REVIEW ARTICLE

Ecology of Candida -associated Denture Stomatitis

Ejvind Budtz-Jrgensen
From the Department of Gerodontology and Removable Prosthodontics, University of Geneva, Geneva, Switzerland Correspondence to: Ejvind Budtz-Jrgensen, Section de me decine dentaire, GERAD, 19 rue Barthe lemy-Menn, CH-1205 Geneva, Switzerland. Tel: + 41 22 382 9131; Fax: + 41 22 372 94 97; E-mail: ejvind.budtz-jorgensen@medecine.unige.ch

Microbial Ecology in Health and Disease 2000; 12: 170185 Introduction of a prosthesis into the oral cavity results in profound alterations of the environmental conditions as the prosthesis and the underlying mucosa become colonized with oral microorganisms, including Candida spp. This may lead to denture stomatitis, a non-specic inammatory reaction against microbial antigens, toxins and enzymes produced by the colonizing microorganisms. The role of Candida in the etiology of denture stomatitis is indicated by an increased number of yeasts on the mucosa and the dentures, increased levels of anti-Candida antibody titres in affected individuals and the clinical improvement of the mucosa due to eradication of the yeast ora. The colonization of the tting denture surface by Candida depends on several factors including adherence of yeast cells, interaction with oral commensal bacteria, redox potential of the site, and surface properties of the acrylic resin. The pathogenicity of denture plaque can be enhanced by factors stimulating yeast propagation, such as poor oral hygiene, high carbohydrate intake, reduced salivary ow and continuous denture wearing. The more important factors which can modulate the host-parasite relationship and increase the susceptibility to Candida -associated denture stomatitis may be ageing, malnutrition, immunosuppression, radiation therapy, diabetes mellitus, and possibly treatment with antibacterial antibiotics. To control plaque formation on the tting denture surface and the underlying mucosa it is important to install appropriate oral and denture hygiene measures as well as denture wearing habits. The Candida infection associated with denture stomatitis is a relatively harmless condition in healthy individuals; however, the infection may spread in susceptible individuals. Key words : denture plaque, oral candidosis, oral microora, host-parasite relationship.

In adults, the resident oral microora remains relatively stable and to some extent in harmonious balance with the host. This stability or microbial homeostasis is not a passive response to the environment, but is the result of a dynamic balance being achieved from numerous interactions between different microbial species and host microbial-interactions. The composition of the oral microora varies at different surfaces within the mouth because of the respective physical and biological properties of each site. These properties include the presence of receptors for microbial adhesion, the redox potential of the site, and the provision of essential nutrients (1). Age related changes in the oral microora of young individuals are primarily due to tooth eruption and hormonal changes (2). However, age-related changes can also occur in healthy dentate individuals. These changes include an increased prevalence of staphylococci, lactobacilli and A. 6iscosus with age, especially after the age of 70 years (3). Placement of a prosthesis in the oral cavity results in profound alterations of the environmental conditions as the prosthesis becomes colonized with oral microorganisms and cuts off the underlying mucosa from the mechanical cleansing effect of the tongue and the free ow of saliva with its antimicrobial substances. One consequence
Taylor & Francis 2000. ISSN 0891-060X

of denture wearing among others is an increase of the rate of Candida carriage and infection by this yeast, an observation which has been documented for many years (4, 5). This is further illustrated by the fact that the yeasts tend to disappear from the oral cavity when the teeth are extracted, but that the mouth is recolonized when dentures are worn (6). Denture stomatitis is the term used for the chronic inammatory changes of the denture bearing mucosa, which is characterized by erythema of the palate and the alveolar ridges (7). Strains of the genus Candida are very often involved as a causative factor in denture stomatitis. Still, this condition is not a specic disease entity as other causal factors exist, such as bacterial infection or mechanical irritation (7, 8). Mechanical irritation may possibly play a predisposing role by increasing the turnover of the epithelial cells, hence the barrier function of the epithelium is reduced and its penetration by microbial antigens is possibly enhanced (9, 10). It is the purpose of this review to outline the ecology of the oral microora in denture wearers, i.e. the denture plaque on the tting denture surface and the underlying mucosa with particular emphasis on Candida species, and to discuss the factors which may alter the host-parasite balance, including the composition of the microora.
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ORAL PATHOGENS ASSOCIATED WITH DENTURE STOMATITIS Microbial plaque on removable dentures covering the palate causes denture stomatitis in up to 69% of denture wearers (7). Yeasts may play a role in the aetiology as indicated by the increased number of yeasts on the inamed mucosa and the dentures and increased levels of anti-Can dida antibody titres in colonized individuals (11, 12). Furthermore, antimycotic treatment suppressing the yeast ora often produces clinical improvement of the inamed mucosa (13). In one clinical experiment the relationship between the effect of treatment with amphotericin B for two weeks and the number of CFU of bacteria/cm2 and yeasts/ cm2 in 7-day-old denture plaque was studied (14). There was a signicant correlation between initially high yeast counts and improvement of the clinical condition of the palatal mucosa following antimycotic treatment. In some patients, only bacteria were grown and antimycotic treatment had no effect which indicated that bacteria also may be involved as pathogens. This is supported by immunologic studies showing elevated antibody titres against commensal oral bacteria such as streptococci and lactobacilli in stomatitis patients (15). In the same study (14) a sequential analysis of yeast and bacterial counts of 2-day or 7-day-old denture plaque was carried out in ve patients before and after antifungal therapy. The bacterial counts of both 2-day-old and 7-dayold plaque showed insignicant variations throughout the study and were not affected by treatment with amphotericin B. On the other hand, the yeasts were eradicated after antifungal therapy but were recovered again at day 9 after antifungal therapy had been withdrawn. According to experimental studies on animals there is direct evidence that an acrylic plate covering the palatal mucosa favors colonization by Candida. Thus, it was possible to recover Candida from the palatal mucosa of monkeys after the palate had been covered for 23 weeks (16); however, a spontaneous infection as a detectable lesion was not observed. According to an early suggestion by Bartels (17) the dentures may keep pathogenic species of micro-organisms, such as C. albicans, in contact with the mucosa for long periods of time to permit the microbial metabolic products initiate an inammatory response. This assumption has been substantiated further by the fact that it was essential to cover the mucosa in order to produce an experimental infection with C. albicans in the palate of monkeys, and which resembled clinically denture stomatitis (16, 18). Dentures, therefore, seem to provide environmental conditions both for the colonization and propagation of Candida species in the oral cavity giving rise to clinical lesions. COMPOSITION OF DENTURE PLAQUE ASSOCIATED WITH HEALTHY ORAL MUCOSA Using the method of applying self-adhesive water-proof

tape to the tting denture surface made it possible to remove undisturbed plaque samples of known age repeatedly without any inconvenience for the patient and leaving the denture intact (19). Using this technique the total viable anaerobic counts of bacteria per cm2 tape after 7 days in the mouth on the denture base in contact with a healthy palatal mucosa varied from 4 104 and 5 108 per cm2 in 17 individuals studied (the yeast counts varied between B 50 and 1.5 106 per cm2) (19). The median viable bacterial count was 2 107 and the median yeast count 4 102. Repeated sampling in the same person within 2 months yielded much more uniform results, the largest intra-individual variation being a 10-fold difference in total viable counts. An electron microscopic examination of the deposits on the tape and an examination of the gram-stained smears prepared from the tape samples revealed that the composition of 7-day-old plaque resembled that of old denture plaque. This plaque constitutes a mixed bacterial ora dominated by gram-positive cocci and short rods (20, 21). The denture plaque shows many similarities to the bacterial deposits on natural teeth, in particular plaque in occlusal ssures (22). A subsequent microbiological study was carried out to characterise the predominant cultivable microora of plaque on removable dentures in individuals with healthy oral mucosa (23). In this study, plaque from the tting surface of full upper dentures in 8 individuals with healthy palatal mucosa was examined. To characterise the predominant cultivable ora, 916 isolates i.e. 100 128 from each denture sample were subcultured from anaerobic roll-tubes for further identication. In this study, high dilutions of suspensions of denture plaque were used to characterize the microora. Using this technique, microorganisms constituting small proportions of the ora are eliminated; still, all samples yielded from 2 14 different species of those commonly found in tooth-surface plaque. However, there was large individual variation in predominant species and their proportions. Thus, streptococci constituted up to 81% of the isolates in one individual whereas in another no streptococci could be cultured. Altogether streptococci constituted 43% (mean) of the isolates with varying proportions of S. milleri, S. mutans, S. sali6arius, S. mitior, and S. sanguis. Staph. aureus made up 8% (mean) (Table I); gram-positive rods constituted 37% (mean). Among these, A. israelii, A. naeslundii, A. 6iscosus and A. odontolyticus were the most common species. Lactobacilli were isolated only from two of the denture samples, constituting 21% and 48%. Among the gram-negative cocci, only V. par6ula was common, constituting 10% of the isolates. Gram-negative rods were isolated from three denture samples but only in small proportions. Cultures for yeasts on Sabouraud agar were positive for ve of the denture samples and the yeast counts corresponded to 0.002% (median) of the total vi-

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able counts. In this study, anaerobic growth conditions were used to favour growth of the strict and the facultative anaerobes known to predominate in dental plaque. This may account for the apparent absence of aerobes such as Neisseria species. However, both cultural and electron microscopic studies indicate that denture plaque in individuals with healthy oral mucosa shows great similarity to tooth surface plaque (20, 23, 24). A more recent study showed Bacteroides in 96% of 51 edentulous subjects with complete dentures together with mutans streptococci (84%) and lactobacilli (92%) indicating that these microorganisms are a part of the normal ora in denture wearers (25). A further characterization of the yeast ora in denture plaque in individuals with healthy oral mucosa was made in a randomly selected population of 465 persons above the age of 65 years wearing a removable maxillary denture (26). Of these, 172 individuals (35%) had clinically healthy oral mucosa. Yeasts were isolated in 86%; C. albicans was grown in pure or mixed cultures in 75% and other yeast species in 11%. Of a total of 191 isolates C. albicans constituted 65%, C. glabrata 15%, C. tropicalis 9%, C. mycoderma 4% and other yeast species 7%. COMPOSITION OF DENTURE PLAQUE ASSOCIATED WITH DENTURE STOMATITIS To study the predominant cultivable ora of denture plaque associated with denture stomatitis plaque was collected from the tting denture surface in 8 patients affected by this condition (27). Serial dilutions were cultured anaerobically and 100 colonies were picked from each plaque sample for subculture and purication. In all, 1249 isolates

Table I
Predominant culti6able bacterial ora of old denture plaque (% of isolates) in stomatitis patients and denture wearers with healthy oral mucosae (27). Stomatitis Gram-positive cocci Streptococcus species Staphylococcus species Gram-positive rods Actinomyces species Proprionibacterium species Eubacterium species Lactobacillus species Gram-negative cocci Veillonella species Unclassied Gram-negative rods Bacteroides species Actinobacillus actino mycetemcomitans Unclassied 43 36 7 40 13 3 22 15 0 15 0.7 0.6 0.1 Healthy mucosa 51 43 8 37 26 0.8 0.1 10 11 10 1 1 0.7 0.3

were subcultured corresponding to 138 196 isolates per patient. As was the case from denture plaque from individuals with healthy oral mucosa there was large intersample variations in cultivable species and their proportions. The predominant ora of each denture sample consisted of 7 24 species. Streptococci were present in all 8 samples (patients) and constituted 36% (mean) of the isolates with varying proportions of S. mitior, S. milleri, S. mutans, S. sali6arius, and S. sanguis (Table I). Staphylococci were cultured from all samples and made up 7% (mean) of the isolates. Gram-positive rods constituted 40% (mean) of the isolates. Among these, A. 6iscosus and A. israelii were the most common species. Lactobacilli were present in 5 of the denture samples, where they constituted large proportions (18 40%) of the isolates. Propionibacterium species were isolated in small proportions from all samples. Gram-negative cocci were found in 7 denture samples, constituting 10 28% of the ora. A further classication of these species was not possible. Gram-negative rods (Bacteroides species, A. actinomycetemcomitans ) made up less than 1% of the isolates in 3 denture samples. In this study also anaerobic culture conditions were used which may explain the absence of strictly aerobic bacteria. It can be concluded from these two microbiological studies carried out on 8 denture wearers with healthy oral mucosa and 8 denture wearers affected by denture stomatitis that the denture plaque is composed of essentially similar bacterial ora, except for the proportions of various gram-positive rods and gram-negative cocci (23, 27). In both instances, there were large intraindividual variations in the composition of the bacterial ora of denture plaque. Regarding the composition of the yeast ora in patients affected by denture stomatitis there is no evidence that it differs from that observed in non-infected carriers of Can dida. In the aforementioned epidemiologic study of yeasts in elderly denture wearers 291/465 randomly selected persons showed clinical evidence of denture stomatitis (26). Yeasts were cultivated in 93% of the individuals with C. albicans isolated in pure or mixed culture with other yeast species in 86% of the patients. Of a total of 412 isolates, C. albicans constituted 66%, C. torulopsis 15%, C. tropicalis 7%, C. mycoderma 4% and other yeast species 8%. These gures correspond almost exactly to those observed in denture wearers with healthy oral mucosa. Apparently, there is no important difference in the composition of the resident oral ora on the tting denture surface in patients affected by denture stomatitis and those carrying Candida and having clinically healthy oral mucosa. This is unexpected since the presence of an inammatory reaction of the mucosa in contact with the contaminated denture is likely to have some effect on the composition of the resident oral microora. However, quantitative cultural

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studies of bacteria and yeasts showed that the bacterial counts of 1-week-old denture plaque in stomatitis patients were about 10 times higher than those observed in denture wearers with healthy oral mucosa (14)). Furthermore, the corresponding yeast counts were about 100 times higher in stomatitis patients compared with the denture wearers with healthy oral mucosa (27, 28). When comparing different test areas of the tting denture surface of a maxillary denture, no difference was found regarding bacterial and yeast counts from 1-weekold denture plaque accumulated on pieces of self-adhesive tape (29). On the other hand, the yeast counts from a test area located on the buccal denture ange were signicantly lower than those originating from the tting denture surface whereas the bacterial counts were similar. These results indicate that the environmental conditions beneath a denture base favour yeast colonization and are different from those present on the buccal denture ange. The diagnosis, Candida -associated denture stomatitis, should therefore be retained as Candida species are probably involved as an etiologic factor in a majority of clinical cases. However, with regard to treatment of the disease and establishing effective preventive measures, it is important to realize that yeasts constitute a minor fraction of the resident microbial ora on dentures and the underlying mucosa. Other studies have investigated the overgrowth of yeasts and bacteria on the mucosa in stomatitis patients. Using smear techniques, impression cultures, imprint cultures or various miniaturized culture test systems, it was found that the mucosa was more densely colonized by yeasts in stomatitis patients and that there was a topographical relationship between the inamed mucosal sites and the occurrence of yeast colonies (3035). In one study, the microora of normal and inamed palatal tissues was examined by culturing a suspension of ground palatal biopsy specimens (36). The total microbial counts were higher in tissues from stomatitis lesions than from non-pathological palatal tissue; however, no signicant differences were found in the frequency isolation of any specic type of microorganism, except that Candida were isolated from the pathologic tissue and not from healthy tissue. Other studies have conrmed that the resident bacterial ora of the mucosa in denture stomatitis is mainly Gram-positive, the predominant species being streptococci, staphylococci and lactobacilli (3740). The number of microorganisms residing on the palatal mucosa is considerably less than the corresponding colonization of the denture surface. The reason for this is probably that the microorganisms are partly eliminated with the shedding of the epithelial cells.

STRUCTURE OF DENTURE PLAQUE Transmission and scanning electron microscopic studies of denture plaque have shown that the bacteria predominated the microora of patients both with and without denture stomatitis (20, 40, 41). Yeast cells are usually seen among the bacteria in the stomatitis-associated plaque, although in some sections the plaque comprised mainly yeasts. The ultrastructure of these deposits resembles dental plaque elsewhere on solid surfaces in the oral cavity (22); thus, the microorganisms are held together in an intermicrobial matrix, and the adherence of the deposits to the denture surface seems to be mediated through an electron dense layer, structurally similar to that of the acquired dental pellicle (20). On the basis of the ultrastructure most of the organisms present are cocci and short rods, although lamentous organisms are also present (20, 41). Further, the majority of these microorganisms were classiable as Gram-positive which is in agreement with cultural studies both from the mucosa and the tting denture surface (23, 27, 37). The ultrastructural studies also showed that the majority of the bacteria seemed well preserved indicating that they were viable at the time of xation. This implies that the bacteria are metabolizing actively, with the possible liberation of toxic substances, which may elicit the clinical changes associated with denture stomatitis. Evidence for active metabolism in denture plaque is indicated by the fact that sucrose rinses resulted in a drop of the pH of the denture plaque associated with an aggravation of denture stomatitis (42, 43). These electron microscopic studies have further conrmed that there is no perceptible difference in the composition of denture plaque between patients with denture stomatitis and denture wearers with clinical healthy palatal mucosa. Yeasts cells constituted a minor portion of the denture plaque microorganisms and were observed only in stomatitis patients. Quantitative cultural studies indicate that plaque on the tting surface of the maxillary denture develops very fast as the bacterial counts of 2- and 7-day-old plaque were similar (14, 29). There is evidence that microorganisms are retained in the intracellular spaces of the supercial palatal epithelial cells from where they may act as sources of plaque development on the tting denture surface (44). The cultural and ultrastructural studies of denture plaque indicate that it is the quantity of denture plaque rather than its composition that is important for the development of denture stomatitis (20, 23, 27). This is supported by clinical and epidemiological studies showing a correlation between the denture plaque scores and the severity of denture stomatitis (8, 45 47). However, in spite of the small numerical proportion of yeasts in denture plaque, clinical improvement is usually seen following antimycotic treatment (30, 45, 48, 49). In addition, a correlation was demonstrated between the severity of the

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Table II
Factors affecting adhesion of yeasts (60). Factors related to yeast cells Medium/cultivation Phenotype Germ tubes/Hyphae Extracellular polymeric material Floccular/brillar surface layers Mannan Chitin Hydrophobicity Proteinase/phospholipase Cellular lipids Factors related to host cells Cell source Mucosal cell size and viability Fibronectin Fibrin Sex hormones Yeast carriers versus patients with overt candidosis Environmental factors Cations pH Sugars Saliva Humoral antibody and serum Antibacterial drugs Bacteria Dentures

erythema of the palatal mucosa and the degree of colonization of the mucosa by Candida (50). It is noteworthy from this study that denture wearers with glossitis showed increased yeast counts, not only from the oral mucosa but also from the tting denture surface, compared with patients without glossitis. This supports the opinion that the infection has its origin beneath the maxillary denture and from that area can spread to involve other mucosal sites (51).

YEAST COLONIZATION OF THE FITTING DENTURE SURFACE The colonization of the tting denture surface by Candida depends on several factors including the adherence of yeast cells, the possible effect of oral commensal bacteria on colonization and adherence of the yeasts, as well as the surface properties of the acrylic resin (52). The species composition of the yeast ora on the tting denture in individuals affected by denture stomatitis is similar to that encountered in other yeast-associated lesions of the oral mucosa, with C. albicans identied in about 85% of the cases (26, 53). The fact that the same yeast species were isolated at baseline and 18 months later in residents of long-term care facilities underlines the chronicity of the infection, caused by yeasts constituting a part of the resident microora of denture plaque (54). However, among the denture wearers with healthy oral mucosa some

of those who were initially carriers of Candida became negative; others who were originally Candida negative became positive and in some the yeast species isolated changed. A possible explanation of this could be that being unable to colonize the oral cavity, the yeasts did not become part of the resident ora or that they were too few in number to be detected regularly by culture. In a study on yeast colonization of the oral cavity, the throat, the dentures and feces in patients with denture stomatitis before and after local treatment with Mycostatin, it was found that before antifungal treatment similar species were isolated from the four sites (34); during oral topical antifungal treatment there was a signicant reduction of the number of positive cultures of yeasts from the oral sites and the stool samples. However, after cessation of treatment the mycotic ora was largely reestablished in most subjects during 2 weeks. Many other studies have shown a very temporary effect of both topical and systemic antifungal agents in the treatment of denture stomatitis with relapse of the infection after 2 4 weeks (49, 55 59). This indicates that the alimentary tract forms an ecological system from mouth to rectum and, in uncompromised individuals, is colonized with yeasts throughout its length. Thus, the infection becomes reestablished beneath the tting denture surface if the primary predisposing factors are not controlled, i.e. oral and denture hygiene as well as appropriate denture wearing habits. The adhesion of microorganism to a surface is a prerequisite for the colonization of that surface (Table II). The adherence of C. albicans to epithelial cells or the tting denture surface is mediated by adhesins, a specialized surface structure or receptor molecule by which the microorganism is able to attach itself to a surface (60, 61). The outermost layer, which is the one most likely to be involved in adhesion is brillar and probably mannoprotein in nature (62 64). Its synthesis in 6itro is conditioned by the composition of the growth medium and its formation as well as the yeast adherence to acrylic surfaces is enhanced in the presence of high concentrations of glucose and certain other sugars (65, 66). The ability of adherence of Candida species to saliva-coated acrylic resin may play a decisive role in the ability to establish itself on the denture surface and there seems to exist a relationship between the pathogenicity of the yeast strain and its adhesive capacity (67, 68). Several other factors may inuence the adherence of yeast strains to acrylic resins. Laboratory experiments have shown that saliva and the denture pellicle highly promotes the adherence of C.albicans to acrylic resin and that a glycoprotein on the yeast surface may be involved in this event (69 71). In addition, a coating of parotid saliva signicantly increased the binding of C. albicans to denture acrylic compared to submandibular/sublingual saliva (72). Most likely, the adherence of C. albicans to the denture

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surfaces is mediated by selected salivary components (73). However, also serum proteins derived from the inammatory exudate associated with denture stomatitis increase in 6itro the adherence of C. albicans to acrylic resin (74). In a study on the composition of the acquired denture pellicle in stomatitis patients and healthy controls both types of pellicle contained salivary amylase, mucin, lysozyme, albumin, and SIgA (75); however, in immunoblots of acquired denture pellicle from patients with stomatitis, additional serum components, pellicle degradation products and C. albicans cell components were also identied. Since bacteria constitute the major part of the denture plaque microora, studies have been conducted to estimate the importance of bacteria for the adhesion of yeasts to denture acrylic. An early in 6i6o study showed that C. albicans adhered to plastic rods in a medium containing sucrose but was easily detached by slight movements of the rod (76). However, in mixed cultures of C. albicans and S. mutans, the Candida tended to grow supercially on the surface of a polysaccharide layer formed by the cocci which had colonized the rod surface and was strongly adherent. These ndings were conrmed in a subsequent study showing that rm adhesion of C. albicans to acrylic resin occurred when the yeasts were incubated simultaneously with S. mutans in the presence of glucose (77). In addition to producing changes in candidal adherence, bacterium-yeast interactions may involve coaggregation, growth stimulation or growth inhibition (78). There are data suggesting that the process of coaggregation involve a protein on the Candida surface that may interact with carbohydrate or carbohydrate-containing molecules on the surface of the bacteria, e.g. Actinomyces or Streptococcus (79, 80). On the other hand, some in 6itro studies indicate that Streptococcus species may suppress Candida adhesion to acrylic strips as preincubation of the strips in a bacterial suspension at a high concentration resulted in a consistent reduction in candidal adhesion (81). It is difcult from these in 6itro studies on the interaction of bacteria and yeasts resulting in plaque formation on denture acrylic resin to draw any parallels to the clinical situation. In the relatively stagnant area on the tting denture surface, plaque tends to be more acidogenic, thereby favouring growth of streptococci and Candida species, the adhesion of these microorganisms to the denture surface and their subsequent coaggregation. In addition, differences in surface topography and chemistry of the denture resin may affect the initial adherence of bacteria and yeasts. Thus, adhesion and retention of both bacteria and yeasts are increased on rough denture base surfaces of acrylic resin or cobalt-chromium (8284). Indeed, in one in 6itro study penetration by yeasts of the contamined denture surface occurred after 8 to 24 hours incubation (85).

PATHOGENIC EFFECTS OF CANDIDA Candida species may cause disease by tissue invasion, by producing potent virulence factors, or by inducing a hypersensitive state. It has been clearly demonstrated that tissue invasion by Candida, limited to the supercial keratotic or parakeratotic epithelial layers, occurs extremely seldom in denture stomatitis and that relatively few yeast cells are usually revealed in mucosal smears (31, 86, 87). On the contrary, long laments (pseudohyphae of Candida) are usually abundant in smears obtained from the tting denture surface. In experimental Candida associated denture stomatitis in animals, infection appears to be associated with a transformation of the blastospore form of C. albicans into the mycelial form (16, 88, 89). In these studies, it was found that after removal of the palatal acrylic appliance a resolution of the lesions took place although C. albicans persisted in its blastospore form. This is no evidence that the mycelial phase is the only pathogenic form of C. albicans as both the blastospore and mycelial forms can adhere, invade and proliferate in an infected host (90). Probably, the blastospore to mycelial transformation is the result of the environmental conditions under the plate, such as low oxygen tension, low pH and accumulation of shed epithelial cells. In contrast to many well documented pathogenic bacteria, the pathogenic Candida species are not characterized by dominant virulence factors. Among the potential virulence factors of Candida are the extracellular acid proteinases capable of degrading keratin, collagen, serum albumin and saliva proteins (91 93). In fact, high proteolytic activity in 6itro is characteristic of the more in 6i6o virulent Candida species, with C. albicans ranking highest followed by C. tropicalis, C. parapsilosis and C. glabrata (94). Indeed, the degree of expression of secreted aspartyl proteinases for C. albicans, C. tropicalis and C. parapsilosis correlated with the rate of yeast growth in saliva, pH drop, and reduction of the total salivary protein concentration (95). The activity of the proteinases is pH-dependent as they undergo a denaturation at pH ] 7.5 (96). Apparently, there was no differences in the proteolytic activity of Candida species cultured from stomatitis patients as compared with isolates from denture wearers with healthy oral mucosa (97). It is not known to which extent these enzymes are produced in denture plaque; however, the low pH (45) which can occur in denture plaque, particularly after sugar intake (42, 43), favours the activation of these enzymes. The potential harmful effects of the proteinases with respect to the pathogenesis of denture stomatitis could be a degradation of the keratin of the epithelium as well a cleavage of IgA1, IgA2 of the serous exudate or of secretory IgA which is the major immunoglobulin of human mucous membranes (98, 99). Thus, the activity of the

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candidal proteases might also enhance the pathogenic potential of the bacterial components of the denture plaque (27) by cleavage of salivary antibacterial immunoglobulin. In fact, under experimental conditions a candidal infection was shown to produce a marked increase of the permeability of the rat palatal mucosa (100). Thus, it appears that yeasts present in the denture plaque adversely affects the barrier function of the oral mucosa and reduce the protective effect of saliva on the mucosal surface.

Oral hygiene Most authors seem to agree that a signicant correlation exists between large amounts of plaque on the dentures and denture stomatitis (30, 47, 48, 106). Furthermore, subjects who reported soaking their dentures every night had signicantly lower plaque scores than subjects who soaked occasionally, who again had lower plaque scores than subjects who never soaked their dentures (46). A multivariate analysis showed a signicant relationship between maxillary denture plaque, inappropriate oral hygiene habits and the presence of denture stomatitis. Furthermore, microbial sampling carried out from a standardised site on the tting denture surface produced microbial counts which correlated with the clinical score for denture cleanliness and which was signicantly higher in stomatitis patients compared with denture wearers with healthy mucosa (107). Control of denture plaque by introducing meticulous oral and denture hygiene by mechanical or chemical means (45, 108, 109) or more appropriate denture wearing habits (110) may improve the health of the palatal mucosa. Polishing or glazing the tissue-tting surface of the denture is also conducive to improved denture hygiene and a decrease of the yeast counts (111, 112).

HYPERSENSITIVITY TO CANDIDA The inammatory response in denture stomatitis represents a complex immune response both a humoral and cellular immune reaction to the plaque deposits on the denture base or the mucosa. By means of various immunological techniques the presence of IgG, IgA, IgM, complement factors, T-lymphocytes and macrophages were demonstrated in the inammatory cell inltrate (101). However, the extent to which bacterial or candidal antigens contribute to the inammation is not known. There is experimental evidence that a delayed-type hypersensitivity reaction against C. albicans contributes to the inammation. In experimental Candida -associated denture stomatitis re-inoculation with C. albicans produced histologic evidence of a delayed hypersensitivity reaction dominated by a subepithelial lymphocyte inltration (16). The experimental infection also resulted in a T-cell response against Candida as measured in 6itro by means of the leukocyte migration test; however, intraepithelial invasion by yeasts was not observed (102). On the other hand, when the immune response was suppressed by treatment of the animals with immunosuppressive drugs, thrush-like lesions developed and yeast invasion of the epithelium occurred (102, 103). An increase in mitotic activity of the palatal epithelium was demonstrated during induction of the palatal candidosis in rats, a reaction which could be an attempt to clear the invading yeasts from the supercial epithelial layers (89). This could explain why epithelial atrophy rather than yeast invasion of the epithelium is a characteristic feature of denture stomatitis associated with oral candidosis.

Carbohydrate intake According to in 6itro studies, dietary sugars may facilitate candidal adhesion to denture acrylic surfaces and increase the resistance of C. albicans against salivary lactoferrin (113 116). There is also experimental evidence that a carbohydrate rich diet supported the oral colonization of rats by C. albicans, inoculated in the yeast and mycelial phases (117). Finally, addition of glucose to nutrientdepletet saliva produced an exceptional growth of C. albicans, despite the presence of a nutrient competing bacterial salivary ora (118). In clinical terms, a high carbohydrate intake was presumed to be the direct cause of oral candidosis in four denture wearers (119) and Ritchie et al. (120) reported aggravation of symptoms in patients with denture stomatitis when their carbohydrate intake was raised above normal levels. In two experimental studies on denture wearers with or without denture stomatitis it was found that the pH of denture plaque was lower in stomatitis patients, that mouth rinsing with a sucrose solution produced a more important drop in pH compared with the denture wearers with healthy mucosa, and that mouth rinsing with sucrose produced an aggravation of denture stomatitis (43, 121). An increase in the number of yeasts on the palatal mucosa and the tting denture surface was found in all subjects with clinical signs of aggravated or initiated denture stomatitis.

MODULATION OF DENTURE PLAQUE PATHOGENICITY The direct predisposing factor for denture stomatitis is the presence of the dentures in the oral cavity. Thus, denture stomatitis prevails in individuals who wear their dentures both night and day (48, 104) while not wearing the dentures or wearing the dentures only during day-time cause resolution or amelioration of the inammatory condition (54, 105).

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pH of denture plaque As mentioned, continuous denture wearing is associated with the occurrence of denture stomatitis. One of the pathogenic mechanisms could be that continuous denture wearing causes a decrease of pH at the palatal mucosa, but particularly at the denture base (42, 122). These ndings may be ascribed to a large acid producing potential of this plaque due to the content of S. mutans, lactobacilli and yeasts. The lower pH values may also be related to a lower saliva ow beneath the dentures. In subjects and regions of the mouth with a low saliva ow, a low pH of both fasting and carbohydrate-exposed dental plaque has been recorded (123). Reduced saliva ow was followed by aggravation and prolongation of experimental candidosis below maxillary plates in monkeys (18) and low buffering capacity of saliva is associated with high salivary yeast counts (124). A direct damage of the oral mucosa by acids produced by the denture plaque does not seem likely; however, the acid environment could activate the extracellular phospholipases and the acid proteinases of Candida, while further promoting yeast adhesion to the palatal surface could increase their pathogenic potential (125 127). Sali6a ow Saliva is important for the maintenance of healthy oral mucosae. This is illustrated by the fact that experimental oral candidosis becomes more invasive and persists longer if the salivary secretion is suppressed (18, 128). Furthermore, oral yeast counts in elderly subjects were signicantly higher in those with reduced salivary ow rates (124, 129). Saliva contains several substances that retard the growth of bacteria and yeasts in 6itro, such as lysozyme, lactoferrin, peroxidases, histidine, amylase, and Table III
Host -defence mechanisms in Candida -associated denture stomatitis (7). First line of defence Physical factors Mucous membrane Salivary ow Tongue movements Oral microbial interference Salivary substances Enzymes (lactoferrin, lysozymes etc.) Secretory antibodies (SIgA) Histidins Leucocyte candidacidal activity Phagocytosis Polymorphonuclear leucocytes Monocytes and macrophages Tissue antibodies Serum-derived antibodies Cell-mediated immunity

sialic acid (130 134). Thus, lyzozyme causes hydrolysis in the peptidoglycan layer of bacterial cell walls, kills C. albicans at high concentrations, and reduces the secretion of aspartyl proteinase by C. albicans at low concentration; lactoferrin in parotid uid inhibits the growth of C. albi cans in 6itro by chelating iron, thereby competing for this essential nutrient; salivary peroxidases and amylase have antimicrobial activity; and histidine-rich salivary peptides have been identied which, in the laboratory, are capable of inhibiting the growth or of killing Candida albicans. There is no evidence that the concentration of the salivary antimicrobial agents decline with age (135); however, defense factors which are derived from the gingival crevicular uid are decreased in the absence of teeth. Furthermore, resting saliva ow rates are signicantly lower in elderly than in younger subjects which could represent an important predisposing condition for yeast colonization and denture stomatitis (136, 137). In addition the retention of glucose in the oral cavity is increased when salivary secretion rate is decreased thereby predisposing for yeast adherence and colonization of the tting denture surface (138). MODULATION OF HOST-PARASITE RELATIONSHIP Multiple factors predispose to oral candidosis by modulating the host-parasite relationship which may also be pertinent to Candida -associated denture stomatitis (139). This is illustrated by the observation that in elderly individuals or patients in geriatric units a breakdown of the natural defenses against Candida colonization seems to take place (140, 141). Thus, the frequency of carriage, the intensity of yeast colonization, and multispecies carriage all increased as a function of age both in denture wearers and non-denture wearers. The more pertinent causes of modied host responses in elderly denture wearers are impaired immune responses, diabetes, cancer, radiation therapy and antibiotic or immunosuppressive therapy. Immune responses in denture stomatitis Potential protective immune mechanisms against Candida infection comprise specic immunity (serum and salivary antibiotics, cell-mediated immunity, activation of cytotoxic cells) and non-specic immunity (opsonization, phagocytosis, complement activation, macrophage activation, antifungal proteins) (Table III) (7, 142). Immunohistochemical studies have shown that such immunological reactions take place in the inamed palatal tissues of denture stomatitis (101, 143); however, the specicity of these reactions against antigens from C. albicans has not been ascertained. The anti-Candida serum antibody titer is normally elevated in patients with denture stomatitis, indicating that the Candida infection is not associated with an impaired humoral immune response (11, 144, 145); however, the protective effect of serum antibodies is probably of minor

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importance in this type of supercial candidosis (146). On the other hand, elevated level of IgA and SIgA (secretory IgA) against C. albicans were demonstrated in patients with denture stomatitis (147, 148). These antibodies may be a  rst-line  of defence against candidosis, and may function in the oral environment by aggregating the organisms and/or preventing their adherence to the mucosa or the denture (149, 150). However, a close-tting denture may cut off the access of the salivary antibodies to the denture-epithelial interface. T-cell and macrophage mediated activation of the immune system is important in the host-defence mechanisms in oral candidosis (151, 152). In experimental oral candidosis in monkey and mouse a primary Candida infection stimulated cellular immunity to a degree that a subsequent infection was rarely detectable and resulted in a typical local delayed-type hypersensitivity reaction (102, 153). Delayed-type skin hypersensitivity to C. albicans is widely distributed in adult populations with 50 85% showing a positive reaction (154). In patients with denture stomatitis the incidence of delayed-type skin hypersensitivity reaction to Candida antigen was lower than in denture wearers with healthy oral mucosa (155). It was suggested that the patients with the negative skin reaction might have acquired the Candida infection because the protective effect of cell-mediated immunity was absent. In a subsequent in 6itro study using the leukocyte migration technique to assess the cell-mediated immune response of the peripheral lymphocytes a negative reaction was observed more often in patients with a severe infection (156). However, the immune reaction was restored consistently after the infection was abolished. This might indicate that a chronic Candida infection in the oral cavity may lead to some degree of suppression of cell-mediated immunity against C. albicans, as expressed by the peripheral lymphocytes, and similar to the suppression observed in women with chronic candidal vaginitis (157159). It is possible that a severe chronic Candida infection may induce suppressor B-cell activity resulting in a depressed T-cell responsiveness (160). It is unknown whether a suppressed T-cell response of the peripheral blood lymphocytes reects an impaired immune response in the oral mucosa. Malnutrition in elderly denture wearers might be an underlying condition for an impaired immune response and predisposing to oral yeast carriage and subsequent infection (161). There is evidence that low vaginal cell concentrations of beta-carotene, an antioxidant with immunoenhancing properties, may alter the local immune response resulting in disturbances in the vaginal ora, overgrowth of yeasts, and the development of vaginal candidosis (162). As there are many similarities between the pathogenesis of candidal vaginitis and candidal denture stomatitis, this hypothesis might also be relevant with regard to denture stomatitis. Accordingly, adequate dietary intake of carrots, green-leafy vegetables, and other beta-carotene-rich sources may have a potential preventive

role against the development of Candida -associated denture stomatitis. Immunosuppression Systemic candidosis among hospitalized patients with acute leukemia may be due to a reduction in T-lymphocyte activity associated with a granulocytopenia (163). Local use of corticosteroids favors the development of oral candidosis (164, 165). These agents show many effects on the various types of cells, particularly on the CD4 + T cells (166). In a mouse model it was shown that local use of corticosteroids signicantly reduced the local level of CD + 4 T cells and that the number of C. albicans showed a parallel increase of up to 400 times the baseline level (167). Levels returned to normal once the treatment ended. The topical steroid application resulted in a disappearance of intraepithelial CD4 + T cells in the mucosa and a massive depletion of T cells in the regional lymphnodes. Systemic use of corticosteroids potentiated experimental oral candidosis in monkeys, probably by suppressing the non-specic inammatory responses and cell-mediated immunity against C. albicans (103). In denture wearers free cortisol in saliva may provide a selective growth advantage for oral Candida sp. (168). Furthermore, stress is associated with increased levels of cortisol in plasma and saliva and compromises cell-mediated immunity (169). Chronic stress could thus predispose for Candida -associated denture stomatitis as cortisol in saliva supports yeast growth and cortisol in plasma suppresses cell-mediated immunity. There is also evidence that C. albicans is able to produce an immunosuppressive toxin, gliotoxin, which was isolated in vaginal samples of 3 women with severe vaginal candidosis, but not in controls without vaginal candidosis (170). It is not known whether this mycotoxin is produced by Candida harboured in denture plaque or on the mucosa covered by the denture. Radiation therapy Candidosis is an infection that can contribute signicantly to the morbidity associated with radiation therapy of the oropharyngeal mucosa. During radiation therapy there is an increase of the yeast counts and an increase in the clinical signs of infection (171, 172). The causes of the increased risk of oral candidosis are decreased secretion of saliva and a decrease of salivary lactoferrin level, the latter inhibiting normally Candida cell growth and adhesion (173). These changes persist in patients with xerostomia that continues after radiation therapy. In a study on 27 consecutive patients receiving radiation to the head and neck, the patients were followed to assess risk factors for the development of oral candidosis (174). The presence of dentures (either partial or complete) was associated with a greater risk of pretreatment colonization in denture wearers (71%) than non-denture wearers and was associated

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with a greater number of positive cultures during and after treatment, with heavier Candida growth. The presence of dentures and their continuing pattern of use must therefore be assessed in these patients. Appropriate denture wearing habits should be introduced (110) and prophylactic use of antimycotic antibiotics for oral use and chlorhexidine for denture disinfection (175) should be considered. Diabetes mellitus There are some early observations indicating that diabetes mellitus, which has a prevalence of 1030% among older adults (176) may be associated with oral candidosis, particularly in denture wearers (177, 178). Cawson (179) reported on some cases of oral candidosis in denture wearers with diabetes and spontaneous remission of angular candidal lesions and denture stomatitis was observed when the diabetes was controlled (180). Finally, in patients with controlled diabetes, raised salivary glucose concentrations were observed (118); unsterilized samples of saliva from diabetes patients stimulated the growth of C. albicans in 6itro compared with saliva samples from controls. In some studies, the oral carriage rate of Candida has been estimated to be as high as 80% and increase in the yeast counts has also been observed (181). A more recent study found oral Candida infection in 12% of diabetic patients but in none of the closely matched controls (182). It was also found that the adhesion of C. albicans to buccal epithelial cells of diabetic patients was signicantly greater than to epithelial cells from non-diabetics. In a well-controlled study on 70 denture wearers with diabetes and 58 controls without diabetes, denture stomatitis associated with candidal colonization was observed signicantly more frequently in the diabetes patients (183); however, the frequency of candidal colonization was not signicantly increased in the diabetic patients as compared to the controls although the density of Candida species on the palatal mucosa was signicantly higher in the patients. In the aforementioned study it was also found that the in 6itro adherence of C. albicans to epithelial cells originating from the subjects was increased in diabetic patients versus controls; in diabetic patients with denture stomatitis versus diabetic patients without denture stomatitis; and in controls with denture stomatitis versus controls without denture stomatitis. It was suggested that reason for this could be accumulation of glycosylation products in epithelial cells originating from diabetic patients or high levels of glycogen in the epithelial cells originating from the inamed mucosa. Raised levels of IgG anti-Candida antibody and complement components exuding through the inamed mucosa, and not removed completely by the washes of the epithelial cells prior to the in 6itro assay, could probably also enhance the adherence of Candida. In conclusion, it seems that denture stomatitis is more common and more severe in patients with diabetes than in subjects with normal glucose metabolism. The reasons for this

could be increased adherence of Candida to epithelial cells in diabetic patients or impaired neutrophil function, the later found to be a predisposing condition for oral candidosis (184).

Antibiotic therapy The normal oral bacterial ora inhibits the colonization with Candida ssp. and, in situations where the normal ora is suppressed such as during treatment with broad-spectrum antibiotics, the colonization of the oral cavity may be greatly increased (185, 186). In experimental palatal candidosis in monkeys, prolonged topical treatment with tetracycline resulted in a more intense proliferation of Candida beneath the plate covering the mucosa and a more intense inammation than that caused by Candida alone (16). In experimental oral candidosis in rats, orally administrated tetracycline was able to enhance candidal colonization, invasive infection and the number and size of candidal lesions of the tongue (187 189). Experimental studies on the effect of antibiotics on gastrointestinal tract colonization of mice by C. albicans indicated that antibiotics with broad-spectrum activity that included anaerobes were associated with the highest increases in yeast counts compared with antibiotics with minimal aerobic activity (190). In a case-control study a clear relationship was found between prescribing of an oral antibiotic and the subsequent prescription of a vaginal antifungal drug (191). The diagnosis of vaginal candidosis was not conrmed by culturing; however, it was suggested that the increased frequency of vaginal symptoms was caused by an overgrowth of Candida following a suppression of the bacterial ora by broad-spectrum bactericidal antibiotics. As far as the oral cavity is concerned, topical treatment of herpetiform ulcers with tetracycline resulted in acute atrophic candidosis in 9 of 14 patients (192). Systemic antibiotics may possibly result in sufcient levels of antibiotics in saliva to suppress the oral bacterial ora (193). However, in a double-blind study on 96 male subjects followed for 6 months, those who received continuous tetracycline therapy did not show a higher prevalence of denture stomatitis, angular cheilitis, or positive yeast cultures compared with subjects receiving placebo (194). It is possible that the concentration of antibiotics in saliva, is not high enough to affect the balance of the mixed oral microbial ora or that the access to the denture-mucosa interface is too limited. Antibiotic therapy probably plays a minor role compared to the oral hygiene level and the denture wearing habits as a predisposing condition for denture stomatitis.

CONCLUSIONS Denture stomatitis is probably the most common presentation of oral fungal infections, affecting up to 50 to 60% of

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all denture wearers. The principal site for yeast colonization is the denture itself and the colonization on the tting denture surface is much heavier than that of the underlying mucosa. The yeast colonization associated with denture wearing is not caused by a comprehensive change of the oral microenvironment since the composition of the bacterial ora is essentially the same as in dental plaque associated with caries, i.e. a Gram-positive ora of which the predominant microorganisms are Streptococcus, Acti nomyces, and Lactobacillus species. However, also Staphy lococcus species were isolated regularly in denture plaque although they are not considered to be resident oral microorganisms. Yeast counts constitute on average 0.002% of the total viable counts in cases of healthy mucosa and 0.3% in stomatitis patients. The principal yeast isolated is C. albicans, but others include C. glabrata, C. tropicalis, C. parapsilosis, C. guilliermondii, and C. krusei. Considering the similarity in microora of denture plaque in stomatitis and mucosal health, as well as its large intraindividual variation, the quantity of denture plaque and the availability of nutrients for the microorganisms may be more important than its composition. Denture plaque is formed through colonization by microorganisms from the saliva and the oral mucosa and it develops by microbial adherence, aggregation and growth in the absence of appropriate denture hygiene, free salivary ow, and mucosal cleansing by the tongue. The nutrients for the growth are derived from the diet, the saliva, desquamated epithelial cells and inammatory exudate. In the plaque, a variety of harmful products may be produced by both the yeasts and the bacteria, including enzymes, toxins and microbial antigens. It is not known which products from which organisms provoke the mucosal inammation; however, once the mucosa is inamed its barrier function against microbial products is diminished. Protective immunity in Candida -associated denture stomatitis is mainly linked to SIgA antibodies and cell-mediated immunity. High serum antibodies against C. albi cans may indicate a severe infection. It is noteworthy that a longstanding candidal infection may result in a reversible suppression of in 6i6o and in 6itro cell-mediated immune response of circulating lymphocytes against C. albicans. However, there is no evidence that this represents an impaired immune response of clinical importance. Although Candida -associated denture stomatitis is not a serious condition in healthy persons, appropriate oral and denture hygiene are important measures to control the infection. It should be realized that oral candidosis could be the source of a more generalised Candida infection in seriously ill persons, especially in those subjected to radiation therapy of the orofacial region or prolonged treatment with antibiotics, corticosteroids or immunosuppressive drugs (195, 196).

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