Oropharyngeal and Oesophageal Candidiasis

Oropharyngeal candidiasis (oral thrush) and oesophageal candidiasis are mucosal infections in which Candida, usually Candida albicans, overgrows commensal sites and invades the superficial epithelium. They are the commonest opportunistic infections of advanced HIV and are frequent in people using inhaled corticosteroids, wearing dentures, or receiving chemotherapy.

Oesophageal candidiasis is an AIDS defining condition. It is the commonest cause of oesophagitis in people with HIV and in other T cell deficiency states. Candidaemia from a mucosal source is uncommon without neutropenia.

Mucosal control depends on Th17 immunity (interleukin 17 and interleukin 22), salivary histatins, secretory immunoglobulin A and competing bacteria. Loss of any of these produces mucosal disease without bloodstream infection.

Candida albicans causes most disease. Candida dubliniensis occurs in HIV and in azole exposed patients. Candida glabrata and Candida krusei are selected by repeated fluconazole use, and their presence in oral disease in HIV or cancer patients predicts azole failure.

Fluconazole resistance in Candida albicans arises from repeated exposure. Mechanisms are overexpression of efflux pumps (CDR1, CDR2, MDR1), ERG11 point mutations and overexpression, and gain of function mutations of TAC1, MRR1 and UPC2. Cross resistance runs through the azole class, but posaconazole and voriconazole sometimes retain activity.

Symptoms are soreness, burning, altered taste and difficulty eating. Many patients are asymptomatic. Pharyngeal extension causes odynophagia and should prompt consideration of oesophageal disease.

• Odynophagia, dysphagia and retrosternal pain are typical. Nausea, weight loss and poor oral intake follow.
• Oral thrush is absent in about a quarter to a third of patients, so its absence does not exclude oesophageal disease.
• Endoscopy shows adherent white to yellow plaques that bleed when dislodged. Disease is graded from discrete small plaques to confluent plaques, hyperaemia, ulceration and narrowing.
• Complications are stricture, bleeding, perforation (rare), food impaction and, uncommonly, dissemination.
• Fever is unusual, and suggests another or additional pathogen.

• Oral disease: the diagnosis is clinical. Scrapings in potassium hydroxide or Gram stain show budding yeasts and pseudohyphae. Culture is reserved for failure to respond, recurrent disease, and species identification and susceptibility testing.
• Oesophageal disease: a therapeutic trial of fluconazole is reasonable in a patient with HIV, odynophagia and thrush. Failure to improve within 3 to 5 days prompts endoscopy. Endoscopy with brushings and biopsy is the diagnostic test, and it is performed first when the presentation is atypical or the patient has no thrush.
• Histopathology: yeasts and pseudohyphae invading the squamous epithelium, with periodic acid Schiff or Grocott methenamine silver staining. A positive culture alone does not prove infection, because Candida colonises the oesophagus. Concurrent viral oesophagitis is sought on the same biopsies.
• Susceptibility testing: for refractory disease.
• Immune assessment: HIV test and CD4 count in every patient with unexplained or recurrent disease. Glycaemic assessment, medication review and a search for inherited or autoimmune causes are added when HIV is excluded.

Oropharyngeal candidiasis

Fluconazole is the standard for moderate to severe disease and for HIV. Topical therapy is preferred for mild disease, because it avoids drug interactions and selection of resistance. Dentures are removed at night and cleaned with an antifungal solution or chlorhexidine, and the cause (steroid inhaler, antibiotic) is addressed.

Refractory disease (no response to fluconazole after 7 to 14 days, usually resistant Candida albicans or non albicans species):

Itraconazole oral solution and capsules are not interchangeable. The solution is absorbed better on an empty stomach, and the capsule needs food and gastric acid.

Non pharmacological controls: antiretroviral therapy to restore CD4 counts is the key intervention in HIV. Relapse after immune recovery is uncommon.

Recurrent oropharyngeal candidiasis: suppressive fluconazole 100 mg daily, or 150 mg once weekly, is used only for frequent or severe relapses, because it selects resistance. Routine suppression is not used in HIV, where antiretroviral therapy is preferred.

Infants: nystatin suspension 100 000 units per mL, 1 mL four times daily applied inside the mouth after feeds, for 7 to 14 days, with sterilisation of teats and dummies and treatment of maternal nipple candidiasis. Fluconazole is used for children with HIV or inadequate response: 6 mg per kg on day 1, then 3 mg per kg daily (maximum 200 mg) for 7 to 14 days.

Oesophageal candidiasis

Echinocandins are effective but relapse is more frequent than after fluconazole, particularly in HIV. Treatment is continued until symptoms settle and for at least 14 days. Refractory disease is investigated by endoscopy, culture and susceptibility testing, and for coexisting cytomegalovirus or herpes simplex oesophagitis.

Maintenance: fluconazole 100 to 200 mg daily or 3 times weekly is used for frequent recurrences, while the underlying cause is corrected.

Drug safety and interactions

• Fluconazole: hepatotoxicity, QT prolongation, and inhibition of CYP2C9, CYP2C19 and CYP3A4, which raises levels of warfarin, phenytoin, sulphonylureas, some statins and calcineurin inhibitors. The dose is halved when creatinine clearance is below 50 mL per minute. It is avoided in pregnancy.
• Itraconazole: negative inotropy (avoid in heart failure), hepatotoxicity, strong CYP3A4 inhibition.
• Voriconazole and posaconazole: extensive interactions; level monitoring.
• Echinocandins: few interactions; transaminase rises, infusion reactions.
• Amphotericin B: nephrotoxicity and electrolyte loss.