Candidiasis, Oral and Esophageal

Background

Oropharyngeal candidiasis ("thrush"), a fungal disease of the oral mucosa and tongue, is the most common intraoral lesion among persons infected with HIV. In the absence of other known causes of immunosuppression, oral thrush in an adult is highly suggestive of HIV infection. Although thrush in the absence of esophageal disease is not an AIDS-defining condition, it usually occurs with CD4 counts of <200 cells/µL. Three clinical presentations of thrush are common in people with HIV: pseudomembranous, erythematous, and angular cheilitis. Candida also may infect the esophagus in the form of esophageal candidiasis, which causes dysphagia (difficulty with swallowing) or odynophagia (pain with swallowing). Esophageal candidiasis is an AIDS-defining condition, generally occurring in individuals with CD4 counts of <200 cells/µL. It is the most common cause of esophageal infection in persons with AIDS.

Oropharyngeal and esophageal candidiasis are caused most commonly by Candida albicans, although non-albicans species increasingly may cause disease and may be resistant to first-line therapies.

S: Subjective

Oropharyngeal Candidiasis

The patient may complain of painless white patches on the tongue and oral mucosa, smooth red areas on the dorsal tongue, burning or painful areas in the mouth, a bad or unusual taste, sensitivity to spicy foods, or decreased appetite.

Esophageal Candidiasis

The patient complains of difficulty or pain with swallowing, or the sensation that food is "sticking" in the retrosternal chest. Weight loss is common, and nausea and vomiting may occur. Fever is not common with candidal esophagitis and suggests another cause. The patient may note symptoms of oral candidiasis (as above).

O: Objective

Perform a thorough oropharyngeal examination. Patients presenting with oral candidiasis may be totally asymptomatic, so it is important to inspect the oral cavity thoroughly. Patients with esophageal candidiasis usually have oral thrush and often experience weight loss.

Lesions can occur anywhere on the hard and soft palates, under the tongue, on the buccal mucosa or gums, or in the posterior pharynx.

Pseudomembranous oral candidiasis appears as creamy white, curdlike plaques on the buccal mucosa, tongue, and other mucosal surfaces. Typically, the plaques can be wiped away, leaving a red or bleeding underlying surface. Lesions may be as small as 1-2 mm, or they may form extensive plaques that cover the entire hard palate.

Erythematous oral candidiasis presents as one or more flat, red, subtle lesions on the dorsal surface of the tongue or the hard or soft palate. The dorsum of the tongue may show loss of filiform papillae.

Angular cheilitis causes fissuring and redness at one or both corners of the mouth and may appear alone or in conjunction with another form of oral Candida infection.

A: Assessment

A partial differential diagnosis for the two conditions is as follows:

Oropharyngeal Candidiasis

  • Oral hairy leukoplakia
  • Abrasion of the mucosa or a topical burn
  • Bacterial gingivitis
  • Periodontitis

Esophageal Candidiasis

  • GERD
  • Cytomegalovirus (CMV)
  • Herpes simplex virus (HSV)
  • Aphthous ulceration

P: Plan

Diagnostic Evaluation

Oropharyngeal candidiasis

Clinical examination alone usually is diagnostic. If the diagnosis is unclear, organisms may be detected on smear or culture if necessary.

  • On a potassium hydroxide (KOH) preparation of a smear collected by gentle scraping of the affected area with a wooden tongue depressor, visible hyphae or blastospheres on KOH mount indicate Candida infection.
  • Culture is diagnostic and may detect non-albicans species in cases resistant to first-line therapies. Sensitivities also may be needed in such cases to diagnose azole-resistant infections.

Esophageal candidiasis

A presumptive diagnosis usually can be made with a recent onset of typical symptoms, especially in the presence of thrush, and empiric antifungal therapy may be started as a diagnostic trial. If the patient fails to improve clinically after 3-7 days of therapy, endoscopy should be performed for a definitive diagnosis.

Treatment

Treatment of oropharyngeal candidiasis

  • Oral therapy is convenient and very effective as first-line treatment. Note that azole antifungal drugs are not recommended for use during pregnancy. Topical therapy is less expensive, safe for use during pregnancy, and effective for mild to moderate disease. All therapies should be given for 7-14 days.
  • Preferred oral therapy: Fluconazole 100 mg PO QD
  • Preferred topical therapy:
    • Clotrimazole troches 10 mg dissolved in the mouth 5 times daily
    • Miconazole mucoadhesive tablet 50 mg PO QD
  • Alternative oral therapy:
    • Itraconazole oral solution 200 mg PO QD
    • Posaconazole oral solution 400 mg PO BID for 1 day, then 400 mg PO QD
      (Note: These agents may present a greater risk of drug interactions (see "Potential ARV Interactions," below) and hepatotoxicity than do fluconazole or topical treatments)
  • Alternative topical therapy: Nystatin oral suspension 4-6 mL "swish and swallow" QID or 1-2 pastilles 4-5 times daily

Treatment of esophageal candidiasis

  • Duration of therapy: 14-21 days
  • Preferred therapy:
    • Fluconazole 100 mg PO (up to 400 mg) QD; IV therapy can be given if the patient is unable to swallow pills.
    • Itraconazole oral solution 200 mg PO QD
  • Alternative therapy:
    • Voriconazole 200 mg PO or IV BID
    • Posaconazole 400 mg PO BID
    • IV therapy with an echinocandin (caspofungin, micafungin, anidulafungin), or amphotericin, if the patient is unable to tolerate PO therapy (Note: Treatment with echinocandins is associated with a higher rate of relapse; see "Potential ARV Interactions," below, regarding potential drug-drug interactions between voriconazole or posaconazole and ARVs)

Treatment of refractory candidiasis

Oral or esophageal candidiasis that does not improve after at least 7-14 days of appropriate antifungal therapy can be considered refractory to treatment. The primary risk factors for development of refractory candidiasis are CD4 counts of <50 cells/µL and prolonged, chronic antifungal therapy (especially with azoles). In such cases, it is important to confirm the diagnosis of candidiasis. As noted, other infections such as HSV, CMV, and aphthous ulcerations can cause similar symptoms. Once refractory candidiasis is confirmed, several treatment options are available, including the following:

  • Posaconazole 400 mg PO BID
  • Itraconazole oral solution ≥200 mg PO QD
  • Voriconazole 200 mg PO or IV BID (see "Potential ARV Interactions," below)
  • Therapy with an echinocandin (caspofungin 50 mg QD; micafungin 150 mg QD; anidulafungin 100 mg for 1 dose, then 50 mg QD), or amphotericin B deoxycholate or lipid preparation
    (Note: Treatment with echinocandins is associated with a higher rate of relapse. See "Potential ARV Interactions," below, for information on potential drug interactions.)

The choice of treatment depends upon anticipated drug-drug interactions, the patient's preferences and tolerability, availability of medications, and the provider's experience. Consult with an HIV or infectious disease expert for advice about treatment regimens.

Maintenance therapy

Use caution when considering chronic maintenance therapy, because it has been associated with refractory and azole-resistant candidiasis, as noted above. Fluconazole 100 mg PO QD or TIW can be effective for patients who have had multiple or severe recurrences of oral disease (azole sensitive). Fluconazole 100-200 mg PO QD or posaconazole 400 mg PO BID (see "Potential ARV Interactions," below) can be considered for patients who have had frequent or severe recurrent esophageal candidiasis.

There are no data to guide this decision; it is reasonable to discontinue maintenance therapy in patients who achieve immunologic responses on fully suppressive ART (i.e., with an increase in CD4 count to ≥200 cells/µL). Patients with fluconazole-refractory oropharyngeal or esophageal disease who respond to IV echinocandins are recommended to take posaconazole or voriconazole suppression until they achieve immune reconstitution on ART, because of high relapse rates.

Potential ARV Interactions

There may be significant drug-drug interactions between certain systemic antifungals (particularly itraconazole, voriconazole, and posaconazole) and ritonavir-boosted protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), elvitegravir/cobicistat, or maraviroc. Some combinations are contraindicated and others require dosage adjustment of the ARV, the antifungal, or both. Check for adverse drug interactions before prescribing. For example, voriconazole use is not recommended for patients taking ritonavir-boosted PIs, and dosage adjustment of both voriconazole and NNRTIs may be required when voriconazole is used concurrently with NNRTIs. See relevant tables in the U.S. Department of Health and Human Services Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, or consult with an expert.

Patient Education

  • Patients should maintain good oral hygiene by brushing teeth after each meal.
  • A soft toothbrush should be used to avoid mouth trauma.
  • Advise patients to rinse the mouth of all food before using lozenges or liquid medications.
  • Tell patients to avoid foods or liquids that are very hot in temperature or very spicy.
  • Patients who have candidiasis under a denture or partial denture should remove the prosthesis before using topical agents such as clotrimazole or nystatin. When not in use, the prosthesis should be stored in a chlorhexidine solution.
  • Pregnant women and women who may become pregnant should avoid azole drugs (e.g., fluconazole, itraconazole, voriconazole) during pregnancy because they can cause skeletal and craniofacial abnormalities in infants.
  • Patients should be informed of proper storage of oral solutions (e.g., refrigeration requirements).

References

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Abbreviations for Dosing Terminology

BID
twice daily
BIW
twice weekly
IM
intramuscular (injection), intramuscularly
IV
intravenous (injection), intravenously
PO
oral, orally
Q2H, Q4H, etc.
every 2 hours, every 4 hours, etc.
QAM
every morning
QD
once daily
QH
every hour
QHS
every night at bedtime
QID
four times daily
QOD
every other day
QPM
every evening
TID
three times daily
TIW
three times weekly