Download Ecology of Candida-associated Denture Stomatitis

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Ecology of Candida-associated Denture Stomatitis
Ejvind Budtz-Jørgensen
From the Department of Gerodontology and Removable Prosthodontics, University of Geneva, Geneva,
Switzerland
Correspondence to: Ejvind Budtz-Jørgensen, Section de médecine dentaire, GERAD, 19 rue Barthélemy-Menn,
CH-1205 Geneva, Switzerland. Tel: + 41 22 382 9131; Fax: + 41 22 372 94 97; E-mail: [email protected]
Microbial Ecology in Health and Disease 2000; 12: 170–185
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-specific inflammatory 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
flora. The colonization of the fitting 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 flow 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 fitting 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 microflora, host-parasite relationship.
In adults, the resident oral microflora 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 microflora
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 microflora 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 flow 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
inflammatory 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 specific 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 microflora in denture wearers, i.e. the denture
plaque on the fitting 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 microflora.
Microbial Ecology in Health and Disease
Ecology of Candida-associated denture stomatitis
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 inflamed
mucosa and the dentures and increased levels of anti-Candida antibody titres in colonized individuals (11, 12). Furthermore, antimycotic treatment suppressing the yeast flora
often produces clinical improvement of the inflamed 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 significant 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 five patients before and after antifungal
therapy. The bacterial counts of both 2-day-old and 7-dayold plaque showed insignificant 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 2–3 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 inflammatory 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
171
tape to the fitting 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 B50 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 flora 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 fissures (22).
A subsequent microbiological study was carried out to
characterise the predominant cultivable microflora of
plaque on removable dentures in individuals with healthy
oral mucosa (23). In this study, plaque from the fitting
surface of full upper dentures in 8 individuals with healthy
palatal mucosa was examined. To characterise the predominant cultivable flora, 916 isolates i.e. 100 – 128 from
each denture sample were subcultured from anaerobic
roll-tubes for further identification. In this study, high
dilutions of suspensions of denture plaque were used to
characterize the microflora. Using this technique, microorganisms constituting small proportions of the flora 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 five of the denture samples and the yeast
counts corresponded to 0.002% (median) of the total vi-
172
E. Budtz-Jørgensen
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 flora in denture wearers (25).
A further characterization of the yeast flora 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 flora of denture
plaque associated with denture stomatitis plaque was collected from the fitting 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 purification. In all, 1249 isolates
Table I
Predominant culti6able bacterial flora of old denture plaque (% of
isolates) in stomatitis patients and denture wearers with healthy
oral mucosae (27).
Gram-positive cocci
Streptococcus species
Staphylococcus species
Gram-positive rods
Actinomyces species
Proprionibacterium species
Eubacterium species
Lactobacillus species
Gram-negative cocci
Veillonella species
Unclassified
Gram-negative rods
Bacteroides species
Actinobacillus actinomycetemcomitans
Unclassified
Stomatitis
Healthy mucosa
43
36
7
40
13
3
51
43
8
37
26
0.8
–
22
15
0
15
0.7
0.6
0.1
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 flora 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 flora. A further classification 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 flora, 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 flora of denture
plaque.
Regarding the composition of the yeast flora in patients
affected by denture stomatitis there is no evidence that it
differs from that observed in non-infected carriers of Candida. 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
figures 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 flora on the fitting 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 inflammatory reaction of
the mucosa in contact with the contaminated denture is
likely to have some effect on the composition of the
resident oral microflora. However, quantitative cultural
Ecology of Candida-associated denture stomatitis
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 fitting 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 flange were
significantly lower than those originating from the fitting
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 flange.
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 flora 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 inflamed mucosal sites
and the occurrence of yeast colonies (30–35). In one
study, the microflora of normal and inflamed 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 significant differences were found in the frequency
isolation of any specific type of microorganism, except
that Candida were isolated from the pathologic tissue
and not from healthy tissue. Other studies have confirmed that the resident bacterial flora of the mucosa
in denture stomatitis is mainly Gram-positive, the predominant species being streptococci, staphylococci and
lactobacilli (37–40). 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.
173
STRUCTURE OF DENTURE PLAQUE
Transmission and scanning electron microscopic studies of
denture plaque have shown that the bacteria predominated
the microflora 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 filamentous organisms are also present (20, 41).
Further, the majority of these microorganisms were classifiable as Gram-positive which is in agreement with cultural studies both from the mucosa and the fitting 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
fixation. 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 confirmed 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
fitting 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 superficial palatal
epithelial cells from where they may act as sources of
plaque development on the fitting 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
174
E. Budtz-Jørgensen
Table II
Factors affecting adhesion of yeasts (60).
Factors related to yeast cells
Medium/cultivation
Phenotype
Germ tubes/Hyphae
Extracellular polymeric material
Floccular/fibrillar 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 fitting 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 fitting 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 flora on the fitting denture in
individuals affected by denture stomatitis is similar to that
encountered in other yeast-associated lesions of the oral
mucosa, with C. albicans identified 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 microflora 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 flora 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 significant reduction of the number of positive cultures of yeasts
from the oral sites and the stool samples. However, after
cessation of treatment the mycotic flora 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 fitting 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 fitting
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 fibrillar 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 influence 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
significantly 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
Ecology of Candida-associated denture stomatitis
surfaces is mediated by selected salivary components (73).
However, also serum proteins derived from the inflammatory 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
identified.
Since bacteria constitute the major part of the denture
plaque microflora, 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 superficially on the
surface of a polysaccharide layer formed by the cocci
which had colonized the rod surface and was strongly
adherent. These findings were confirmed in a subsequent
study showing that firm 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 difficult 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
fitting 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 (82–84). Indeed, in one in 6itro study penetration by yeasts of the
contamined denture surface occurred after 8 to 24 hours
incubation (85).
175
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 superficial 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 filaments (pseudohyphae of Candida) are usually
abundant in smears obtained from the fitting 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 (4–5)
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
176
E. Budtz-Jørgensen
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.
HYPERSENSITIVITY TO CANDIDA
The inflammatory 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 inflammatory cell infiltrate
(101). However, the extent to which bacterial or candidal
antigens contribute to the inflammation is not known.
There is experimental evidence that a delayed-type hypersensitivity reaction against C. albicans contributes to
the inflammation. In experimental Candida-associated
denture stomatitis re-inoculation with C. albicans produced histologic evidence of a delayed hypersensitivity
reaction dominated by a subepithelial lymphocyte
infiltration (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 superficial 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.
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 inflammatory condition
(54, 105).
Oral hygiene
Most authors seem to agree that a significant 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 significantly 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 significant 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 fitting denture surface produced microbial counts which correlated with the clinical score for
denture cleanliness and which was significantly 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-fitting
surface of the denture is also conducive to improved
denture hygiene and a decrease of the yeast counts (111,
112).
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 flora (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 fitting denture surface was found
in all subjects with clinical signs of aggravated or initiated
denture stomatitis.
Ecology of Candida-associated denture stomatitis
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 findings
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 flow beneath the dentures. In subjects and regions of
the mouth with a low saliva flow, a low pH of both fasting
and carbohydrate-exposed dental plaque has been
recorded (123). Reduced saliva flow 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 flow
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 significantly higher in those with reduced salivary flow 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 flow
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
177
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 fluid inhibits the growth of C. albicans 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 identified 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
fluid are decreased in the absence of teeth. Furthermore,
resting saliva flow rates are significantly 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 fitting 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 modified 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 specific immunity (serum and salivary
antibiotics, cell-mediated immunity, activation of cytotoxic
cells) and non-specific 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 inflamed palatal tissues of denture stomatitis
(101, 143); however, the specificity 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
178
E. Budtz-Jørgensen
importance in this type of superficial 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 first-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-fitting 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 (157–159). 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 reflects 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 flora,
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 significantly 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-specific inflammatory 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 significantly
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
Ecology of Candida-associated denture stomatitis
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 10–30% 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 significantly 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 significantly more
frequently in the diabetes patients (183); however, the
frequency of candidal colonization was not significantly
increased in the diabetic patients as compared to the
controls although the density of Candida species on the
palatal mucosa was significantly 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 inflamed mucosa. Raised levels of IgG anti-Candida antibody
and complement components exuding through the inflamed 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
179
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 flora inhibits the colonization
with Candida ssp. and, in situations where the normal flora
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
inflammation 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 confirmed 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
flora 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 sufficient levels of antibiotics in saliva to suppress the oral bacterial flora (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 flora 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
180
E. Budtz-Jørgensen
all denture wearers. The principal site for yeast colonization is the denture itself and the colonization on the fitting
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 flora is essentially the same as in dental plaque
associated with caries, i.e. a Gram-positive flora of which
the predominant microorganisms are Streptococcus, Actinomyces, and Lactobacillus species. However, also Staphylococcus 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 microflora 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
flow, and mucosal cleansing by the tongue. The nutrients
for the growth are derived from the diet, the saliva,
desquamated epithelial cells and inflammatory 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 inflammation; however, once the mucosa is inflamed
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. albicans 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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