© Springer-Verlag Berlin Heidelberg 2015
Edvaldo Antonio Ribeiro Rosa (ed.)Oral Candidosis10.1007/978-3-662-47194-4_5
5. Acute Oral Erythematous Candidosis
Institute of Science and Technology, Oral Biopathology Program and Department of Environmental Engineering, Universidade Estadual Paulista/UNESP, São José dos Campos, Brazil
Institute of Science and Technology, Oral Biopathology Graduate Program, Universidade Estadual Paulista/UNESP, São José dos Campos, Brazil
Cristiane Yumi Koga Ito
Acute erythematous candidiasis (EC) is cited as the most frequent clinical manifestation among AIDS patients, after pseudomembranous form. Among HIV-positive patients, it was reported as the most commonly observed oromucosal lesion. Higher prevalence of this condition was observed in patients with CD4/CD8 ratio <0.30 and CD4 levels ≤200 cells/mm. Based on these evidences, the presence of EC has been suggested as a marker to diagnose the immune status of HIV-infected individuals.
Acute oral erythematous candidosisECOral candidiasisProsthesis-associated acute erythematous candidiasisAnti-Candida activityAzole antifungals
Acute erythematous candidiasis (EC) is frequently cited as the most frequent clinical manifestation among AIDS patients, after pseudomembranous form (Tirwomwe et al. 2007). Among HIV-positive patients, it was reported as the most commonly observed oromucosal lesion (Gaurav et al. 2011; Bodhade et al. 2011; Sharma et al. 2006). Higher prevalence of this condition was observed in patients with CD4/CD8 ratio <0.30 (Gaurav et al. 2011) and CD4 levels ≤200 cells/mm (Gonçalves et al. 2013). Based on these evidences, the presence of EC has been suggested as a marker to diagnose the immune status of HIV-infected individuals.
Decrease in the prevalence of erythematous candidiasis has been reported after HAART- era in several places worldwide (Gonçalves et al. 2013; Lourenço et al. 2011; Gaurav et al. 2011). Percentages of erythematous candidiasis occurrence among HIV-positive patients undergoing HAART varies from 7 % to 16 % (Gaitan Cepeda et al. 2008). Some studies observed that HAART promoted an overall reduction in the occurrence of HIV-associated oral lesions and erythematous candidiasis was the clinical form that decreased most (Lourenço et al. 2011).
However, this reduction tendency was not observed in all populations. Previous study reported that the prevalence of EC among pediatric Nigerian patients was not reduced by HAART (Adebola et al. 2012). Also, in a Spanish cohort of HIV-positive patients, no reduction of EC was observed after the introduction of HAART (Ceballos-Salobreña et al. 2004).
EC is also frequently observed among end-stage renal disease patients (Thorman et al. 2009; Al-Mohaya et al. 2009) and type 2 diabetes mellitus, representing a challenge for the health maintenance of these patients. Acute erythematous candidiasis associated to hypopharyngeal lesions was reported in patients under treatment with topical intranasal steroids (Kyrmizakis et al. 1999).
Acute erythematous candidiasis clinically presents as localized erythema. It is usually associated to burning sensation and loss of filiform papillae at tongue dorsum (Neville et al. 2009). Although the palate or buccal mucosa may be involved, the most common site of infection is the dorsum of the tongue (Ellepola and Samaranayake 2000; Farah et al. 2010). This variant was also referred as “antibiotic sore mouth,” due to its association with chronic use of broad-spectrum antibiotics (Soysa et al. 2008) and corticosteroids (Ellepola and Samaranayake 2001). The use of broad-spectrum antibiotics facilitates the overgrowth of C. albicans by suppressing the normal oral bacterial microflora (Williams et al. 2011). The clinical presentation of erythematous tongue with papillary atrophy also occurs in association with other disorders, including iron deficiency anemia, vitamin B12 deficiency, and poorly controlled diabetes mellitus and accurate differential diagnosis is necessary (Giannini and Shetty 2011).
The diagnosis of candidiasis is based on clinical findings, and it is confirmed by the identification of blastospores and pseudohyphae in stained smears sampled from the lesion, by the identification of colonies cultured on Sabouraud culture medium or by histological examination (Samaranayake 2006; Worthington et al. 2007; Scully 2004).
The smear is valuable for differentiating between yeast and hyphae forms, but it is less sensitive than culture methods (Williams and Lewis 2000). Due to the lower number of Candida cells isolated from erythematous candidiasis lesions when compared to pseudomembranous form, negative results are occasionally obtained when direct examination is used (Terai and Shimahara 2009). In the diagnosis of erythematous candidiasis, examinations are reported to yield false-negative results in 25 % of culture tests and 42.5 % of microscopic examinations (Terai and Shimahara 2009). For this reason, more recently, the combination of fluorescent staining (Fungiflora Y) and observation using a portable fluorescent microscope was suggested for the diagnosis of oral erythematous candidiasis (Okamoto et al. 2013).
Diagnosis of erythematous candidiasis should be clinically differentiated from thermal traumatic lesions, erosive lichen planus and lichenoid reactions, lupus erythematosis, erythema multiforme, pernicious anemia and epithelial dysplasia (Farah et al. 2000).
Due to the opportunistic nature of the disease, the priority in the treatment of oral candidiasis is the resolution of any identifiable predisposing factor. Therefore, acquiring a complete medical history is an essential element for the selection of the treatment (Krishnan 2012).
For patients with prosthesis-associated acute erythematous candidiasis, besides correction of inadequate devices, the improvement of hygiene is an important step of the treatment. The prescription of a denture cleaner with antifungal properties, such as 0.2 % chlorhexidine digluconate, associated to the removal of the dentures at night is the standard protocol (Farah et al. 2010). The xerostomia caused by medication or underlying disease may be controlled by saliva substitutes (Gonsalves et al. 2008).
Some predisposing factors are difficult or impossible to eradicate, such as occurrence of leukemia or AIDS. In such cases, prophylactic reduction in oral levels of Candida plays an important role (Lalla et al. 2013). Also in these cases, the reduction may be achieved by hygiene practices, including toothbrushing and the use of antimicrobial mouthwash.
Several mouthwashes have anti-Candida activity, including those with triclosan, chlorhexidine digluconate, and formulations containing essential oils (Pusateri et al. 2009). The formulations with natural plant extracts usually contain thymol, eucalyptol, or bioflavonoids (Fine 1988). The anti-Candida activity of these compounds is related to the rupture of cell membrane or enzyme inhibition. Higher efficacy of commercial mouthwashes (Corsodyl, Listerine, and Oraldene) on biofilms in vitro when compared to azole antifungal agents was previously reported (Ramage et al. 2011) and corroborates its prescription in cases of oral candidal infections.
The most commonly used classes of conventional antifungal drugs are the polyenes and azoles. Polyenes class includes amphotericin B and nystatin. They act by direct binding with the ergosterol in fungal cell membrane. The binding polyene-ergosterol induces leakage of cytoplasmic contents leading to fungal cell death (Sanglard and Bille 2002). However, polyenes at therapeutic concentrations exhibit a higher degree of toxicity in humans. Moreover, their use is limited due to the poor intestinal absorption. Topical application in the form of lozenges and oral suspensions are most commonly used for the treatment of oral fungal infection.
Azole antifungals show fungistatic activity rather than fungicidal (Andes 2003). The mechanism of action is most frequently lanosterol demethylase enzyme inhibition, which is a cytochrome P-4503A-dependent enzyme involved in the synthesis of ergosterol (Sanglard and Bille 2002). After depletion of ergosterol from yeast cells, inhibition of fungal growth and impaired membrane permeability are observed (Nimmi et al. 2010).
Itraconazole and fluconazole are most frequently administered for the treatment of oral candidiasis and have the advantage of good intestinal absorption. Furthermore, fluconazole is secreted in saliva at high levels, making this agent particularly suitable for the treatment of oral infection (Force and Nahata 1995). The use of miconazole oral gel was effective in the treatment of acute candidiasis caused by the use of topical intranasal steroids (Kyrmizakis et al. 1999).
Unfortunately, in recent years, the prevalence of resistance to conventional antifungal drugs increased considerably (Redding et al. 2000). This resistance may be resultant of several mechanisms (White et al. 2002), including increased production of lanosterol demethylase. Changes in the demethylase enzyme structure make the cell less susceptible to the action of the azole.
Additionally, the successful treatment of candidiasis may be impaired where there is an established biofilm. Biofilms exhibit significantly greater tolerance to traditional antifungals (Ramage et al. 2002). As this form is frequently found in oral milieu, this is an additional challenge in the treatment of oral infections.
Alternative strategies have been suggested to the treatment of oral fungal infections, including modification of biomaterials to inhibit Candida adhesion (Chandra et al. 2005; Price et al. 2005; Redding et al. 2009). Quaternary ammonium silane-functionalized methacrylate (QAMS) is synthesized macromonomer with activity against Candida albicans biofilms (Gong et al. 2012