Oropharyngeal candidiasis treated with triamcinolone aerosol

in patients acetonide

William W. Pingleton, M.D., Roger C. Bone, M.D., Gerald R. Kerby, M.D., and William E. Ruth, M.D. Kansas City, Kan.

Thirty asthmatic patients participating in a trial of triamcinolone acetonide aerosol were evaluated to determine the relationships among symptoms of sore throat or hoarseness, the appearance of the throat on physical examination, and the presence of yeasts on pharyngeal culture. Observations were recorded prior to aerosol therapy and repeated after 2 wk, 4 wk, 6 wk, 4 mo, and 6 mo of therapy. A total of 15 patients (5070) experienced sore throat or hoarseness, 15 (50%) had yeasts cultured ffom the pharynx on at least one occasion, and I I (37%) at some point had an abnormal throat examination; however, there was no predictable relationship between symptoms or abnormal physical examinations and the presence of a positive culture. The frequency of positive cultures did not change significantly during the observation period. Twelve patients had positive yeast cultures on 50% or more of their samples. The incidence of symptoms was not sigficantly increased in these chronically colonized patients. Symptoms were usually transient, and discontinuation of the aerosol or antifungal therapy was unnecessary. Triamcinolone aerosol was not associated with signijcantly increased phatyngeal colonization with yeasts in this 6-mo study. Existing chronic colonization is not necessarily a contraindication to triamcinolone therapy. Sore throat and hoarseness are usually unrelated to yeast infection in patients using triamcinolone acetonide aerosol.

Recent reports concerning corticosteroid aerosols have substantiatedtheir usefulnessin the management of patients with asthma.le8 Trials with beclomethasone dipropionate4-* and triamcinolone acetonidelT3 demonstrate clinical improvement in steroid-dependent asthmatic patients. Most patients have been able to reduce dosageor totally eliminate oral steroids with disappearanceof Cushingoid features. These agents appear to be free of significant systemic corticosteroid side effects.l-* Candida infection of the mouth and throat has been reported as the only important side effect; however, there has been a marked variation in its documentedincidence. In studies with beclomethasonethe incidence has varied from 13%s to 77%.l” These frequencies were often based on random cultural surveys. Only one

prospective study examining the frequency of yeast colonization as a function of duration of therapy with beclomethasonehasbeenreported.lo Unfortunately in that study the diagnosis of oropharyngeal candidiasis was initially made by visual inspection alone. Also data concerning the total number of cultures obtained and the intervals at which cultures were obtained and patients examined were not reported. The frequency of oropharyngeal candidiasis with triamcinolone has not been examined; however, the symptoms of sore throat and hoarsenesshave been reported as common complications of this agent.‘, 2 The present study was designed to prospectively evaluate the relationships among the symptoms of sore throat and hoarseness, the appearance of the throat on physical examination, and the presenceof yeast on throat culture.

From the Department of Internal Medicine, University of Kansas Medical Center. Drug study supported by Lederle Laboratories, Pearl River, N. Y. Received for publication March 15, 1977. Accepted for publication July 25, 1977. Reprint requests to: William W. Pingleton, M.D., Assistant Professor of Medicine, University of Kansas Medical Center, 39th & Rainbow Blvd., Kansas City, Kan. 66103.

METHODS

Vol. 60, No. 4, pp. 254-258

Thirty stable adult asthmatic patients enrolled in an open-label trial of triamcinolone acetonide formed the study group. Twenty-one of the group were steroid-dependent with an average daily dose of 14 mg of prednisone a day. The duration of prednisone therapy ranged from 1 to 18 yr and averaged 6 yr. All of these individuals were well known

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Oropharyngeal

to the investigators, and multiple attempts to withdraw corticosteroids over a period of years had been unsuccessful. Steroid-independent patients were individuals whose disease required continuous use of oral bronchodilators and were not optimally controlled. Triamcinolone acetonide prepared in a freon aerosol was administered through an adaptor designed to minimize deposition in the oral cavity. In the present study patients received triamcinolone acetonide in the dosage of 800 mcg/day for the first 12 wk. In 2 individuals, after the initial 12 wk of the study, dosage was increased to a maximum of 1,600 mcg/day. In both of these individuals the dose was increased in an attempt to gain better clinical control of asthmatic symptoms and permit further prednisone reduction. The triamcinolone dose was left at the 1,600 mcgiday level in the 2 patients for the remainder of the 6-mo study period. All patients were questioned for symptoms of sore throat or hoarseness prior to the institution of triamcinolone. In no instance were symptoms present. During the baseline pretreatment period, cultures for fungi were obtained and the physical appearance of the throat was recorded. These observations were repeated after 2,4, and 6 wk, and again after 4 and 6 mo of triamcinolone therapy. One patient was lost to follow-up after the initial 6 wk of the study, and 1 patient was dropped from the study at the end of 12 wk because of definite worsening of her asthma throughout the period of taking the aerosol. Additionally, there were 2 instances of missed clinic appointments. Therefore, this survey includes a total of 174 clinic visits. Patients were questioned in an unstructured fashion about the presence of upper respiratory tract symptoms at the time of each clinic visit, and their responses were recorded. A “checklist” format was not used since this might exaggerate the frequency of a positive response. No attempt was made to have a standard observer perform all of the throat examinations. This pattern of multiple examiners (a total of 9 different examiners participated) parallels the situation that will exist when this agent is marketed and thousands of individual physicians will perform upper respiratory examinations upon patients who develop the complaints of sore throat or hoarseness. An abnormal throat examination was defined as any visible abnormality and ranged from mild erythema to marked erythema or white patches. Undoubtedly a patient complaining of sore throat may bias the frequency with which an abnormal examination was recorded. Once again, however, these kinds of bias are identical to those that will occur when this agent is released for widespread use. The fungal cultural method involved dry swabbing of the tonsillar areas and posterior pharynx. Within 3 hr of the specimen collection it was inoculated on a Sabouraud’s medium, Sabouraud’s with chloramphenicol and cyclohexamide, and on triphenol tetrozolium chloride (TTC) medium with neomycin. Sabouraud’s cultures were observed at room temperature for 4 wk, or until positive. The TTC cultures were observed for 7 to 10 days at 37” C. The screening method used to identify Can&da a&cans, when a positive culture occurred, involved transfer to Levine’s eosin methylene blue agar, incubation in COP, followed by

candidiasis with triamcinolone

acetonide aerosol

255

microscopic observation of filamentous colonies bearing clusters of blastospores. Patients were monitored additionally with hemogram, blood chemistry, and plasma cortisol. Hemogram and chemistries were performed at baseline and at 6 mo. Plasma cortisol was measured at 8 A.M. at baseline and every 4 wk thereafter. All medications, including prednisone, were withheld on the morning of a clinic visit until the blood samples had been obtained. Of the 174 clinic visits, throat cultures were obtained and reported on 169 occasions with only 5 cultures being lost. A total of 97% of all of the planned cultures were successfully obtained and tabulated. Statistical analysis was performed using the Fisher’s exact test in an attempt to demonstrate an association between either an abnormal throat examination or the presence of upper respiratory tract symptoms and the existence of a positive throat culture for Candidu. Comparisons were made at the time of each clinic visit. An evaluation of the association between symptoms and an abnormal examination was performed. The frequency of positive cultures at each clinic visit was compared to that of the baseline prior to triamcinolone aerosol therapy. A p value of < 0.05 was considered significant.

RESULTS In general, our overall patient response to triamcinolone acetonide was comparable to that reported by others. l-3 Patients experienced improvement in, or maintenance of, their good subjective and clinical status while on triamciolone. The average oral pred-

nisone dose after 6 mo had been reduced from the initial 14 mglday to 1.5 mg/day. Fifteen of 21 initially

steroid-dependent

withdrawn

patients

were

completely

from systemic corticosteroids.

Average

FEV, had increased slightly from baseline values despite the prednisone reduction or elimination.

Hemograms, blood chemistries, roentgenograms, and electrocardiograms were unchanged during the follow-up period. Most patients in the study were on alternate-day prednisone dosage prior to beginning the aerosol. Only 3 patients demonstrated diminished plasma cortisols initially; however, during the study the initially reduced cortisol values all returned to normal values.

During the 6-mo follow-up, only 9 patients remained totally without pharyngeal or laryngeal symptoms and had consistently negative throat cultures and normal throat examinations. Symptoms of sore throat or hoarseness occurred in 15 patients or 50% of the group (Table I) and were elicited on 13% of all clinic visits. In terms of the abnormality on throat examination, white patches were observed on only 3 occasions; in 2 instances the throat cultures grew members of the Candida species other than Candida albicans. The other throat fungal culture was negative. An abnormal throat examination was recorded at some time

256 Pingleton et al.

TABLE

I. Occurrence

J. ALLERGY

of abnormalities

in 30 patients

Number of patients with abnormality

Symptoms Abnormal throat examinations Cultures (+) for yeast

Percent of total patient group with abnormality

Number of visits abnormality was present

Percent of visits abnormality was present

50% 37%

23 17

13% 10%

15

50%

48

28%

II. Frequency of (+) yeast cultures as a function of duration of aerosol therapy

Baseline 2 wk* 4 wk* 6 wk* 4 mo* 6 mo*

on 174 visits

15 11

TABLE

Time

CLIN. IMMUNOL. OCTOBER 1977

Patients with positive cultures

7/29 patients (24%) 9/29 patients (31%) 7/30 patients (23%) 8/28 patients (29%) 7/27 patients (26%) 8/26 patients (30.7%)

*Not significantlydifferentfrom baseline. in one third of the group and was found on 10% of all visits. Overall, a positive culture for Candida albicans was obtained at some point in 50% of patients in the qroup, and on 28% of all clinic visits. At the same time, as can be seen in Table II, there was no significant change in the frequency of positive cultures with increasing duration of aerosol therapy. The relationship between a positive Candida albicans culture and the presence of either symptoms of sore throat or an abnormal throat examination is illustrated in Table III. As can be seen, the frequency of symptoms was increased in the presence of a positive Candida culture at each visit; however, this association only reached statistical significance at the time of the 4-mo visit, and there was no predictable relationship between these two variables. There was no significant association between an abnormal examination and a positive throat culture. Table III also demonstrates a significant association between symptoms and an abnormal examination at!the time of the 4-wk and 6-wk visits. In only 4 instances were there simultaneous occurrences of symptoms of sore throat or hoarseness, an abnormal throat examination, and positive culture. In each of these 4 instances, the throat examination returned to normal and the symptoms subsided within a few days. By the time the throat culture results were received there was no clinical indication for antifungal treatment. There were 12 patients in the study who had chronic throat colonization with yeast (defined as a

positive culture on 50% or more of the occasions sampled). When the patients with chronic colonization were examined for abnormal throat examinations or for symptoms of sore throat and hoarseness and compared to patients who had only random positive cultures or to those who were never positive, no significant differences occurred.

DISCUSSION The relationship between the colonization of the upper respiratory tract with yeast and the administration of corticosteroid aerosols has rarely been examined in a prospective fashion. The reported frequency of oropharyngeal candidiasis as a complication of use of these agents has been extremely variable and to some degree dependent upon the definition of oropharyngeal candidiasis, i.e., whether simply based on a positive pharyngeal culture, a positive culture in a patient with symptoms, or on the occurrence of a positive culture in a patient with symptoms and white patches on physical examination. The relationship between positive throat cultures for yeasts and the presence of symptoms has remained unclear. In a study using beclomethasone dipropionate, Willey and co-workers” reported that only 33% of patients with thrush (defined as visible white patches with a positive culture for Candida) complained of sore throat or hoarseness, while 24% of patients without thrush as defined above and 48% of patients on placebo aerosol in a British Medical Research Council TriallO with beclomethasone had similar symptoms. Unfortunately, the study by Willey was based on a single cultural survey; however, they suggested that perhaps there was no direct correlation between the presence of thrush and the occurrence of symptoms. A report by Williams, Kane and Shim using triamcinolone acetonide in 21 asthmatic patients suggested that 11 of the patients developed hoarseness, but there were no reported data concerning the presence of Candida in the upper airway. Laryngoscopy performed in 6 patients revealed a “dry larynx and sluggish movement” of the larynx. They sug-

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Oropharyngeal

candidiasis

abnormal

examinations,

TABLE Ill. Relationships among symptoms, at the time of each visit -A. Percent of patients with symptoms

with triamcinolone

and positive

acetonide

throat

aerosol

257

cultures

--

- culture

+ culture Baseline 2 wk

--

4 wk 6 wk 4 mo 6 mo

B. Percent --

of patients

(O/7 patients) 44% (4/9 patients) 29% (217 patients) 25% (2/8 patients) 43% (3/7 patients) 13% (I /8 patients) 0%

with abnormal

physical

0% (O/22 patients) 15% (3/20 patients) 22% (5/23 patients) 5% (l/20 patients) 5% (l/20 patients) 1 I % (2/18 patients)

Baseline

- culture

C. Percult

@‘patients

0% (0 /7 patients)

33% (3/9 14% (l/7 25% (2/8 14% (l/7 13% (l/8 with abnormal

patients) patients) patients) patients) patients)

physical

*Differences

0.11

0.53 0.19 0.04* 0.69

9% (2/22 (2/20 9% (2/23 10% (2/20 5% (l/20 0% (01I8

10%

patients) patients) patients) patients) patients) patients)

Fisher’s

exact p

0.57 0.16

0.56 0.32 0.46 0.31

examination

Symptoms

Baseline 2 wk 4 wk 6 wk 4 mo 6 mo

exact p

examination

+ culture

2 wk 4 wk 6 wk 4 mo 6 mo

Fisher’s

0% (0 patients) 40% (2/5 patients) 100% (3/3 patients) 75% (3/4 patients) 50% (I /2 patients) 0% (O/2 patients)

No symptoms

0% (O/30 patients) 20% (5/25 patients) 15% (4/27 patients) 0% (O/24 patients) 12% (3/26 patients) 4% ( l/26 patients)

Fisher’s

exact p

0.33 0.009” 0.001* 0.27 0.93

were statistically significant.

gested that the symptoms might be due to the drying action of the spray on the vocal cords and perhaps to a local steroid myopathy. Kriz and co-workers, in a 4-wk study with triamcinolone acetonide, reported no difference in the frequency of side effects among patients using triamcinolone aerosol and those using a placebo aerosol. Hoarseness, oral lesions, and thirst were complaints of equal frequency in both groups. In their study of 25 patients, only suspicious oral lesions were cultured for fungi and none were found to be positive. Serum precipitins to Candida were performed after completion of the study and were negative except for one patient in the placebo group. In the present study we have demonstrated that complaints of sore throat and hoarseness and development OFsome visible abnormality on throat examination are frequent occurrences in patients using triamcinolone acetonide. At the same time, these abnormalities appear to bear no predictable relationship to the presence of yeast in cultures from the upper respiratory tract. One patient in the study had persistent hoarseness. The larynx was examined with a fi-

beroptic bronchoscope and appeared normal. Brushings of the larynx were negative on culture for Candida. Symptoms in the majority of patients in this study tended to be transient and improved with increasing duration of aerosol therapy. No patient in the study required discontinuation of the aerosol or antifungal treatment. A previous study with dexamethasone aerosol’* suggested that patients with chronic colonization of the respiratory tract with Candida should not be treated with that agent since they were more likely to develop clinically significant infection. When compared to those patients with only random positive cultures or to those who were always culturally negative, the twelve chronically colonized patients in our study did not have significantly greater frequency of sore throat, hoarseness, or abnormal throat examination. We conclude that the symptoms of sore throat and hoarseness are common in patients using triamcinolone aerosol. However, these symptoms and the appearance of the throat on physical examination bear no predictable relationship to the presence of Candidu

258 Pingleton et

al.

on throat cultures. Since in general the incidence of symptoms was slightly higher in the presence of a positive culture, the possibility of some relationship still exists. The incidence of Can&da colonization of the pharynx did not increase during the 6 months of triamcinolone therapy. When symptoms occur they are often transient, and discontinuation of the aerosol or antifungal therapy was not necessaryin any of our patients. Moreover, chronic colonization of the upper respiratory tract did not appear to be a contraindication to therapy with this agent in this 6-month study. The possible deleterious effect of fungal colonization beyond this period of time is unknown. The causeof the upper respiratory tract symptoms remains unknown but perhaps is related to the effects of the propellant, as has been suggestedby others.‘, 2, l1 REFERENCES 1. Kriz, R. J., Chmelik, F., DoPico, G., Reed, C. E.: A shortterm double-blind trial of aerosol triamcinolone acetonide in steroid-dependent patients with severe asthma, Chest 69455, 1976. 2. Williams, M. H., Kane, C., and Shim, C. C.: Treatment of asthma with triamcinolone acetonide delivered by aerosol, Am. Rev. Respir. Dis. 109:538, 1974. 3. Falliers, C. J.: Triamcinolone acetonide aerosols for asthma. I.

J. ALLERGY

4.

5.

6.

7.

8.

9.

10.

11.

12.

CLIN. IMMUNOL. OCTOBER 1977

Effective replacement of systemic corticosteroid therapy, J. ALLERGY CLIN IMMUNOL. 57:1, 1976. Fletcher, C. M.: The long-term evaluation of beclomethasone dipropionate in childhood asthma, Postgrad. Med. J. Sl(supp1 4):90, 1975. Brown, H. M., Storey, G., and George, W. H. S.: Beclomethasone dipropionate: A new steroid aerosol for the treatment of allergic asthma, Br. Med. J. 1:585, 1972. Bulow, K. B., and KaIen, A. N.: Local and systemic effects of beclomethasone inhalation in steroid-dependent asthmatic patients, Curr. Ther. Res. 16~110, 1974. Hodson, M. E., Batten, J. C., Clarke, S. W., and Gregg, 1.: Beclomethasone dipropionate aerosol in asthma, Am. Rev. Respir. Dis. 110:403, 1974. Smith, A. P., Booth, M., and Davey, A. J.: A controlled trial of beclomethasone dipropionate for asthma, B? J. Dis. Chest 67:208, 1973. McAllen, M. K., Kochanowski, S. J., and Shaw, K. M.: Steroid aerosols in asthma: Assessment of bethamethasone valerate in a 12-month study of patients on maintenance treatment, Br. Med. J. 1:171, 1974. Medical Research Council (1974) Preliminary Report of the Brompton HospitallMRC Collaborative Trial, Lancet 2:303, 1974. Willey, R. F., Milne, L. J. R., Crompton, G. K., and Grant, I. W. B.: Beclomethasone depropionate aerosol and oropharyngeal candidiasis, Br. J. Dis. Chest 70:32, 1976. Dennis, M., and Itkin, I. H.: Effectiveness and complications of aerosol dexamethasone phosphate in severe asthma, J. ALLERGY3570, 1964.

Oropharyngeal candidiasis in patients treated with triamcinolone acetonide aerosol.

Oropharyngeal candidiasis treated with triamcinolone aerosol in patients acetonide William W. Pingleton, M.D., Roger C. Bone, M.D., Gerald R. Kerby,...
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