Management of Chronic Atrophic Candidiasis (Denture Stomatitis)—A Narrative Review

One of the most common oral diseases affecting people wearing dentures is chronic atrophic candidiasis or denture stomatitis (DS). The aim of the paper is to provide an update on the pathogenesis, presentation, and management of DS in general dental practice settings. A comprehensive review of the literature published in the last ten years was undertaken using multiple databases, including PubMed via MEDLINE, EMBASE, and Scopus. The eligible articles were analyzed to identify evidence-based strategies for the management of DS. Despite its multifactorial nature, the leading cause of DS is the development of oral Candida albicans biofilm, which is facilitated by poor oral and denture hygiene, long-term denture wear, ill-fitting dentures, and the porosity of the acrylic resin in the dentures. DS affects between 17 and 75% of the population wearing dentures, with a slight predominance in elderly females. The mucosal denture surfaces and posterior tongue are the common sites of DS, and the affected areas exhibit erythema, the swelling of the palatal mucosa and edema. Oral and denture hygiene protocols, adjusting or re-fabricating poorly adapting dentures, smoking cessation, avoiding nocturnal denture wear, and the administration of topical or systemic antifungals are the mainstay of management. Alternate treatments such as microwave disinfection, phytomedicine, photodynamic therapy, and incorporation of antifungals and nanoparticles into denture resins are being evaluated for the treatment of DS but require further evidence before routine use in clinical practice. In summary, DS is the most common oral inflammatory lesion experienced by denture wearers. Most patients with DS can be managed in general dental practice settings. Effective management by general dental practitioners may be supported by a thorough understanding of the pathogenesis, the recognition of the clinical presentation, and an awareness of contemporary treatment strategies.


Introduction
Chronic atrophic candidiasis, commonly referred to as denture stomatitis (DS), is the most prevalent multifactorial, chronic inflammatory oral condition amongst denture wearers [1,2]. It affects edentulous people who wear complete or partial dentures, as well as those who use intraoral removable orthodontic appliances and obturators [3].
DS most commonly involves the palate and is more likely to be observed in patients with acrylic dentures than prostheses fabricated using other materials or in other locations [4,5]. As elderly people are more likely to use dentures, the condition is far more prevalent in older populations. However, DS is also seen in healthy, younger people who wear dentures [6].

Classification, Prevalence, and Clinical Presentation
The first recognized classification of DS was proposed by Newton in 1962 [29], which still remains in use and groups DS as follows: Type I: manifests as localized mucosal inflammation induced by trauma. Type II: Diffuse involvement of the denture-bearing mucosa (Figures 1-3).
oids and antibiotics, and hematological disorders. These factors might contribute by compromising an individual's resistance to combat the disease [7,9,14,15,21,22]. Recently, De Souza et al. [28] reported that individuals with low socioeconomic status are more likely to develop DS due to poor access to routine medical care. An association relationship between DS and other diseases, such as pneumonia and bacterial endocarditis, is also reported [3,19,28].

Classification, Prevalence, and Clinical Presentation
The first recognized classification of DS was proposed by Newton in 1962 [29], which still remains in use and groups DS as follows: Type I: manifests as localized mucosal inflammation induced by trauma. Type II: Diffuse involvement of the denture-bearing mucosa (Figures 1-3).  ported [3,19,28].

Classification, Prevalence, and Clinical Presentation
The first recognized classification of DS was proposed by Newton in 1962 [29], still remains in use and groups DS as follows: Type I: manifests as localized mucosal inflammation induced by trauma. Type II: Diffuse involvement of the denture-bearing mucosa (Figures 1-3).   Diffuse involvement of the denture-bearing mucosa in a patient with an upper par denture. Figure 3. Diffuse involvement of the denture-bearing mucosa mirroring the partial denture base Type III: Additionally known as inflammatory papillary hyperplasia, the dentu bearing mucosa shows a granular appearance ( Figure 4). Although Newton's classification is clinically useful for grading the hyperemia denture-bearing mucosa, it does not accurately reflect the severity and extent of the d ease [30].
A classification system has been proposed by Barbeau et al. [31] that subdivides Ne ton types into additional categories based on the extent of the lesions. The classificati put forth by Schwartz et al. [32] subdivides Newton types I, II, and III based on the sev ity of inflammation using a score ranging from zero to six. Recently, Neppelenbroek et [30] proposed a modified Newton classification based on three clinical features: (a) a pearance (I, II, and III), (b) the degree of inflammation of the palatal denture-bearing m cosa per quadrant, and (c) the degree of erythema (slight or intense redness). These sco for the three criteria are combined to rank the severity of DS using a total of 24 points. Type III: Additionally known as inflammatory papillary hyperplasia, the denturebearing mucosa shows a granular appearance ( Figure 4).  Figure 2. Diffuse involvement of the denture-bearing mucosa in a patient with an upper partia denture.

Figure 3.
Diffuse involvement of the denture-bearing mucosa mirroring the partial denture base.
Type III: Additionally known as inflammatory papillary hyperplasia, the denture bearing mucosa shows a granular appearance ( Figure 4). Although Newton's classification is clinically useful for grading the hyperemia o denture-bearing mucosa, it does not accurately reflect the severity and extent of the dis ease [30].
A classification system has been proposed by Barbeau et al. [31] that subdivides New ton types into additional categories based on the extent of the lesions. The classificatio put forth by Schwartz et al. [32] subdivides Newton types I, II, and III based on the sever ity of inflammation using a score ranging from zero to six. Recently, Neppelenbroek et a [30] proposed a modified Newton classification based on three clinical features: (a) ap pearance (I, II, and III), (b) the degree of inflammation of the palatal denture-bearing mu cosa per quadrant, and (c) the degree of erythema (slight or intense redness). These score for the three criteria are combined to rank the severity of DS using a total of 24 points.
One in every three denture wearers suffers from DS, the most common oral mucosa lesion associated with removable dentures [28]. The prevalence of DS ranges from 60 t Although Newton's classification is clinically useful for grading the hyperemia of denturebearing mucosa, it does not accurately reflect the severity and extent of the disease [30].
A classification system has been proposed by Barbeau et al. [31] that subdivides Newton types into additional categories based on the extent of the lesions. The classification put forth by Schwartz et al. [32] subdivides Newton types I, II, and III based on the severity of inflammation using a score ranging from zero to six. Recently, Neppelenbroek et al. [30] proposed a modified Newton classification based on three clinical features: (a) appearance (I, II, and III), (b) the degree of inflammation of the palatal denture-bearing mucosa per quadrant, and (c) the degree of erythema (slight or intense redness). These scores for the three criteria are combined to rank the severity of DS using a total of 24 points.
One in every three denture wearers suffers from DS, the most common oral mucosal lesion associated with removable dentures [28]. The prevalence of DS ranges from 60 to 70% in denture wearers who exhibit clinical signs and symptoms [18,21]; however, this percentage may be up to 75% if asymptomatic patients are included [33].
The common sites of development of DS are the palate, tonsillar area, maxillary ridge, and posterior tongue [34,35]. In addition, Sartawi et al. [21] reported multiple small papillary nodules and papillary proliferations on the labial surface and labial mucosa, respectively. The conditions are rare in mandibular denture-bearing areas due to the washing action of saliva to clear the biofilm accumulation [36].
DS manifests clinically as variable mucosal erythema with or without dispersed petechiae in the areas covered by the denture base. The affected mucosa often has a palpable shape that mirrors the overlying denture. Despite the angry appearance of the affected mucosa due to marked erythema, most patients do not report any soreness. However, a minority of patients may report irritation of the affected oral mucosa, ulcerations, or a burning sensation, dysgeusia, dysphagia, and halitosis. Concurrent lesions commonly associated with DS include angular cheilitis, atrophic glossitis, and pseudomembranous or hyperplastic candidiasis [7,19,21]. The presence of prolonged inflammation may enhance the patient's chance of developing cardiovascular disease, diabetes, pulmonary disease, and lead to the progression of systemic infections. [19,28].
Given that DS is commonly encountered in general dental practice settings and a plethora of research on this topic has been published in recent years, this article aims to provide an update on the management of DS.

Methods
A scoping search was initially carried out to identify and estimate the volume of primary studies on DS.

Eligibility Criteria
The scoping search was used to map key search terms and develop the inclusion and exclusion criteria, as summarized below.
The inclusion criteria are as follows: •

Information Sources
All types of peer-reviewed research on DS that were published from January 2012 to December 2022. The literature from relevant databases, including Embase, Scopus, and Web of Science, were included in the review. In addition, a hand search of relevant publications was performed using Google Scholar with the reference lists of the retrieved papers from the above databases.

Data Screening
All of the identified articles were imported into EndNote ® , version X9 (Calrivate plc, London, UK), Clarivate Analytics. After the removal of duplicates, two reviewers independently screened the titles and abstracts. A full-text screening was conducted for the studies that adhered to the inclusion criteria. Any disagreements were resolved by consensus.

Study Selection
The results of the search and study selection are shown in the PRISMA flow chart in Figure 5. The total number of studies identified was 2663 (2657 from the databases and six reports from the grey literature). After the removal of duplicates, 1062 articles were included in the title and abstract screening. Of these, 935 from the databases and six from the grey literature were excluded, and 121 articles were considered for a full-text screening. Finally, 49 articles were selected for inclusion, including 34 randomized controlled clinical trials and 15 systematic reviews (Table 1). and/or "Denture sore mouth," and/or "Denture," and/or "Candidiasis," and/or "Candidaassociated denture stomatitis."

Data Screening
All of the identified articles were imported into EndNote ® , version X9 (Calrivate plc, London, UK), Clarivate Analytics. After the removal of duplicates, two reviewers independently screened the titles and abstracts. A full-text screening was conducted for the studies that adhered to the inclusion criteria. Any disagreements were resolved by consensus.

Study Selection
The results of the search and study selection are shown in the PRISMA flow chart in Figure 5. The total number of studies identified was 2663 (2657 from the databases and six reports from the grey literature). After the removal of duplicates, 1062 articles were included in the title and abstract screening. Of these, 935 from the databases and six from the grey literature were excluded, and 121 articles were considered for a full-text screening. Finally, 49 articles were selected for inclusion, including 34 randomized controlled clinical trials and 15 systematic reviews (Table 1). The data in the selected studies were collated to dissect the existing literature relating to the management of DS. The studies focused on a range of treatments for DS, including antifungal agents, lasers, photodynamic therapy, microwave radiation, phytomedicine using natural products, and antimicrobial agents. Of the 34 RCTs, 31 were evaluated in the 15 systematic reviews [37][38][39][40][41][42][43][44][45][46][47][48][49][50] included in this study. The main findings of the systematic reviews based on RCTs are summarized in Table 1. The data in the selected studies were collated to dissect the existing literature relating to the management of DS. The studies focused on a range of treatments for DS, including antifungal agents, lasers, photodynamic therapy, microwave radiation, phytomedicine using natural products, and antimicrobial agents. Of the 34 RCTs, 31 were evaluated in the 15 systematic reviews [37][38][39][40][41][42][43][44][45][46][47][48][49][50] included in this study. The main findings of the systematic reviews based on RCTs are summarized in Table 1.
Only three RCTs were not evaluated by any of the 15 systematic reviews included in this study. All three RCTs focused on the efficacy of different antimicrobial agents to reduce the Candida colonization of dentures but showed a moderate-to-high risk of bias. Auon et al. (2015) reported that the overnight immersion of dentures in 0.12% chlorhexidine digluconate and 0.2% cetylpyridinium chloride is effective in reducing the Candida colonization of acrylic dentures [51]. Badaró et al. (2020) [52] reported an RCT that showed an efficacy of 0.25% sodium hypochlorite as a disinfectant for denture cleaning. Finally, Procópio et al. (2022) [53] reported on the benefits of incorporating minimum inhibitory concentrations of antimicrobials (nystatin or chlorhexidine diacetate) in denture liners.

Discussion
General dental practitioners may find it challenging to assimilate the vast amount of information on the management strategies for DS and apply it effectively in their clinical practice [21]. A systematic approach to the management of DS requires dentists to identify and control the local and systemic risk factors associated with DS. Patients should be advised on meticulous plaque control and the avoidance of the nocturnal wearing of dentures, usually for eight hours per day [21,54]. Existing dentures must be evaluated for any potential flaws relating to fit and texture and managed appropriately, including the possibility of replacement dentures. Addressing the underlying risk factors, oral hygiene measures, and appropriate antifungal therapy is likely to be effective in resolving the majority of cases. A schematic management of DS is summarized in Figure 6.
an efficacy of 0.25% sodium hypochlorite as a disinfectant for denture cleaning. Finally, Procópio et al. (2022) [53] reported on the benefits of incorporating minimum inhibitory concentrations of antimicrobials (nystatin or chlorhexidine diacetate) in denture liners.

Discussion
General dental practitioners may find it challenging to assimilate the vast amount of information on the management strategies for DS and apply it effectively in their clinical practice [21]. A systematic approach to the management of DS requires dentists to identify and control the local and systemic risk factors associated with DS. Patients should be advised on meticulous plaque control and the avoidance of the nocturnal wearing of dentures, usually for eight hours per day [21,54]. Existing dentures must be evaluated for any potential flaws relating to fit and texture and managed appropriately, including the possibility of replacement dentures. Addressing the underlying risk factors, oral hygiene measures, and appropriate antifungal therapy is likely to be effective in resolving the majority of cases. A schematic management of DS is summarized in Figure 6.

Identification of Risk Factors
The local and systemic risk factors for DS must be evaluated comprehensively with a thorough medical, dental, and social history and eliminated/controlled where appropriate.
(a) Oral and denture hygiene protocol Meticulous oral hygiene, including prosthesis care, is important in achieving the resolution of DS [55]. Riberio et al. [2] proposed a hygiene protocol that has shown to be effective in reducing the inflammation associated with DS and involves the following:

•
Brushing the hard palate for 2 min, three times a day with soft toothbrush bristles and water; • During the day, brush the dentures for 2 min, three times a day, with a denture brush and neutral, non-abrasive liquid soap; Figure 6. A schematic management of DS.

Identification of Risk Factors
The local and systemic risk factors for DS must be evaluated comprehensively with a thorough medical, dental, and social history and eliminated/controlled where appropriate.
(a) Oral and denture hygiene protocol Meticulous oral hygiene, including prosthesis care, is important in achieving the resolution of DS [55]. Riberio et al. [2] proposed a hygiene protocol that has shown to be effective in reducing the inflammation associated with DS and involves the following:

•
Brushing the hard palate for 2 min, three times a day with soft toothbrush bristles and water; • During the day, brush the dentures for 2 min, three times a day, with a denture brush and neutral, non-abrasive liquid soap; • Before going to bed at night, soak the dentures in 150 mL of 0.25-0.5% sodium hypochlorite for 10-20 min, followed by the overnight storage of the dentures in fresh, clean water at room temperature.
Although mechanical cleaning is a quick and straightforward method to control plaque, it can result in the wear of the denture base materials, leading to flaws on the surface of the dentures that encourage the growth of biofilms and pigmentation [56,57]. In contrast, there are several options for using chemical cleansers, including hypochlorite, peroxides, and enzymes, with sodium hypochlorite being the preferable agent. Denture wearers prefer chemical denture cleansers because they are easy to use, affordable, and they have been effective in reducing biofilm formation [58,59]. However, repeatedly soaking the dentures in hypochlorite may lead to discoloration of the dentures. The use of chlorhexidine gel with anti-discoloration systems (e.g., Curasept 0.5%) can be used to reduce Candida colonization on PMMA resin with minimal discoloration and limited changes to the mechanical properties of PMMA [60].
High-frequency electromagnetic radiation, such as microwaves, can either cause cell death by changing the structure of the cell and the permeability of its membrane or can cause cell death through an interaction between the electromagnetic field created by the microwaves and the molecules of the cell [47]. Microwave ovens have been recommended as a simple and cost-effective method for cleaning prostheses. It can be an effective alternative to antifungal medications for the treatment of DS [47].
Da Costa et al. [37] reported that microwave disinfection was more effective than topical miconazole alone. It produced mycological and clinical results comparable to an overnight soak in a solution of 0.2% chlorhexidine and 0.02% sodium hypochlorite. Although there is no standardized procedure for cleaning and disinfecting dentures in a microwave, a disinfection protocol at 650 W for 3 min once a week for two consecutive weeks has been recommended to prevent and treat DS with minimal possible denture damage [37]. However, such claims should be confirmed by further long-term clinical studies.
(b) Antifungal therapy Antifungals are often prescribed in conjunction with other measures to treat established cases of DS. Polyenes (nystatin and amphotericin B) and Azoles, which are categorized into triazoles (itraconazole and fluconazole) and imidazoles (clotrimazole, ketoconazole, isoconazole, miconazole, and tioconazole) are the two classes of antifungals that are most frequently used for DS treatment [54]. Azole antifungals potentiate the effects of oral anticoagulant warfarin, and this needs to be discussed with the patient's physician to adjust the dosage of the drug appropriately. The usual duration of antifungal therapy is up to 14 days.
Topical antifungal medications, such as nystatin, which are available as dry powders, lozenges (pastilles), and suspensions, are effective against most Candida species.
• Dry powder forms: Approximately 1 /8 teaspoonful of dry powder is added to 4 ounces of water and stirred thoroughly. The medicine can then be used as a mouthwash/gargle; • Lozenges (pastilles): Need to be held in the mouth and allowed to dissolve slowly over 15-30 min; • 1-2 Tablets or lozenges may be used 3-5 times/day; • Oral suspensions: Hold 4 to 6 milliliters (mL) in the mouth for a few minutes, then swish it around, and gargle before swallowing it. Repeat four times/day.
Patients with full or partial dentures may need to soak their dentures nightly in a nystatin oral suspension to eliminate the fungus from the dentures. In rare cases, when this does not eliminate the fungus, it may be necessary to have new dentures made.
Miconazole is available as an oral gel (24 mg/mL). A small pea-sized amount (2.5 mls) of the gel is applied over the affected area 2-4 times/day. It can also be applied to the fitting surface of an upper denture before placing the denture in the mouth. Repeat this 3-4 times daily.
Systemic therapy has been recommended for DS in cases where topical medications are ineffective, such as in individuals who need special care or in patients with systemic comorbidities, such as diabetes or immunosuppression [54,61]. Systemic antifungal drugs that have undergone the most extensive research and are the most effective are fluconazole and itraconazole [54].
A study by Vidya et al. [62] demonstrated that incorporating fluconazole and ketoconazole antifungal agents into tissue conditioners positively inhibited Candida albicans growth. Similarly, Shaikh et al. [63], through their systematic review, reported that the addition of nystatin to tissue conditioners proved beneficial.
Although numerous antifungal medications are available, DS frequently recurs following antifungal therapy, which necessitates retreatment with antifungals. The persistence of Candida biofilms on the mucosa and inert prosthetic surfaces could contribute to DS relapse. Common impediments to complete recovery include reduced patient compliance, immunodeficiency, and drug resistance associated with frequent daily dosages and the unjustified use of antifungals over time. Regardless of the choice of DS therapy, factors related to the prostheses, such as poor oral and denture hygiene, the nocturnal wear of dentures, and failure to replace old faulty prostheses, contribute to lesion relapse [28,64].
It is also worth mentioning that although fluconazole is one of the most popular systemic antifungals, it only has a fungistatic action against C. albicans, which may result in fluconazole resistance after prolonged use. [65] There is emerging evidence that the combination of fluconazole with other drugs, such as myriocin [66] (a fungus-derived antibiotic), may result in a synergistic effect that may potentiate the effects of fluconazole against C. albicans. However, such interventions need further evidence before routine clinical use.
(c) Nanoparticles and antimicrobials Silver (Ag), titanium dioxide (TiO 2 ), zinc oxide (ZnO), and zirconium dioxide (ZrO 2 ) nanoparticles have been shown to exhibit antimicrobial properties. Silver nanoparticles (AgNPs) demonstrate antimicrobial activity due to their ability to damage cell membranes and could be added to PMMA in a concentration of 3-3.5 wt% to reduce C. albicans colonization [67]. Similarly, the addition of TiO 2 and halloysite clay in PMMA can also reduce the colonization of the dentures by C. albicans [68] The application of an antimicrobial coating on denture surfaces has been suggested to inhibit Candida albicans adhesion by creating smooth denture surfaces [69]; however, the coating obliterates surface details and tissue adaptability, which may have an impact on denture retention. Additionally, mechanical and chemical denture hygiene may damage the coating, resulting in a rougher surface with a higher propensity for microbial colonization [14].
Conflicting results are reported regarding the applications of nanoparticles or antimicrobials for the treatment of DS. Bajunaid [70] recommended the use of various antimicrobial and protein-repellent agents to prevent Candida albicans from adhering to acrylic dentures. However, the addition of these antimicrobials can compromise the mechanical properties of acrylic commensurate with the concentration of antimicrobials. On the contrary, An et al. [70], in their systematic review, reported that there was insufficient evidence to support the effectiveness of adding antimicrobial agents to acrylic. Similar findings are reported by other studies [71].

(d) Photodynamic therapy
Photodynamic therapy (PDT), also termed photodynamic antimicrobial chemotherapy, photo radiation therapy, and photo chemotherapy, has recently gained popularity as a potential antifungal treatment modality [72]. The most popular photosensitizers used in dentistry are methylene blue, toluidine blue ortho, and indocyanine green.
A review of recent publications has shown that PDT was just as effective as conventional antifungal medications, particularly nystatin, in the clinical remission of DS and considerably reducing the colony-forming units (CFU/mL) of Candida species from dentures [18,35,39,42,43]. However, the recurrence of DS following PDT has also been reported [18]. Since PDT is recommended as an alternative to conventional antifungal medication, more rigorous research with longer follow-up is required before their inclusion in clinical practice. One study by Yousef et al. [73] recommends PDT combined with low-level laser therapy and miconazole gel for the efficient treatment of Candida-induced DS, with a higher cure rate and lower recurrence.

(e) Phytomedicine
Phytomedicine, which has existed since the dawn of human civilization, can be defined as herbal or natural products with therapeutic and medicinal values [74]. Natural products are said to be effective in treating DS because they have improved the clinical and microbiological aspects of the condition [45].
Natural products such as curcumin, propolis, green tea, clove and cinnamon oils, chitosan, garlic, ginger, Zataria multiflora, Artemisia, Schinus terebinthifolius raddi, Uncaria tomentosa, Pelargonium graveolens, Equisetum giganteum, Melaleuca alternifolia, Punica granatum, Ricinus communis, henna, thymoquinone, and aloe-vera have been used in the treatment of DS (Silveira et al., 2021). These products can be applied topically or as loaded emulgels. Previous studies have suggested that the incorporation of natural products into the acrylic resin denture base material might be effective in preventing Candida albicans adhesion.
Compared to traditional antifungals, these products have a better taste, comparable efficacy, fewer side effects, and higher patient satisfaction [45,65,74] Several natural products have been studied for the treatment of DS. Despite the encouraging results reported in the literature when using natural products, more clinical research is needed to furnish appropriate scientific evidence to support the use of natural products for DS management [45].

Conclusions
DS represents the most common inflammatory reaction in denture wearers. Although DS has a multifactorial etiology, infection with oral Candida albicans is the most recognized etiological agent. Observing oral and denture hygiene regimens, adjusting or re-fabricating poorly adapting dentures, smoking cessation, avoiding nocturnal denture wear, and the administration of topical or systemic antifungal drugs are recommended for effective healing of the inflammatory lesions of DS. Alternate treatments, such as microwave disinfection, phytomedicine, photodynamic therapy, and the incorporation of antifungals and nanoparticles into denture resins are widely reported in the literature but further evidence is required before such alternate treatment options can be recommended routinely. Funding: Open access funding was provided by the Qatar National Library. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.

Data Availability Statement:
Data is contained within the article.

Conflicts of Interest:
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.