Oral Candidiasis

Opportunistic infection of the oral mucosa by Candida species, most often Candida albicans, which is a commensal of the oral cavity in 30 to 60 percent of healthy people. Disease represents a shift from commensal to pathogenic behaviour, which means the essential clinical task is to identify what changed in the host.

Pathogenesis

Candida albicans is a dimorphic organism. The yeast form is commensal; conversion to the invasive hyphal form, with expression of adhesins and secretion of aspartyl proteinases and phospholipases, allows epithelial penetration and disease. This conversion is enabled by disruption of the normal bacterial flora, by reduced salivary flow with loss of its antifungal proteins, by epithelial change, and by impaired cellular immunity, particularly the Th17 pathway.

Non albicans species, which matter for treatment

Candida glabrata, C. krusei, C. tropicalis and C. parapsilosis account for an increasing proportion, particularly in patients previously exposed to azoles. C. krusei is intrinsically resistant to fluconazole and C. glabrata frequently has reduced susceptibility. Identification and sensitivity testing therefore matter in refractory disease.

Classification

• Pseudomembranous candidiasis, that is thrush: white curd like plaques that wipe off leaving an erythematous, sometimes bleeding base.
• Erythematous or atrophic candidiasis: red painful mucosa without plaques, occurring on the palate and dorsum of the tongue. Acute forms follow antibiotics; chronic forms occur under dentures.
• Chronic hyperplastic candidiasis, or candidal leukoplakia: a white plaque that does not rub off, most often at the commissures, associated with smoking, and carrying a malignant transformation risk of around 9 to 40 percent. It must be biopsied.
• Denture stomatitis, classified by Newton: type I with pinpoint hyperaemia, type II with diffuse erythema confined to the denture bearing area, type III with granular or papillary hyperplasia.
• Angular cheilitis, that is angular stomatitis or perlèche: fissuring and erythema at the commissures, frequently mixed Candida and Staphylococcus aureus infection, associated with reduced vertical dimension in edentulous patients, iron and B vitamin deficiency.
• Median rhomboid glossitis: a depapillated rhomboid area on the midline dorsum of the tongue anterior to the circumvallate papillae.
• Chronic mucocutaneous candidiasis: persistent candidal infection of skin, nails and mucosa, associated with defects in Th17 immunity, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy, and thymoma.

Predisposing factors, which are the substance of the diagnosis

Local:

• Inhaled corticosteroids used without rinsing and spitting after use, which is the commonest cause in otherwise well adults.
• Dentures, particularly worn overnight and poorly cleaned.
• Xerostomia from drugs, radiotherapy, Sjögren syndrome or dehydration.
• Broad spectrum antibiotics.
• Smoking.
• Poor oral hygiene.
• High carbohydrate diet.
• Orthodontic appliances.

Systemic:

• Diabetes mellitus, particularly when poorly controlled.
• HIV infection. Oral candidiasis is frequently the first clinical manifestation, and oesophageal candidiasis is an AIDS defining illness.
• Malignancy, chemotherapy and radiotherapy to the head and neck.
• Systemic corticosteroids and other immunosuppression.
• Extremes of age: neonates and the frail elderly.
• Nutritional deficiency: iron, folate, vitamin B12 and zinc.
• Endocrine disease: hypothyroidism, hypoparathyroidism, hypoadrenalism.
• Haematological malignancy and neutropenia.

• Frequently asymptomatic, particularly pseudomembranous disease in infants.
• Oral soreness and burning, which is prominent in erythematous disease and which may be the only complaint with no visible plaques.
• Altered or metallic taste, and reduced taste.
• Sensitivity to acidic, spicy and hot food.
• Cotton wool sensation in the mouth.
• Dysphagia and retrosternal odynophagia, which indicate oesophageal involvement and which change the management and the required investigation entirely.
• Angular soreness and cracking at the commissures.
• Denture discomfort and looseness.

Examination

• Pseudomembranous: white or creamy plaques on the buccal mucosa, palate, tongue and oropharynx, which wipe off with a gauze or tongue depressor leaving an erythematous, sometimes bleeding, base. This wiping test distinguishes it from leukoplakia and lichen planus, which do not rub off.
• Erythematous: smooth red painful areas, classically on the palate mirroring the denture outline, and depapillation of the tongue dorsum.
• Hyperplastic: adherent white plaques, typically bilateral at the commissures, which do not rub off.
• Angular cheilitis with fissuring, crusting and erythema at the angles.
• Examine the whole oral cavity, oropharynx and the denture fitting surface.
• Examine for cutaneous and nail candidiasis, and for signs of underlying systemic disease.

Red flags

• Any white patch that does not rub off, which requires biopsy to exclude dysplasia and carcinoma, since hyperplastic candidiasis, leukoplakia and early squamous cell carcinoma are indistinguishable clinically.
• Ulceration, induration or a mass.
• Dysphagia or odynophagia, indicating oesophageal candidiasis.
• Extensive or recurrent disease in an adult with no obvious local cause, which requires HIV testing and diabetes screening.
• Failure to respond to appropriate treatment, which requires culture with sensitivities, biopsy and investigation of the host.

Usually clinical, but investigation is directed at confirming the organism where the response is poor and at identifying the underlying cause, which is the more important task.

• Oral swab for fungal culture from the lesion, with speciation and sensitivity testing where the disease is recurrent or refractory.
• Oral rinse or imprint culture, which quantifies the fungal load and is more useful than a simple swab for erythematous disease.
• Smear with potassium hydroxide, periodic acid Schiff or Gram staining, showing yeasts and pseudohyphae. The presence of hyphae rather than yeast alone supports invasive disease rather than commensal carriage.
• Biopsy of any non removable white plaque, of hyperplastic lesions, and of anything that fails to resolve after 2 weeks of adequate treatment. Send for histology with periodic acid Schiff staining, which demonstrates hyphae invading the parakeratin layer, and assess for epithelial dysplasia.
• Blood glucose and HbA1c in every adult with unexplained oral candidiasis.
• HIV testing, which should be routine in an adult with unexplained, extensive or recurrent oral candidiasis. This is one of the highest yield HIV tests in clinical practice and is frequently omitted.
• Full blood count, ferritin, vitamin B12, folate and zinc.
• Thyroid function and, where the picture suggests it, assessment for hypoadrenalism and hypoparathyroidism.
• Salivary flow assessment and investigation for Sjögren syndrome where xerostomia is prominent, with anti Ro and anti La antibodies and consideration of labial gland biopsy.
• Upper gastrointestinal endoscopy where there is dysphagia or odynophagia, since oesophageal candidiasis requires systemic therapy and, in an adult without an obvious cause, indicates significant immunodeficiency.

Differential diagnosis and the discriminating feature

• Oral lichen planus: white lacy Wickham striae, bilateral, does not rub off, may have erosive areas. Note that candidal superinfection of lichen planus is common and both may need treating.
• Leukoplakia and erythroplakia: do not rub off, require biopsy.
• Squamous cell carcinoma: induration, ulceration, fixation.
• Geographic tongue, that is benign migratory glossitis, with migrating depapillated areas surrounded by a white border.
• Hairy leukoplakia: vertically corrugated white plaques on the lateral tongue, not removable, caused by Epstein Barr virus and strongly associated with HIV.
• Chemical burn from aspirin or other agents held against the mucosa.
• Traumatic keratosis from cheek biting or a sharp tooth.
• Coated tongue, which is debris and not infection.

Treating the fungus without addressing the predisposing factor guarantees recurrence, and identifying that factor is the more important half of the consultation.

Correct the predisposing factors

• Rinse the mouth with water and spit after every inhaled corticosteroid dose, and use a spacer device. Explain and demonstrate this, since patients are often told it and rarely do it.
• Denture hygiene: remove dentures overnight, clean daily with a brush, and soak overnight in chlorhexidine 0.2 percent, or in dilute sodium hypochlorite for acrylic dentures without metal components. Assess denture fit and refer for relining or replacement where the fit is poor.
• Optimise glycaemic control.
• Manage xerostomia with saliva substitutes, frequent sips of water, sugar free chewing gum, and pilocarpine 5 mg three times daily where appropriate, with attention to contraindications including asthma, bradycardia and narrow angle glaucoma.
• Smoking cessation.
• Correct iron, folate, vitamin B12 and zinc deficiency.
• Review and rationalise antibiotic and corticosteroid use.
• Improve oral hygiene, including tongue cleaning.

Topical antifungal therapy, which is first line for uncomplicated disease

• Nystatin oral suspension 100000 units per mL, 1 mL held in the mouth for several minutes and then swallowed, four times daily, continued for 7 days after clinical resolution, usually 14 days in total. It is not absorbed, so it is safe in pregnancy and in patients on multiple medications. Its sucrose content is a concern in diabetics and for dental caries with prolonged use.
• Miconazole oral gel 24 mg/mL, 2.5 mL applied four times daily after food and held in the mouth, for 7 days beyond resolution. It is more effective than nystatin. Critically, miconazole is absorbed sufficiently to inhibit CYP2C9 and CYP3A4 and produces clinically significant interactions with warfarin, causing dangerous rises in the international normalised ratio, and with statins, ciclosporin, phenytoin and sulfonylureas. Check the drug list before prescribing it and avoid it in anticoagulated patients.
• Amphotericin B lozenges where available.
• Chlorhexidine 0.2 percent mouthwash as an adjunct, though it should not be used within 30 minutes of nystatin, which it inactivates.
• For angular cheilitis: miconazole 2 percent cream with hydrocortisone 1 percent, or fusidic acid 2 percent ointment where Staphylococcus aureus is likely, applied to the angles twice daily for 10 to 14 days, together with correction of the vertical dimension of the dentures and of any nutritional deficiency. Treat the intraoral reservoir at the same time, since angular cheilitis recurs if intraoral candidiasis persists.
• For denture stomatitis: treat the denture as well as the mouth, since the denture acrylic harbours biofilm and is the reservoir. Apply antifungal to the fitting surface of the denture.

Systemic antifungal therapy

Indications: failure of topical therapy, extensive disease, oesophageal involvement, immunocompromise, and inability to use topical agents.

• Fluconazole 50 to 100 mg orally once daily for 7 to 14 days for oropharyngeal disease. A loading dose of 200 mg on day 1 may be used.
• Oesophageal candidiasis: fluconazole 200 to 400 mg orally daily for 14 to 21 days.
• In HIV with severe disease: fluconazole 200 mg daily, with antiretroviral therapy being the definitive treatment.
• Itraconazole oral solution 200 mg daily for 7 to 14 days in fluconazole refractory disease, taken on an empty stomach for the solution formulation, which has better bioavailability than capsules.
• Posaconazole and voriconazole for azole refractory disease, guided by sensitivities.
• Echinocandins such as caspofungin, or intravenous amphotericin B, for severe refractory disease and in the profoundly immunocompromised.
• Fluconazole cautions: hepatotoxicity requiring liver function monitoring with prolonged use, QT prolongation, and extensive CYP2C9 and CYP3A4 interactions with warfarin, phenytoin, statins, ciclosporin, tacrolimus and sulfonylureas. It is teratogenic at higher doses and should be avoided in the first trimester.

Prophylaxis

Considered in patients receiving head and neck radiotherapy, in prolonged neutropenia, and in recurrent disease in the immunocompromised. Fluconazole 50 to 100 mg daily, or topical agents, weighing benefit against the emergence of azole resistant non albicans species.

Special situations

• Neonatal thrush: nystatin suspension 1 mL four times daily. Treat the mother's nipples simultaneously with miconazole cream if breastfeeding, since reinfection between mother and infant is otherwise continuous. Sterilise dummies and bottle teats.
• Chronic hyperplastic candidiasis: treat with a prolonged systemic antifungal course of 2 to 4 weeks, address smoking, and biopsy. Re biopsy if the lesion persists after treatment, since the dysplasia risk is real and this lesion requires surveillance.
• Chronic mucocutaneous candidiasis: long term antifungal suppression and investigation for the underlying immune defect and associated endocrinopathy.

Follow up

Review at 2 weeks. Failure to resolve requires culture with speciation and sensitivities, biopsy, and reassessment of the host, particularly for undiagnosed HIV or diabetes. Any residual white patch after successful antifungal treatment must be biopsied.