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The inflammation produced by corticosteroid inhalers in the

ORIGINAL ARTICLE
pharynx in asthmatics
Bhalla, R.K., Taylor, W., Jones, A.S. & Roland, N.J.
Department of Otolaryngology ⁄ Head & Neck Surgery, University Hospital Aintree, Liverpool, UK
Accepted for publication 29 September 2008
Clin. Otolaryngol. 2008, 33, 581–586

Objectives: To investigate inflammation of the pharyn- had significantly higher pharyngitis scores (P = 0.0204).
geal mucosa caused by inhaled corticosteroids. Similarly, weakness of voice (P = 0.0234), hoarseness
Design: Prospective, cross-sectional, single-blinded (P < 0.001) and sore throat (P < 0.001) were also more
study. common in those patients that used an inhaled cortico-
Setting: University Hospital Aintree, Liverpool, UK. steroid on a regular basis. To our surprise, however, cel-
Patients: Fifty adults were recruited from two local gen- lular markers of inflammation did not corroborate the
eral practices and from general ENT clinics at our Uni- appearances of clinical examination. We found that the
versity hospital. Patients were allocated to one of four five most important discriminators, between those that
groups according to use of inhaled corticosteroids and were using inhaled corticosteroid therapy regularly and
the presence of adverse local side effects. those that were not, to be intra-epithelial inflammatory
Main outcome measures: Scores achieved on a respira- cells (scdf )1.2939); age (scdf 0.8389); use of a spacer
tory symptom questionnaire. Histological markers of device (scdf 0.5456); sore throat (scdf 0.4230) and throat
inflammation and their correlation with pharyngitis. Sta- irritation (scdf 0.4015). The groups were significantly
tistical modelling included univariate and multivariate different (P < 0.0001). The statistical model used, classi-
analyses, which included multiple linear and logistic fied 68% of the cases correctly into their respective
regression, and discriminant analysis. groups.
Results: The regular use of inhaled corticosteroids pre- Conclusions: Inhaled corticosteroids predispose to phar-
disposed subjects to hoarseness, weakness of voice, sore yngitis and an inflammatory infiltrate. However, the clini-
throat and throat irritation (P < 0.0001). Pharyngitis was cal diagnosis of pharyngitis does not correlate well with
significantly different between the groups (P < 0.0001). cellular inflammatory infiltrate and is therefore, not a
Furthermore, those not using an inhaled corticosteroid reliable measure of underlying inflammation. We advo-
regularly had little or no clinically apparent pharyngitis, cate caution in the use of pharyngeal erythema as a mea-
whereas those using an inhaled corticosteroid regularly sure of underlying inflammation.

by reducing the transcription of interleukins 3 and 5. The


Introduction
consummate effect is to reduce the production of inflam-
The pharynx is susceptible to inflammatory changes as a matory mediators.2,3 Vasconstrictive effects reduce bron-
consequence of inhaled corticosteroid use. This may be chial mucosa oedema and thickening and beta-adrenergic
because up to 80% of the inhaled dose is deposited on responsiveness is enhanced. The long-term use of inhaled
the pharyngeal mucosa prior to being swallowed.1 An corticosteroids may decrease the immediate response to
accurate explanation is difficult however, as corticoster- allergen and exercise by reducing the number of mast
oids are powerful anti-inflammatory agents. cells in the airway.4 The benefits of inhaled corticoster-
Glucocorticoids are thought to suppress inflammation oids are unquestionable. However, adverse mucosal effects
in asthma by increasing the synthesis of lipocortin-1 or causing inflammation may result in pain, a chronic sore
throat, hoarseness and odynophagia.5,6 Subsequent com-
pliance with therapy can be hampered by the local side
Correspondence: R.K. Bhalla, Consultant ENT ⁄ Head & Neck Surgeon,
effects.
Department of Otorhinolaryngology, Manchester Royal Infirmary,
Oxford Road, Manchester M13 9WL, UK. Tel.: +44 161 276 4426; fax: The complications of inhaled corticosteroid therapy are
+44 161 276 5003; e-mail: rajiv.bhalla@cmmc.nhs.uk not uncommon. More than 60% of one sample group of
 2008 The Authors
Journal compilation  2008 Blackwell Publishing Ltd • Clinical Otolaryngology 33, 581–586 581
582 R.K. Bhalla et al.

children using inhaled corticosteroids were afflicted by at the study. There were no patients using nebulised prepa-
least one local side effect in daily life.7 Several studies rations. Patients were advised to stop over-the-counter or
have assessed the frequency of oropharyngeal and laryn- prescription, topical or systemic antihistamines at least
geal candidiasis.8,9 Dysphonia usually resolves after stop- 7 days prior to enrolment in the study. None of the
ping inhaled corticosteroid therapy.10 patients were taking leukotriene inhibitors.
Little is known about the very action that causes
inflammation and indeed, whether there is an underlying
Allocation to study groups
susceptibility in the pharyngeal mucosa of asthmatics.
Furthermore, no cellular assessment of inflammation has Subjects were allocated to one of four groups on the basis
been made in asthmatics. This study has provided a base- of inhaled corticosteroid use and adverse symptoms at
line comparison of normal and asthmatic pharyngeal the outset of the study (Table 1). Asthmatic patients were
mucosa. It also examines whether pharyngitis is a reliable deemed symptomatic if they used an inhaled corticoste-
indicator of underlying cellular inflammatory infiltrate. roid and had hoarseness, pharyngeal discomfort or sore
throat of more than one-month duration. Other causes of
these symptoms were excluded by history and thorough
Methods
ENT examination. Seasonal asthmatics gave a history of
The study design was prospective, cross-sectional and sin- using their inhalers infrequently, for example ‘once a
gle-blinded. month’ or ‘over the summer months’, but had been diag-
nosed as asthmatic by their general practitioner because
of variability in peak flows. These individuals were either
Recruitment
not or very infrequently using their inhaled corticosteroid
Fifty volunteers were recruited from two local general during the period of the study.
practices and from general ENT clinics at our University
hospital. An assessment of inhaler technique was made at
Exclusion criteria
the point of recruitment, and guidance provided if the
technique of delivery was found to be sub-optimal, with Subjects were excluded if other causes of pharyngeal or
special reference to sufficient shaking of the canister prior laryngeal disease were identified at the initial assessment.
to inhalation, breathing and timing of delivery with inspi- These included a history of reflux, malignancy, vocal fold
ration. Patients were also educated regarding the function lesions or neurological causes of dysphonia. Those using
of their corticosteroid inhaler versus the short or long-act- topical intranasal steroids to treat co-existent inflamma-
ing b2-agonist and the benefits of compliant use at the tory or allergic nasal disease were excluded. Those with
prescribed regimen. an upper respiratory tract infection in the preceding
4 weeks, who were medically unfit because of intercurrent
disease, or had chronic obstructive pulmonary disease,
Ethical considerations
were excluded. Poorly controlled asthmatics requiring
The local research and ethics committee approved a pro-
tocol for the study, patient information sheet and patient
Table 1. Description of study groups
consent form. Patients were allocated a study number for
anonymity. Group Description

A Normal healthy volunteers. (4)


Inclusion criteria B Seasonal asthmatics: patients using inhalers
(rescue and ⁄ or preventer medications) infrequently,
Individuals over the age of 18 and able to partake in and asymptomatic. (12)
informed consent. The healthy controls (group A) did C Asthmatic patients using inhaled corticosteroids
not have documented respiratory disease and were not regularly, and were symptomatic. (25)
using inhaled corticosteroids, short or long-acting b2- D Asthmatic patients using inhaled corticosteroids
agonists or topical intranasal steroids. Asthmatics (groups regularly, and were asymptomatic. (9)
B–D) had a baseline predicted FEV1 of >60% and <90%. Symptomatic asthmatics were defined as those using an
An increase in FEV1 of >12% after reversibility testing inhaled corticosteroid with adverse symptoms of hoarseness,
had been established during the preceding 6 months. pharyngeal discomfort and ⁄ or sore throat of more than one-
Subjects using inhaled corticosteroids were required to month duration.
have done so for at least 30 consecutive days leading into Numbers in each group are given in parentheses.
 2008 The Authors
Journal compilation  2008 Blackwell Publishing Ltd • Clinical Otolaryngology 33, 581–586
The inflammation produced by corticosteroid inhalers 583

systemic steroid or antibiotic therapy in the preceding were neutrophils. Those characteristic of chronic inflam-
4 weeks and those who had been hospitalised or suffered mation were lymphocytes and plasma cells. The presence
an acute asthma attack in the preceding 3 months were of eosinophils and macrophages was also recorded. Vas-
excluded. Patients using Seretide (Allen & Hanburys Ltd, cular markers of inflammation included oedema, vessel
Uxbridge, England) were excluded. Seretide is a combina- dilation and congestion. The degree of penetration of
tion of fluticasone propionate and salmeterol, a long- connective tissue papillae into the overlying squamous
acting b2-agonist. Inclusion of this group would potentially epithelium was gauged. Epithelial thickness, basal cell
have confounded the results, as it would have been hyperplasia and parakeratosis were recorded. Histopatho-
impossible to attribute inflammation solely to the inhaled logical findings were graded as present or absent, or as 1
corticosteroid. (normal), 2 (mild inflammation) or 3 (marked inflamma-
tion).
Data collection
Statistical analysis
Subjects withheld their short-acting b2-agonist for 6 h
and long-acting b2-agonist for 12 h prior to assessment. For comparisons between groups, the Kruskal–Wallis H
An asthma and allergy history determined eligibility for test was applied. For comparisons between the two active
inclusion. A respiratory symptom questionnaire was com- groups, C and D, the Mann–Whitney U test was utilised.
pleted. This tool had been designed, piloted and used in For all calculations, the Bonferoni correction was used
a prior prevalence study. Pharyngeal discomfort at the because of the large number of variables studied. The
time of assessment was scored subjectively using a multivariate analysis included multiple linear and logistic
ten-centimetre visual analogue scale. A thorough ENT regression, and discriminant analysis. The discriminant
examination was performed. The lead investigator alone, analysis technique was used for categorising data and had
utilising his clinical acumen as a practicing ENT physi- similarities with multiple logistic regression, but with the
cian, graded pharyngeal inflammation as 0 (none), 1 advantage of being able to study more than two catego-
(mild), 2 (moderate) or 3 (severe). Pharyngeal assess- ries. The variables assessed included age, smoking, dura-
ment was controlled with regard to headlight and room tion of asthma, duration of inhaled corticosteroid use,
lighting. Candida infection was determined by skin use of a spacer device, onset of adverse side effects after
prick test and identification of fungal hyphae in the his- commencing inhaled corticosteroid therapy, concurrent
tological specimens. A standardised biopsy of the pos- b2-agonist use, symptom reporting (cough, sore throat,
terior pharyngeal wall was taken. Histological specimens throat irritation, hoarseness, weakness of voice, aphonia),
were examined without prior knowledge of the donor pharyngitis and histological markers of inflammation
(investigator-blind). (epithelial thickness, basal cell hyperplasia, parakeratosis,
extension of connective tissue papillae into the overlying
squamous epithelium and vascular markers such as
Pharyngeal biopsy technique
oedema, dilation or congestion).
After spraying the posterior pharyngeal wall mucosa with
4% Lidocaine to provide surface anaesthesia, a biopsy
Results
was taken using micro-cupped laryngeal forceps. The pos-
terior pharyngeal wall, for the purpose of this study, was The fifty recruited volunteers were allocated to their
the mucosal surface of the throat that extended from the respective groups according to the definitions provided
soft palate in a mouth-breathing patient to the level of earlier. The age range was 20–81 years, median 59 years.
the depressed tongue. The most inflamed area was There were 26 males. There were seven smokers: one in
selected as the biopsy site. The specimen was fixed in the normal group and two each in the other three groups.
Formalin and processed for histological examination. In this sample, smoking did not appear to predispose to
statistically significant adverse symptoms. Skin prick test-
ing excluded Candida as a cause for pharyngitis in the
Histopathological examination
entire sample. Furthermore, histological examination did
One investigator examined histological specimens blindly. not detect fungal hyphae in any of the sample.
Specimens were stained with haematoxylin and eosin. Pharyngitis was graded in all fifty individuals (Fig. 1).
The squamous epithelium and underlying connective tis- The median and mean discomfort scores in inhaled corti-
sue were assessed. Markers of acute and chronic inflam- costeroid users were 3.7 and 3.45 respectively. On this
mation were graded. Cells typical of acute inflammation scale, 0 indicated no discomfort caused by the inhaled
 2008 The Authors
Journal compilation  2008 Blackwell Publishing Ltd • Clinical Otolaryngology 33, 581–586
584 R.K. Bhalla et al.

14 1.3621). Between groups C and D, hoarseness and phar-


yngitis were highly correlated (P = 0.0015, OR = 12.3204
12 None & P = 0.0049, OR = 8.7481).
Mild
Moderate
The discriminant analysis technique was used for cate-
10
Severe gorising data and had similarities with multiple logistic
regression, but with the advantage of being able to study
8
more than two categories. For the purpose of this analy-
sis, the normal and seasonal asthmatics were considered
6
as one group because of the paucity of adverse symptoms
in the latter group. Therefore, with reference to three
4
study groups (normals ⁄ seasonal asthmatics versus asymp-
2
tomatic asthmatics versus symptomatic asthmatics), we

0 (a)
A B C D
Severity of pharyngitis at clinical examination

Fig. 1. Bar chart to illustrate the severity of pharyngitis at clini-


cal examination. Group A were healthy volunteers; Group B
were seasonal asthmatics; Group C were symptomatic asthmatics
using inhaled corticosteroids regularly; and Group D were
asymptomatic asthmatics, also using inhaled corticosteroids reg-
ularly (see Table 1).

corticosteroid and 10 indicated the most severe discomfort


imaginable.

Biopsy data

All fifty biopsies were adequate for assessment of inflam-


matory infiltrate. Lymphocytes and plasma cells, markers
of chronic inflammation, predominated over other cell (b)
types in the connective tissue, with greater subsequent
migration of lymphocytes into the squamous epithelium
(Fig. 2). Although pharyngitis was commoner in asthmat-
ics (P < 0.0001), this was not reflected in either the
inflammatory infiltrate or the other markers of inflamma-
tion (epithelial thickness, basal cell hyperplasia, parakera-
tosis, extension of connective tissue papillae into the
overlying squamous epithelium and vascular markers
such as oedema, dilation or congestion).

Statistical modelling

The multivariate analysis included multiple linear and


logistic regression, and discriminant analysis. For the
multiple linear and logistic regressions, the stepwise pro-
cedure was used and all variables were included in the
model. As the model was refined, the non-significant Fig. 2. Photomicrographs showing: (a) A chronic inflammatory
variables were removed leaving only those that were sig- infiltrate of lymphocytes and plasma cells in the squamous epi-
nificant. Consequently, both weakness of voice and phar- thelium and underlying connective tissue, (b) A high-powered
yngitis were positively correlated from group A to D view with marked oedema of the connective tissue and associ-
(P = 0.0234, Odds Ratio [OR] = 1.227 & P = 0.0395, OR ated blood vessel dilatation.
 2008 The Authors
Journal compilation  2008 Blackwell Publishing Ltd • Clinical Otolaryngology 33, 581–586
The inflammation produced by corticosteroid inhalers 585

were interested to know if a model built of the variables But why would an anti-inflammatory steroid preparation
could then successfully classify the three disease groups, cause inflammation in the upper airway? This observation
i.e. to tell us if the variables in the model were important is very likely to be multifactorial and may depend on
and, of course, different between the disease categories. several factors (Table 2). Snoring was not evaluated or
The results of this analysis showed a large Eigenvalue of controlled for as a potential risk factor within the context
3.2465 with a P-value of P = 0.0003. This indicated a of this study, but the investigators accept that mouth-
large difference between the three groups. Based on a cut- breathing in general may well have contributed to phar-
off of 0.40, the five most important discriminators (in yngitis. However, as discussed in the methodology,
order of importance) with their standardised coefficients patients did not have significant sinonasal disease that
of the discriminant functions (scdf) were: the presence of warranted topical intranasal steroid use. Further research
intra-epithelial inflammatory cells (scdf )1.2939); age is undoubtedly required to evaluate a potential associa-
(scdf 0.8389); use of a spacer device (scdf )0.5456); sore tion between mouth-breathing ⁄ snoring and pharyngitis.
throat (scdf )0.4230) and throat irritation (scdf 0.4015).
A negative sign denoted an inverse effect. Assessment of
Current measures to reduce the risk of oropharyngeal
the mahalanobis distance between the groups with signifi-
inflammation
cance values showed that the three test groups (nor-
mal ⁄ seasonal asthmatics versus asymptomatic asthmatics Unfortunately, the management of unwanted side effects
versus symptomatic asthmatics) were all very significantly is wholly unsatisfactory. Sufferers are advised to gargle
different and, in particular, the asymptomatic and symp- after using the inhaler and commence using a spacer
tomatic were different based on the variables we have. device.13 However, despite stringent compliance to these
The model used classified 68% of the cases correctly into measures, there remains a group of asthmatics that con-
the three groups. tinue to be affected by corticosteroid local side effects.
This is not surprising as up to 80% of an inhaled dose
may deposit in the oropharynx.14
Discussion

Synopsis of key findings Clinical applicability of this study

Inhaled corticosteroids, when used for any length of time, Prior to this investigation, it has been assumed that phar-
may initiate pharyngeal and laryngeal complications. yngitis and cellular inflammatory infiltrate must be posi-
These include throat irritation and soreness, hoarseness tively correlated. Although we have shown that asthmatics
and voice weakness. Oral and oropharyngeal opportunis- using corticosteroid inhalers regularly had a significantly
tic infections, particularly Candida albicans, are frequently increased risk of hoarseness, voice weakness, soreness and
encountered.8 Other complications include perioral der-
matitis and tongue hypertrophy.11,12 We found that the
most troublesome functional complications were cough
during inhalation and dysphonia. Frequent complaints Table 2. Factors that may contribute towards inflammation of
the airways
were of a dry sensation in the throat, of the voice repeat-
edly breaking up, inability to raise the voice effectively Possible irritant Mechanism of irritation
and a lack of confidence in the speaking voice. Steroid Preparation
The implications of these unwanted side effects are Carrier substance
far reaching and often hamper compliance. Any patient Dose of steroid
presenting with the symptoms described, above all else, Dosing regimen
requires investigation to exclude an underlying neo- Propulsion Inhaler device
plasm. If no malignancy is found, the patient can be Propellant
reassured that the symptoms are attributable to the Intrinsic inflammation Irritable airways of
inhaled corticosteroid. asthmatics
Mechanical irritation Cough
Inter-current Rhinosinusitis
Suggested mechanisms of pharyngeal inflammation in inflammatory disease Post-nasal catarrh
asthmatics Inter-current Smoking
inflammatory stimuli Environmental pollutants
Little is actually known about the mechanism by which Noxious workplace agents
inhalers cause inflammation of the pharyngeal mucosa.
 2008 The Authors
Journal compilation  2008 Blackwell Publishing Ltd • Clinical Otolaryngology 33, 581–586
586 R.K. Bhalla et al.

throat irritation compared with normals and seasonal 3 Taylor I.K. & Shaw R.J. (1993) The mechanism of action of cor-
asthmatics, there was no relationship between pharyngeal ticosteroids in asthma. Respir. Med. 87, 261–277
appearance and inflammatory infiltrate. Therefore, a clini- 4 Barnes P.J. (1993) Anti-inflammatory therapy for asthma. Annu.
Rev. Med. 44, 229–242
cally red pharynx may have had very little in the way of
5 Babu S. & Samuel P. (1988) The effect of inhaled steroids on
inflammatory infiltrate and conversely, one that appeared the upper respiratory tract. J. Laryngol. Otol. 102, 592–594
relatively normal may in fact have had a substantial infil- 6 Williamson I.J., Matusiewicz S.P., Brown P.H. et al. (1995) Fre-
trate. The clinical inference was that a normal or near- quency of voice problems and cough in patients using pressur-
normal pharynx on inspection did not exclude an asth- ised aerosol steroid preparations. Eur. Respir. J. 8, 590–592
matic from having a substantial mucosal inflammatory 7 Dubus J.C., Marguet C., Deschildre A. et al. (2001) Local side
reaction, with the ensuing side effects already alluded to. effects of inhaled corticosteroids in asthmatic children: influence
of drug, dose, age and device. Allergy 56, 944–948
8 Hanania N.A., Chapman K.R. & Kesten S. (1995) Adverse effects
Conflict of interest of inhaled corticosteroids. Am. J. Med. 98, 196–208
9 Barnes P.J., Pedersen S. & Busse W.W. (1998) Efficacy and
None to declare. safety of inhaled corticosteroids. Am. J. Respir. Crit. Care Med.
157, S1–S53
10 DelGaudio J.M. (2002) Steroid inhaler laryngitis: dysphonia
Declaration caused by inhaled fluticasone therapy. Arch. Otolaryngol. Head
Neck Surg. 128, 677–681
Mr RK Bhalla wrote the paper. Dr W Taylor assessed the
11 Held E., Ottervanger V., Petersen S. et al. (1997) Perioral der-
histological specimens. Professor AS Jones provided sta-
matitis in children under steroid inhalation therapy. Ugeskr. Lae-
tistical analysis. Mr NJ Roland supervised the study and ger 157, 7002–7003
also provided editorial advice. Mr RK Bhalla accepts full 12 Linder N., Kuint J., German B. et al. (1995) Hypertrophy of the
responsibility for the integrity of the article. tongue associated with inhaled steroid therapy in premature
infants. J. Paediatr. 127, 651–653
13 Selroos O., Backman R., Forsen K.O. et al. (1994) Local side
References effects during 4-year treatment with inhaled corticosteroids –
a comparison between pressurised metered-dose inhalers and
1 Inhaler devices for asthma. Drug Ther. Bull. 38, 9–14
Turbohaler. Allergy 49, 888–890
2 Schleimer R.P. (1990) Effects of glucocorticoids on inflamma-
14 Lipworth B.J. (1995) New perspectives on inhaled drug delivery
tory cells relevant to their therapeutic applications in asthma.
and systemic bioactivity. Thorax 50, 105–110
Am. Rev. Respir. Dis. 141, S59–S69

 2008 The Authors


Journal compilation  2008 Blackwell Publishing Ltd • Clinical Otolaryngology 33, 581–586