INTRODUCTION — Candida infections can involve mucous membranes (eg, oropharyngitis, esophagitis, and vulvovaginitis) or be focally or systemically invasive. The clinical manifestations, diagnosis, and treatment of esophageal candidiasis in adults will be reviewed here. Topic reviews that provide an overview of Candida infections, as well as those that discuss oropharyngeal candidiasis in adults and children, are presented elsewhere. (See "Overview of Candida infections" and "Oropharyngeal candidiasis in adults" and "Candida infections in children" and "Clinical manifestations and diagnosis of Candida infection in neonates".)
EPIDEMIOLOGY — The causative organism of esophageal candidiasis is almost always C. albicans, although other species (Candida glabrata or Candida krusei) are occasionally identified [1,2]. (See "Biology of Candida infections".)
Candidal esophagitis is typically seen in patients with human immunodeficiency virus (HIV) who have advanced immunosuppression (CD4 count <100 cells/microL) [2,3]. It is also seen in patients without HIV, such as those who have hematologic malignancies, are hematopoietic cell transplant recipients, have solid organ cancer and are receiving cytotoxic chemotherapy, and, less commonly, those taking inhaled corticosteroids [1,4]. Invasive Candida infections can also be seen in patients with idiopathic CD4+ lymphocytopenia. (See "Evaluation of the patient with HIV, odynophagia, and dysphagia" and "Idiopathic CD4+ lymphocytopenia".)
CLINICAL MANIFESTATIONS — The hallmark of esophageal candidiasis is pain on swallowing. Patients usually localize their pain to a discrete retrosternal area.
Patient with esophagitis often have evidence of oropharyngeal candidiasis (thrush) on exam; however, the absence of thrush does not preclude the diagnosis of esophagitis. Conversely, some patients with thrush may have asymptomatic esophagitis, as was demonstrated in a study of 22 patients with cancer, in which 10 patients had thrush and no symptoms of esophagitis, despite having evidence of esophagitis on endoscopy and positive cultures [1]. However, the clinical significance of these findings is unclear.
A more detailed discussion of the clinical manifestations of oropharyngeal disease is presented elsewhere. (See "Oropharyngeal candidiasis in adults", section on 'Clinical manifestations'.)
DIAGNOSIS — The diagnosis of esophageal candidiasis should be considered in immunocompromised patients who present with odynophagia. (See "Approach to the evaluation of dysphagia in adults".)
The diagnosis is usually made at endoscopy when white mucosal plaque-like lesions are noted (picture 1). Confirmatory biopsy shows the presence of yeasts and hyphae invading mucosal cells, and culture reveals Candida.
An alternative diagnostic approach in immunocompromised patients, particularly those with thrush, is to treat with oral fluconazole on the basis of the patient's history and physical exam findings. Odynophagia due to candidiasis should improve within several days. If symptoms do not improve after approximately 72 hours, endoscopy and biopsy should be performed since it is likely that a disease other than or in addition to Candida esophagitis is present [2,5]. The threshold for doing endoscopy is lower in patients without evidence of oral thrush since other etiologies may be causing the patient's symptoms.
The differential diagnosis of esophageal candidiasis includes other infectious etiologies (eg, cytomegalovirus, herpes simplex virus), medication-induced esophagitis, and inflammatory conditions such as eosinophilic esophagitis [6]. The frequency of coinfection was illustrated in a study of 110 patients with HIV presenting with esophageal symptoms; among the 52 patients with Candida esophagitis, concomitant infection with cytomegalovirus was noted in 22 and with herpes simplex virus in 2 [2]. A more detailed discussion of the evaluation of odynophagia and dysphagia in patients with HIV is presented elsewhere. (See "Evaluation of the patient with HIV, odynophagia, and dysphagia".)
TREATMENT
Indications — Symptomatic patients with candidal esophagitis require antifungal therapy. (See 'Regimens for nonpregnant adults' below and 'Treatment during pregnancy' below.)
Sometimes, a patient may not have signs and symptoms of esophagitis but has Candida identified on esophageal brushings that were obtained during the evaluation of a different process. In this setting, the diagnosis (and the decision to treat) needs to be made on a case-by-case basis to determine if the findings are consistent with colonization or active disease. When making this decision, clinicians should take into account the patient's risk factors for esophagitis as well as the other findings noted on endoscopy.
Regimens for nonpregnant adults
Initial therapy — Patients with candidal esophagitis should be treated with systemic antifungal therapy (table 1) [7]; it should never be managed with topical agents [5]. The general duration of treatment is 14 to 21 days [8]. Intravenous therapy may be required initially in patients with severe disease who cannot take oral therapy.
For most patients, we suggest fluconazole due to its excellent efficacy, ease of administration, and low risk of toxicity [8-11]. We administer 400 mg orally or intravenously on day 1, then 200 to 400 mg daily. In a number of studies, the effectiveness of fluconazole therapy for treatment of candidal esophagitis has ranged from 80 to 90 percent [5,12-17]. Voriconazole, itraconazole oral solution, posaconazole oral suspension, isavuconazole, echinocandins, and amphotericin B have been found to have comparable efficacy to fluconazole for initial treatment of esophageal candidiasis [12-21], but these agents are not usually used because they are associated with more side effects (amphotericin B and azoles), more drug-drug interactions (azoles), and an increased risk of relapse when standard doses are used (echinocandins) [15-17,20].
On rare occasion, a patient may have infection with a non-albicans species. When a patient has infection due to a fluconazole-resistant C. glabrata, an echinocandin is preferred because of cross-resistance among the azoles. By contrast, voriconazole may be effective if C. krusei is the cause of esophagitis [22]. In patients with infection due to a non-albicans species, susceptibility testing of the isolate is important to help select the correct antifungal agent. (See "Management of candidemia and invasive candidiasis in adults".)
Patients whose esophagitis is refractory to fluconazole — Some patients with documented candidal esophagitis do not respond to initial treatment with fluconazole. This may be due to infection with a non-albicans species or emergence of drug resistance to fluconazole [23-26]. In patients with HIV, risk factors for developing resistance include advanced immunosuppression and chronic exposure to azoles [26].
For patients who were empirically treated with fluconazole but had no response, endoscopy should be performed to obtain cultures and evaluate for an alternative etiology. (See 'Diagnosis' above.)
For patients with documented esophageal candidiasis due to C. albicans that is refractory to fluconazole after one week of treatment, we increase the dose of fluconazole (maximum of 800 mg fluconazole daily). If symptoms still persist after several days, repeat endoscopy should be performed to obtain cultures and sensitivity and to make sure that another disease is not causing the symptoms. If another condition is not found, a different antifungal agent should be administered, pending the results of the cultures; the choice of agent depends in part upon whether the patient is able to tolerate oral medications and the previously obtained antifungal susceptibility profile, if available (table 1).
●Patients who can take oral therapy – For patients who can take oral therapy, we suggest oral voriconazole, posaconazole, itraconazole oral solution, or isavuconazole (table 1). There is no preferred therapy in this setting, and the choice of agent depends upon factors such as side effect profile and risk of drug interactions. Treatment should be modified pending the results of the culture; many times, fluconazole resistance portends resistance to other azoles as well. Treatment should be continued for 28 days.
Several studies have evaluated the use these azoles for treatment of refractory esophageal candidiasis, and they appear to be effective in about 60 to 70 percent of patients [19,27,28]. As an example, in one study, posaconazole oral suspension (400 mg twice daily) led to a clinical response in 32 of 43 patients (74 percent) with endoscopically documented esophageal candidiasis, which had been refractory to primary therapy with itraconazole or fluconazole [28]. The role of the extended-release posaconazole tablet in the treatment of esophageal candidiasis has not been studied.
●Patients who require intravenous therapy – In patients with refractory disease who require intravenous therapy (eg, those with severe disease), we typically initiate an echinocandin (caspofungin, micafungin, and anidulafungin) rather than amphotericin B, which is more toxic. However, amphotericin B should be used for treatment of Candida infections that are resistant to echinocandins. Dosing recommendations are described in the table (table 1).
When clinically improved, many patients are able to transition to an oral azole (based upon the culture results) to complete a 28-day course.
The doses of echinocandins used for treatment of esophageal candidiasis are higher than those used for candidemia (table 1). Although echinocandins have been found to be effective for the treatment of Candida esophagitis in several studies [15-17,20,29-31], there are higher rates of relapse when standard doses of echinocandins are compared with azoles [15-17,20]. However, when higher doses of micafungin (150 mg daily) were used in a randomized trial comparing micafungin with fluconazole 200 mg daily, outcomes were similar (85 and 89 percent of patients remained recurrence free four weeks post treatment in the micafungin and fluconazole arms, respectively) [20].
Although most studies of echinocandins have looked at the treatment of initial disease, one study found that caspofungin appears to be effective in the treatment of esophageal candidiasis resistant to fluconazole [32]. In this retrospective analysis of 17 patients with esophagitis who had resistant isolates or a refractory clinical infection (no improvement after one week of fluconazole therapy), caspofungin led to a favorable clinical response in the majority of patients with in vitro resistant isolates (11 of 14) and in those with clinically refractory disease (7 of 11). Follow-up studies to assess recurrence rates were not done.
Treatment during pregnancy — Amphotericin B is the treatment of choice for pregnant women with esophageal candidiasis during the first trimester [33]. Lipid formulations (3 to 4 mg/kg intravenously [IV] daily) are generally preferred. Although liposomal amphotericin B is less studied than the deoxycholate formulation, the risk of toxicity is reduced.
Oral azoles are teratogenic and should not be used during the first trimester. After the first trimester, the decision must be individualized. Detailed information on the risks of using azoles during pregnancy is presented elsewhere. (See "Candida vulvovaginitis: Treatment", section on 'Pregnancy'.)
There are no human data regarding the use of echinocandins in pregnancy.
Adverse effects of therapy — Azole therapy can be associated with gastrointestinal upset, and prolonged administration can cause hepatotoxicity. Voriconazole is the only azole associated with visual disturbances, and it has a higher risk of rash, including photosensitivity, than other azoles. To assess for adverse events, we follow patients clinically and monitor aminotransferase for those who require prolonged treatment. (See "Pharmacology of azoles", section on 'Adverse effects'.)
For those taking voriconazole, we also monitor trough levels to reduce the risk of toxicity. Therapeutic drug monitoring for other azoles is typically not warranted when short courses of therapy are administered. (See "Pharmacology of azoles", section on 'Adverse effects' and "Pharmacology of azoles", section on 'Drug interactions' and "Pharmacology of azoles", section on 'Voriconazole'.)
Echinocandins are very well tolerated but require IV administration. Drug interactions are uncommon because, unlike the azoles, these drugs are not metabolized via the cytochrome p450 pathway [34]. (See "Pharmacology of echinocandins", section on 'Adverse effects'.)
Amphotericin is associated with nausea as well as a decline in glomerular filtration rate and electrolyte disturbances. (See "Pharmacology of amphotericin B", section on 'Adverse effects'.)
Suppressive therapy — In immunocompromised patients with recurrent disease, we do not routinely use suppressive therapy because treatment of individual episodes with fluconazole is effective and less likely to result in azole resistance [35].
However, for patients with multiple closely spaced episodes of esophageal candidiasis, providers may choose to initiate suppressive therapy to reduce the risk of recurrences [35]. We typically administer fluconazole (100 to 200 mg orally), which can be administered daily or three times per week [7,8]; for most patients, we prefer once-daily dosing to reduce the risk of developing resistance. Posaconazole oral suspension (400 mg orally twice daily) is also an option but is generally reserved for those who prefer a liquid formulation and those who have disease that is refractory to fluconazole.
Suppressive therapy should be stopped when the underlying defect in cell-mediated immunity can be corrected (eg, when CD4 count is >200 cells/microL or viral load is controlled in patients with HIV).
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Candidiasis" and "Society guideline links: Opportunistic infections in adults and adolescents with HIV".)
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●Basics topic (see "Patient education: Upper endoscopy (The Basics)")
●Beyond the Basics topic (see "Patient education: Upper endoscopy (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology − Candida species can be associated with infections involving mucosal membranes, including the esophagus. The majority of these infections are related to Candida albicans, although other species (Candida glabrata or Candida krusei) are occasionally identified. Candidal esophagitis is typically seen in immunocompromised patients, such as patients with HIV who have advanced immunosuppression, those who have hematologic malignancies or are hematopoietic cell transplant recipients, and those who have solid organ cancer and are receiving cytotoxic chemotherapy. (See 'Epidemiology' above.)
●Clinical manifestations − The hallmark of esophageal candidiasis is odynophagia or pain on swallowing. Patients with esophagitis often have evidence of oropharyngeal disease (thrush) on exam; however, the absence of thrush does not preclude the diagnosis. (See 'Clinical manifestations' above.)
●Diagnosis − The diagnosis of Candida esophagitis is usually made through endoscopy with a biopsy of white mucosal plaque-like lesions. Histology demonstrates the presence of yeast and hyphae invading mucosal cells with a culture confirming Candida. An alternative diagnostic approach, particularly in immunocompromised patients with oropharyngeal candidiasis, is to treat with systemic antifungal agents on the basis of the patient's history. Odynophagia due to candidiasis should improve within several days. Endoscopy can be pursued if empiric therapy does not lead to symptom resolution. (See 'Diagnosis' above.)
●Treatment − Patients with symptomatic candidal esophagitis should be treated with systemic antifungal therapy (table 1).
•Initial therapy − For most nonpregnant patients, we suggest initial therapy with fluconazole rather than other agents (Grade 2B). Although almost all systemic antifungal agents appear to be effective, we prefer fluconazole due to its ease of administration, lack of toxicity, reduced risk of drug interactions, and lower cost. However, on rare occasion, when a patient has infection due to C. glabrata or C. krusei, an alternative agent is required since fluconazole is typically not effective. (See 'Initial therapy' above.)
•Treatment during pregnancy − For pregnant patients, amphotericin B is the treatment of choice during the first trimester since oral azoles are teratogenic and should not be used. After the first trimester, the decision must be individualized. (See 'Treatment during pregnancy' above.)
•Disease resistant to fluconazole − For patients with documented esophageal candidiasis due to C. albicans that is refractory to fluconazole after one week of treatment, we increase the dose of fluconazole (maximum dose 800 mg). If symptoms still persist after several days, then endoscopy should be performed to obtain repeat cultures and to make sure that another disease is not causing the symptoms. If another condition is not found, an alternative antifungal agent should be administered, pending the results of cultures (table 1). Treatment for refractory disease is usually 28 days. (See 'Patients whose esophagitis is refractory to fluconazole' above.)
•Suppressive therapy − In immunocompromised patients with recurrent disease, we suggest not routinely using suppressive therapy (Grade 2C). Treatment of individual episodes with fluconazole is effective and less likely to result in azole resistance. (See 'Suppressive therapy' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Kieren Marr, MD, who contributed to an earlier version of this topic review.
