Esophageal Candidiasis as a Complication of Inhaled Corticosteroids

Esophageal candidiasis as a complication of inhaled corticosteroids Michael R Simon, MD*†; William L Houser, MD*†; Kurtis A Smith, MD†; and P Michael Long, PhD*‡

Background: Oropharyngeal candidiasis is a well-described side effect of inhaled corticosteroids. Nevertheless, few cases of esophageal candidiasis have been reported. Objective: To present a patient with esophageal candidiasis associated with inhaled corticosteroids. Methods: Case report. Results: Our patient is a 70-year-old white woman with a 20-year history of intrinsic asthma, well controlled on triamcinolone acetonide 400 ␮g, ipratropium bromide 36 ␮g, and pirbuterol acetate 400 ␮g, each inhaled four times daily. She reported no oral steroid use for ⬎4 years and that she always rinsed her mouth following triamcinolone acetonide inhalation. The patient had gastritis with peptic ulcer disease in the past and developed worsening dyspeptic pain and heartburn. Following discontinuation of cimetidine and initiation of ranitidine without improvement, esophagogastroduodenoscopy was performed. Several small white patches in the mid and distal esophagus could not be removed with pressure. A biopsy confirmed the diagnosis of candidal esophagitis. Following a 4-week course of fluconazole, the patient was clinically improved and follow-up esophagogastroduodenoscopy was normal. There was no evidence of underlying cellular immunosuppression, malignancy, or diabetes mellitus and no history of recent antibiotic usage. Delayed skin tests revealed 5 ⫻ 5 mm induration to dermatophytin. Delayed hypersensitivity to Candida and mumps tests was absent. There was strong in vitro lymphocyte transformation and a positive immediate skin test response to Candida. ELISA for human immunodeficiency virus was negative. T and B cell counts were normal with CD4 ⫽ 630/mm3, CD8 ⫽ 520/mm3, and absolute B cell ⫽ 120/mm3. It is possible that this patient’s immediate hypersensitivity response to Candida suppressed her delayed response. Candidal esophagitis is a rare, yet important, complication of inhaled corticosteroid use. Conclusion: Immunocompetent patients on inhaled corticosteroids with medically unresponsive symptoms of esophagitis should be investigated for esophageal candidiasis. Ann Allergy Asthma Immunol 1997;79:333– 8.

INTRODUCTION Inhaled corticosteroids are an essential component in the anti-inflammatory From the Departments of *Pediatrics, †Internal Medicine, and ‡Pathology, Wayne State University School of Medicine, and the †V A Medical Center, Detroit, Michigan. Supported by the Department of Veterans Affairs. Presented in abstract form at the annual meeting of the American College of Allergy and Immunology, San Francisco, California, November 5, 1994. Received for publication January 24, 1997. Accepted for publication in revised form April 15, 1997.

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treatment of asthma.1–3 Their use has allowed many patients to discontinue oral corticosteroid therapy and, therefore, significantly minimize or eliminate their well-described side effects.4,5 The side effects of inhaled corticosteroids include dryness of the mouth and throat, hoarseness, and oropharyngeal and laryngeal candidiasis.6 – 8 The prevalence of oropharyngeal candidiasis associated with inhaled corticosteroids has been reported to be as high as 34%.7 Candidal esophagitis, however, is a rare complication with only four

cases reported, three of which do not document an immunologic evaluation.9,10 We present a patient with esophageal candidiasis associated with inhaled corticosteroids and her historical and laboratory evaluation. LABORATORY METHODS Lymphocyte thymidine incorporation was performed using standard techniques.11 Lymphocytes were obtained by Ficoll-Hypaque density-gradient centrifugation of preservative-free heparinized (Sigma, St. Louis, MO) blood, then suspended, and adjusted to 2 ⫻ 106 mononuclear cells/mL with minimal essential medium (Gibco, Grand Island, NY), N-[2-hydroxyethyl]piperazine-N⬘-[2-ethanesulfonic acid] buffer (25 mmol) (Calbiochem, La Jolla, CA), L-glutamine (4 mmol) (Gibco) and 40% AB negative serum. Aliquots of 0.1 mL containing 2 ⫻ 105 mononuclear cells were placed in flat bottomed microtiter wells with additional volumes of minimal essential media. Mitogens [phytohemagglutin P (Burroughs Wellcome, Research Triangle, NC) 5 ␮g/mL, pokeweed mitogen (Gibco) 20 ␮g/mL, and concanavalin A (Calbiochem) 50 ␮g/mL] and candidal antigen (Greer, Lenoir, NC) (1:20 dilution) were added to a final volume of 0.2 mL. All cultures were run in triplicate. Mitogens and candidal antigen were incubated at four and six days, respectively, at 37 °C in a 5% CO2 humidified atmosphere. Tritiated thymidine (Dupont/NEN, Boston, MA) (0.5 ␮Ci, 6.7 Ci/mmol) 0.05 mL was added to each well for the last two hours of incubation. Cells were harvested with a multiple automated cell harvester and deposited on filter paper disks. Biosafe scintillation fluid (Research Products International, Mount Prospect, IL) was added to each vial, and the cells were counted in a scintillation counter. Mean

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cell disintegrations per min (dpm) ⫾ standard error was determined for each set of triplicate cultures. Stimulation index (SI) was derived by dividing the mean dpm of stimulated cultures by the mean dpm with no mitogen or candidal antigen. Candidacidal studies12 were performed with polymorphonuclear (PMN) cells diluted to 2.5 ⫻ 107/mL. Candida albicans organisms, strain 10231, (American Type Culture Collection, Rockville, MD) were concentrated to 2.5 ⫻ 107/mL. Test specimens totaling 1 mL were made with 0.1 mL of patient or control cells, 0.1 mL of Candida suspensions, 0.1 mL autologous plasma, and Hanks’ balanced salt solution. Control specimens were run containing Candida suspensions, 0.1 mL plasma, Hanks’ balanced salt solution, or Candida suspensions and Hanks’ balanced salt solution without plasma. Viable and nonviable Candida organisms were counted in duplicate. For test specimens, 200 Candida organisms were counted, while 100 were counted for the three control specimens. Results were reported as the mean number of Candida counted and as the percentage killed. Anti-CD4, anti-CD8, anti-CD19, and anti-CD16/CD56 (Simultest, Becton Dickenson, San Jose, CA) were used to label CD4, CD8, B, and NK cells, respectively, prior to counting in a flow cytometer in the clinical laboratory at the VA Medical Center, Cleveland, OH. Pneumococcal antibody titers were performed by ELISA (Specialty Laboratories, Santa Monica, CA). Delayed hypersensitivity skin testing was performed with intermediate strength tuberculin purified protein derivative (PPD) (Parke Davis, Morris Plains, NJ), mumps skin test antigen (Connaught, Swiftwater, PA), and 1: 100 weight by volume dilutions of candidal antigen and dermatophytin (both from Walter Reed Army Medical Center, Washington, DC). Intradermal injections with 0.10 mL of each antigen were placed on the forearms and the resulting induration and induration were read at 20 minutes and 48 hours.

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CASE REPORT The patient is a 70-year-old white woman with a 20-year history of intrinsic asthma well controlled on triamcinolone acetonide 400 ␮g, ipratropium bromide 36 ␮g, and pirbuterol acetate 400 ␮g, each inhaled 4 times daily. She reported no oral steroid use for at least 4 years and that she always rinsed her mouth following inhalation of triamcinolone acetonide. The patient had gastritis with peptic ulcer disease in the past and began to develop worsening upper abdominal dyspeptic pain and heartburn. Following a medication change from cimetidine to ranitidine without improvement, an esophagastroduodenoscopy was performed. The past history was remarkable for hypertension, glaucoma, chronic rhinitis, hypothyroidism following partial thyroidectomy, diverticulitis with partial colectomy, degenerative joint disease, and chronic recurrent sinusitis. The patient has had two previous blood transfusions and no antibiotic usage within the previous 3 months. There was no evidence of underlying immunosuppression, malignancy, or diabetes mellitus. Additional concurrent medications include azatadine, 1 mg, beclomethasone nasal spray 2 sprays, triamterene 50 mg, hydrochlorothiazide 25 mg, and dipivefrin 0.1% ophthalmic 1 drop to each eye, all twice daily; fosinopril sodium 10 mg, sucralfate 1 g, levothyroxine 0.1 mg and ferrous sulfate 325 mg all once daily; docusate sodium 100 mg, apra-

clonidine 0.5% ophthalmic 1 drop to each eye, both thrice daily; and pilocarpine 2% ophthalmic 1 drop to each eye 4 times daily. RESULTS Esophagogastroduodenoscopy An esophagogastroduodenoscopy was performed and several white patches in the mid and distal esophagus were found. These patches could not be removed with the application of pressure using the endoscope. A biopsy revealed squamous atypia with a dense population of yeast and hyphae which confirmed the diagnosis of esophageal candidiasis. A 2-week course of fluconazole was given and repeat endoscopy revealed visual persistence of the candidiasis. After an additional 2-week course of fluconazole, the patient was improved clinically and follow-up endoscopy was normal. Triamcinolone acetonide was discontinued and nedocromil sodium was started without any recurrence of symptoms. Delayed Hypersensitivity Skin Testing (Table 1) All tests were done with 0.1 mL antigen and were read for induration and erythema at 20 minutes and 48 hours. Candidal antigen 1:100 injection resulted in a 10 ⫻ 10-mm wheal without a flare at 20 minutes and no reaction at 48 hours. Dermatophytin 1:100 injection resulted in a 10 ⫻ 12-mm wheal without a flare but with a 5 ⫻ 5-mm wheal and a 5 ⫻ 5-mm flare at 48 hours. Mumps skin test antigen injec-

Table 1. Skin Tests* 20 min

48 hr

Antigen Induration Candida albicans 1:100 Dermatophytin 1:100 Mumps antigen PPD†

10 10 5 10

⫻ 10 mm ⫻ 12 mm ⫻ 6 mm ⫾ 7 mm

Erythema

Induration

Erythema

none none 9 ⫻ 10 mm none

none 5 ⫻ 5 mm none none

none 5 ⫻ 5 mm 4 ⫻ 4 mm none

* Intradermal injections with 0.10 mL of each antigen were placed on the forearms and the resulting induration and erythema were read at 20 minutes and 48 hours. A diluent control was not used. Since the mumps skin test antigen wheal size at 20 minutes was the smallest, it was considered as a negative control in order to interpret the immediate responses to the other antigens conservatively. † Purified protein derivative, intermediate strength.

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tion resulted in a 5 ⫻ 6-mm wheal and a 9 ⫻ 10-mm flare at 20 minutes and only 4 ⫻ 4-mm erythema at 48 hours. PPD injection resulted in a 7 ⫻ 10-mm wheal but no flare at 20 minutes and no reaction at 48 hours. A diluent control was not used. Since the mumps skin test antigen wheal size at 20 minutes was the smallest, it was considered as a negative control in order to interpret the immediate responses conservatively. The candidal and dermatophytin antigens can then be considered to have caused 1⫹ reactions (“more than two times the control wheal size regardless of erythema”).13 Laboratory Studies (Tables 2–5) This patient’s ELISA for human immunodeficiency virus was negative. Her T and B cell markers were normal with a CD4 count ⫽ 630/mm3 (48%) (normal 580 to 1929/mm3), CD8 count ⫽ 520/mm3 (40%) (normal 359 to 1199/mm3), and B cell count ⫽ 120/ mm3 (normal 84 to 587/mm3). Natural killer cells constituted 6% of the cell count (normal 5% to 15%). Her in vitro lymphocyte thymidine incorporation revealed normal responses to phytohemmaglutinin P (13,077 ⫾ 3,108 dpm), pokeweed mitogen (23,075 ⫾ 2,662 dpm), and concanavalin A (17,927 ⫾ 3,169 dpm) as well as candidal antigen (14,843 ⫾ 3,518 dpm). This patient’s leukocytes killed 46% of Candida organisms while control leukocytes killed 34%. Evaluation of this patient’s humoral immunity on two occasions revealed total serum IgG ⫽ 995 and 1040 mg/dL (normal ⫽ 694 to 1618 mg/dL), IgA ⫽ 126 and 101 mg/dL (normal ⫽ 68 to 378 mg/dL), and IgM ⫽ 124 and 92 mg/mL (normal ⫽ 60 to 263 mg/

dL). IgG subclass determination revealed IgG1 ⫽ 1000 and 1005 mg/dL (normal ⫽ 450 to 900 mg/dL), IgG2 ⫽ 237 and 242 mg/dL (normal ⫽ 180 to 530 mg/dL), IgG3 ⫽ 51 and 43 mg/dL (normal ⫽ 13 to 80 mg/dL), and IgG4 ⫽ ⬍6 and 7 mg/dL (normal ⫽ 8 to 100 mg/dL). Pneumococcal antibody titers (Table 5) were low normal for type 3, and low for types 7F, 9N, and 14. Our patient was a non-responder to serotype 7F with a postvaccination titer of 170 ng antibody nitrogen (normal ⬎500). There was a weak response (less than 4-fold increase in titers) to serotypes 3, and 9N, and a normal response to serotype 14 two weeks following vaccination with pneumococcal vaccine (Pnu-Imune, Lederle, Pearl River, NJ, Danish serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F 33F). DISCUSSION Candida albicans colonizes the esophagus in approximately 20% of healthy adults.14 Esophageal infections exist when the organisms adhere to the epithelium. Such infections may occur in patients with immune suppression due to malignant disease, chronic metabolic or infectious disease, or immunosuppressive drug therapy.15 Inhaled corticosteroids are known to cause infection with Candida albicans in the oropharynx; however, they have only been associated with Candida esophagitis in two previous reports.9,10 Deposition of the drug in the esophagus occurs after swallowing. Colonization and infection with Candida appear to follow. Factors that mitigate the likelihood of Candida esophagitis associ-

Table 2. T and B Cell Markers and Human Immunodeficiency Virus ELISA Test

Patient’s Result

Normal Value

ELISA for HIV* CD4 cell count CD8 cell count B cell count CD4 percentage CD8 percentage

negative 630/mm3 520/mm3 120/mm3 48% 40%

negative 580–1929/mm3 359–1199/mm3 84–587/mm3 42–59% 21–36%

* Human immunodeficiency virus.

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ated with inhaled corticosteroids such as mouth rinsing, spacer devices, and mucosal immunity may be responsible for the paucity of cases. The previously reported patients had used budesonide or high dose beclomethasone. No previous reports have been associated with inhaled triamcinolone. Our patient did not use oral steroids, which eliminated the possibility of a drug-induced immunosuppression. One of the previously reported patients with esophageal candidiasis associated with high dose beclomethasone had mild hypogammaglobulinemia and impairment of neutrophil canThe latter didacidal activity.9 abnormality may have contributed to the subsequent development of Candida esophagitis. As with that patient, our patient has a defect in her humoral immunity. She is unable to respond to polysaccharide antigens. Three additional immunocompetent patients who developed retrosternal pain and/or dysphagia following inhaled budesonide therapy and had biopsy-confirmed esophageal candidiasis have been described.10 In our study, as in previous reports of Candida esophagitis, the patients complained of abdominal pain, retrosternal pain (heartburn), and/or dysphagia prompting an evaluation, and subsequent diagnosis. A high index of suspicion in patients using inhaled corticosteroids who present with symptoms of esophagitis is required. In contrast, esophageal candidiasis may be underdiagnosed in patients with mild symptoms or partially controlled symptoms. Patients with symptoms unresponsive or partially responsive to empirical treatment for gastroesophageal reflux should be evaluated for esophageal candidiasis. The patient described in this report had not used systemic corticosteroids, and had normal T and B cell markers, a positive lymphocyte transformation response to phytohemagglutinin, pokeweed mitogen, concanavalin A, and Candida, and a negative ELISA for human immunodeficiency virus indicating no underlying cellular immunodeficiency. In addition, candidacidal

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studies revealed no significant abnormalities. Our patient did lack the ability to respond to polysaccharide antigens which indicates a defect in her humoral immunity. The lack of delayed skin test reactivity to Candida, in spite of markedly positive lymphocyte thymidine incorporation in response to Candida, may be explained by the inhibition of delayed hypersensitivity by the immediate response in this patient. Our patient’s lack of an in vivo delayed hypersensitivity response to Candida may have predisposed her to the development of esophageal candidiasis. Suppression of the delayed response by an immediate hypersensitivity reaction at the site of antigen injection was first reported with ragweed antigen.16 Several other studies document individuals with absent delayed hypersensitivity in the presence of immediate hypersensitivity to trichophytin,17,18 tuberculin,19 Penicillium and Cladosporium,18 and Staphylococcus.20,21 The suppression of the delayed response by the immediate response may be the result of H2 histamine receptorinduced suppression of mononuclear cell function.22 This may occur by more than one mechanism. The first entails histamine-induced intracellular lymphocyte23,24 and monocyte25 accumulation of cAMP. Elevated intracellular cAMP concentrations, in turn, inhibit concanavalin A-stimulated mononuclear cell thymidine incorporation26 and T cell interleukin 2 receptor expression27 and interleukin 2 mRNA induction28 and interleukin 2 production.29 It also inhibits monocyte antibody-dependent cell-mediated cytotoxicity25 and chemotaxis.30 The second mechanism involves histamineinduced elaboration of a soluble suppressor factor from T cells by acting through the H2 receptor.31,32 This histamine-induced suppressor factor is produced by T8 cells33 and can suppress phytohemmaglutinin-induced34 and mixed lymphocyte reaction-induced mononuclear cell thymidine incorporation.33 Additional evidence that histamineinduced mononuclear cell effects are

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Table 3. Lymphocyte Tritiated Thymidine Incorporation in vitro Mitogen1 or Antigen2

Disintegrations/min, Stimulation Index dpm ⴞ Standard (stimulated dpm/ Error unstimulated dpm)

Phytohemagglutinin, 5 ␮g/mL Pokeweed mitogen, 20 ␮g/mL 1 Concanavalin A, 50 ␮g/mL 1 Unstimulated 2 Candida 2 Unstimulated

13,077 ⫾ 3,108 23,075 ⫾ 2,662 17,927 ⫾ 3,169 271 ⫾ 125 14,843 ⫾ 3,518 282 ⫾ 92

1 1

48 85 66 53

Normal Range, dpm 9,500–45,000 13,600–35,500 8,400–44,000 100–850 4,000–26,000 100–850

* Disintegrations per minute of tritium are a measure of activation of the lymphocytes by mitogen or antigen and indicate cellular immune reactivity. 14-day or 26-day cultures.

Table 4. Candidacidal Studies with Patient’s Polymorphonuclear Cells* Viable Candida

Non-viable Candida

% Killing

132 106 96 94 98

68 92 4 6 2

34 46 4 6 2

Control cells and plasma Patient’s cells and plasma Control plasma Patient’s plasma Buffer

* Viable and nonviable Candida organisms were counted in duplicate. For test specimens, 200 Candida organisms were counted while 100 were counted for the three control specimens. Results were reported as the mean number of Candida counted and as the percentage killed. Neither the control subject’s nor the patient’s plasma were candidacidal.

Table 5. Pneumococcal Antibody Concentrations Before and Following Vaccination with Pneumococcal Vaccine* Pneumococcal Antibody Type

Concentration ng ab Concentration N/mL Baseline, (3 ng ab N/mL determinations) Postvaccination

3

307 ⫾ 127(s.d.)

960

7F 9N 14

73 ⫾ 6 (s.d.) 183 ⫾ 42 (s.d.) 160 ⫾ 10 (s.d.)

170 650 1240

Concentration ng ab N/mL Reference Range 200 baseline; or ⬎500 postvaccination, with 2–4X increase ⫽ weak response, 4X increase ⫽ good response same same same

* This patient was a nonresponder to serotype 7F with a postvaccination titer of 170 ng antibody nitrogen (normal ⬎500). There was a weak response (less than 4-fold) increase in titers of serotypes 3, and 9N, and a normal response to serotype 14 2 weeks following vaccination with the pneumococcal vaccine.

probably due to histamine binding to the H2 histamine receptor is that cimetidine, an H2 histamine receptor antagonist, causes increased phytohemaglutinin-32,35–38 concanavalin A-39 and pokeweed mitogen-induced thymidine incorporation.35,36 An additional study suggests that cimetidine blocks the production of histamine-induced suppressor factor.40 Furthermore, cimeti-

dine-induced augmentation of delayed hypersensitivity is seen in vivo.41– 44 CONCLUSIONS An association between inhaled corticosteroids and esophageal candidiasis has been described. Deposition of the drug in the esophagus after swallowing, and subsequent colonization and infection with Candida, appear to fol-

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low. Mitigating factors such as mouth rinsing, spacer devices, and mucosal immunity may be responsible for the paucity of cases. Esophageal candidiasis, however, may be underdiagnosed in patients with mild symptoms or partially controlled symptoms. A thorough history, physical examination, and laboratory evaluation are required to evaluate such patients for underlying immunodeficiency. A high index of suspicion is required to identify patients at risk for the development of esophageal candidiasis. Suppression of the delayed-type hypersensitivity reaction (type IV) in vivo by the immediate hypersensitivity reaction (type I) is suggested in this patient with no underlying cellular immunodeficiency and lymphocytes highly reactive to Candida in vitro. This case report may increase physician awareness of the association between Candida esophagitis and inhaled corticosteroid use and lead to further evaluation of this association.

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Requests for reprints should be addressed to: Michael R Simon, MD 111F V A Medical Ctr 4646 John R St Detroit, MI 48201

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