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Steroid Inhaler Laryngitis
Dysphonia Caused by Inhaled Fluticasone Therapy
John M. DelGaudio, MD
Arch Otolaryngol Head Neck Surg. 2002;128:677-681.
ABSTRACT
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Objective To describe a condition that is referred to as steroid
inhaler laryngitis, a clinical entity that is caused by the use of
inhaled fluticasone propionate and manifested by dysphonia, throat clearing,
and fullness.
Design Case series.
Setting An outpatient clinic of an academic referral center.
Patients The study population consisted of 20 patients with reactive airway disease
and dysphonia who were receiving inhaled fluticasone therapy and who were
diagnosed as having steroid inhaler laryngitis during the period from January
1998 to June 2000.
Intervention Cessation of inhaled fluticasone therapy when possible, as well as treatment
of other underlying causes of dysphonia, such as laryngopharyngeal reflux
and infectious processes.
Main Outcome Measure The resolution of dysphonia with cessation of inhaled fluticasone therapy.
Results Patients with steroid inhaler laryngitis were found to have laryngeal
findings ranging from mucosal edema, erythema, and thickening to leukoplakia,
granulation, and candidiasis. Patients with more severe mucosal findings were
more likely to have laryngopharyngeal reflux as well. Resolution of dysphonia
occurred only after discontinuation of the inhaled fluticasone therapy.
Conclusions Steroid inhaler laryngitis is a form of chemical laryngopharyngitis
induced by topical steroid administration. Symptoms and physical findings
mimic laryngopharyngeal reflux, but only respond completely to discontinuation
of the inhaled steroid therapy. The otolaryngologist should be familiar with
this cause of dysphonia.
INTRODUCTION
THE OTOLARYNGOLOGIST–head and neck surgeon is frequently asked
to evaluate a patient with the main complaint of dysphonia. There are many
causes for dysphonia, including neoplasm, trauma, vocal abuse syndromes, neuromuscular
disorders, functional voice disorders, and chemical injury such as laryngopharyngeal
reflux (LPR). In my practice, I have become increasingly aware of another
type of chemical injury to the larynx that can result in dysphonia, especially
in patients with reactive airway disease (RAD) who are being treated with
inhaled fluticasone propionate.
Fluticasone propionate (Flovent) has become the most commonly prescribed
steroid inhalent for patients with asthma and RAD because of its potency and
safety margin. It also is the most potent steroid used in inhaled form, with
activity 9 times greater than that of fluocinolone acetonide, 2 to 5 times
greater than that of budesonide, and twice that of beclomethasone dipropionate.1-3 It has a greater topical
potency, longer tissue retention, and a longer elimination half-life than
beclomethasone. Orally administered medication is rapidly metabolized on the
first pass through the liver, resulting in less than 1% oral bioavailability
compared with 11% for budesonide, 20% for flunisolide, and more than 80% for
prednisolone.4 The Physicians'
Desk Reference reports the incidence of dysphonia to be approximately
1% to 8%, a rate that is similar to that of other inhaled steroids, with increasing
frequency at higher dosages.5 Clinical studies
have reported the incidence of dysphonia with all inhaled steroids to be as
high as 55%.6-11
An increasing number of patients who are using fluticasone are being
referred for evaluation of dysphonia. This type of dysphonia is not responsive
to treatment of other causes of dysphonia, but improves with cessation of
inhaled fluticasone therapy. The spectrum of vocal cord changes that has been
seen is more extensive than has been described in previous publications on
dysphonia resulting from inhaled steroid treatment,8, 12
ranging from minimal to severe. In 2 cases, the vocal fold changes were severe
enough to prompt direct laryngoscopy and biopsy, with these cases occurring
before these changes were recognized as part of a clinical entity that is
referred to as steroid inhaler laryngitis (SIL).
The severity of the vocal cord mucosal changes is likely a result of the greater
potency of fluticasone compared with other inhaled steroids. In many of the
patients with severe vocal cord changes due to SIL, there may be a synergistic
effect with LPR. Herein, representative cases are presented and the various
findings of SIL are described.
PATIENTS AND METHODS
Records were reviewed retrospectively to January 1998, and cases were
evaluated prospectively from June 2000. I evaluated all patients who were
referred for a primary diagnosis of dysphonia in the tertiary care otolaryngology–head
and neck surgery clinic at Emory University, Atlanta, Ga. The patients' records
were reviewed for demographic data, comorbidities, time at onset of dysphonia
and other laryngopharyngeal symptoms, medications used (specifically inhalants)
and the date of initiation of treatment, upper aerodigestive tract physical
findings, diagnostic tests performed, and outcomes of treatment.
REPORT OF CASES
CASE 1
In February 1998, a 50-year-old female speech therapist presented with
a 3-month history of hoarseness and vocal fatigue. She had experienced exacerbation
of her asthma during an upper respiratory infection, for which she had been
treated with 2 courses of antibiotics. At that time, fluticasone therapy (220
µg twice daily) was also initiated. The dysphonia began some time during
the treatment for the upper respiratory infection. Other symptoms included
frequent throat clearing and postnasal drip. The patient was treated with
voice rest, with minimal improvement. Examination of her larynx revealed bilateral
severe vocal cord and arytenoid hyperemia, as well as interarytenoid mucosal
thickening and leukoplakia (Figure 1).
She received a diagnosis of LPR and was treated with omeprazole sodium (20
mg twice daily) and behavioral modifications. There was mild improvement,
but the patient continued to have daily hoarseness. The dosage of omeprazole
sodium therapy was increased to 60 mg/d, with further mild improvement but
no resolution of the hoarseness. After 5 months of treatment, the patient
underwent a 24-hour pH study (while not taking omeprazole) that confirmed
pathological reflux at the upper esophageal sphincter (pH<4 for 1.8% of
study). The dosage was then increased to 80 mg/d, and ranitidine hydrochloride
(300 mg to be taken at bedtime) was added to the regimen. After 1 year of
treatment, the patient continued to have hoarseness and abnormal laryngeal
findings. A 24-hour pH study with an intragastric probe revealed almost complete
acid suppression during therapy (intragastric pH<4 for 1.2% of study).
Examination of the larynx at that time revealed similar findings, as well
as slight bilateral bowing of the vocal cords, which was thought to represent
the coexistence of muscle tension dysphonia.
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Figure 1. Case 1. Before treatment. Rigid
laryngoscopy (70° scope) reveals vocal cord hypervascularity, as well
as severe interarytenoid mucosal thickening and hyperkeratosis.
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During this period of treatment, the patient had 2 mild exacerbations
of her RAD. Since the LPR treatment was not resolving her hoarseness completely,
and because of the temporal relationship between symptom onset and the start
of fluticasone therapy, the therapy was discontinued and the patient's medication
was changed to oral montelukast sodium (Singulair). She had resolution of
her hoarseness within 4 weeks and has not had a recurrence in more than 2
years. She has been on a therapeutic maintenance regimen of low-dose proton
pump inhibitors for her LPR.
CASE 2
In January 1998, a 51-year-old man, 8 months after undergoing a single
left lung transplantation for idiopathic pulmonary fibrosis, was referred
for evaluation of hoarseness and cough. He had developed a nonproductive cough
1 month earlier and been started on a regimen of fluticasone propionate (220
µg twice daily). The dosage was increased to 440 µg twice daily
less than 1 month later. The patient subsequently developed hoarseness and
throat clearing in addition to his cough. He did admit to some heartburn.
Laryngeal examination revealed diffuse glottic erythema, granularity and leukoplakia
of the vocal cords, and pale, thickened interarytenoid mucosa (Figure 2A). The diagnosis of LPR was made, and the patient began
a regimen of omeprazole sodium (20 mg twice daily) and behavioral modifications.
Over the course of the next several months of omeprazole sodium therapy, at
a dosage of up to 60 mg/d, he had mild to moderate improvement of his cough
and hoarseness, while his heartburn resolved. At times, the omeprazole therapy
was discontinued, and the patient's symptoms quickly worsened. The findings
of laryngeal examination never improved significantly. In January 1999, the
patient underwent direct laryngoscopy and biopsy of the vocal cords because
of persistent leukoplakia and granulation. Pathological examination revealed
only granulation and acute inflammation, with no evidence of dysplasia or
fungal elements. The patient's hoarseness and other symptoms persisted. In
April 1999, he underwent a pH study, the findings of which confirmed the presence
of pathological reflux. Since his symptoms did not resolve with aggressive
reflux therapy, the possibility that the steroid inhalers were contributing
to his hoarseness was entertained, and the fluticasone therapy was discontinued.
Within approximately 6 weeks, he had significant improvement of his voice
and almost complete resolution of the leukoplakia and granulation, as well
as reduction of the vocal cord erythema (Figure 2B). He has continued intermittent use of proton pump inhibitors
and his voice has returned to normal.
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Figure 2. Case 2. A, Before treatment. Rigid
laryngoscopy (70°) shows mucosal edema, granularity, hyperemia, and diffuse
leukoplakia. B, Nearly 2 years after cessation of fluticasone propionate therapy,
examination reveals significant improvement of the appearance of the larynx.
Patient has persistent mild vocal cord edema and minimal areas of hyperkeratosis,
probably because of persistent untreated laryngopharyngeal reflux and chronic
cough resulting from low-level long-term rejection of lung transplant.
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CASE 3
In May 2001, a 41-year-old woman was referred for evaluation of chronic
sinusitis, at which time she was noted to have a deep, hoarse voice. She admitted
to having been hoarse for approximately 4 years. She had severe RAD and had
been using fluticasone propionate (880 µg twice daily) for 4 years,
in addition to salmeterol xinafoate (Serevent) and ipratropium bromide (Atrovent).
She was also taking omeprazole sodium (20 mg/d) for gastroesophageal reflux,
which had been documented by a pH study. She had had multiple previous episodes
of oral candidiasis as well. Examination of her larynx revealed diffuse laryngeal
granularity, erythema, and thickening of the mucosa, with diffuse punctate
white patches consistent with laryngeal candidiasis (Figure 3A). Her vocal cord mobility was also slightly reduced bilaterally,
although this did not affect the glottic airway. Becaue of her severe RAD,
her pulmonologist did not believe that reducing the dosage of the fluticasone
therapy was in her best interest. Two weeks of fluconazole therapy was therefore
prescribed. Her LPR was more aggressively treated with esomeprazole magnesium
(40 mg/d), and she was instructed regarding behavioral modifications. Follow-up
examination of the larynx at 1 week and 1 month after initiation of treatment
revealed resolution of the candidiasis, with improvement but persistence of
the edema, erythema, and granularity (Figure
3B).
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Figure 3. Case 3. A, Laryngeal candidiasis
and steroid inhaler laryngitis, with mucosal edema, thickening, and white
patches that are characteristic of infection with Candida. B, Resolution of candidiasis after antifungal therapy, with persistence
of edema and erythema due to persistent inhaled fluticasone therapy (70°
rigid laryngoscopy).
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CASE 4
In April 2001, a 58-year-old woman was referred for a 2-month history
of hoarseness. Two months before the onset of the hoarseness, fluticasone
propionate therapy (88 µg twice daily) had been initiated. Immediately
before the hoarseness began, the dosage of the fluticasone propionate therapy
was increased to 220 µg twice daily. Examination of the vocal cords
revealed mild vocal cord congestion (Figure
4). The fluticasone therapy was discontinued, and the patient's
voice improved during the next month.
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Figure 4. Case 4. Mild vocal cord congestion
and interarytenoid thickening that developed during inhaled fluticasone propionate
therapy (70° rigid laryngoscopy).
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RESULTS
Twenty patients were identified who were diagnosed as having SIL during
the study period from January 1998 to September 2001. Approximately 1 to 2
new cases per month are now recognized and diagnosed as SIL resulting from
inhaled fluticasone therapy. All the patients received a diagnosis of RAD,
with most having other comorbidities, including LPR or gastroesophageal reflux.
Most patients, especially those who received treatment earlier in the course
of this review, were treated for other suspected causes of dysphonia before
the role of inhaled fluticasone therapy in the pathogenesis of the problem
was recognized. Two patients underwent microlaryngoscopy with vocal cord biopsy
to rule out dysplasia or malignancy prior to definitive diagnosis. All patients
had significant or total improvement of their voice after cessation of inhaled
fluticasone therapy, usually within 4 to 6 weeks. Unfortunately, some patients
could not discontinue the use of inhaled fluticasone owing to the severity
of their RAD.
All patients had the primary symptom of dysphonia, with varying severity.
Other symptoms included frequent throat clearing and throat fullness. Physical
findings ranged from mild laryngeal changes, including edema, erythema, and
mucosal thickening, to more dramatic changes, including leukoplakia, granulation,
and laryngeal candidiasis.
COMMENT
Steroid inhalers are the first line of treatment for RAD of all severity.
It has long been known that one of the most common adverse effects of inhaled
steroid therapy is irritation of the upper aerodigestive tract. Common symptoms
include pharyngitis, hoarseness, throat clearing, and cough. These symptoms
occur with all steroid inhalant preparations, and appear to be dose related.6, 8-9,12 It is
likely that the steroid, not the propellant, is responsible for the local
adverse effects in the laryngopharynx. Patients inhaling beclomethasone were
5 times more likely to have hoarseness than patients treated with the propellant
without the steroid.9 The Physicians' Desk Reference reports the incidence of hoarseness for
the various steroid inhaler preparations to range from 1% to 9%, compared
with 0 to 3% for nonsteroid inhalers.5 Clinical
studies show the incidence of hoarseness to be much higher, occurring in as
many as 55% of patients who use steroid inhalers.6-11
Of the inhaled steroids, fluticasone has a greater topical potency and greater
tissue retention and half-life.4 Clinical reports
of the incidence of dysphonia with fluticasone are limited, and clinical studies
report an incidence that ranges from only 2% to 6%.2-3,13
The onset of dysphonia can occur at any time during fluticasone therapy, but
in the patients described herein it most commonly manifested shortly after
the onset of treatment, as in the first 3 case reports, or after an increase
in the dosage, as in the fourth case.
The physical changes that are seen in the larynx of patients using inhaled
fluticasone range from minimal to severe. Mild physical findings include edema
and erythema. Moderate changes include mucosal thickening and vocal cord bowing.
The most dramatic changes include leukoplakia, granulation, and laryngeal
candidiasis. Many of these findings can also be seen with LPR, and differentiating
these 2 possible pathogenetic factors can be difficult if one is not familiar
with SIL, as happened in the first 2 cases. Physical findings may be minimal
in patients with dysphonia caused by the use of steroid inhalers, with only
mild edema of the vocal cords, as in case 4. The changes appear to be the
result of a mucosal inflammatory reaction to the steroid. Two patients in
our series underwent biopsy of severely diseased vocal cords, and pathological
examination of the specimens revealed only acute inflammation and granulation,
as in case 2.
In 1983, Williams et al12 described 14
patients whose dysphonia was attributed to the use of steroid inhalers (budesonide,
beclomethasone, and betamethasone). Nine of these patients were reported to
have adductor palsies of the vocal cords, manifesting as vocal cord bowing.
The cause was theorized to be a local steroid myopathy. All 14 patients recovered
normal vocal cord movement and appearance after they discontinued using the
steroid inhaler, and they had a recurrence when they switched to a different
steroid preparation. Hoarseness was thought to be due to candidiasis in 3
patients and to psychogenic causes in 2 patients (because no abnormalities
were found on their vocal cord examinations). Of interest, aside from the
bowing and the candidiasis, the results of laryngeal examinations in all 14
patients were described as normal, with no mucosal abnormalities reported.
In case 1, the patient had significant mucosal changes at presentation but
did not develop vocal cord bowing until approximately 1 year after starting
inhaled fluticasone therapy. At the time, the bowing was incorrectly attributed
to muscle tension dysphonia rather than a manifestation of SIL. The prominent
mucosal changes seen in this group of patients may be attributable to fluticasone's
greater potency and tissue affinity compared with other inhaled steroid preparations.
Babu and Samuel8 evaluated the upper
aerodigestive tracts of 48 consecutive patients who were receiving inhaled
steroid therapy (beclomethasone). While 20% of patients admitted to voice
changes, 46% had "congested erythematous vocal cords" on examination, and
8.5% were reported to have adductor palsies, with vocal cord bowing. Williamson
et al6 used a questionnaire to determine the
prevalence of upper aerodigestive tract symptoms in 255 patients who were
using inhaled steroid preparations: 58% reported voice or throat symptoms,
with a 39% incidence of hoarseness and a 40% incidence of throat clearing.
The symptoms were found to increase when the dosages of inhaled steroid therapy
were higher.
Oral and pharyngeal candidiasis is a known adverse effect of inhaled
steroid therapy, with an incidence of up to 13% using the criteria of typical
physical findings and positive culture results.8-9
Cultures that are positive for Candida have been
found in up to 50% of cases involving patients who use steroid inhalers, irrespective
of symptoms and physical findings.10 Findings
of clinical infection include erythema and edema of the mucosa, with white
exudative patches, as seen in patient 3 (Figure 3A). Treatment involves the use of oral antifungal agents.
Reduction or cessation of inhaled steroid therapy should be undertaken if
the condition does not clear up with antifungal therapy. The use of spacers
to reduce the oral deposition of steroid appears to reduce the occurrence
of oral candidiasis but not the degree of laryngopharyngeal symptoms, and
may increase the symptoms by delivering a larger amount of steroid to the
larynx and pharynx. Fairfax et al14 reported
a case of laryngeal aspergillosis resulting from inhaled fluticasone therapy.
Treatment involved cessation of inhaled fluticasone therapy and aggressive
antifungal therapy.
The most severe cases that were experienced in the patient population
described herein involved the coexistence of LPR with SIL. The laryngeal changes
in SIL are similar to the changes that can be found in patients with LPR,
including edema, erythema, and interarytenoid mucosal thickening. Before SIL
was recognized as a distinct clinical entity, all these patients were treated
aggressively for LPR, with only partial resolution of symptoms. Only after
the patients discontinued using the steroid inhaler did they have complete
resolution of their throat symptoms, especially their hoarseness. Adequate
treatment of severe SIL requires cessation of steroid inhaler therapy, if
possible, and aggressive treatment of underlying LPR, if present. Mild symptoms
of SIL with mild vocal cord changes were adequately treated with cessation
of their inhaled steroid therapy. It is likely that most patients with mild
symptoms of SIL do not seek medical attention for their laryngopharyngeal
symptoms.
CONCLUSIONS
Steroid inhaler laryngitis is a distinct clinical entity with symptoms
localized to the upper aerodigestive tract, including hoarseness, throat clearing,
and cough. Laryngeal findings can range from minimal to severe. Patients with
severe laryngeal changes are more likely to have significant LPR coexistent
with SIL. Adequate treatment involves cessation or reduction of inhaled steroid
therapy and treatment of underlying LPR, if present. The otolaryngologist
needs to be able to recognize this condition and be familiar with its treatment.
Any workup of dysphonia requires a thorough history of inhaler use.
AUTHOR INFORMATION
Accepted for publication November 2, 2001.
Corresponding author: John M. DelGaudio, MD, Department of Otolaryngology–Head
and Neck Surgery, Emory University School of Medicine, 1365 Clifton Rd NE,
Atlanta, GA 30322 (e-mail: john_delgaudio{at}emoryhealthcare.org).
From the Department of Otolaryngology–Head and Neck Surgery,
Emory University School of Medicine, Atlanta, Ga.
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