Diagnosis: Isolated Cheilitis Secondary to Candida Albicans
Oral candidiasis is an opportunistic infection caused by an overgrowth of Candida species, most commonly Candida albicans. The carriage prevalence of Candida varies from 45% to 65% in healthy infants, 30% to 55% in normal adults and 50% to 65% in people who wear removable dentures.1 Prevalence further increases to 65% to 88% in those residing in acute and long-term care facilities,2-4 90% of patients with acute leukemia undergoing chemotherapy5 and up to 95% of patients with HIV.6 C albicans, C glabrata and C tropicalis represent more than 80% of isolates from clinical infection.7
States of transient immunosuppression predispose an individual to candidal overgrowth. Endogenous risk factors include infancy and old age, pregnancy, immunocompromised states, diabetes mellitus and other endocrinopathies resulting in chronically elevated serum glucose, Sjögren syndrome-induced xerostomia, nutritional deficiencies and poor overall health.8 Exogenous risk factors encompass poor nutritional diet, antibiotic and immunosuppressive medications, cigarette smoking, ill-fitting oral prostheses, chronic local irritation or trauma, local radiation and poor oral hygiene.9
Clinical Presentation
Candida can be a commensal organism in the oral cavity and is largely asymptomatic in healthy individuals. Overgrowth, however, can lead to local discomfort, an altered taste sensation, dysphagia from esophageal overgrowth resulting in poor nutrition, easy bleeding in affected areas and impaired tissue recovery. Areas of the mouth most heavily colonized by Candida are the posterior dorsal tongue, palate and buccal mucosa.10
The most common presentations of oral candidiasis include acute pseudomembranous candidiasis, acute atrophic candidiasis, chronic hyperplastic candidiasis, chronic atrophic candidiasis, median rhomboid glossitis and angular cheilitis. Acute pseudomembranous candidiasis (“thrush”) accounts for at least one-third of cases of oral candidiasis and presents as loosely adherent curd-like plaques, which can be scraped to reveal an erythematous base. Acute atrophic candidiasis (“antibiotic sore mouth”) in contrast presents with burning/sore erythematous patches on the buccal mucosa and tongue and may represent a continuum with thrush whose pseudomembranes have been shed.11
Chronic hyperplastic candidiasis is characterized by adherent white plaques on the buccal mucosa and lateral tongue, with histology showing candidal hyphae in a hyperplastic epithelium.12 There is an association with smoking and smoking cessation may lead to complete resolution.13 Chronic atrophic candidiasis (“denture stomatitis”) is common in denture wearers and shows erythema and edema in areas of denture occlusion. Median rhomboid glossitis presents as an ovoid or rhomboid erythematous patch on the mid-posterior dorsal tongue. Candida has been reported in over 80% of biopsies and cases typically resolve with topical antifungal therapy.14 Angular cheilitis (“perleche”) arises as fissuring at the labial commissures and is associated with deep skin folds along the melolabial and nasolabial regions.
Other more atypical forms of oral candidiasis have been reported as well. Linear gingival erythema manifests as a beefy red line along the gingival margin of 1 or more teeth. It was first reported in HIV patients, though healthy children have also been affected.15 Antifungal therapy and periodontal referral is recommended to prevent necrotizing periodontitis.16 “Cheliocandidiasis” has been reported as a persistent 1 cm to 2 cm erosion typically on the middle lower vermilion.17 Candida has been isolated in about 80% of reported cases and remission often occurs rapidly upon antifungal treatment.
Diagnosis of oral candidiasis involves history and clinical exam supplemented by further studies. Lesions may be scraped for smears and prepped with Gram stain, methylene blue or potassium hydroxide to reveal yeast and pseudohyphae. Samples from oral rinse, scraping or biopsy can be sent for fungal culture to support a diagnosis. Furthermore, biopsies can be performed and evaluated on hematoxylin and eosin, methylene blue, periodic acid–Schiff or Grocott methenamine-silver stains to confirm fungal elements.
Differential Diagnosis
The differential diagnosis includes allergic contact dermatitis, irritant contact dermatitis, atopic cheilitis, actinic cheilitis or drug-induced cheilitis. A few of the common culprit allergens inducing allergic contact cheilitis include parabens, fragrance, nickel sulfate, vitamin E, propolis, lanolin, sorbic acid, sorbitan sesquioleate derivatives, cetostearyl alcohol derivatives, butylated hydroxytoluene and propylene glycol.18,19 A thorough history and exam including review of the personal care products used on the lips is essential.
Management
Management of isolated oral candidiasis typically involves a combination of addressing underlying risk factors, oral hygiene and topical antifungal therapy. Correction of risk factors is important for fungal clearance and maintenance, such as improving nutritional state, adjusting ill-fitting oral prostheses and managing underlying disease states. Injectable filler might be considered for deep skin grooves associated with recalcitrant angular cheilitis. Regular brushing of the entire oral mucosa and daily disinfection of dentures should be performed.
Topical antifungals are the first-line pharmaceutical intervention for uncomplicated oral candidiasis. Nystatin, a polyene, is the most widely used topical agent for the treatment of oral candidiasis and is typically effective 3 to 4 times daily over a 2-week course.20 Topical imidazoles (clotrimazole, miconazole, ketoconazole, econazole) are another option to be considered for a 2- to 3-week course. Less commonly used topicals include amphotericin B or gentian violet. Allylamines (terbinafine, naftifine), though fungicidal against dermatophytes, are fungistatic against C albicans and are less often used as a first-line agent for candidiasis.
In cases resistant to initial therapy, one might consider culture and sensitivity testing. Increasing use of antifungals in immunocompromised patients may be selecting for more resistant strains. In 1 study of 50 oral candida isolates in HIV and tuberculosis positive individuals, azole resistance ranged from 14.2% to 41.1% depending on the azole used.21 In the same study, nystatin resistance was 11.9% and there was no resistance to amphotericin B. Multiple resistance mechanisms to azoles in candida have been identified including mutations in ERG11 altering azole affinity to lanosterol demethylase, drug efflux via ABC transporters (eg, MDR1, CDR1, CDR2), tolerance to methylated sterols via ERG3 mutation, biofilm formation and utilization of host cholesterol.22
Our Patient
The patient had been referred for patch testing to evaluate for allergic contact dermatitis; however, candida was suspected based on physical exam and cultures were performed for further evaluation (Figure 1). Cultures for bacteria and fungus were obtained from affected vermilion that grew C albicans in addition to 2+ mixed gram-positive and gram-negative organisms. She was treated with nystatin (100,000 unit/g) ointment and began to experience rapid improvement in symptoms within 4 days (Figure 2). At follow-up appointment in 2 months, her lip dermatitis had completely resolved (Figure 3).
Figure 2. Improvement in symptoms 4 days after initiating nystatin ointment.
Figure 3. Complete resolution of cheilitis noted at 2 month follow-up.
Our patient’s presentation of isolated bilateral upper and lower lip involvement without other oral sequelae of candidiasis is atypical and does not appear to fit into previously described classifications. The initial lack of response to econazole is interesting and may have been due to azole resistance, which has been rising as noted previously. Her history of heart transplant is no doubt a significant risk factor for oral candidiasis. In a recent study evaluating oral candida species in orthotopic heart transplant patients with matched controls, yeast prevalence was significantly higher in the transplant group (88% vs 56%, respectively).23 To our knowledge, this represents a new presentation of candidiasis to consider in the differential of lip dermatitis especially in susceptible patients.
Conclusion
Oral candidiasis is a common disease with a variety of presentations occurring especially in individuals with risk factors for local immunosuppression. Drug resistance to antifungals is rising and should be considered in patients with candidiasis who do not appear to respond to initial therapy. Our patient’s presentation of isolated upper and lower lip dermatitis without other oral involvement appears to be a novel presentation which should be considered in the differential for cheilitis.
Dr. Chang is resident physician with the department of dermatology at Duke University Medical Center in Durham, NC.
Dr. Lampel is assistant professor with the department of dermatology at Duke University Medical Center in Durham, NC.
Disclosure: The authors report no relevant financial relationships.
References
1. Arendorf TM, Walker DM. The prevalence and intra-oral distribution of Candida albicans in man. Arch Oral Biol. 1980;25(1):1-10.
2. Aldred MJ, Addy M, Bagg J, Finlay I. Oral health in the terminally ill: a cross sectional pilot survey. Spec Care Dentist. 1991;11(2):59-62.
3. Cumming CG, Wight C, Blackwell CL, Wray D. Denture stomatitis in the elderly. Oral Microbiol Immunol. 1990;5(2):82-85.
4. Holbrook WP, Hjorleifsdottir DV. Occurrence of oral Candida albicans and other yeast-like fungi in edentulous patients in geriatric units in Iceland. Gerodontics. 1986;2(5)153-156.
5. Rodu B, Carpenter JT, Jones MR. The pathogenesis and clinical significance of cytologically detectable oral candida in acute leukaemia. Cancer. 1988;62(9):2042-2046.
6. Dupont B, Graybill JR, Armstrong D, Laroche R, Touzé JE, Wheat LJ. Fungal infections in AIDS patients. J Med Vet Mycol. 1992;30(suppl 1):19-28.
7. Odds FC. Candida and Candidosis. 2nd ed. London: Bailliere Tindall; 1988.
8. Scully C, el-Kabir M, Samaranayake LP. Candida and oral candidosis: a review. Crit Rev Oral Biol Med. 1994;5(2):125-157.
9. Akpan A, Morgan R. Oral candidiasis. Postgrad Med J. 2002;78(922):455-459.
10. Vazquez JA, Sobel JD. Mucosal candidiasis. Infect Dis Clin North Am. 2002;16(4):793-820.
11. Samaranayake LP, Keung Leung W, Jin L. Oral mucosal fungal infections. Periodontol 2000. 2009;49:39-59.
12. Sharon V, Fazel N. Oral candidiasis and angular cheilitis. Dermatol Ther. 2010;23(3):230-242.
13. Silverman S Jr, Luangjarmekorn L, Greenspan D. Occurrence of oral Candida in irradiated head and neck cancer patients. J Oral Med. 1984;39(4):194-196.
14. Budzt-Jörgenson E. Etiology, pathogenesis, therapy and prophylaxis of oral yeast infections. Acta Odontol Scand. 1990;48(1):61-69.
15. Odden K, Schenck K, Koppang H, Hurlen B. Candidal infection of the gingiva in HIV-infected persons. J Oral Pathol Med. 1994;23(4):178-183.
16. Reznik DA. Oral manifestations of HIV disease. Top HIV Med. 2005;13(5):143-148.
17. Terai H, Shimahara M. Cheilitis as a variation of Candida-associated lesions. Oral Dis. 2006;12(3):349-352.
18. Scheman A, Jacob S, Katta R, et al. Part 3 of a 4-part series. Lip and common dental care products: trends and alternatives: data from the American Contact Alternatives Group. J Clin Aesthet Dermatol. 2011;4(9):50-53.
19. Schena D, Fantuzzi F, Girolomoni G. Contact allergy in chronic eczematous lip dermatitis.Contact allergy in chronic eczematous lip dermatitis. Eur J Dermatol. 2008;18(6):688-692.
20. Epstein JB. Antifungal therapy in oropharyngeal mycotic infections. Oral Surg Oral Med Oral Pathol. 1990;69(1):32-41.
21. Ramesh N, Priyadharsini M, Sumathi CS, Balasubramanian V, Hemapriya J, Kannan R. Virulence factors and anti fungal sensitivity pattern of Candida Sp. isolated from HIV and TB patients. Indian J Microbiol. 2011;51(3):273-278.
22. Bondaryk M, Kurza¸tkowski W, Staniszewska M. Antifungal agents commonly used in the superficial and mucosal candidiasis treatment: mode of action and resistance development. Postepy Dermatol Alergol. 2013;30(5):293-301.
23. Ribeiro PM, Bacal F, Koga-Ito CY, Junqueira JC, Jorge AO. Presence of Candida spp. in the oral cavity of heart transplantation patients. J Appl Oral Sci. 2011;19(1):6-10.
A 64-year-old immunosuppressed female with history of heart transplant presented with several month history of lip dermatitis affecting the bilateral upper and lower vermilion (Figure 1). Symptoms included burning, irritation and pain. She had tried topical steroids (desonide cream, hydrocortisone valerate ointment) and econazole cream without improvement. She had also tried avoidance of all personal care products to the area except petrolatum to the lips, also without improvement. Physical examination revealed erythema, slight edema and moist white plaques involving the mucosal lips and crossing the vermilion border. There was no other involvement of oral, nasal, ocular or genital mucosa and no adenopathy was appreciated.
