Chronic Candida albicans otitis media in children with immunodeficiency.

Abstract

Acute otitis media is a very common childhood infection. Moreover, chronic otitis media is a problem of considerable magnitude as evidenced by the fact that tympanostomy tube placement in one of the most frequent surgical procedures performed in children.1Candida albicans is a common pathogen in children; it causes localized infections of the skin and mucous membranes in immunologically normal children and invasive or disseminated disease in immunodeficient patients.2 To date, however, there are very few reports of C. albicans otitis media in children. We report two children with functional antibody deficiency and chronic C. albicans otitis media. The infection was promptly eradicated in both children with oral antifungal therapy. Patient 1. A 6-year-old girl presented for evaluation of chronic, recurrent infections, including otitis media, sinusitis, bronchitis and pneumonia. Despite tympanostomy tube placement she continued to have recurrent otitis media. Laboratory studies revealed a normal white blood cell count and differential. Serum concentrations of IgG, IgA, IgM, IgE and IgG subclasses were normal. The patient was HIV-seronegative. Lymphocyte populations and in vitro lymphocyte responses to mitogens and alloantigens were normal. Tests for total hemolytic complement and nitroblue tetrazolium reduction were normal. The patient had positive delayed-type hypersensitivity skin tests to Candida and tetanus toxoid antigens. Serum concentrations of antibody to tetanus and diphtheria toxoids were normal, and the titers increased appropriately after booster immunizations. However, serum concentrations of antibody to pneumococcal serotypes 3, 7, 9 and 14 were below 100 ng/ml. Repeat testing 1 month after 23-valent pneumococcal vaccine revealed no antibody response to any of the serotypes tested. A diagnosis of antibody deficiency with normal immunoglobulins was made,3, 4 and the patient was treated with monthly infusions of intravenous immunoglobulin (IVIG). IVIG therapy resulted in a substantial reduction in the frequency and severity of sinopulmonary infections, but she developed chronic otitis media associated with persistent otorrhea. At 8 years of age the patient was hospitalized for further evaluation and treatment of the chronic otitis media. Physical examination revealed copious purulent drainage from the right tympanostomy tube. Initial cultures of the drainage from the tympanostomy tube yielded Staphylococcus aureus, Pseudomonas aeruginosa and C. albicans. Broad spectrum intravenous antibiotic therapy was begun, but after 3 days the ear discharge remained unchanged. A repeat culture of the middle ear drainage through the tympanostomy tube yielded a pure growth of C. albicans. Therapy was changed to oral ketoconazole, 200 mg/day (5 mg/kg/day); all other antibiotics were discontinued. The otorrhea resolved within 3 days, and by 3 weeks, the right tympanic membrane appeared normal and the tympanostomy tube was patent and dry. Ketoconazole therapy was continued for a total of 2 weeks. There has been no recurrence of the Candida otitis during the ensuing 6 years. Patient 2. A 3-year-old girl presented for evaluation of chronic, recurrent infections including otitis media, sinusitis, bronchitis and pneumonia. Tympanostomy tubes were placed at 18 months of age, but she continued to have recurrent of otitis media. Examination revealed that the tympanostomy tubes were out and there was a large perforation of the right tympanic membrane. Laboratory studies revealed a normal white blood cell count and differential. Serum concentrations of IgG, IgA, IgM, IgE and IgG subclasses were normal. The patient was HIV-seronegative. Lymphocyte populations and in vitro lymphocyte responses to mitogens and alloantigens were normal. Tests for total hemolytic complement and nitroblue tetrazolium reduction were normal. The patient had positive delayed-type hypersensitivity skin tests to Candida and tetanus toxoid antigens. Serum concentrations of antibody to tetanus and diphtheria toxoids were extremely low, despite prior immunizations. Moreover serum concentrations of antibody to pneumococcal serotypes 3, 7, 9 and 14 were below 100 ng/ml. The patient received tetanus and diphtheria toxoid booster immunizations and a 23-valent pneumococcal vaccine. Repeat testing 4 months later revealed no antibody response to any of the antigens. She was then reimmunized with the same antigens, and repeat testing 1 month later again demonstrated no antibody response to tetanus, diphtheria or pneumococcal vaccines. A diagnosis of antibody deficiency with normal immunoglobulins was made,3, 4 and the patient was treated with monthly IVIG. IVIG therapy resulted in a substantial reduction in the frequency and severity of the sinopulmonary infections. At 5 years of age the patient presented with a 1 month history of persistent purulent drainage from the right ear. Examination revealed thick, white discharge through a perforation of the right tympanic membrane. The otorrhea persisted despite therapy with oral antibiotics and topical antibiotic drops for 1 month. A culture of the middle ear drainage yielded an abundant growth of C. albicans and a few colonies of S. aureus. The patient was treated with oral fluconazole, 100 mg/day (4 mg/kg/day). Within 2 days there was a marked reduction in the otorrhea. One week after treatment was begun the ear was completely dry and the perforation of the tympanic membrane was noticeably smaller. Fluconazole therapy was continued for a total of 2 weeks. Two months later the perforation had healed and the tympanic membrane appeared normal. There has been no recurrence of the Candida otitis media during the ensuing 4 years. Discussion. The patients in this report had chronic C. albicans otitis media accompanied by persistent otorrhea. Both patients had underlying immunodeficiency characterized by the absence of functional antibody with normal serum immunoglobulin concentrations.3, 4 Nevertheless the infections cleared promptly after therapy with ketoconazole in one patient and fluconazole in the other patient. The diagnosis of chronic C. albicans otitis was established in our patients by culture of the persistent middle ear drainage. We feel confidant that C. albicans was the cause of the chronic otitis in our patients rather than a harmless contaminant. First neither patient had evidence of otitis externa, a potential source of Candida contamination.5 Second both patients had a prompt and complete clinical response to antifungal therapy. A number of studies have examined the microbiology of chronic suppurative otitis media in children. Pseudomonas aeruginosa and S. aureus are the major pathogens recovered from chronically draining middle ears.6-8C. albicans has rarely been implicated as a cause of chronic suppurative otitis media in children.6 Recently Cohen and Thompson9 reported 10 children with chronic fungal otitis media and persistent otorrhea. C. albicans was recovered from 5 patients and several other Candida species were recovered from the remaining patients. The patients were reported to be immunologically normal, but 4 patients did not have immunologic testing, and the results of immunologic tests were not given in the other 6 patients. All patients treated with ketoconazole had an excellent response. Our patients were similar to the children reported by Cohen and Thompson,9 but both patients in this report had immunodeficiency characterized by antibody deficiency with normal immunoglobulins.3, 4 The contribution of the immunodeficiency to the development of chronic C. albicans otitis in our patients is difficult to determine. Intact T cell function is critical to the host's defense against C. albicans, but the immune response to the organism is broad based and involves virtually every aspect of the immune system.2 Nevertheless C. albicans is not a major cause of infection in patients with pure antibody immunodeficiency.10 Patient 1 had immunodeficiency limited to defective antibody responses to polysaccharide antigens. Patient 2 had defective antibody responses to protein and polysaccharide antigens. We did not measure serum antibody to C. albicans in either patient. The patients in the present report had normal T cell numbers and function. Moreover both patients had intact cell-mediated responses to Candida as measured by positive delayed-type hypersensitivity skin tests. Thus it is likely that chronic antibiotic use rather than the immunodeficiency per se was the major factor in the development of the chronic Candida otitis in our patients. Chronic antibiotic therapy may have altered the normal flora of the external ear canal and allowed C. albicans to colonize the canal with subsequent spread to the middle ear through disrupted tympanic membranes. Treatment with oral antifungal agents resulted in prompt and long lasting clearance of the C. albicans infection in both patients. Ketoconazole and fluconazole are synthetic azolederived antifungal agents with activity against C. albicans as well as other fungal species. The availability of these agents has greatly improved our ability to treat a variety of fungal infections in many patient groups, particularly patients with human immunodeficiency virus infection.11 C. albicans infection should be considered in the differential diagnosis of chronic suppurative otitis media associated with chronic otorrhea. The diagnosis is easily established by culture of the middle ear drainage. Oral antifungal agents appear to be very effective in eradicating the infection. Jay A. McDonald, M.D.*[ Frank T. Saulsbury, M.D. Department of Pediatrics; University of Virginia Health Sciences Center; Charlottesville, VA