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Case 1: Discussion

Epidemiology

Oropharyngeal candidiasis occurs frequently among HIV-infected individuals, particularly those with more advanced immune suppression. The diagnosis of oral candidiasis is a CDC category B diagnosis (in the 1993 CDC classification system)[1]. In addition, the presence of oropharyngeal candidiasis is an indication for initiating prophylaxis for Pneumocystis pneumonia and for initiating antiretroviral therapy. The development of oral candidiasis generally reflects an imbalance in the normal ecological environment of the oral cavity. Although HIV-related immune suppression is typically the most important risk factor for candidiasis, other factors can contribute, including use of antibiotics that change normal bacterial flora, use of corticosteroids, use of chemotherapeutic drugs, presence of diabetes, decreased salivary flow rates, and wearing dentures. Considering the strong association of HIV infection and oropharyngeal candidiasis, HIV assessment and testing is recommended for any person who presents with oropharyngeal candidiasis and does not have a known risk factor for oropharyngeal candidiasis[2]. Among HIV-infected patients with oral candidiasis, Candida albicans is the most common species involved[3], but non-albicans species, such as such as C. dubliniensis, C. glabrata and C. tropicalis, also cause disease[4,14].

Clinical Manifestations

Among HIV-infected persons, four different manifestations of oral candidiasis can occur: pseudomembranous candidiasis (thrush), atrophic (erythematous) candidiasis, angular cheilitis (perleche), and rarely, hyperplastic candidiasis. Pseudomembranous candidiasis typically manifests as creamy white plaque or patches on oral tissues that can usually be scraped off with a tongue blade ( Figure 1 and Figure 2); if the mouth is very dry or if the condition is more chronic, the plaques can be more adherent. The appearance of the underlying mucosal surface may vary from a relatively normal appearance to bright red. Erythematous candidiasis manifests as flat red patches anywhere on the oral mucosa, most commonly on the hard palate (Figure 3), attached gingival or buccal mucosa, or the dorsal surface of the tongue (Figure 4). With involvement of the tongue, filiform papilla may disappear and these areas appear as "bald" patches (Figure 5). Patients with pseudomembranous or erythematous candidiasis often complain of a burning sensation in their mouth and of altered taste. Hyperplastic candidiasis is seen with chronic mucosal colonization by Candida with very superficial invasion of the epithelium. Inflammatory responses result in epithelial proliferation, inflammation, and edema that result in the appearance of a "bubbly" or pebbled surface (Figure 6). This type of response is often seen under dentures. Angular cheilitis typically manifests as erythema and splitting of the corners of the mouth (Figure 7 and Figure 8). Less often, patients develop superficial erosions and crusting. Angular cheilitis usually occurs in conjunction with other intra-oral manifestations of candidiasis. If not treated, angular cheilitis can persist as a chronic, non-healing lesion. Because patients with advanced HIV disease and oral candidiasis may have concomitant esophageal candidiasis, they should be asked about dysphagia and odynophagia.

Diagnosis

In most clinical situations, the presumptive diagnosis of oral candidiasis is made based on the typical clinical appearance[5]. In this situation, the presumptive diagnosis is strengthened if the patient responds to an empiric trial of antifungal therapy. Patients with pseudomembranous candidiasis can be destinguished from those with oral hairy leukoplakia by scraping the lesions with a tongue blade: the candidiasis plaques are usually removed whereas lesions caused by the oral hairy leukoplakia are not affected by scraping. When the clinical diagnosis of oral candidiasis is not clear, the diagnosis can be confirmed by obtaining a direct smear and performing either a potassium hydroxide (KOH) wet mount or a Gram's stain. The KOH wet mount typically shows presence of yeasts or pseudohyphae, and the Gram's stain typically shows gram-positive staining organisms that are much larger than bacteria. Obtaining oral fungal cultures is generally reserved for situations when patients do not respond to therapy and anti-fungal resistance is suspected.

Treatment

Routine primary prophylaxis is not recommended[5], mainly because oropharyngeal candidiasis has a very low attributable mortality and regular use of antifungal agents can lead to the development of drug-resistant Candida species[6]. For patients who have angular cheilitis with no evidence of intra-oral candidiasis, topical antifungal creams are generally sufficient for therapy (Figure 9). In the 2009 United States Guidelines for the Prevention and Treatment of Opportunistic Infections, fluconazole (Diflucan) is recommended as the drug of choice for patients with oropharyngeal candidiasis based on its good efficacy, convenience, and tolerance (Figure 10)[5]. Topical therapy with either clotrimazole (Mycelex) troches, nystatin (Mycostatin) suspension or pastilles, and miconazole (Oravig) mucoadhesive tablet are all considered acceptable as preferred initial therapy[5]. For patients taking topical therapy with clotrimazole and who have dry mouth, taking small sips of water over 10 minutes can be helpful. Alternative therapy consists of itraconazole (Sporanox) oral solution and posaconazole (Noxafil) oral solution. Although itraconazole solution is probably as effective as fluconazole, it is not as well tolerated. Posaconazole appears to be very effective, but it is very expensive. Systemic therapies with itraconazole tablets or ketoconazole (Nizoral) is not recommended[5]. Regardless of which regimen is used, therapy should generally continue for 10 to 14 days. Episodic treatment of clinical episodes is strongly preferred over chronic suppressive therapy, mainly because of lower cost with episodic therapy and the concern for development of antifungal drug resistance with chronic therapy[2]. Initiating antiretroviral therapy would likely play a critical role in minimizing the need to treat recurrent episodes of oropharyngeal candidiasis. A detailed discussion of drug-resistant candidiasis will be reviewed in Case 4 in this same section (Oral Manifestations).

Key Treatment Studies

Multiple studies have compared different regimens for the treatment of oropharyngeal candidiasis. In one small study of patients with oropharyngeal candidiasis, fluconazole (50 mg once daily) appeared superior to ketoconazole (200 mg once daily)[7]. In a study that involved 334 patients with oral candidiasis, fluconazole (100 mg once daily) and topical clotrimazole troches (10 mg 5 times per day) had similar initial clinical response rates, but clotrimazole was associated with a higher rate of return of symptoms during the second week of follow-up[8]. Itraconazole tablets have shown comparable results with ketoconazole, but inferior results compared with fluconazole[9]. Itraconazole solution, however, achieves higher serum levels and is more effective than itraconazole tablets[10]. In a study that involved 244 patients, similar rates of clinical responses and early relapse rates were observed with fluconazole (100 mg once daily x 14 days), itraconazole solution (100 mg bid x 7 days), and itraconazole solution (100 mg once daily x 14 days)[11]. In a similar study involving 179 patients, equivalent response rates occurred with fluconazole (100 mg once daily x 14 days), itraconazole solution (200 mg once daily x 7 days), and itraconazole solution (200 mg once daily x 7 days)[12]. A more recent study found posaconazole oral solution equivalent to fluconazole[13]. For patients unlikely to adhere to a 7 to 14 day treatment, a study showed a single high dose of fluconazole (750 mg) was as effective as a standard 14-day course of fluconazole[15].

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    Figure 1. Pseudomembranous Candidiasis (Thrush) in Pharynx

    Extensive creamy white patches characteristic for pseudomembranous candidiasis (thrush).


    Figure 1
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    Figure 2. Pseudomembranous Candidiasis (Thrush) on Lips and Gums

    Extensive white plaques along the upper gums and lips in a patient with pseudomembranous candidiasis (thrush).


    Figure 2
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    Figure 3. Erythematous (Atrophic) Candidiasis in Upper Mouth

    Intra-oral view showing erythema of the hard palate.


    Figure 3
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    Figure 4. Diffuse Erythematous (Atrophic) Candidiasis of Tongue

    This patient has diffuse loss (atrophy) of normal tongue papillae. On left lateral aspect of the tongue, faint oral hairy leukoplakia is also visible.


    Figure 4
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    Figure 5. Localized Erythematous (Atrophic) Candidiasis of Tongue

    View of tongue showing patchy loss (atrophy) of tongue papillae that is often described as bald patches. More prominent lesions are visible on the right side of tongue.


    Figure 5
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    Figure 6. Hyperplastic Candidiasis

    View of palate in a patient with hyperplastic candidiasis. The inflammation and edema manifest as a "bubbly" or pebbled appearance on the surface of the mouth. The patient does not have upper teeth.


    Figure 6
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    Figure 7. Angular Cheilitis

    Mild angular cheilitis manifested as splitting at the corner of the mouth.


    Figure 7
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    Figure 8. Prominent Angular Cheilitis

    This patient has marked fissuring at the corner of the right side of the mouth.


    Figure 8
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    Figure 9. Treatment of Angular Cheilitis Caused by Candida

    Abbreviations: bid = twice daily; d = day


    Figure 9
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    Figure 10. Treatment of Initial Episode of Oropharyngeal Candidiasis

    Abbreviations: bid = twice daily; qid = four times per day

    This table is based on recommendations from: Kaplan JE, Benson C, Holmes KK, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1-207.


    Figure 10