Candida-Associated Denture Stomatitis: Clinical Relevant Aspects

Candida-associated denture stomatitis is a common fungal infection that affects removable denture wearers. Although Candida spp are considered commensal fungal in the oral cavity, changes in local and/or systemic predisposing factors related to the host conditions may lead to pathogenic form and cause disease. The clinical manifestations are usually associated with the predisposing factors, changing from no symptoms to severe pain and difficulty swallowing. The therapeutic strategies commonly adopted in the clinical practice are the use of topical and/or systemic antifungal, in addition to removing mechanically the plaque from denture surfaces and from underlying mucosa and giving instructions about the correct oral hygiene to the patient. In this context, considering the high prevalence of this disease, a review about the etiology, risk factors, clinical manifestations and therapy management of these patients is of utmost importance.


Introduction
Candida-associated denture stomatitis is a predominantly fungal infection that affects the human oral cavity [1]. Although Candida spp may be involved during infection, Candida albicans are considered the main pathogens, and have been found in a commensalism form in the oral cavities of adults and children, without any clinical disease [2]. These microorganisms are encountered in the dentition, tongue, cheeks, palatal mucosa, restorative materials and oral prostheses [3].
However, local and/or systemic predisposition factors may lead commensal microorganisms to pathogenic form, providing an oral environment adequate to the adhesion of microorganisms to the denture surface and mucosal epithelial cells [4]. This is followed by cell multiplication, organization and secretion of extracellular matrix, resulting in the formation of biofilm, a three-dimensional structure extremely organized [5].
Also, C. albicans may be found in two major forms, yeast and hyphae form. The yeast form is usually associated with mucosal commensalism, although the conversion yeast-to-hyphae is commonly related to the invasion of superficial layers of the oral epithelium, leading to clinical infection [6].

Epidemiology
Although C. albicans have been the main pathogens of Candidaassociated denture stomatitis (CADS), Candida glabrata, Candida tropicalis and Candida parapsilosis have been found less frequently [7,8]. Some factors favor the development of C. albicans biofilms, such as its capability to stick and proliferate through the denture surfaces and oral mucosal epithelial and produce a complex and heterogeneous bacterial biofilm [9]. CADS has been found in 60-65% of the denture wearers with more diffused clinical manifestations, but considering the patients that do not manifest clinical signs of inflammation and infection, this percentage increases to 75% [9,10]. It was reported that CADS is the most common oral mucosal lesion associated with removable dentures [11], and affects one in every three complete denture wearers [12].

Risk factors
The changes from commensal to pathogenic form of Candida spp are typically caused by local and/or systemic predisposing factors related to the host conditions, favoring the development of the disease. While the local factors provide an adequate oral environment to biofilm development, the systemic factors influence the defense host mechanisms [2,9].

Local factors
The local factors are important to favor the biofilm accumulation in the oral environment. In this context, different factors such as irradiation, trauma, xerostomy, complete denture wearers, poor dental hygiene, smoking, carbohydrate-rich diet and environmental pH will be discussed.
The irradiation is considered a risk factor, considering that leads to hyposalivation [13]. Also, xerostomy is another condition that reflects the decrease or the complete absence of saliva [14], reducing the ability of cleaning and buffering of saliva. Furthermore, previous study showed that patients with xerostomy induce changes that reflect in the normal microbial communities, favoring the proliferation of bacteria as Staphylococcus aureus, that inhibits the normal adaptation of the commensal fungal [10].
Cigarette smoke may favor CADS, considering the changes that cause in the oral cavity, influencing on saliva, oral commensal bacteria and fungi, especially Candida, the main fungal related to CADS [15].
Another important factor is trauma. Although trauma alone does not induce to generalize CADS, it should be considered that trauma acts as a co-factor, favoring the adhesion and penetration of the yeasts in the oral epithelium mucosa of the host [16]. Denture trauma due to poorly adapted denture is an important co-factor of CADS.
Complete denture wearers are also a risk factor, considering that Candida spp are frequently found on oral mucosa and on denture surfaces [3,17]. In addition, it was observed that the presence of C. albicans in the oral cavity in patients with dentures was higher than in patients who do not use dentures [17]. Furthermore, poor oral hygiene favors the biofilm development [18], and it is important to have correct oral hygiene instructions.
A carbohydrate-rich diet also favors the microorganisms' adhesion and proliferation, taking into account that the carbohydrates are the primary and preferred nutrient source for Candida spp [19], and may modulate biofilm development on denture surface by affecting both structural features and virulence factor in C. albicans biofilms [20].
Finally, the environmental pH may act as a potential inducer of biofilm development [21], and previous study showed that acidic pH (pH 5.5) may be more favorable for biofilm formation [22].

Systemic factors
There are a lot of systemic conditions that may influence the development of CADS. Here, it will be emphasized the diabetes, chemotherapy, hemophilia and immunosuppressed patients.
Diabetes mellitus is one of the chronic systemic factors with major influence of the oral environment [23]. Considering the lower glycemic control, the high glucose level on oral fluid and the immune dysregulation, the diabetes frequently causes xerostomy, which favors fungal proliferation [24].
Furthermore, patients undergoing chemotherapy are particularly affected by CADS, due to high sensibility of the oral tissues to the toxic effects of chemotherapy. Antineoplastic drugs act on proliferating cells without distinguishing the normal cells from cancerous cells. In this context, the constant cell renewal of the oral mucosa, the complex microbiota (greatly altered with the use of anticancer drugs), xerostomy, neutropenia and immunosuppression resulted from the treatment facilitate proliferation of Candida spp in the oral environment [25].
Hemophilia is another important risk factor for CADS. A previous study showed that 64% of hemophiliacs' patients had pre-existing infections or reduction in salivary flow [26]. Finally, the major risk factor for the proliferation of C. albicans is immunosuppression, which changes the homeostasis of human host. It was revealed that 87.5% of the HIV-positive patients were Candida positive in saliva [26].

Clinical manifestations
There are several forms of oral candidiasis, such as Pseudomembranous Candidiasis, Erythematous Candidiasis, Angular Cheilitis and Chronic Hyperplastic Candidiasis. Here we will emphasize the CADS, a type of erythematous candidiasis that occurs under a removable denture.
Clinical characteristics may range from no symptoms to severe pain and difficulty swallowing [2,27]. The most common signs include changes in color and texture of the mucosa, dry mouth, painful symptomatology and erythematous aspect [28]. Newton (1962) proposed a classification of the disease based on clinical aspects of the lesions: punctiform hyperemia (class I), diffuse hyperemia (class II) and granular hyperemia (class III) [29].
Punctiform hyperemia (Class I): hyperemia signs of the minor palatine salivary glands; there is an erythematous punctiform aspect, and small or diffuse areas in palate may be affected.
Diffuse hyperemia (Class II): smooth and atrophic mucosa, with erythematous aspect under the denture. It is considered the most common aspect of CADS.
Granular hyperemia (Class III): more common in dentures with suction chambers. Affect the central region of the palate, with rough and nodular appearance of the mucosa.
It is important to highlight that the therapeutic test is a widely used diagnostic measure, which consists of prescribing topical antifungals and evaluate if there is a regression of signs and symptoms of the disease, to observe if the clinical manifestations are related to CADS. When there is a regression of the lesion after the treatment, ranging from 7 to 14 days, it may be assumed that the clinical manifestations were associated with CADS [30].

Therapy strategies
The treatment of CADS consists in removing the etiological agent, give instructions for the patient in relation to oral hygiene of denture surface and oral mucosa and treat the affected tissue. In addition, the professional should evaluate the necessity to construct another denture, considering that infected prosthetic devices typically must be removed [31].
While the patient uses the denture, the miconazole 2% has been successfully used, being commercially available in form of gel, and can be applied directly in the denture surface previously cleaned. It should be used 2 to 3 times a day for one or two weeks, according the patient response [30]. In addition, a topical antifungal agent widely used for the treatment of CADS is nystatin, which can be used on the oral mucosa several times a day, being available as a liquid suspension, cream and pastille [2].
When the therapy via topical antifungal agents does not lead to clinical improvement of the patient, the use of systemic antifungal agents is recommended, especially in immunosuppression patients. The fluconazole (FLZ) has been extensively used, taking into account that has lower toxicity, it is highly bioavailable in oral formulations, and less expensive in relation to other antifungal agents [32]. It is recommended a single and daily dose, being the first dose of 400 mg and subsequent daily doses of 100 mg for one or two weeks [33]. Another systemic antifungal agent is ketoconazole, which is absorbed from the gastrointestinal tract and must be administered in a single dose of 200 mg during 14 days. This is a hepatotoxic drug and can cause cardiac arrhythmias when used in combination with antihistamines or macrolide antibiotics [34,35]. For a long time, amphotericin B was used in the treatment of CADS. However, it is extremely nephrotoxic and is administered intravenously, being nowadays less used in CADS therapy.

Conclusion
The knowledge about Candida -associated denture stomatitis is of utmost importance in clinical practice. The professional should recognize the possible risk factors for CADS and the clinical manifestations, in order to indicate the correct treatment for the patients.