- Email: [email protected]
Acoustic Analysis in Asthmatics and the Influence of Inhaled Corticosteroid Therapy
Acoustic Analysis in Asthmatics and the Influence of Inhaled Corticosteroid Therapy *,†R. K. Bhalla, *,†G. Watson, *,†W. Taylor, *,†A. S. Jones, and *,†N. J. Roland, *yLiverpool, United Kingdom Summary: The impact of sustained inhaled corticosteroid (ICS) therapy on the larynx and pharynx was assessed using a prospective, cross-sectional, and investigator-blinded study conducted at the University Hospital Aintree, Liverpool, UK. Forty-six adults recruited from two local general practices and from general ENT clinics at our University hospital were investigated for the study. Patients were allocated to three groups according to ICS use. Laryngeal effects were measured by correlating the results of a vocal performance questionnaire, a respiratory symptom questionnaire, and measurements obtained by computerized speech analysis. Sustained vowels and connected speech were analyzed in normal and asthmatic subjects. Acoustic analysis was correlated with cellular markers of inflammation after biopsy. Regular ICS users had significantly more pharyngeal inflammation and throat discomfort (P < 0.0001). Vocal performance was also worse in this group (P < 0.0001). They were more likely to have hoarseness, weakness of voice, aphonia, sore throat, throat irritation, and cough (P < 0.0001). All these variables were directly related to one another (P < 0.0001). Multiple linear regression analysis showed that jitter was a good objective measure of hoarseness (P < 0.05). Regular ICS users were significantly more likely to have abnormal jitter, shimmer, and closed-phase quotient scores (P < 0.0001). There was no difference between the groups in the observed parameters of inflammation (P > 0.01). A higher pharyngitis score did not correlate with any of the histological markers of inflammation (P > 0.01). Local side effects are more common in asthmatics that use ICS regularly. Measures of laryngeal function are significantly worse in regular ICS users. However, histological markers and oropharyngeal redness are not reliable measures of inflammation. Key Words: Acoustic–Inflammation–Corticosteroid–Inhaler–Dysphonia. INTRODUCTION Inhaled corticosteroids (ICSs) are irritants of the pharyngeal and laryngeal mucosal surfaces. It is not known whether the steroid component of the inhaled preparation or its propellant is responsible for causing this irritation. It is a common misconception that the local side effects of ICS are well established but surprisingly, there are very few studies on the subject. After our review in the Chest journal,1 we are keen to highlight the problem through specific studies such as the current article. Local side effects can include pain, a chronic sore throat, habitual throat clearing, and laryngeal irritation with subsequent dysphonia. Troublesome candidiasis can aggravate local complications.2,3 Neither fungal infections nor steroid-induced adductor myopathy, however, have been found to be the primary cause of dysphonia.4 Often, dysphonia is the result of several detrimental factors that can include chronic cough, drug dosing regime, delivery device, laryngeal infection, smoking, reflux, muscle tension, and effectiveness of implemented precautions such as the use of a spacer device or gargling. The clinical consequence of complications of ICS therapy is hampered compliance and hoarseness. The mucosal complications of corticosteroid deposition are difficult to explain. The local complications may arise because up to 80% of the inhaled dose is deposited on the mucosal surfaces of the pharynx and larynx before being swallowed.5
Accepted for publication November 1, 2007. From the *Department of Otolaryngology, University Hospital Aintree, Liverpool, United Kingdom; and the yDepartment of Head & Neck Surgery, University Hospital Aintree, Liverpool, United Kingdom. Address correspondence and reprint requests to Dr. R. K. Bhalla, Department of Otolaryngology/Head & Neck Surgery, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL UK. E-mail: [email protected] Journal of Voice, Vol. 23, No. 4, pp. 505-511 0892-1997/$36.00 Ó 2009 The Voice Foundation doi:10.1016/j.jvoice.2007.11.001
Frequent administration of high dose ICS is known to be associated with an increased risk of local side effects.6–8 These studies also highlighted that the type of device used to propel the drug into the airways may be partly responsible for the onset of the complications. Consequently, it is of no surprise that cessation of ICS therapy usually produces a resolution of symptoms.9 Laryngeal complications of asthma are poorly understood. Observations after assessment with videostrobolaryngoscopy include vocal fold mucosal changes, such as hyperemia and plaque-like changes.10 Our own observations detected appearances consistent with chronic laryngitis. Although dysphonia is frequently attributed to bowed vocal folds caused by intrinsic laryngeal muscle weakness, there is little evidence to support this mechanism.4 Observed functional sequelae of vocal fold changes include reduced amplitude of vibration and a reduction in mucosal wave propagation.10 Computerized speech analysis has detected cycle-to-cycle irregularities and reduced maximum phonation time in dysphonic asthmatics.4 There is no comparative data examining hoarseness in asthmatics. The aim of this study was to investigate the vocal complications of ICS therapy. The acoustic analysis was correlated with pharyngeal inflammation. This comprehensive assessment of vocal performance has provided useful baseline comparative data for normal subjects and ICS users. METHODS Study design The study design was prospective, cross-sectional, and investigator-blinded. Recruitment Forty-six volunteers were recruited from two local general practices and from general ENT clinics at our University
506 hospital. The study was conducted over a 6-month period. The final number of patients recruited to the study was a direct reflection of the study duration. Volunteers were allocated to one of three groups on the basis of ICS use and asthma history (Table 1). The nonasthmatic healthy volunteers of group A served as the control group for this study. Although all ICS were hydrofluoroalkane propelled, no distinction was made for the type of steroid used. Occasional ICS users were asthmatics who used their inhalers infrequently, perhaps ‘‘once a week’’ or ‘‘over the summer months.’’ They had been diagnosed as asthmatic by their general practitioner because of variability in peak flows. These individuals were either not or very infrequently using their ICS during the period of the study. In this study, these individuals have been called seasonal asthmatics. Regular ICS users used their inhaler at least once a day. Ethical considerations The local research and ethics committee approved a protocol for the study, patient information sheet, and patient consent form. Patients were allocated a study number for anonymity. Inclusion criteria Any healthy, competent individual over the age of 18 years was able to partake in informed consent. A baseline predicted forced expiratory volume in 1 second (FEV1) was >60% and <90%. An increase in FEV1 of >12% after reversibility testing had been established during the preceding 6 months and was not repeated in this study. Regular ICS users were required to have done so for at least 30 consecutive days leading into the study. There were no patients using nebulized preparations. Exclusion criteria Patients were excluded if potential or actual causes of pharyngeal or laryngeal disease were identified at the initial assessment. These included a history of reflux, malignancy, vocal fold lesions, or neurological causes of dysphonia. Those using intranasal steroids to treat coexistent inflammatory or allergic nasal disease were excluded. Those with an upper respiratory tract infection in the preceding 4 weeks, who were medically unfit as a result of intercurrent disease, or had chronic obstructive pulmonary disease were excluded. Those with a recent history of exacerbation of their asthma, requiring oral steroid therapy, antibiotic therapy, or both in the preceding 4 weeks, were excluded. Also, those who had been hospitalized or suffered an acute asthma attack in the preceding 3 months were excluded. Patients using Seretide (Allen & Hanburys Ltd, Uxbridge, England) were excluded. Seretide is a combination preparation of fluticasone propionate and salmeterol, a longacting b2-agonist. Inclusion of this group that were consistently using an inhaled long-acting b2-agonist would potentially have confounded the results, as any side effects would have been difficult to attribute solely to either drug. Data collection An asthma and allergy history determined eligibility for inclusion. Patients withheld their short-acting b2-agonist for 6 hours
Journal of Voice, Vol. 23, No. 4, 2009
TABLE 1. Description of Block Randomization Groups Group A
B C
Description Normal healthy volunteers, not using any inhaled or intranasal medications. Occasional ICS users (seasonal asthmatics). Regular ICS users.
and long-acting b2-agonist for 12 hours before their assessment. This allowed for a washout period for these infrequently used medications in this well-controlled group of asthmatic patients. Respiratory symptom and vocal performance questionnaires were completed. The respiratory symptom questionnaire was designed by the lead investigator. A novel symptom questionnaire was deemed necessary, because those in use targeted vocal dysfunction at a single point in time without addressing putative causative factors. The pilot questionnaire was distributed to 20 patients who had definite symptoms of pharyngolaryngitis because of ICSs. This sample was recruited from ENT clinics. The pilot study enabled us to simplify the questionnaire, to incorporate further questions based on symptom expansion, and to present it in a format that would be more easily analyzed at a later date. The vocal performance questionnaire had previously been validated.11 A thorough ENT examination was performed. The lead investigator alone, using his clinical acumen as a practicing ENT physician, graded pharyngolaryngeal inflammation as 0 (none), 1 (mild), 2 (moderate), or 3 (severe). Acoustic analysis was performed after a standardized biopsy of the posterior pharyngeal wall. Histological specimens were examined without prior knowledge of the donor (investigator-blind). Acoustic analysis All recruited subjects were English speakers from the UK. A voice recording of a sustained vowel /a/ and connected speech were made using a digital audiotape (DAT) recorder. Recordings were standardized using a fixed microphone at a distance of 30 cm from the subject’s mouth. All voice recordings were made in a soundproof booth to minimize erroneous background noise. A volume consistent with a normal speaking voice was used. Acoustic analysis was performed using Speech Studio (Laryngograph Ltd, London, UK). Measures included jitter (pitch-period perturbation), shimmer (amplitude perturbation), and closed-phase quotient (the proportion of time the vocal folds were in the closed state—abnormal in both muscular tension and poor closure with phonatory gap). Jitter and shimmer furnished us with an objective analysis of hoarseness. The closed-phase quotient measurements afforded an appreciation of whether laryngeal dysfunction could be attributed to an intrinsic myopathy of the larynx, with poor subsequent glottal closure, or an unnatural time in apposition, as seen in chronic laryngitis. All measures of normalcy were supplied by Laryngograph Ltd (London, UK).
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Pharyngeal biopsy technique After spraying the posterior pharyngeal wall mucosa with 4% lidocaine to provide surface anesthesia, a biopsy was taken using microcupped laryngeal forceps. The posterior pharyngeal wall, in this study, was the mucosal surface of the throat that extended from the soft palate in a mouth-breathing patient to the level of the depressed tongue. The most inflamed area was selected as the biopsy site. The specimen was fixed in formalin and processed for histological examination.
25 20
Number
R.K. Bhalla, et al
15 10 5 0
Normal
Seasonal asthmatic
Regular ICS user
Group
RESULTS Questionnaire data The 46 recruited volunteers were allocated to their respective groups on the basis of ICS use and asthma history (Figure 1). The age range was 21–79 years, median 46 years. There were 22 males. The patients in the treatment groups B and C were using ICSs either occasionally, in accordance with the seasonal definition given earlier, or at least once a day (regular), respectively. There were no smokers. Pharyngitis was graded in all 46 individuals (Figure 2A). The regular ICS users had significantly more pharyngeal inflammation than either the normals or the seasonal asthmatics (P < 0.0001). The discomfort scores (median and range) showed an increase in discomfort with increased frequency of ICS use (Figure 2B). On this scale, 0 indicated no discomfort caused by the ICS and 10 indicated the most severe discomfort imaginable. This
difference was significant (P < 0.0001). Vocal performance also deteriorated with more frequent ICS use (Figure 3). In this questionnaire, a patient with a normal voice scored 12/60 and one with a maximally debilitating dysphonia scored 60/60. These scores were also significantly different (P < 0.0001). The regular ICS users were more likely to experience hoarseness, weakness of voice, aphonia, sore throat, throat irritation, and cough than either of the other groups (P < 0.0001) (Figure 4A–F). All these variables were directly related to
A 12
Pharyngitis scores:
10 8
Number
Statistical analysis The data were tested for normality using the Shapiro-Wilk test for nonparametric data. The Bonferroni correction was used because of the large number of variables studied. The significance level was P < 0.01. The Kruskal-Wallis analysis of variance (ANOVA) was used to explore comparative data. The MannWhitney U test was used in the pairwise comparisons for those not on steroids or on occasional steroids versus those on a regular steroid regime. A Spearman rank correlation matrix was used to examine for directly and inversely related variables. Multivariate analysis was performed with the categorical modeling and multiple linear regression procedures in the statistical analysis system (SAS).12
FIGURE 1. Bar chart showing numbers recruited to study groups.
6 4 2 0
Normal
Seasonal asthmatic
Chronic ICS user
Group None
B 12
Mild
Moderate
Severe
Discomfort scores:
10
Visual analogue score
Histopathological examination Histological specimens were stained with hematoxylin and eosin. The same pathologist, using a blinded technique, assessed all specimens. The squamous epithelium and underlying connective tissue were assessed. Markers of acute and chronic inflammation were graded. Cells typical of acute inflammation were neutrophils. Those cells characteristic of chronic inflammation were lymphocytes and plasma cells. Vascular markers of inflammation included edema, vessel dilation, and congestion. The degree of penetration of connective tissue papillae into the overlying squamous epithelium was gaged. Other measures of inflammation included epithelial thickness, basal cell hyperplasia, and parakeratosis. Histopathological findings were graded as present or absent, or as 1 (normal), 2 (mild inflammation), or 3 (marked inflammation).
8 6 4 2 0
Normal
Seasonal asthmatic
Regular ICS user
Group
FIGURE 2. Graphs to illustrate (A) the difference in pharyngitis scores between the treatment groups, and (B) the visual analog scores for discomfort caused by ICS therapy (range and median).
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(P > 0.01). The biopsies from the regular ICS users did, however, exhibit greater edema than the specimens from either of the other two groups (P < 0.0001). On its own, without other positive markers of inflammation, edema was not significant for inflammation attributable to regular ICS use. A higher pharyngitis score did not correlate with any of the histological markers of inflammation (epithelial thickness, basal cell hyperplasia, parakeratosis, or increased inflammatory cell infiltrate) (P > 0.01).
50 45 40
Number
35 30 25 20 15 10 5 0
Normal
Seasonal asthmatic
Chronic ICS user
Group
FIGURE 3. Graph to illustrate the results of the vocal performance questionnaire, showing the deleterious impact of ICS therapy (range and median).
one another (P < 0.0001). Hoarseness, a weak voice, sore throat, throat irritation, and cough were also positively correlated with a higher pharyngitis score (P < 0.0001). Jitter Values of <1% were deemed normal. Between 1% and 10%, results were deemed abnormal. Results >10% were severely abnormal. Multiple linear regression analyses showed that jitter was a good objective measure of hoarseness (P < 0.05). The regular ICS users were significantly more likely to have abnormal jitter scores than either of the other two groups (P < 0.0001) (Figure 5A,B). Shimmer Values of <5% were deemed normal. Between 5% and 10%, results were deemed abnormal. Results >10% were severely abnormal. The regular ICS users were significantly more likely to have abnormal shimmer scores than either of the other two groups (P < 0.0001) (Figure 5C,D). Closed-phase quotient Values of 40–55% were deemed normal. Values >55% implied that the vocal folds were remaining in apposition for an abnormally prolonged time. Values <40% implied poor glottal closure and a phonatory gap. The regular ICS users were significantly more likely to have abnormal closed-phase quotient scores than either of the other two groups (P < 0.0001) (Figure 5E,F). Inflammation All histological specimens had adequate epithelium and connective tissues for assessment. There was no difference between the groups in the observed parameters of inflammation (epithelial thickness, basal cell hyperplasia, parakeratosis, vessel dilatation, or vessel congestion; P > 0.01). Although there was a greater penetration of papillae from the connective tissue layer into the overlying epithelium in ICS users, this difference was not significant (P > 0.01) (Figure 6). Also, there was no difference between the groups in the inflammatory cell infiltrate in either the epithelium or the underlying connective tissue
DISCUSSION Surface deposition of ICSs should not cause mucosal inflammation. Few complications are anticipated because corticosteroids are powerful antiinflammatory agents. The occurrence of vocal and pharyngeal side effects is deemed to be multifactorial. The corticosteroid drug compound, propellant, dosing regime, and inhaler device are felt to be partly responsible. However, there may be an intrinsic hypersensitivity in the airways of asthmatics that makes them more susceptible to the irritant effects of inhaler preparations, their propellants, or their lubricants. This phenomenon is termed airway hyperresponsiveness, and is a fundamental component of the asthmatic inflammatory process.13 Asthma is now understood to be a disease of chronic inflammation along large and small airways, with episodes of reversible airways obstruction and airway hyperresponsiveness causing clinical symptoms.14,15 Exposure of an individual may, therefore, cause breathlessness, chest tightness, cough, and wheeze.16 The gross pathology of asthmatic airways displays lung hyperinflation, smooth muscle hypertrophy, lamina reticularis thickening, mucosal edema, epithelial cell sloughing, cilia cell disruption, and mucous gland hypersecretion.17 Comorbidities such as laryngopharyngeal reflux, rhinitis, and postnasal catarrh may prime the pharyngeal and laryngeal mucosas.18,19 Additional mucosal irritation may be caused by exogenous stimuli such as smoking, diesel fumes, or workplace noxious substances. Further mechanical irritation may be produced by a chronic cough or habitual throat clearing. Measures for the evaluation of dysphonia have included jitter (the average percentage pitch-period variation between consecutive pitch-cycles),20 shimmer and noise-to-harmonic ratio,21 videostrobolaryngoscopy, and electroglottography. The different analyses are deemed complementary and collectively provide information regarding vocal quality and laryngeal function.22 We elected to use both jitter and shimmer measurements in their analysis in an effort to increase the sensitivity of dysphonia assessment. The closed-phase quotient measurements provided an indication as to whether any detected laryngeal dysfunction was because of intrinsic myopathy and subsequent phonatory gap, or because of increased time of apposition as a consequence of chronic laryngitis. Videostrobolaryngoscopic and electroglottographic studies to evaluate dysphonia in asthmatics are well documented.4,10,23 Perceptual voice quality evaluation by a professional jury of listeners is currently considered to be the most reliable and complete means of evaluating pathologic voice. However, the techniques are difficult to perform in routine clinical practice
R.K. Bhalla, et al
A
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Acoustic Analysis and Corticosteroid Therapy in Asthmatics Hoarseness:
D
12
Sore throat: 16 14
10
12
Number
Number
8 6 4
10 8 6 4
2 0
2 Normal
Seasonal asthmatic
0
Reular ICS user
Normal
Group Never Occasionally
B
Some of the time Most of the time
Seasonal asthmatic
Regular ICS user
Group All of the time
Never Occasionally
E
Weakness of voice:
Some of the time Most of the time
All of the time
Throat irritation: 12
10 9
10
8
8
Number
Number
7 6 5 4
6 4
3 2
2
1 0
Normal
Seasonal asthmatic
0
Regular ICS user
Normal
Group Never Occasionally
C
Some of the time Most of the time
Regular ICS user
Group All of the time
Aphonia:
14
Seasonal asthmatic
Never Occasionally
F
12
Some of the time Most of the time
All of the time
Persistent cough: 12 10
10
Number
Number
8 8 6
6
4
4
2
2
0 Normal
Seasonal asthmatic
Regular ICS user
0
Normal
Group Never Occasionally
Some of the time Most of the time
Seasonal asthmatic
Regular ICS user
Group All of the time
Never Occasionally
Some of the time Most of the time
All of the time
FIGURE 4. Bar charts to illustrate the prevalence of (A) hoarseness; (B) weakness of voice; (C) aphonia; (D) sore throat; (E) throat irritation; and (F) persistent cough in the study groups. and the results can lack reproducibility.24 We do acknowledge, however, that incorporating the results of perceptual studies could well enhance future studies of laryngeal dysfunction. Similarly, the values for jitter, shimmer, and closed-phase quotient measurements pertaining to normalcy were not age-correlated because these data were not available at the time of this study. A closer collaboration with the designers of the speech analysis software would undoubtedly benefit further research in this area.
In this study, acoustic analyses examined both sustained vowel sound (/a/) and continuous speech, because sustained vowel sounds alone have been shown to be an inadequate clinical index to the dysphonic severity of continuous speech.25 Furthermore, signal contamination for frequency perturbation values has been shown to be consistently minimal with digital audiotape recorders (DATs). Similarly, recorder effect on shimmer (amplitude perturbation) measures was lowest in DAT.26
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A
Normally spoken vowel – jitter: 70
D
Normally spoken sentence – shimmer: 30 25
Shimmer scores
Jitter scores
60 50 40 30 20
15 10 5
10 0
20
Normal
Seasonal asthmatic
0
Regular ICS user
Normal
Group Normally spoken sentence – jitter: 70
E
Jitter scores
60 50 40 30 20 10 0
Normal
Seasonal asthmatic
Normally spoken vowel – closed-phase quotient:
Regular ICS user
80 70 60 50 40 30 20 10 0
Normal
Group Normally spoken vowel – shimmer: 40
Shimmer scores
35 30 25 20 15 10 5 0
Normal
Seasonal asthmatic
Seasonal asthmatic
Regular ICS user
Group
Regular ICS user
Group
F
Normally spoken sentence - closed-phase quotient: Closed-phase quotient scores
C
Regular ICS user
Group
Closed-phase quotient scores
B
Seasonal asthmatic
80 70 60 50 40 30 20 10 0
Normal
Seasonal asthmatic
Regular ICS user
Group
FIGURE 5. Graphs to show (A) jitter scores for normally spoken vowel; (B) jitter scores for normally spoken sentence; (C) shimmer scores for normally spoken vowel; (D) shimmer scores for normally spoken sentence; (E) closed-phase quotient scores for normally spoken vowel; and (F) closed-phase quotient scores for normally spoken sentence (range and mean).
The results show that regular ICS users are more likely to experience abnormal laryngeal and pharyngeal complications compared with either normal subjects or seasonal asthmatics. These included the laryngeal complications of hoarseness, weak voice, aphonia and troublesome chronic cough, and the pharyngeal problems of sore throat and irritation. Regular ICS users were also found to have more severe dysphonia compared to either of the other groups, as represented by the highly significant jitter, shimmer, and closed-phase quotient scores. Abnormally increased closed-phase quotient scores in this group were most likely to have been a manifestation of chronic laryngitis and bulkier vocal folds. Classical pharyngitis, whether absent or present, was not found to be a reliable measure of inflammation. This is the first such study whose sole purpose was to objectively investigate and document voice changes in asthmatics. Although we were able to control for propellant, the type of steroid was more difficult to control for, because patients were
reluctant to destabilize their asthma. We acknowledge that the type of steroid may be an important factor in the etiology of local side effects, given the differences in potency and pharmacodynamics. Nevertheless, the clear objective of this study was to examine the impact of regular ICS use on local side effects. Future studies may focus their intentions on the effect of different steroids and, perhaps, different propellants. A closer correlation between voice changes and measures of lung function would also be useful, as would voice studies and airflow measures (FEV1; midflow) after a bronchodilator. Conservative measures to avert the risk of complications of ICS therapy, such as gargling or spacer devices have an unpredictable response.27 Indeed, unless the advice provided is simple to understand and easily put into practice, compliance remains poor and complications continue to occur.28 Should complications occur, then either an alternative delivery device29 or a proprietary drug30 could be considered. Both measures have been shown to provide identical asthma control but with
R.K. Bhalla, et al
Acoustic Analysis and Corticosteroid Therapy in Asthmatics
0
Mid 1/3
Lower 1/3
Upper 1/3
Depth of papillae Chronic ICS user
Seasonal asthmatic
Normal
FIGURE 6. Graph to illustrate the extension of papillae from the connective tissue into the overlying epithelium as a marker of inflammation in the three study groups.
fewer detrimental side effects. For this reason, the most appropriate drug and delivery device are essential considerations when prescribing for asthma control.
CONCLUSION Local side effects are more common in asthmatics who use ICS regularly. Measures of laryngeal function are significantly worse in regular ICS users. However, histological markers and oropharyngeal redness are not reliable measures of inflammation. REFERENCES 1. Roland NJ, Bhalla RK, Earis J. The local side effects of inhaled corticosteroids: current understanding and review of the literature. Chest. 2004;126: 213-219. 2. Hanania NA, Chapman KR, Kesten S. Adverse effects of inhaled corticosteroids. Am J Med. 1995;98:196-208. 3. Barnes PJ, Pedersen S, Busse WW. Efficacy and safety of inhaled corticosteroids. Am J Respir Crit Care Med. 1998;157:S1-S53. 4. Lavy JA, Wood G, Rubin JS, Harries M. Dysphonia associated with inhaled steroids. J Voice. 2000;14:581-588. 5. Inhaler devices for asthma. Drug Ther Bull. 2000;38:9-14. 6. Fabbri L, Burge PS, Croonenborgh L, Warlies F, Weeke B, Ciaccia A, Parker C. Comparison of fluticasone propionate with beclomethasone dipropionate in moderate to severe asthma treated for one year. Thorax. 1993;48:817-823. 7. Ayres JG, Lundback B, Harris TA. High dose fluticasone propionate, 1mg daily, versus fluticasone propionate, 2mg daily, or budesonide, 1.6mg daily, in patients with chronic severe asthma. International Study Group. Eur Respir J. 1995;8:579-586.
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8. Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet. 2003;361:1071-1076. 9. DelGaudio JM. Steroid inhaler laryngitis: dysphonia caused by inhaled fluticasone therapy. Arch Otolaryngol Head Neck Surg. 2002;128:677-681. 10. Mirza N, Kasper Schwartz S, Antin-Ozerkis D. Laryngeal findings in users of combination corticosteroid and bronchodilator therapy. Laryngoscope. 2004;114:1566-1599. 11. Webb AL, Carding PN, Deary IJ, MacKenzie K, Steen N, Wilson JA. Optimising outcome assessment of voice interventions, I: reliability and validity of three self-reported scales. J Laryngol Otol. 2007;29:1-5. 12. SAS Institute Inc.. User’s Guide: Statistics Version [8.2]. 5th ed.). Cary, NC: SAS Institute Inc.; 1985. 13. Boulet LP. Physiopathology of airway hyperresponsiveness. Curr Allergy Asthma Rep. 2003;3:166-171. 14. Szefler SJ. The natural history of asthma and early intervention. J Allergy Clin Immunol. 2002;109:S549-S553. 15. Magnussen H. Inhalation therapy for bronchial asthma: strategies and targets. Curr Opin Pulm Med. 2003;9:S3-S7. 16. Currie GP, Jackson CM, Lipworth BJ. Does bronchial hyperresponsiveness in asthma matter? J Asthma. 2004;41:247-258. 17. Fireman P. Understanding asthma pathophysiology. Allergy Asthma Proc. 2003;24:79-83. 18. Fass R, Achem SR, Harding S, Mittal RK, Quigley E. Review article: supra-oesophageal manifestations of gastro-oesophageal reflux disease and the role of night-time gastro-oesophageal reflux. Aliment Pharmacol Ther. 2004;20:26-38. 19. Bonet Agusti M, Casan Clara P. Dysphonia produced by corticoid inhalation: truth or myth? Arch Bronconeumol. 1995;31:415-417. 20. Jones TM, Trabold M, Plante F, Cheetham BM, Earis JE. Objective assessment of hoarseness by measuring jitter. Clin Otolaryngol Allied Sci. 2001;26:29-32. 21. Carding PN, Steen IN, Webb A, MacKenzie K, Deary IJ, Wilson JA. The reliability and sensitivity to change of acoustic measures of voice quality. Clin Otolaryngol Allied Sci. 2004;29:538-544. 22. Hartl DM, Hans S, Crevier Buchman L, Laccourreye O, Vaissiere J, Brasnu D. Dysphonia: current methods of evaluation. Ann Otolaryngol Chir Cervicofac. 2005;122:163-172. 23. Hone SW, Donnelly MJ, Robertson J, Coakley R, O’Neill S, Walsh MJ. Dysphonia and inhalation of corticoids: a prospective study. Rev Laryngol Otol Rhinol (Bord). 1996;117:331-333. 24. Webb AL, Carding PN, Deary IJ, MacKenzie K, Steen N, Wilson JA. The reliability of three perceptual evaluation scales for dysphonia. Eur Arch Otorhinolaryngol. 2004;261:429-434. 25. Wolfe V, Cornell R, Fitch J. Sentence/vowel correlation in the evaluation of dysphonia. J Voice. 1995;9:297-303. 26. Jiang J, Lin E, Hanson DG. Effect of tape recording on perturbation measures. J Speech Lang Hear Res. 1998;41:1031-1041. 27. Selroos O, Backman R, Forsen KO, et al. Local side effects during 4-year treatment with inhaled corticosteroids—a comparison between pressurised metered-dose inhalers and turbohaler. Allergy. 1994;49:888-890. 28. Yokoyama H, Nakajima Y, Yamamura Y, Iga T, Yamada Y. Investigation of mouth washing by patients after inhaling corticosteroids. Yakugaku Zasshi. 2005;125:455-461. 29. Brocklebank D, Wright J, Cates C. Systematic review of clinical effectiveness of pressurised metered dose inhalers versus other hand held inhaler devices for delivering corticosteroids in asthma. Br Med J. 2001;323:896-900. 30. Sharpe M, Jarvis B. Inhaled mometasone furoate: a review of its use in adults and adolescents with persistent asthma. Drugs. 2001;61:1325-1350.
Accepted for publication November 1, 2007. From the *Department of Otolaryngology, University Hospital Aintree, Liverpool, United Kingdom; and the yDepartment of Head & Neck Surgery, University Hospital Aintree, Liverpool, United Kingdom. Address correspondence and reprint requests to Dr. R. K. Bhalla, Department of Otolaryngology/Head & Neck Surgery, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL UK. E-mail: [email protected] Journal of Voice, Vol. 23, No. 4, pp. 505-511 0892-1997/$36.00 Ó 2009 The Voice Foundation doi:10.1016/j.jvoice.2007.11.001
Frequent administration of high dose ICS is known to be associated with an increased risk of local side effects.6–8 These studies also highlighted that the type of device used to propel the drug into the airways may be partly responsible for the onset of the complications. Consequently, it is of no surprise that cessation of ICS therapy usually produces a resolution of symptoms.9 Laryngeal complications of asthma are poorly understood. Observations after assessment with videostrobolaryngoscopy include vocal fold mucosal changes, such as hyperemia and plaque-like changes.10 Our own observations detected appearances consistent with chronic laryngitis. Although dysphonia is frequently attributed to bowed vocal folds caused by intrinsic laryngeal muscle weakness, there is little evidence to support this mechanism.4 Observed functional sequelae of vocal fold changes include reduced amplitude of vibration and a reduction in mucosal wave propagation.10 Computerized speech analysis has detected cycle-to-cycle irregularities and reduced maximum phonation time in dysphonic asthmatics.4 There is no comparative data examining hoarseness in asthmatics. The aim of this study was to investigate the vocal complications of ICS therapy. The acoustic analysis was correlated with pharyngeal inflammation. This comprehensive assessment of vocal performance has provided useful baseline comparative data for normal subjects and ICS users. METHODS Study design The study design was prospective, cross-sectional, and investigator-blinded. Recruitment Forty-six volunteers were recruited from two local general practices and from general ENT clinics at our University
506 hospital. The study was conducted over a 6-month period. The final number of patients recruited to the study was a direct reflection of the study duration. Volunteers were allocated to one of three groups on the basis of ICS use and asthma history (Table 1). The nonasthmatic healthy volunteers of group A served as the control group for this study. Although all ICS were hydrofluoroalkane propelled, no distinction was made for the type of steroid used. Occasional ICS users were asthmatics who used their inhalers infrequently, perhaps ‘‘once a week’’ or ‘‘over the summer months.’’ They had been diagnosed as asthmatic by their general practitioner because of variability in peak flows. These individuals were either not or very infrequently using their ICS during the period of the study. In this study, these individuals have been called seasonal asthmatics. Regular ICS users used their inhaler at least once a day. Ethical considerations The local research and ethics committee approved a protocol for the study, patient information sheet, and patient consent form. Patients were allocated a study number for anonymity. Inclusion criteria Any healthy, competent individual over the age of 18 years was able to partake in informed consent. A baseline predicted forced expiratory volume in 1 second (FEV1) was >60% and <90%. An increase in FEV1 of >12% after reversibility testing had been established during the preceding 6 months and was not repeated in this study. Regular ICS users were required to have done so for at least 30 consecutive days leading into the study. There were no patients using nebulized preparations. Exclusion criteria Patients were excluded if potential or actual causes of pharyngeal or laryngeal disease were identified at the initial assessment. These included a history of reflux, malignancy, vocal fold lesions, or neurological causes of dysphonia. Those using intranasal steroids to treat coexistent inflammatory or allergic nasal disease were excluded. Those with an upper respiratory tract infection in the preceding 4 weeks, who were medically unfit as a result of intercurrent disease, or had chronic obstructive pulmonary disease were excluded. Those with a recent history of exacerbation of their asthma, requiring oral steroid therapy, antibiotic therapy, or both in the preceding 4 weeks, were excluded. Also, those who had been hospitalized or suffered an acute asthma attack in the preceding 3 months were excluded. Patients using Seretide (Allen & Hanburys Ltd, Uxbridge, England) were excluded. Seretide is a combination preparation of fluticasone propionate and salmeterol, a longacting b2-agonist. Inclusion of this group that were consistently using an inhaled long-acting b2-agonist would potentially have confounded the results, as any side effects would have been difficult to attribute solely to either drug. Data collection An asthma and allergy history determined eligibility for inclusion. Patients withheld their short-acting b2-agonist for 6 hours
Journal of Voice, Vol. 23, No. 4, 2009
TABLE 1. Description of Block Randomization Groups Group A
B C
Description Normal healthy volunteers, not using any inhaled or intranasal medications. Occasional ICS users (seasonal asthmatics). Regular ICS users.
and long-acting b2-agonist for 12 hours before their assessment. This allowed for a washout period for these infrequently used medications in this well-controlled group of asthmatic patients. Respiratory symptom and vocal performance questionnaires were completed. The respiratory symptom questionnaire was designed by the lead investigator. A novel symptom questionnaire was deemed necessary, because those in use targeted vocal dysfunction at a single point in time without addressing putative causative factors. The pilot questionnaire was distributed to 20 patients who had definite symptoms of pharyngolaryngitis because of ICSs. This sample was recruited from ENT clinics. The pilot study enabled us to simplify the questionnaire, to incorporate further questions based on symptom expansion, and to present it in a format that would be more easily analyzed at a later date. The vocal performance questionnaire had previously been validated.11 A thorough ENT examination was performed. The lead investigator alone, using his clinical acumen as a practicing ENT physician, graded pharyngolaryngeal inflammation as 0 (none), 1 (mild), 2 (moderate), or 3 (severe). Acoustic analysis was performed after a standardized biopsy of the posterior pharyngeal wall. Histological specimens were examined without prior knowledge of the donor (investigator-blind). Acoustic analysis All recruited subjects were English speakers from the UK. A voice recording of a sustained vowel /a/ and connected speech were made using a digital audiotape (DAT) recorder. Recordings were standardized using a fixed microphone at a distance of 30 cm from the subject’s mouth. All voice recordings were made in a soundproof booth to minimize erroneous background noise. A volume consistent with a normal speaking voice was used. Acoustic analysis was performed using Speech Studio (Laryngograph Ltd, London, UK). Measures included jitter (pitch-period perturbation), shimmer (amplitude perturbation), and closed-phase quotient (the proportion of time the vocal folds were in the closed state—abnormal in both muscular tension and poor closure with phonatory gap). Jitter and shimmer furnished us with an objective analysis of hoarseness. The closed-phase quotient measurements afforded an appreciation of whether laryngeal dysfunction could be attributed to an intrinsic myopathy of the larynx, with poor subsequent glottal closure, or an unnatural time in apposition, as seen in chronic laryngitis. All measures of normalcy were supplied by Laryngograph Ltd (London, UK).
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Pharyngeal biopsy technique After spraying the posterior pharyngeal wall mucosa with 4% lidocaine to provide surface anesthesia, a biopsy was taken using microcupped laryngeal forceps. The posterior pharyngeal wall, in this study, was the mucosal surface of the throat that extended from the soft palate in a mouth-breathing patient to the level of the depressed tongue. The most inflamed area was selected as the biopsy site. The specimen was fixed in formalin and processed for histological examination.
25 20
Number
R.K. Bhalla, et al
15 10 5 0
Normal
Seasonal asthmatic
Regular ICS user
Group
RESULTS Questionnaire data The 46 recruited volunteers were allocated to their respective groups on the basis of ICS use and asthma history (Figure 1). The age range was 21–79 years, median 46 years. There were 22 males. The patients in the treatment groups B and C were using ICSs either occasionally, in accordance with the seasonal definition given earlier, or at least once a day (regular), respectively. There were no smokers. Pharyngitis was graded in all 46 individuals (Figure 2A). The regular ICS users had significantly more pharyngeal inflammation than either the normals or the seasonal asthmatics (P < 0.0001). The discomfort scores (median and range) showed an increase in discomfort with increased frequency of ICS use (Figure 2B). On this scale, 0 indicated no discomfort caused by the ICS and 10 indicated the most severe discomfort imaginable. This
difference was significant (P < 0.0001). Vocal performance also deteriorated with more frequent ICS use (Figure 3). In this questionnaire, a patient with a normal voice scored 12/60 and one with a maximally debilitating dysphonia scored 60/60. These scores were also significantly different (P < 0.0001). The regular ICS users were more likely to experience hoarseness, weakness of voice, aphonia, sore throat, throat irritation, and cough than either of the other groups (P < 0.0001) (Figure 4A–F). All these variables were directly related to
A 12
Pharyngitis scores:
10 8
Number
Statistical analysis The data were tested for normality using the Shapiro-Wilk test for nonparametric data. The Bonferroni correction was used because of the large number of variables studied. The significance level was P < 0.01. The Kruskal-Wallis analysis of variance (ANOVA) was used to explore comparative data. The MannWhitney U test was used in the pairwise comparisons for those not on steroids or on occasional steroids versus those on a regular steroid regime. A Spearman rank correlation matrix was used to examine for directly and inversely related variables. Multivariate analysis was performed with the categorical modeling and multiple linear regression procedures in the statistical analysis system (SAS).12
FIGURE 1. Bar chart showing numbers recruited to study groups.
6 4 2 0
Normal
Seasonal asthmatic
Chronic ICS user
Group None
B 12
Mild
Moderate
Severe
Discomfort scores:
10
Visual analogue score
Histopathological examination Histological specimens were stained with hematoxylin and eosin. The same pathologist, using a blinded technique, assessed all specimens. The squamous epithelium and underlying connective tissue were assessed. Markers of acute and chronic inflammation were graded. Cells typical of acute inflammation were neutrophils. Those cells characteristic of chronic inflammation were lymphocytes and plasma cells. Vascular markers of inflammation included edema, vessel dilation, and congestion. The degree of penetration of connective tissue papillae into the overlying squamous epithelium was gaged. Other measures of inflammation included epithelial thickness, basal cell hyperplasia, and parakeratosis. Histopathological findings were graded as present or absent, or as 1 (normal), 2 (mild inflammation), or 3 (marked inflammation).
8 6 4 2 0
Normal
Seasonal asthmatic
Regular ICS user
Group
FIGURE 2. Graphs to illustrate (A) the difference in pharyngitis scores between the treatment groups, and (B) the visual analog scores for discomfort caused by ICS therapy (range and median).
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(P > 0.01). The biopsies from the regular ICS users did, however, exhibit greater edema than the specimens from either of the other two groups (P < 0.0001). On its own, without other positive markers of inflammation, edema was not significant for inflammation attributable to regular ICS use. A higher pharyngitis score did not correlate with any of the histological markers of inflammation (epithelial thickness, basal cell hyperplasia, parakeratosis, or increased inflammatory cell infiltrate) (P > 0.01).
50 45 40
Number
35 30 25 20 15 10 5 0
Normal
Seasonal asthmatic
Chronic ICS user
Group
FIGURE 3. Graph to illustrate the results of the vocal performance questionnaire, showing the deleterious impact of ICS therapy (range and median).
one another (P < 0.0001). Hoarseness, a weak voice, sore throat, throat irritation, and cough were also positively correlated with a higher pharyngitis score (P < 0.0001). Jitter Values of <1% were deemed normal. Between 1% and 10%, results were deemed abnormal. Results >10% were severely abnormal. Multiple linear regression analyses showed that jitter was a good objective measure of hoarseness (P < 0.05). The regular ICS users were significantly more likely to have abnormal jitter scores than either of the other two groups (P < 0.0001) (Figure 5A,B). Shimmer Values of <5% were deemed normal. Between 5% and 10%, results were deemed abnormal. Results >10% were severely abnormal. The regular ICS users were significantly more likely to have abnormal shimmer scores than either of the other two groups (P < 0.0001) (Figure 5C,D). Closed-phase quotient Values of 40–55% were deemed normal. Values >55% implied that the vocal folds were remaining in apposition for an abnormally prolonged time. Values <40% implied poor glottal closure and a phonatory gap. The regular ICS users were significantly more likely to have abnormal closed-phase quotient scores than either of the other two groups (P < 0.0001) (Figure 5E,F). Inflammation All histological specimens had adequate epithelium and connective tissues for assessment. There was no difference between the groups in the observed parameters of inflammation (epithelial thickness, basal cell hyperplasia, parakeratosis, vessel dilatation, or vessel congestion; P > 0.01). Although there was a greater penetration of papillae from the connective tissue layer into the overlying epithelium in ICS users, this difference was not significant (P > 0.01) (Figure 6). Also, there was no difference between the groups in the inflammatory cell infiltrate in either the epithelium or the underlying connective tissue
DISCUSSION Surface deposition of ICSs should not cause mucosal inflammation. Few complications are anticipated because corticosteroids are powerful antiinflammatory agents. The occurrence of vocal and pharyngeal side effects is deemed to be multifactorial. The corticosteroid drug compound, propellant, dosing regime, and inhaler device are felt to be partly responsible. However, there may be an intrinsic hypersensitivity in the airways of asthmatics that makes them more susceptible to the irritant effects of inhaler preparations, their propellants, or their lubricants. This phenomenon is termed airway hyperresponsiveness, and is a fundamental component of the asthmatic inflammatory process.13 Asthma is now understood to be a disease of chronic inflammation along large and small airways, with episodes of reversible airways obstruction and airway hyperresponsiveness causing clinical symptoms.14,15 Exposure of an individual may, therefore, cause breathlessness, chest tightness, cough, and wheeze.16 The gross pathology of asthmatic airways displays lung hyperinflation, smooth muscle hypertrophy, lamina reticularis thickening, mucosal edema, epithelial cell sloughing, cilia cell disruption, and mucous gland hypersecretion.17 Comorbidities such as laryngopharyngeal reflux, rhinitis, and postnasal catarrh may prime the pharyngeal and laryngeal mucosas.18,19 Additional mucosal irritation may be caused by exogenous stimuli such as smoking, diesel fumes, or workplace noxious substances. Further mechanical irritation may be produced by a chronic cough or habitual throat clearing. Measures for the evaluation of dysphonia have included jitter (the average percentage pitch-period variation between consecutive pitch-cycles),20 shimmer and noise-to-harmonic ratio,21 videostrobolaryngoscopy, and electroglottography. The different analyses are deemed complementary and collectively provide information regarding vocal quality and laryngeal function.22 We elected to use both jitter and shimmer measurements in their analysis in an effort to increase the sensitivity of dysphonia assessment. The closed-phase quotient measurements provided an indication as to whether any detected laryngeal dysfunction was because of intrinsic myopathy and subsequent phonatory gap, or because of increased time of apposition as a consequence of chronic laryngitis. Videostrobolaryngoscopic and electroglottographic studies to evaluate dysphonia in asthmatics are well documented.4,10,23 Perceptual voice quality evaluation by a professional jury of listeners is currently considered to be the most reliable and complete means of evaluating pathologic voice. However, the techniques are difficult to perform in routine clinical practice
R.K. Bhalla, et al
A
509
Acoustic Analysis and Corticosteroid Therapy in Asthmatics Hoarseness:
D
12
Sore throat: 16 14
10
12
Number
Number
8 6 4
10 8 6 4
2 0
2 Normal
Seasonal asthmatic
0
Reular ICS user
Normal
Group Never Occasionally
B
Some of the time Most of the time
Seasonal asthmatic
Regular ICS user
Group All of the time
Never Occasionally
E
Weakness of voice:
Some of the time Most of the time
All of the time
Throat irritation: 12
10 9
10
8
8
Number
Number
7 6 5 4
6 4
3 2
2
1 0
Normal
Seasonal asthmatic
0
Regular ICS user
Normal
Group Never Occasionally
C
Some of the time Most of the time
Regular ICS user
Group All of the time
Aphonia:
14
Seasonal asthmatic
Never Occasionally
F
12
Some of the time Most of the time
All of the time
Persistent cough: 12 10
10
Number
Number
8 8 6
6
4
4
2
2
0 Normal
Seasonal asthmatic
Regular ICS user
0
Normal
Group Never Occasionally
Some of the time Most of the time
Seasonal asthmatic
Regular ICS user
Group All of the time
Never Occasionally
Some of the time Most of the time
All of the time
FIGURE 4. Bar charts to illustrate the prevalence of (A) hoarseness; (B) weakness of voice; (C) aphonia; (D) sore throat; (E) throat irritation; and (F) persistent cough in the study groups. and the results can lack reproducibility.24 We do acknowledge, however, that incorporating the results of perceptual studies could well enhance future studies of laryngeal dysfunction. Similarly, the values for jitter, shimmer, and closed-phase quotient measurements pertaining to normalcy were not age-correlated because these data were not available at the time of this study. A closer collaboration with the designers of the speech analysis software would undoubtedly benefit further research in this area.
In this study, acoustic analyses examined both sustained vowel sound (/a/) and continuous speech, because sustained vowel sounds alone have been shown to be an inadequate clinical index to the dysphonic severity of continuous speech.25 Furthermore, signal contamination for frequency perturbation values has been shown to be consistently minimal with digital audiotape recorders (DATs). Similarly, recorder effect on shimmer (amplitude perturbation) measures was lowest in DAT.26
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Journal of Voice, Vol. 23, No. 4, 2009
A
Normally spoken vowel – jitter: 70
D
Normally spoken sentence – shimmer: 30 25
Shimmer scores
Jitter scores
60 50 40 30 20
15 10 5
10 0
20
Normal
Seasonal asthmatic
0
Regular ICS user
Normal
Group Normally spoken sentence – jitter: 70
E
Jitter scores
60 50 40 30 20 10 0
Normal
Seasonal asthmatic
Normally spoken vowel – closed-phase quotient:
Regular ICS user
80 70 60 50 40 30 20 10 0
Normal
Group Normally spoken vowel – shimmer: 40
Shimmer scores
35 30 25 20 15 10 5 0
Normal
Seasonal asthmatic
Seasonal asthmatic
Regular ICS user
Group
Regular ICS user
Group
F
Normally spoken sentence - closed-phase quotient: Closed-phase quotient scores
C
Regular ICS user
Group
Closed-phase quotient scores
B
Seasonal asthmatic
80 70 60 50 40 30 20 10 0
Normal
Seasonal asthmatic
Regular ICS user
Group
FIGURE 5. Graphs to show (A) jitter scores for normally spoken vowel; (B) jitter scores for normally spoken sentence; (C) shimmer scores for normally spoken vowel; (D) shimmer scores for normally spoken sentence; (E) closed-phase quotient scores for normally spoken vowel; and (F) closed-phase quotient scores for normally spoken sentence (range and mean).
The results show that regular ICS users are more likely to experience abnormal laryngeal and pharyngeal complications compared with either normal subjects or seasonal asthmatics. These included the laryngeal complications of hoarseness, weak voice, aphonia and troublesome chronic cough, and the pharyngeal problems of sore throat and irritation. Regular ICS users were also found to have more severe dysphonia compared to either of the other groups, as represented by the highly significant jitter, shimmer, and closed-phase quotient scores. Abnormally increased closed-phase quotient scores in this group were most likely to have been a manifestation of chronic laryngitis and bulkier vocal folds. Classical pharyngitis, whether absent or present, was not found to be a reliable measure of inflammation. This is the first such study whose sole purpose was to objectively investigate and document voice changes in asthmatics. Although we were able to control for propellant, the type of steroid was more difficult to control for, because patients were
reluctant to destabilize their asthma. We acknowledge that the type of steroid may be an important factor in the etiology of local side effects, given the differences in potency and pharmacodynamics. Nevertheless, the clear objective of this study was to examine the impact of regular ICS use on local side effects. Future studies may focus their intentions on the effect of different steroids and, perhaps, different propellants. A closer correlation between voice changes and measures of lung function would also be useful, as would voice studies and airflow measures (FEV1; midflow) after a bronchodilator. Conservative measures to avert the risk of complications of ICS therapy, such as gargling or spacer devices have an unpredictable response.27 Indeed, unless the advice provided is simple to understand and easily put into practice, compliance remains poor and complications continue to occur.28 Should complications occur, then either an alternative delivery device29 or a proprietary drug30 could be considered. Both measures have been shown to provide identical asthma control but with
R.K. Bhalla, et al
Acoustic Analysis and Corticosteroid Therapy in Asthmatics
0
Mid 1/3
Lower 1/3
Upper 1/3
Depth of papillae Chronic ICS user
Seasonal asthmatic
Normal
FIGURE 6. Graph to illustrate the extension of papillae from the connective tissue into the overlying epithelium as a marker of inflammation in the three study groups.
fewer detrimental side effects. For this reason, the most appropriate drug and delivery device are essential considerations when prescribing for asthma control.
CONCLUSION Local side effects are more common in asthmatics who use ICS regularly. Measures of laryngeal function are significantly worse in regular ICS users. However, histological markers and oropharyngeal redness are not reliable measures of inflammation. REFERENCES 1. Roland NJ, Bhalla RK, Earis J. The local side effects of inhaled corticosteroids: current understanding and review of the literature. Chest. 2004;126: 213-219. 2. Hanania NA, Chapman KR, Kesten S. Adverse effects of inhaled corticosteroids. Am J Med. 1995;98:196-208. 3. Barnes PJ, Pedersen S, Busse WW. Efficacy and safety of inhaled corticosteroids. Am J Respir Crit Care Med. 1998;157:S1-S53. 4. Lavy JA, Wood G, Rubin JS, Harries M. Dysphonia associated with inhaled steroids. J Voice. 2000;14:581-588. 5. Inhaler devices for asthma. Drug Ther Bull. 2000;38:9-14. 6. Fabbri L, Burge PS, Croonenborgh L, Warlies F, Weeke B, Ciaccia A, Parker C. Comparison of fluticasone propionate with beclomethasone dipropionate in moderate to severe asthma treated for one year. Thorax. 1993;48:817-823. 7. Ayres JG, Lundback B, Harris TA. High dose fluticasone propionate, 1mg daily, versus fluticasone propionate, 2mg daily, or budesonide, 1.6mg daily, in patients with chronic severe asthma. International Study Group. Eur Respir J. 1995;8:579-586.
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8. Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet. 2003;361:1071-1076. 9. DelGaudio JM. Steroid inhaler laryngitis: dysphonia caused by inhaled fluticasone therapy. Arch Otolaryngol Head Neck Surg. 2002;128:677-681. 10. Mirza N, Kasper Schwartz S, Antin-Ozerkis D. Laryngeal findings in users of combination corticosteroid and bronchodilator therapy. Laryngoscope. 2004;114:1566-1599. 11. Webb AL, Carding PN, Deary IJ, MacKenzie K, Steen N, Wilson JA. Optimising outcome assessment of voice interventions, I: reliability and validity of three self-reported scales. J Laryngol Otol. 2007;29:1-5. 12. SAS Institute Inc.. User’s Guide: Statistics Version [8.2]. 5th ed.). Cary, NC: SAS Institute Inc.; 1985. 13. Boulet LP. Physiopathology of airway hyperresponsiveness. Curr Allergy Asthma Rep. 2003;3:166-171. 14. Szefler SJ. The natural history of asthma and early intervention. J Allergy Clin Immunol. 2002;109:S549-S553. 15. Magnussen H. Inhalation therapy for bronchial asthma: strategies and targets. Curr Opin Pulm Med. 2003;9:S3-S7. 16. Currie GP, Jackson CM, Lipworth BJ. Does bronchial hyperresponsiveness in asthma matter? J Asthma. 2004;41:247-258. 17. Fireman P. Understanding asthma pathophysiology. Allergy Asthma Proc. 2003;24:79-83. 18. Fass R, Achem SR, Harding S, Mittal RK, Quigley E. Review article: supra-oesophageal manifestations of gastro-oesophageal reflux disease and the role of night-time gastro-oesophageal reflux. Aliment Pharmacol Ther. 2004;20:26-38. 19. Bonet Agusti M, Casan Clara P. Dysphonia produced by corticoid inhalation: truth or myth? Arch Bronconeumol. 1995;31:415-417. 20. Jones TM, Trabold M, Plante F, Cheetham BM, Earis JE. Objective assessment of hoarseness by measuring jitter. Clin Otolaryngol Allied Sci. 2001;26:29-32. 21. Carding PN, Steen IN, Webb A, MacKenzie K, Deary IJ, Wilson JA. The reliability and sensitivity to change of acoustic measures of voice quality. Clin Otolaryngol Allied Sci. 2004;29:538-544. 22. Hartl DM, Hans S, Crevier Buchman L, Laccourreye O, Vaissiere J, Brasnu D. Dysphonia: current methods of evaluation. Ann Otolaryngol Chir Cervicofac. 2005;122:163-172. 23. Hone SW, Donnelly MJ, Robertson J, Coakley R, O’Neill S, Walsh MJ. Dysphonia and inhalation of corticoids: a prospective study. Rev Laryngol Otol Rhinol (Bord). 1996;117:331-333. 24. Webb AL, Carding PN, Deary IJ, MacKenzie K, Steen N, Wilson JA. The reliability of three perceptual evaluation scales for dysphonia. Eur Arch Otorhinolaryngol. 2004;261:429-434. 25. Wolfe V, Cornell R, Fitch J. Sentence/vowel correlation in the evaluation of dysphonia. J Voice. 1995;9:297-303. 26. Jiang J, Lin E, Hanson DG. Effect of tape recording on perturbation measures. J Speech Lang Hear Res. 1998;41:1031-1041. 27. Selroos O, Backman R, Forsen KO, et al. Local side effects during 4-year treatment with inhaled corticosteroids—a comparison between pressurised metered-dose inhalers and turbohaler. Allergy. 1994;49:888-890. 28. Yokoyama H, Nakajima Y, Yamamura Y, Iga T, Yamada Y. Investigation of mouth washing by patients after inhaling corticosteroids. Yakugaku Zasshi. 2005;125:455-461. 29. Brocklebank D, Wright J, Cates C. Systematic review of clinical effectiveness of pressurised metered dose inhalers versus other hand held inhaler devices for delivering corticosteroids in asthma. Br Med J. 2001;323:896-900. 30. Sharpe M, Jarvis B. Inhaled mometasone furoate: a review of its use in adults and adolescents with persistent asthma. Drugs. 2001;61:1325-1350.