reviews

The Local Side Effects of Inhaled

Corticosteroids*
Current Understanding and Review of the
Literature
Nicholas J. Roland, MD; Rajiv K. Bhalla, BSc(Hons); and John Earis, MD

The frequent use of inhaled corticosteroids (ICSs), especially at higher doses, has been
accompanied by concern about both systemic and local side effects. The systemic complications
of ICSs have been extensively studied and are well-documented in the literature. There are
comparatively few studies reporting on the local complications of ICSs. Compared with systemic
side effects, the local side effects of ICSs are considered to constitute infrequent and minor
problems. However, while not usually serious, these local side effects are of clinical importance.
They may hamper compliance with therapy and the symptoms produced may mimic more sinister
pathology. This review considers the prevalence of local side effects, their clinical features, the
potential causes, the role of inhaler devices, and current measures that have been suggested to
avoid the problem. (CHEST 2004; 126:213–219)

Key words: asthma; corticosteroid; inhaler; laryngitis; local side effects; pharyngitis

Abbreviations: BDP ⫽ beclomethasone dipropionate; BUD ⫽ budesonide; DPI ⫽ dry powder inhaler; ICS ⫽ inhaled
corticosteroid; MDI ⫽ metered-dose inhaler; pMDI ⫽ pressurized metered-dose inhaler

G lucocorticoids are the most potent and reliable

of the available agents among the antiinflamma-
tory drugs, and have assumed a major role in the
management of asthma.1 This has subsequently re-
sulted in the widespread use of inhaled corticoste-
roids (ICSs), at higher doses and for longer periods
of time.2
The mode of action of glucocorticoids in suppress-
ing inflammation in asthma is not completely under-
stood. It is thought that a cytoplasmic steroid recep-
*From the Departments of Otolaryngology (Dr. Roland and Mr.
Bhalla) and Respiratory Medicine (Dr. Earis), University Hospi-
tal Aintree, Liverpool, UK.
N.J. Roland and R.K. Bhalla wrote the paper. R.K. Bhalla was
investigating the clinical impact of this problem at the time of
writing. J. Earis was supervising R.K. Bhalla in aspects of his
research. N.J. Roland accepts full responsibility for the integrity
of the article.
Manuscript received May 14, 2002; revision accepted October 2,
2003.
Reproduction of this article is prohibited without written permis-
sion from the American College of Chest Physicians (e-mail:
permissions@chestnet.org).
Correspondence to: Nicholas J. Roland, MD, Department of
Otolaryngology, University Hospital Aintree, Lower Ln, Liver-
pool L9 7AL, UK; e-mail: DrNJRoland@aol.com
tor translocates to the cell nucleus and either induces
increased synthesis of lipocortin-1, an inhibitor of
phospholipase A2 and hence the arachidonic pathway
of inflammatory mediator production, or reduces the
transcription of cytokines such as interleukin-3 and
interleukin-5, and granulocyte-macrophage colony-
stimulating factor.3,4 The vasoconstrictor activity of
corticosteroids aids to reduce bronchial mucosal edema
and thickening, and ␤-adrenergic responsiveness is
enhanced. The late response to allergen exposure is
prevented by an inhibitory action on monocytes and
granulocytes. The long-term administration of inhaled
steroids also may reduce the number of mast cells in
airway mucosa and decrease the immediate response to
allergen and exercise.5,6
The Complications of ICSs
The frequent use of ICSs, especially at higher
doses, has been accompanied by concern about both
systemic side effects and local side effects. The
systemic complications of ICSs have been exten-

www.chestjournal.org CHEST / 126 / 1 / JULY, 2004 213

sively studied and are well-documented in the liter-
ature.2,7 Systemic complications occur because up to
80% of the dose delivered by a conventional me-
tered-dose inhaler (MDI) is swallowed.8 Systemic
side effects are dose-dependent, and obvious differ-
ences exist between ICSs in their ability to cause
systemic glucocorticoid activity. Problems include
the following: calcium and phosphate metabolism
with subsequent risk of osteoporosis9,10; adrenocor-
tical suppression2,11; bruising and skin thinning12,13;
posterior subcapsular cataracts14; and glaucoma.15
It is surprising however, that there are compara-
tively few studies whose sole objective was to report
the local complications of ICSs. It is well-known that
hoarseness and pharyngeal discomfort are common
problems in asthmatic patients using inhalers, espe-
Figure 1. Laryngeal candidiasis in a patient using a steroid
cially among those using inhaled steroid prepara- inhaler. Image recorded by videolaryngoscopy without strobos-
tions.16,17 Compared with systemic side effects, the copy.
local side effects of ICSs are considered to constitute
infrequent and minor problems. However, while not
usually serious, these local side effects are of clinical
the action of ICSs (Fig 2). Little is known about the
importance. They may hamper compliance with
very action that causes the inflammation. Some have
therapy, and the symptoms produced may mimic
speculated that a “residue” from the inhaled sub-
more sinister pathology.
stance irritates the pharyngolaryngeal mucosa. In-
deed, both the propellant and lubricant components
of MDI preparations will have a proinflammatory
Prevalence local effect. This may partly explain the difference in
frequency of local side effects between steroid pres-
Reported prevalences vary significantly depending
surized MDIs (pMDIs) and high-to-medium-high-
on the type of studies, length of observations, and
resistance dry-powder inhalers (DPIs). Low-resis-
methods for recording side effects (questionnaire or
tance steroid DPIs (eg, Rotahaler, Diskhaler, and
inspection). Many trials estimate these symptoms to
Diskus/Accuhaler; GlaxoSmithKline; Research Tri-
occur in the region of 5 to 10% of the treated
population, but no factual scientific evidence is given
to corroborate these claims. Some studies quote
figures of 55 to 58%,16,18 but again these are largely
symptom-based questionnaires. Dubus et al19 used
both a questionnaire and a clinical examination in
children. They found that ⬎ 60% of asthmatic chil-
dren and infants treated with ICSs were affected by
at least one local side effect in daily life. Further-
more, clear distinctions should be drawn between
the clinical diagnosis of oropharyngeal candidiasis
and positive cultures for Candida albicans.

Etiology of Local Side Effects

Several studies have looked at local infective com-
plications of steroid inhaler usage, such as oropha-
ryngeal and laryngeal candidiasis2,7,17 (Fig 1), and
dysphonic problems without candidiasis manifested
as bowing of the vocal folds on phonation.18 To date,
however, there have been no studies to evaluate the
Figure 2. Inflammation of the pharyngolaryngeal mucosa pro-
cause or nature of the inflammatory response at a duced by sustained use of a steroid inhaler. Image recorded by
local level (ie, pharyngeal and laryngeal) produced by videolaryngoscopy without stroboscopy.

214 Reviews
angle Park, NC) are associated with higher frequen-
cies of local side effects because of the greater
oropharyngeal deposition, compared with DPIs, with
a higher inbuilt resistance. Lactose, as a component
of lactose-based DPIs, also may have an irritating
role on the pharyngolaryngeal mucosa. But why
would an antiinflammatory steroid preparation cause
inflammation in the upper airway? The problem is
probably multifactorial, depending on the following
factors:
• The steroid (eg, preparation, carrier substance,
dose of steroid, and regime);
• The manner in which it is propelled into the
airways (ie, the inhaler device);
• Intrinsic inflammation of the upper airway in
asthmatic patients;
• Mechanical irritation because of cough;
• Intercurrent inflammatory disease (eg, rhinitis and
postnasal catarrh); and
• Intercurrent inflammatory stimuli (eg, smoking
and noxious agents in the workplace).
Clinical Features
There is a range of local side effects that includes
perioral dermatitis,20 tongue hypertrophy,21 oral and
oropharyngeal candidiasis,2,7,17 pharyngeal inflam-
mation, laryngeal disorders18 (Fig 3), cough during
inhalation, and a sensation of thirst.19
Pharyngeal disease tends to present with pain,
irritation, or soreness in the throat. The pain may be
aggravated by swallowing (odynophagia), and, on
occasions, patients may present with dysphagia. By
far the most frequent local side effect is hoarseness
Figure 3. Beefy laryngitis causing pronounced hoarseness in a
patient using a steroid inhaler. Image recorded by videolaryngos-
copy without stroboscopy.
www.chestjournal.org
of the voice (dysphonia) due to the action of the
steroid inhaler on the larynx. Cough can be trouble-
some for this same reason. Cough during inspiration
is usually only associated with pMDIs with or with-
out a large-volume spacer. DPIs, with a larger
proportion of fine particles, are practically devoid of
this side effect (eg, reservoir inhalers, Turbohaler
[AstraZeneca; Geneva, Switzerland], and Twisthaler
[Schering-Plough; Kenilworth, NJ]). However,
cough may still be seen as a side effect with DPIs
containing large amounts of lactose (eg, capsule-
based, Diskhaler, and Diskus/Accuhaler).
Dubus et al19 have studied the local side effects of
ICSs in asthmatic children, but most studies have
concentrated on adults. Patients with pharyngeal and
laryngeal disease form a significant part of the
workload in ear-nose-throat surgery clinics. Such
disease can be due to a number of different causes,
including infection and neoplasia. The fact that the
cardinal symptoms of throat cancer are persistent
soreness in the throat and hoarseness of the voice
underpins the importance of excluding other causes
sooner rather than later.
Dysphonia
Dysphonia has been reported in 5 to 50% of
patients using inhaled steroids.2,22 The wide range in
this prevalence is a reflection of the means by which
this data are calculated (ie, as a coincidental finding
in many studies that have ultimately set out to
investigate a different, although associated, prob-
lem). It is also interesting that many studies19 use the
terms dysphonia and hoarseness as different phe-
nomena when, in fact, the difference is very subtle.
Furthermore, it is apparent that dysphonia (or
hoarseness) usually has been assessed only by ques-
tionnaires rather than by any clinical measurement.
A dose-dependent hoarseness has been reported
in 34% of patients treated with beclomethasone
dipropionate (BDP) or budesonide (BUD) when
both ICSs were administered via pMDIs.16 Other
studies23–26 have reported an increased risk of
hoarseness with use of fluticasone propionate com-
pared to BDP, and with pMDIs compared to DPIs.
It has been suggested that the etiology of dysphonia
in some cases is due to a steroid myopathy affecting
the vocal cord muscles. Consequently, there is bilat-
eral adductor vocal fold deformity with bowing of the
folds on phonation.18 This is thought to be an
extremely rare condition, but, in the authors’ opin-
ion, a closer examination using flexible laryngoscopy
and videostroboscopy reveals varying degrees of
myopathy in symptomatic patients. This problem
can, however, be reversed when therapy with the
inhaled steroid is stopped.
CHEST / 126 / 1 / JULY, 2004 215
 In contrast, Shaw and Edmunds27 found dyspho-
nia not to be a problem when they examined 129
children in the age range 6 to 15 years using regular
inhaled BDP, 100 to 1,500 ␮g per day, although no
objective measure of dysphonia was used in this
young age group. Similarly, Agertoft et al28 showed a
comparable incidence of hoarseness in healthy con-
trol subjects and children receiving long-term BUD
therapy via Turbuhaler.
Oropharyngeal Candidiasis
Oropharyngeal candidiasis has a reported inci-
dence of 0 to 70% in ICS users.29 –32 The disparity
here is once again probably related to the differences
in diagnostic criteria. For example, in the study by
Dubus et al19 no cultures were made of Candida, but
the diagnosis was based on clinical findings. This side
effect may be due to a decreased local immunity or
to an increase in salivary glucose levels, which stim-
ulates C albicans growth.32,33 In some cases, the
patient is notably asymptomatic. More significantly,
perhaps, is that a small proportion of patients being
treated with BDP but without clinical evidence of
candidiasis complained of sore throat and hoarse-
ness.29 No explanation for this association was given
in this report.
The association between ICS use and oropharyn-
geal candidiasis is not clear, since there is no appre-
ciable enhancement of C albicans pseudomycelial
growth in vitro by BDP pure substance.29 In all
cases, however, candidiasis is seen where the ICS
was likely to have contacted the oral mucosa.30,34 – 43
It has been suggested that it is perhaps a conse-
quence of immunosuppression at the oral mucosal
surface.2 With current instructions to rinse the
mouth after inhalation, however, this is a much rarer
complication and is usually only seen in patients with
poor mouth hygiene or in conjunction with other
diseases/therapies (eg, diabetes, immunosuppres-
sion, or concomitant oral corticosteroid treatment).
Cough
Cough is an inherent symptom of asthmatic dis-
ease and has been correlated with worse control.44
The occurrence of cough during inhalation has been
observed in more than one third of the children
treated with ICSs.19 It has been proposed44,45 that
this side effect occurs in concurrence with asthma, as
a result of a toxic role of inhaled excipients (oleic
acid) from pMDIs, and from nonspecific irritant
effects of ICSs.
Perioral Dermatitis
Dubus et al19 found perioral dermatitis to be
infrequent in children, and dependent on whether
216
they used a spacer device equipped with facemask
(5%), a nebulizer with facemask, or nebulizer with-
out a mouthpiece (14%). Dermatitis around the
mouth is thought to be due to a direct local effect of
ICSs on the facial skin. There is evidence that BUD
may have an effect on collagen synthesis in the
skin.46 Held et al20 recommended the use of topical
erythromycin or metronidazole in severe cases.
Thirst
A thirsty feeling after ICS delivery may be caused
by throat irritation or as a manifestation of oral
candidiasis. Dubus et al19 found that ⬎ 20% of
children taking an ICS complained of thirst. The
only risk factor was a combined treatment of ICSs
with a long-acting ␤2-agonist.
Tongue Hypertrophy
This is a rarely reported problem. Tongue hyper-
trophy has been described in infants treated with
nebulized BDP for bronchopulmonary dysplasia21
and in asthmatic children treated with nebulized
BUD.19 It is thought to be due to a direct effect of
the ICS causing tongue muscle hypertrophy and
local fat accumulation. The condition resolves after
cessation of the steroid treatment.
Treatment of Local Side Effects
Without a specific diagnosis, it is difficult to
comment on the most appropriate therapy to treat
these problems. No study has been performed to
evaluate the value of any specific treatment. Most
patients are advised to rinse their mouths and oro-
pharynx by gargling with water immediately after
using the inhaler. Provision of a spacer device is an
attempt to minimize laryngeal and pharyngeal dep-
osition of the inhaled material. In one study,24 this
has been shown to be of some benefit, but, in
contrast, another study19 found that cough was a
spacer device-dependent side effect.
Increased dose frequency is known to positively
correlate with the incidence of local side effects.
Toogood et al47 found that twice-daily regimens
reduced the risk of dysphonia and candidiasis com-
pared with administration four times per day. Once-
daily use of BUD delivered via a Turbuhaler is
practically free from local side effects in patients
starting to receive this treatment.24 Previous treat-
ment with other ICSs and devices resulting in local
side effects may result in carryover effects.
Type of Inhaler Device
An ideal inhaler device should deliver a predeter-
mined dose of drug to the lungs, in an easy-to-use,
Reviews
reproducible, and cost-effective manner, with mini-
mal deposition of drug in other sites.22 Both patient
factors and the inhaler device itself can affect drug
delivery. Age, physical disability, or cognitive disabil-
ity may render a patient unable to use certain
devices. Three main methods of dispersing medica-
tion into an aerosol will be described, as follows:
pMDI; DPI; or nebulizer.22 A pMDI may be used
with a spacer device.
pMDIs
In a pMDI, the drug is dissolved or suspended in
a propellant under pressure, and, when activated, a
valve system releases a metered dose of the drug and
propellant. The propellant provides the force to
propel and disaggregate particles. pMDIs may be
manually actuated or breath-actuated. They can be
used alone or in combination with various devices or
adaptations (eg, spacers or extended mouthpieces)
designed to slow the aerosol cloud, reduce oropha-
ryngeal deposition, and promote ease of use.22
The inhaler must emit the drug in a particle size
that can reach the lungs and deposit in the airways.
Airway deposition is probably maximal with a parti-
cle size diameter of 1 to 3 ␮m. Most therapeutic
aerosols are formulated to produce particles with a
diameter of 1 to 5 ␮m. Particles with a diameter of
ⱖ 10 ␮m deposit mainly in the mouth and throat, or
do not enter the upper airway due to abrupt changes
in airflow or the cough reflex.
The following two types of pMDIs are currently in
use: manually actuated pMDIs; and breath-actuated
MDIs. The former type is familiar to many patients
as they have been available for 40 years. They are
convenient to carry, quick to actuate, and generally
inexpensive. For effective drug delivery, however,
they require good coordination and psychomotor
skills to ensure that actuation, inhalation, and breath-
holding occur in precise sequence. Common failings
are not shaking the canister before use, inhaling too
rapidly or “jerkily,” or not holding the breath long
enough at the end of inspiration. The “cold Freon
effect,” in which high-velocity aerosol hits the back
of the throat, also causes patients to stop inhaling
prematurely. Drug delivery varies from 7 to 20%,
depending on the patient’s technique,48,49 and,
again, as much as 80% of the dose deposits in the
oropharynx.50 pMDIs alone are therefore not suit-
able for physically or cognitively impaired adults,51,52
or for most children under the age of 12 years,53 and
this is the reason why a spacer device (see below) is
specifically recommended for patients in these two
age groups.
Breath-actuated MDIs are activated at an inhala-
tory flow rate of about 30 L/min. This reduces the
www.chestjournal.org
need for coordination of actuation and inhalation,
making the device easier to use for elderly, physically
impaired patients.51 The use of these devices should
be reserved for adults and older children. There have
been no efficacy trials assessing the delivery of
corticosteroids using these devices. The devices are
bulkier and less portable than conventional MDIs.
The cold Freon effect is sometimes a problem, and
oropharyngeal deposition of corticosteroids is high.8
All pMDIs contain chlorofluorocarbon propel-
lants, but, because chlorofluorocarbons damage the
ozone layer of the earth,54 their use will be phased
out over the next 3 years or so. Currently, therefore,
there is a transition period to non-ozone-depleting
propellants such as hydrofluorocarbons.55,56
PMDIs With Spacer Devices
Spacer devices are used with pMDIs and are of
the following two broad types: holding chambers;
and extension devices. Holding chambers provide a
reservoir of drug from which the patient breathes,
and are easier for older, frailer patients52 and chil-
dren53 to use. An extension device increases the
distance that the aerosolized drug has to travel
before it is inhaled. This has the effect of slowing the
aerosol and allowing the propellant to evaporate.
This reduces the size of the aerosol droplets and
traps large (nonrespirable) particles within the
spacer, thereby reducing oropharyngeal impaction of
the drug. This has been shown to be of some
benefit,24 since as much as 80% of an inhaled dose of
drug can be deposited on the mucosa of the pharynx
and larynx.50 Drugs should be administered as single
actuations into the spacer and inhaled with minimum
delay after each puff, repeating these actions until
the entire prescribed dose has been given.57 The
canister should be shaken between actuations.
Spacers have been shown to decrease the oropha-
ryngeal deposition of inhaled isotope-labeled aero-
sols and to increase their intrapulmonary deposi-
tion.58,59 Hence, a large-volume spacer reduces the
local unwanted effects of ICSs by decreasing oropha-
ryngeal deposition: effects such as oropharyngeal
candidiasis and a reduction in the amount of absorp-
tion from the alimentary tract.50,57 They should also
be of use in patients with dose-limiting oropharyn-
geal complications, and as a means of reducing drug
costs by effectively delivering the same concentra-
tion of drug without increasing the number of puffs
required per day for effective asthma control.60 A
large-volume spacer is recommended for administer-
ing ICSs via an MDI in children,61 or for giving high
doses in adults.62
Static charge accumulates on the walls of plastic
and polycarbonate spacers, attracting drug particles
CHEST / 126 / 1 / JULY, 2004 217
and, hence, reducing the output of medication in
vitro.63 Washing the spacer in washing-up liquid, and
allowing it to air dry, before its first use and after
monthly intervals, reduces the static charge and
increases the delivery of salbutamol to the lungs.64
Dry Powder Inhalers
DPIs do not require propellants but rely on the
patient’s inspiratory effort to disperse the drug into
small particles and deliver it to the lungs. An inspira-
tory flow rate of 30 L/min is needed to work the most
efficient DPIs, and nearly all adults can achieve this
(adult average, 60 L/min), even when wheezy.65
Oropharyngeal deposition in these is ⱕ 60% of the
delivered dose, and patients should still be advised to
rinse their mouth with water after inhaling from a
DPI to minimize local side effects.24,50 The possible
protective effect of DPIs might be related to the
position of the vocal cords, which are open during
inhalation against resistance.
Inhaler technique needs to be monitored, and
difficulties need to be identified and corrected early.
Acceptability of the prescribed device is likely to
influence adherence to treatment.22 Common prob-
lems include the inability to coordinate actuation and
inspiration precisely enough to use a pMDI, or the
inability to inhale forcefully enough when wheezy to
use a DPI.
Conclusion
In order to establish more effective treatment of
local side effects, they first need to be recognized.
Local side effects are mostly minor and are of little
consequence to the overall health of the patient.
However, patients tend to be afraid of the side
effects of ICSs, and local problems may have a
deleterious effect on compliance. Some of the local
side effects may be dose-dependent, and this em-
phasizes the need to find the lowest effective dose of
an ICS. More importantly, however, the literature
shows that many of the local side effects are device-
dependent, and a change of the inhalation device
should be considered. Precautions such as rinsing
the mouth, gargling, and washing the face after
inhalation also should be recommended.
Last, it is evident from this review that more
observational and randomized controlled trials are
necessary to examine the existing inhalers, and,
specifically, to investigate how and why they cause
local side effects. A prospective strobovideolaryngo-
scopic study to visualize and record on video vocal
cord fold motion, position, and mucosal waves dur-
ing ICS therapy would be of great value and interest.
A relevant study would include a series in which
218
strobovideolaryngoscopic documentation was per-
formed pretherapy as a baseline and then repeated
in every ICS patient who developed hoarseness.
Successful recruitment and analysis would, however,
depend on cooperation and collaboration among
pulmonologists, voice care specialists, and other
laryngologists in the care of asthmatic patients re-
quiring ICS therapy.
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