two months of startingtreatment with inhaled steroids and monthly there-after for about one year.At each clinic visit inquiriesinto the presence of symptoms of sore throat anddysphonia were made, followed by full ENT exami-nation. Patients with a past history of dysphoniawere excluded.

Results

STUDY 1During 18 months 14 patients (seven male) pre-sented with persistent dysphonia while receivinginhaled steroids for chronic asthma. Their mean agewas 58 years (range 38-73).There was excellent agreement between the two

speech therapists in their scoring of the grade ofdysphonia. On only one occasion in one patient didtheir assessments differ and then by only one grade.

Direct laryngoscopy invariably gave a good viewof the larynx whereas indirect examination failed togive any view in three patients because the epiglottisobscured vision. In nine patients a characteristicbilateral adductor vocal cord abnormality ("bow-ing" on phonation) was seen on laryngoscopy. Anexample of this abnormality with normal vocal cordappearances for comparison is shown in figure 1.The type and total daily dose of inhaled treatment,duration of inhaled steroid treatment and durationand grade of dysphonia in these nine patients areshown in table 1. Patient 6 received inhaled steroidson two separate occasions and developed dysphoniaon both. Four patients were also receiving oralmedication: slow release aminophylline (450 mg/day) in two patients, terbutaline sulphate in onepatient (15 mg/day), and prednisolone (5 mg/day) inone other. The duration of inhaled steroid treatmentranged from four to 156 weeks with a mean of 37weeks. The delay between the start of the treatmentand the onset of dysphonia was highly variable; onepatient (No 3) commented that dysphonia began

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Dysphonia caused by inhaled steroids: recognition of a characteristic laryngeal abnormality

Table 1 Details ofnine patients developing an adductor vocal cord abnormality while taking inhaled steroids

Patent Age Sex - Inhaled steroid Additional Duration of Duration of Grade ofNo (y) (total daily inhaled treatment steroid dysphonia dysphonia

dose in pg) (total daily inhalation (w)dose in pg) (w)

1 70 M BDP (400) Salbutamol (200) 92 32 22 51 M BDP (400) Terbutaline (2 mg) 8 3 1

DSCG (160 png)3 73 M BDP (400) Salbutamol (800) 28 28 24 52 F BDP (200) Salbutamol (600) 156 44 2

DSCG (120 mg)5 63 F BDP (R) (800) Salbutamol (R) (1600) 28 12 46 64 M BDP (400) Salbutamol (600) 8 6 1

BV (800) Ipratropium (160) 10 6 1Fenoterol (1600)

7 55 F BV (800) Salbutamol (1600) 30 6 38 69 M Budesonide (400) Salbutamol (800) 6 4l/2 19 57 M Budesonide (400) Salbutamol (800) 4 21/2 3

Mean 37 14-4 2-0

BDP-beclomethasone dipropionate; BV-betamethasone valerate; (R}-inhaled via rotahaler; DSCG-sodium cromoglycate.

Table 2 Appearances ofpharynx and larynx, results offungal studies, and presence or absence ofsore throat in the ninepatients

Patient Appearance of Appearance of Candida SoreNo pharynx larynx albicans throat

cultured

1 Normal Normal2 Normal Hyperaemia3 Normal Normal4 White patches White patches, hyperaemia, + +

voc cord oedema5 White patches White patches + +6 Norma Norma

Normal Normal7 White patches Normal +8 Normal Normal9 Normal Slight vocal cord oedema

Table 3 Possible factors contributing to the adductor vocalcord deformity

Patient Candida Efficient Vocal CigaretteNo albicans inhaler abuse smoking

cultured technique (Nolday)

1 - + _2 - + _3 - + +4 + - + 35 + + + 26 -* + _

+7 +t + - 68 - + _9 - + _

*On two occasions.tPharynx only.

immediately while in another (No 4) it appearedonly after 112 weeks. There was no significantcorrelation between the duration of treatment andthe grade of dysphonia at presentation. Table 2summarises the appearances of the pharynx andlarynx, the results of fungal cultures, and the pres-

ence or absence of sore throat. In most cases thepharynx and larynx appeared normal apart from thevocal cord deformity. There was no suggestion ofmucosal atrophy. Three patients had pharyngealthrush, with the larynx affected in two of them;these two had a sore throat.

Factors which might have a role in thepathogenesis of the vocal cord deformity are shownin table 3. The inhaler technique was efficient in allbut one case. Vocal abuse was present in threecases; in our control group 13 out of 50 hospitaloutpatients had vocal abuse.

With cessation of steroid inhalation the dysphoniaand vocal cord deformity resolved. The typicalcourse of events is shown in figures 2 and 3. Patient1 (fig 2) had taken 400 ,ug beclomethasone di-propionate for 23 months and had had dysphoniafor eight months. The vocal cord abnormality anddysphonia improved and had resolved by 12 weeksafter the inhaled steroid had been stopped. Patient 5(fig 3) had taken beclomethasone dipropionateinhaled as a dry powder for seven months and had

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816 Williams, Baghat, Stableforth, Cayton, Shenoi, SkinnerBDP 400 ,ug/day

23/12__

0

_ Adduction deformity[ Dysphonia as assessed by patient I* Disappeared

2 4 6Time (weeks)

8 10 12

Salbutamol 1600 ,ig/ml

Ipratropium bromide 160,ug/dayFig 2 Resolution ofdysphonia and vocal cord deformity after withdrawal ofinhaled beclomethasonedipropionate (BDP) treatment in patient 1.

BDP (R) 800 ug/day

7/12

3/12 111 34

Adduction detormity3- \i[ Dysphonia as assessed by patient

aa\ * Disappeared

>1

a0

0 4 6 8 10Time (weeks)

Salbutamol (R) 800pug/day

Prednisolone 5mg/day

Fig 3 Resolution ofdysphonia and vocal cord deformity after withdrawal ofinhaled beclomethasonedipropionate (BDP) treatment in patient 5. (R)-inhaled via rotahaler.

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BDP 400 g/dcay

8/52

6/52~IJ-- I

BV 800 )jg/dayI .

_ _ .. .

0S

S- - *

- -- 7---.'_ / -, :. /

0 2 4 6 8 *4 22 24 26 28 30 32THme weeks)

Salbutamol 800 /g iday

A Ipratropijum brom'de 660,ug/day

A Prednsolone 10mrg day

_ Adduction detorm ty = Dysphonia cs assessedby the pat!ent

Dsappeared

Fig 4 Dysphonia and vocal cord deformity in patient 6: resolution after withdrawal ofbeclomethasone dipropionate (BDP) and reappearance after introduction ofbetamethasone (BV).

had dysphonia for three months. The adductiondeformity had resolved by eight weeks after theinhaled steroid had been stopped. The patientthought that his voice had returned to normal withinthe first week after he had stopped inhaling steroid,although dysphonia as assessed by speech therapistspersisted for eight weeks. Inhalation of salbutamolas a dry powder was continued throughout and thedose of prednisolone remained unchanged. Inpatient 6 (fig 4) the patient had receivedbeclomethasone dipropionate for eight weeks andhad had dysphonia for six weeks. Discontinuation ofinhaled steroid led to the improvement and eventualdisappearance of the dysphonia and the vocal corddeformity at six weeks. At follow up examinationeight weeks later the patient remained symptom freewith a normal laryngeal appearance. Commence-ment of treatment with another inhaled steroid,betamethasone valerate, led to a return of theadduction deformity and dysphonia. A summary ofevents for all nine patients is shown in table 4. Therewas a strong correlation between the times taken forthe recovery of normal vocal cord function and ofnormal phonation as judged by the patients (r =

0-97) and speech therapists (r = 0.87). The timetaken for normal vocal cord function to returnranged from four weeks to one year (mean 13.8

weeks) and was not related to the initial grade or

duration of dysphonia at presentation. Full recoveryof phonation and vocal cord function was seen in allpatients.

In patient 6 betamethasone has been continuedfor the last seven months, and vocal cord deformityand mild dysphonia (grade I) persist. Likewiseresumption of beclomethasone dipropionate inhala-tion in patient 1 led to a return of the laryngealabnormality within six weeks, with occasionaldysphonia.There were five dysphonic patients in whom no

adduction deformity of the vocal cords was seen atlaryngoscopy. Details of these patients are shown intables 5 and 6. They had milder dysphonia (meangrade 1.1). Three had laryngeal candidiasis. Theother two had normal laryngeal appearances butwere judged to be tense and anxious, withpsychogenic dysphonia.

STUDY 2

Nine patients (five female) with a mean age of 51years (range 33-69) have been followed for up to 21months (mean 13 months) after starting inhaledsteroids. Patients were examined at monthly inter-vals. Four patients were examined before startinginhaled steroids, while the other five had the initial

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Table 4 Return ofnormal phonation and vocal cord function after cessation ofinhaled steroid treatment

Patient Grade ofdysphonia Weeks taken for normal phonation to return Weeks taken for nornal vocal cordNo at presentation as judged by function to return

Patient Speech therapists

1 2 12 12 122 1 4 4 43 2 6 6 64 2 52 56 525 4 0-5 8 66 1 6 6 67 3 8 33 98 1 8 8 109 3 8 12 19

Mean 2-1 11-6 16-1 13-8

Table 5 Details offive patients taking inhaled steroids with dysphonia but no adductor vocal cord deformity

Patient Age Sex Inhaled steroid Duration of Duration of Grade ofNo (total daily inhaled steroid dysphonia dysphonia

dose in gg) (w) (w)

10 42 F BDP(RR 600) 48 4 111 46 F BDP(R) (1600) 44 16 212 73 F BDP (400 224 32 0-513 38 F BDP (400 12 12 1-514 59 M BDP (450 72 24 0.5

Mean 80 17-6 1.1

BDP-bedomethasone dipropionate; (R)-inhaled via rotahaler.

Table 6 Appearances ofpharynx and larynx and results offungal studies in five patients taking inhaled steroids withdysphonia but no adductor vocal cord deformity

Padent Appearance Appearance Candida SoreNo ofpharynx oflarynx albicans throat

cultured

10 White patches White patches +11* Normal White patches

Vocal cord oedema12 White patches White patches +

Erythema Vocal cord oedema13 Normal Normal14 Normal Normal

*Receiving oral antifungal treatment.

examination within eight weeks (mean five weeks)of starting treatment. During the follow up periodsix patients remained symptom free with no

pharyngeal or laryngeal abnormality, while threepatients developed some abnormalities. Details ofthese patients follow.Patient I A 53 year old woman started to takebeclomethasone dipropionate (400 ,ug/day) bypressurised aerosol. She was instructed in aerosoltechnique and at each clinic visit was judged to havean efficient technique throughout the study of 20months. There was no past history of dysphonia. Anear, nose, and throat examination before treatmentstarted showed nothing abnormal. Twelve weeks

after she had started inhaling beclomethasone di-propionate an adduction abnormality of the vocalcords was observed, although the patient wassymptom free. The dose of beclomethasone wasreduced to 300 ,ug/day and normal vocal cord func-tion was restored one month later. After a furthereight months the abnormality reappeared (nodysphonia being noticed), but it had disappearedone month later. Her dose of beclomethasone wasincreased two months later to 800 ,ug/day; theabnormality subsequently returned and haspersisted while she has been having this treatmentfor the last six months. Occasional dysphonia hasbeen noticed by the patient after prolonged con-versation.Patient 2 A 52 year old woman started to takebeclomethasone dipropionate 800 ,ug/day, deliveredas a dry powder. There was no past history ofdysphonia and an ear, nose, and throat examinationbefore treatment began showed nothing abnormal.Three months later an adduction abnormality of thevocal cords without dysphonia was noted and thesteroid inhalation was stopped. One month later theappearances were normal and remained so over thenext six months.Patient 3 A 57 year old woman was examinedseven weeks after starting beclomethasone dipro-pionate at a dose of 400 ,ug/day. There was no pasthistory of dysphonia. An adductor vocal cordabnormality was observed without dysphonia.

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Steroid inhalation was continued for the next threemonths and the abnormality persisted but withoutsymptoms. The drug was then discontinued and onemonth later the abnormality had disappeared.Beclomethasone dipropionate was then reintro-duced at the same daily dose. Ten weeks later thepatient became dysphonic and the abnormality wasdetected at examination two weeks later. Thesteroid inhalation was again discontinued. Normalphonation returned one week later but the laryngealabnormality took 14 weeks to resolve.

Discussion

Local complications of inhaled steroids includecandidiasis, sore throat, and dysphonia. Theinterrelationship and pathogenesis of these threeconditions have previously not been clear.We have recognised for the first time a

characteristic laryngeal abnormality which appears

to underlie most cases of persistent dysphonia. Innine out of 14 patients there was a bilateral vocalcord adduction deformity, the cords assuming a

bowed or elliptical appearance during phonation.We believe this deformity to be causal-firstly,because the laryngeal abnormality developed andresolved in parallel with dysphonia and, secondly,because an identical abnormality, "phonasthenia,"is a well described cause of dysphonia in myopathicdisorders such as myasthenia gravis and dystrophiamyotonica. In these conditions there is considered tobe a paresis of the phonatory muscles, the internaltensor muscle group being the most commonlyaffected. Dysphonia arises from failure of the vocalcords to approximate completely during phonation,a gap being left for escape of air. We believe thatthis abnormality has not previously been recognisedin dysphonic patients receiving inhaled steroids forthree reasons. Firstly, interest has centred aroundcandidiasis as a cause of dysphonia and laryngo-scopy has usually been performed simply to verify or

exclude the presence of candidiasis rather than toassess vocal cord mobility. Secondly, until theadvent of fibreoptic techniques laryngoscopy hasbeen limited in the conscious patient to an indirectmirror examination, a technique we have found tobe inferior for recognising the abnormal laryngealappearances. Thirdly, direct laryngoscopy with rigidinstruments under general anaesthesia cannot assess

vocal cord mobility.Some cases of dysphonia appear to be due to

candidiasis without any vocal cord abnormality. Infive patients with persistent dysphonia and normalvocal cord mobility, three had laryngeal candidiasis(table 6). We diagnosed the latter when there were

typical white, raised plaques with underlying

erythema. In two of the three cases fungal culturesfor Candida albicans were positive. In the thirdpatient fungal cultures were negative but she wastaking an oral antifungal agent at the time of theexamination. Candidiasis is a well known complica-tion in patients receiving inhaled steroids. Itsreported incidence varies from zero to 91%. Thisvariation depends partly on the diagnostic criteriaadopted by the authors and partly on whether singleor repeated examinations of the pharynx are made.Candida albicans is part of the normaloropharyngeal flora and has been cultured fromthroat swabs in 28%22 and 57%23 of normal sub-jects: hence the diagnosis of candidiasis must be aclinical one. When the strict criteria of typical nakedeye appearances together with positive fungalcultures are used, as in our study, the reported inci-dence of pharyngeal candidiasis is much less vari-able, although it still shows a range from zero to32%.. 78 162024

As well as being the sole cause of dysphonia, can-didiasis may contribute to the vocal cord abnormal-ity by adding an inflammatory component to themyopathic one. Two of our nine patients with vocalcord deformity (table 2) had laryngeal candidiasis.

In some patients with persistent dysphonia novocal cord deformity or candidiasis is seen. We hadtwo patients in this category. Both appeared undulytense and anxious and we believe that theirdysphonia was psychogenic.

Various mechanisms have been suggested for theoccurrence of dysphonia with inhaled steroid treat-ment, including a non-specific mucosal irritationcaused by the freon propellants24 and drying actionof the spray.'7 We have shown a consistent vocalcord deformity, however, to underlie most cases ofpersistent dysphonia. The mechanism of thelaryngeal abnormality we believe to be related to thesteroid rather than the propellant component of theinhaled steroid preparation. Firstly, the laryngealadduction deformity resolved after the inhaledsteroid had been stopped, even though the totalquantity of inhaled propellant was maintained by anappropriate increase in inhaled bronchodilator betaagonist and ipratroprium bromide treatment; thefluorocarbon propellants in aerosols do not differsignificantly in either type or quantity. Secondly,resumption of inhaled steroids in two patients(patients 1 and 6) without any increase in totalpropellant intake led to a return of the abnormality.Thirdly, one patient (patient 5) was taking drypowdered preparations of steroid andbronchodilator, which contain no propellants. In arecent study it was also concluded that dysphoniawas due to the steroid rather than the propellant."In this study it was suggested that vocal cord abuse

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Williams, Baghat, Stableforth, Cayton, Shenoi, Skinnermight be an important contributory factor. Butalthough vocal abuse was present in some of ourpatients it was no more common than in a controlgroup of medical outpatients.

It is clear that all available inhaled steroid prep-arations can cause the laryngeal abnormality andthat a change to a different one at an equivalentdose is unlikely to influence the problem. Probablythe risk of dysphonia due to the adductor vocal corddeformity is related to the total dose and potency ofinhaled steroid preparation. For instance, the twopatients (8 and 9) taking budesonide, which is two tothree times as potent as beclomethasone dipropion-ate,25 both developed dysphonia less than twoweeks after starting the drug; while the patient tak-ing the smallest dose of inhaled steroid, beclo-methasone dipropionate 200 ,ug (patient 4), tookthe longest time (112 weeks) to develop dysphonia.Possibly the vocal cord deformity represents a localsteroid myopathy, but we have no direct evidencefor this. Interestingly dysphonia is seldom reportedin children during inhaled steroid treatment and thismay be explained by the use of a lower total dailydose, as has been suggested;'9 perhaps too theanabolic influence of growth counteracts anydetrimental myopathic effect of the steroid.

In our dysphonic patients sore throat occurredonly when candidiasis was present, although it isclear that most patients with candidiasis aresymptom free. The efficiency or otherwise of thepatient's inhaler technique may have a bearing onthe vocal cord abnormality. An efficient techniquewas found in 90% of patients, a higher percentagethan anticipated from previous surveys, in whichusually 30-40% of patients have been judged tohave an inept technique.2627 Theoretically patientswith an efficient technique may be at greater risk ofdeveloping this abnormality for the followingreason. The branching system of the airways pro-vides an extremely efficient aerodynamic filter andonly 10% of the total dose emitted from an aerosolreaches the conducting airways of the lung.28-3' Theremainder is deposited by inertial impaction, usuallyin the mouth and pharynx. Patients who have aninefficient inhaler technique will therefore depositmore of the drug in the oropharynx. In contrast,patients with an efficient technique will depositmore of the drug in and around the larynx from thestream of particles en route to the lung.

After discontinuation of the inhaled steroid thelaryngeal appearances and the voice invariablyreturned to normal, although this sometimes tookmonths.

We are grateful to Mrs M Constable and Mrs KHaselden for speech analysis, Messrs Allen and

Hanbury for financial support, and Mrs P Jacksonfor secretarial assistance.

References

'Clark TJH. Effect of beclomethasone dipropionate deli-vered by aerosol in patients with asthma. Lancet1972;i:1361-4.

2 Gaddie J, Petrie GR, Reid IW, et al. Aerosolbeclomethasone dipropionate: a dose response studyin chronic bronchial asthma. Lancet 1973;ii:280-1.

3Gaddie J, Petrie GR, Reid IW, et al. Aerosolbeclomethasone dipropionate in chronic bronchialasthma. Lancet 1973;i:691-3.

4Cayton RM, Soutar CA, Stanford CF, et al. Double-blind trial comparing two dosage schedules ofbeclomethasone dipropionate aerosol in the treatmentof chronic bronchial asthma. Lancet 1974;ii:303-7.

5 British Thoracic and Tuberculosis Association. A con-trolled trial of inhaled corticosteroids in patientsreceiving prednisone tablets for asthma. Br J DisChest 1976;70:91-103.

6 Cooper EJ, Grant IWB. Beclomethasone dipropionateaerosol in treatment of chronic asthma. Q J Med1977;46:295-308.

7 Milne LJR, Crompton GK. Beclomethasonedipropionate and oropharyngeal candidiasis. Br Med J1974;iii:797-8.

8 McAllen MK, Kochanowski SJ, Shaw KM. Steroidaerosols in asthma: an assessment of betamethasonevalerate and a 12-month study of patients on main-tenance treatment. Br Med J 1974;1:171-5.

9 Pingleton WW, Bone RC, Kerby GR, et al.Oropharyngeal candidiasis in patients treated withtriamcinolone acetonide aerosol. J Allergy ClinImmunol 1977;60:254-8.

'° Vogt FC. The incidence of candidiasis with use ofinhaled corticosteroids. Ann Allergy 1979;43:205-10.

"Toogood JH, Jennings BA, Greenway RW, et al.Candidiasis and dysphonia complicatingbeclomethasone treatment of asthma. J Allergy ClinImmunol 1980;65:145-53.

12 Toogood JH, Lefcoe NM, Haines DSM, et al. A gradeddose assessment of the efficacy of beclomethasonedipropionate aerosol for severe chronic asthma. JAllergy Clin Immunol 1977;59:298-308.

Brown H Morrow, Storey G, Jackson FA.Beclomethasone dipropionate aerosol in long-termtreatment of perennial and seasonal asthma inchildren and adults: a report of five and half years'experience in 600 asthmatic patients. Br J ClinPharmacol 1977;iv:259-67.

'4 Kerigan AT, Pugsley SO, Cockcroft DW. Substitution ofinhaled beclomethasone dipropionate for ingestedprednisone in steroid-dependent asthmatics. Can MedAssoc J 1973;116:867-70.

"Clark TJH, Costello JF, Soutar CA. The effects ofbeclomethasone dipropionate aerosol given in highdoses to patients with asthma. Postgrad Med J1975;51, suppl 4:72-5.

16 Kass I, Nair SV, Patil KD. Beclomethasone dipropionateaerosol in the treatment of steroid-dependentasthmatic patients. Chest 1977;71:703-7.

' Williams MH, Kane C, Shim CS. Treatment of asthma

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Dysphonia caused by inhaled steroids: recognition of a characteristic laryngeal abnormalitywith triamcinolone acetonide delivered by aerosol.Am Rev Respir Dis-1974;109:538-43.

18 Godfrey S, Hambleton G, Konig P. Steroid aerosols andcandidiasis. Br Med J 1974;iv:325-30 (letter).

19 Gwynn CM, Morrison Smith J. A one year follow-up ofchildren and adolescents receiving regular beclo-methasone dipropionate. Clin Allergy 1974;4:325-330.

20 Cayton RM, Nunn AJ, Turner-Warwick M, et al.Double-blind trial comparing two dosage schedules ofbeclomethasone dipropionate aerosol with a placeboin chronic bronchial asthma. Br J Dis Chest1979;73: 121-32.

21 Kriz RJ, Chmelik F, doPico G, et al. A one year trial oftriamcinolone acetonide aerosol in severe steroid-dependent asthma. Chest 1977;72:36-44.

22 Smits BJ, Prior AP, Arblaster PG. Incidence of candidain hospital in-patients and the effects of antibiotictherapy. Br Med J 1966;i:208-10.

23 Wangaard C, Spector S. Oral candidiasis in long termpatients on beclomethasone dipropionate. AnnAllergy 1977;39:73 (abstract).

24 Willey RF, Milne LJR, Crompton GK, et al. Beclo-methasone dipropionate aerosol and oropharyngealcandidiasis. Br J Dis Chest 1976;70:32-8.

25 Johansson SA, Anderson KE, Brattsand R, et al. Topicaland systemic glucocorticoid potencies of budesonideand beclomethasone dipropionate in man. Eur J ClinPharmacol 1982;22:523-9.

26 Orehek J, Gayrard P, Grimaud CH, et al. Patient error inuse of bronchodilator aerosols. Br Med J 1976;i:76.

27 Earis JE, Bernstein A. Misuse of pressurised nebulisers.Br Med J 1978;i: 1554.

28 Newman SP, Pavia D, Moren F, et al. Deposition ofpressurised aerosols in the human respiratory tract.Thorax 1981;36:52-5.

29 Newhouse MT, Ruffin RE. Deposition and fate of aerol-ised drugs. Chest 1978;73:936-42.

30 Dolovich MB, Killian D, Wolff RK, et al. Pulmonaryaerosol deposition in chronic bronchitis: intermittentpositive pressure breathing versus quiet breathing.Am Rev Respir Dis 1977;115:397-402.

31 Davies DS. Pharmacokinetics of inhaled substances.Postgrad Med J 1975;51, suppl 7: 69-75.

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