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Periodontology 2000, Vol. 49, 2009, 39–59  2009 The Authors.

Printed in Singapore. All rights reserved Journal compilation  2009 Blackwell Munksgaard
PERIODONTOLOGY 2000

Oral mucosal fungal infections


L A K S H M A N P. S A M A R A N A Y A K E , W. K E U N G L E U N G & L I J I A N J I N

The frequency of mucosal and cutaneous fungal guillermondii and Candida krusei are also pathogenic
infections is increasing worldwide. One reason is to humans (129). Candida dubliniensis is a recently
likely to be the virtual ÔepidemicÕ of oral candidal described species first isolated from oral lesions in
infections that manifests in a variety of clinical guises HIV-infected individuals (119). C. dubliniensis has
as a result of the pandemic human immunodefi- now been recovered from many superficial and sys-
ciency virus (HIV) infection (106). These guises range temic oral lesions of various disease conditions,
from the classic pseudomembranous to the newly including periodontitis.
described erythematous variant, and linear gingival Clinically, oral candidiasis can be a frequent and
erythema first described in individuals with HIV significant source of oral discomfort, pain, dysguesia
infection (37). and aversion to food. In some patients with HIV
The remarkably high global incidence and preva- infection, oral candidiasis may also lead to second-
lence of oral candidiasis are results of the multiplicity ary, more distressing, complications, such as
of predisposing factors that facilitates the conversion esophageal candidiasis. A number of effective anti-
of commensal Candida to a parasitic existence. For fungal agents administered either topically or sys-
instance, it has been reported that 84–100% of HIV- temically are available for the management of oral
infected individuals develop at least one episode of candidiasis (49). These range from the classic poly-
colonization with Candida spp. and up to 90% of enes to the azole-group antimycotics, which in-
HIV-infected individuals develop symptomatic cludes the imidazoles and the newer triazoles. Other
psedudomembranous candidiasis or ÔthrushÕ, as it is potentially promising agents under development
classically known (4). Indeed, oropharyngeal candi- include saperconazole and voriconazole. Despite the
diasis can be used to predict the progress of HIV availability of such a multiplicity of agents, thera-
infection, as some 50% of the latter individuals who peutic failure is not uncommon. In oral environ-
present with oral candidiasis develop acquired mental niches the diluent effect of saliva and the
immunodeficiency syndrome (AIDS) within 3 years cleansing action of the oral musculature often tend
(104). The increasing prevalence of these and other to reduce the availability of the antifungals below
compromised patient groups in the community, the the effective therapeutic concentrations. Further-
usage of broad-spectrum antibiotics, cytotoxics and more, Candida biofilms that resist antifungal agent
corticosteroids, common endocrine disorders such as perfusion, on mucosal and inert surfaces such as
diabetes mellitus, and severe nutritional deficiencies prostheses, may also contribute to therapeutic fail-
have resulted in the resurgence of oral candidiasis as ure. Finally, poor compliance as a result of frequent
a relatively common illness [Table 1; (102)]. drug administration and associated adverse effects,
Candida albicans is the principal species associ- coupled with possible underlying immunodeficiency
ated with human oral mycoses (Fig. 1) and is the and emergence of drug resistance, can also impair
most virulent among pathogenic Candida spp. (109). therapy, leading to chronic recurrence of the
One possible reason is the ability of C. albicans to disease.
transform from the blastospore phase to the hyphal In addition to the common ailment of candidiasis,
phase. Germ tubes, which mark the onset of hyphal a number of other fungal infections, such as histo-
growth of C. albicans, are especially incriminated in plasmosis, penicilliosis, coccidioidomycosis and
the pathogenesis of candidiasis (27). However non- mucormycosis, are emerging as not so uncommon
albicans Candida spp., such as Candida glabrata, oral mycoses, particularly in HIV-infected individuals
Candida tropicalis, Candida parapsilosis, Candida (108, 114). In some of these infections, such as South

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Samaranayake et al.

Table 1. Factors that predispose the host to oral can- A


didiasis
Physiological Old age, infancy, pregnancy
Local trauma Mucosal irritation, poor
dental hygiene
Antibiotics Broad-spectrum antibiotics
in particular
Corticosteroids Steroid inhalers, systemic
steroids
Malnutrition High-carbohydrate diet,
iron, folate and vitamin B12
deficiencies
Endocrine disorders Hypoendocrine states (e.g. B
hypothyroidism, AddisonÕs
disease)
Malignancies Including blood disorders
(e.g. acute leukemia,
agranulocytosis)
Immune defects HIV infection, AIDS, thymic
aplasia
Xerostomia Caused by irradiation, drug
therapy, SjögrenÕs
syndrome, cytotoxic
drug therapy

Fig. 1. (A) A photomicrograph of a Gram-stained Candida


American blastomycosis, early signs of the disease albicans culture showing the characteristic (Grecian vase
can manifest on gingival tissue. shaped) blastospores and hyphal elements. (B) A scanning
The following review is divided into two sections. electron micrograph of Candida krusei blastospores
In the first section, oral mucosal manifestations of showing the characteristic Ôlong grain riceÕ appearance of
this particular species.
candidiasis and its management, including a
description of traditional as well as novel antifungal
agents, are provided, while the second section ad- Table 2. Classification of oral candidiasis as proposed
by Samaranayake (103)
dresses the oral manifestations of uncommon and
exotic mycoses. Primary oral candidiasis Secondary oral candidiasis
Acute forms Oral manifestations of
systemic mucocutaneous
Pseudomembranous
candidiasis as a result of
Clinical manifestations of oral Erythematous diseases such as athymic
candidiasis aplasia and candidiasis
Chronic forms endocrinopathy syndrome
Candida infections of the oral mucosa manifest in Hyperplastic
various guises. Hence, classification of oral Candida Nodular
infections is fraught with difficulties. It is generally
Plaque-like
accepted that oral candidiasis can be divided into two
broad categories, namely primary oral candidiasis Erythematous
and secondary oral candidiasis (Table 2) (110). Thus, Candida-associated lesions
candidal infections confined to oral and perioral tis-
Denture stomatitis
sues are considered to be primary oral candidiasis,
and disorders where oral candidiasis is a manifesta- Angular cheilitis
tion of generalized systemic candidal infections are Median rhomboid
categorized as secondary oral candidiasis (10). The glossitis
primary oral candidiases are subdivided into three Linear gingival erythema
major variants, viz.: pseudomembranous, erythema-

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Oral mucosal fungal infections

tous, and hyperplastic. The latter usually manifests as


a chronic lesion, whilst the others in general present
as acute lesions. In addition to these well-defined
candidal lesions, a group of diseases that are termed
ÔCandida-associated lesionsÕ have been described
because their etiology is multifactorial either
with ⁄ without candidal infection ⁄ infestation. These
include Candida-associated denture stomatitis seen
mainly in complete denture wearers, angular cheili-
tis, median rhomboid glossitis and that most recently
described, namely linear gingival erythema.
There are two other candidal conditions described
in the literature that are yet to be acknowledged as Fig. 2. Thrush or pseudomembranous candidiasis lesions
of the buccal and gingival mucosa of a HIV-infected
specific disease entities. They are cheilo-candidiasis
person. Note the extensive white lesions including the
(21) and chronic multifocal candidiasis (53), which gingival margins.
do not fall strictly into any of the variants described
above. Cheilo-candidiasis presents as a chronic,
ulcerative granulating lesion of the vermilion area of
the lower lip. Chronic multifocal candidiasis causes
chronic, erythematous plaque-like lesions in two or
more sites in the mouth, palate or dorsum of the
tongue. These two disease entities will not be
described further in this review.

Primary oral candidiasis


Pseudomembranous candidiasis

Pseudomembranous candidiasis or ÔthrushÕ is classi- Fig. 3. Pseudomembranous candidiasis mixed with ey-
cally an acute infection, but it may persist for months thematous areas of the soft palate in an HIV-infected
person.
or even years in patients using corticosteroids topi-
cally or by aerosol, in HIV-infected individuals and areas, may complain of burning, tenderness or dys-
in other types of immunocompromised patients. phagia. Previous descriptions of a Ôraw, bleedingÕ
Pseudomembranous candidiasis affects approxi- mucosa after removal of the plaques are somewhat
mately 5% of newborns and 10% of debilitated misleading as the candidal hyphae virtually never
elderly subjects, especially those who are terminally penetrate beyond the outermost nonvital keratin
ill and who have serious underlying conditions such layer. If a bleeding surface is encountered then the
as leukemia and other malignancies. Although patient probably has a supervening problem, such as
pseudomembranous candidiasis is considered to be erosive lichen planus or pemphigus.
the classic form of oral candidiasis, this may not be
Erythematous candidiasis
the case as the eyrthematous variant (vide infra)
appears to be a more frequent, yet less commonly Erythematous candidiasis, which was previously
diagnosed form (53). known as antibiotic sore mouth, is associated with
Thrush is characterized by white patches on the corticosteroids, broad-spectrum antibiotics and, re-
surface of the buccal and labial mucosa, tongue and cently, with HIV infection. Erythematous candidiasis
the soft palate (Figs 2 and 3). The lesions develop and may arise as a consequence of persistent acute
form confluent plaques that resemble milk curd and pseudomembranous candidiasis when pseudomem-
can be easily wiped off with a tongue blade or gauze branes are shed, may develop de novo, or in HIV
to reveal an erythematous, erosive base underneath infection may precede pseudomembranous candidi-
(103). The white plaque consists of a tangled mass of asis. Erythematous candidiasis is the most common
fungal hyphae, blastospores, bacteria, inflammatory variant of candidiasis seen in HIV infection (108).
cells, fibrin and desquamated epithelial cells. Pa- Clinically, erythematous candidiasis appears as a red
tients, especially diabetics, with extensive erosive patch often on the mid-posterior dorsum of the

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Samaranayake et al.

Fig. 4. Mixed pseudomembranous and erythematous


candidiasis of the dorsum of the tongue in a patient on Fig. 6. Hyperplastic candidiasis of the buccal mucosal
tetracycline therapy. commissures in a heavy cigarette smoker.

Fig. 7. A Grocott-methanamine-silver stained histopath-


ological section of hyperplastic candidiasis. Black-stained
Fig. 5. Erythematous candidiasis of the hard palate in an hyphal elements invading the epithelium are evident.
HIV-infected individual.

tongue, palate, or buccal mucosa (Fig. 4). Lesions on translucent, whitish areas to large, dense, opaque
the dorsum of the tongue present as depapillated plaques, with hard and rough areas on palpation
areas. A ÔkissingÕ lesion may be seen on the palate (plaque-like lesions). The lesions may also present as
surface opposing the lingual lesion. Palatal erythem- homogenous or speckled lesions (nodular lesions). In
atous lesions are especially common in HIV infection contrast to pseudomembranous candidiasis, the
(Fig. 5). Erythematous candidiasis is usually asymp- hyperplastic candidiasis lesions do not rub off.
tomatic and may remain unnoticed if the clinician is Candida leukoplakias usually occur on the inside
not alert during examination of the oral mucosa. surface of one or both cheeks at the comissural areas
In contrast to the asymptomatic variant of ery- (Fig. 6) and less often on the lateral surfaces of the
thematous candidiasis, a more diffuse erythematous tongue. Candida leukoplakias are associated with
type may be seen in some individuals following malignant transformation; in some reports up to 15%
exposure to broad-spectrum antibiotics, especially may become malignant (127). Histology of hyper-
tetracyclines. Here, the patients complain of a scal- plastic candidiasis is characterized by candidal hy-
ded or burnt sensation of the mouth, although the phae within a hyperplastic epithelium accompanied
dorsal surface of the tongue shows the most dramatic by an inflammatory infiltrate (Fig. 7). Ideally, biopsy
appearance owing to the loss of filiform papillae. This should be performed when lesions do not respond to
condition was previously termed antibiotic sore antifungal medication.
mouth.

Hyperplastic candidiasis Candida-associated lesions


Hyperplastic candidiasis or candidal leukoplakia is In addition to the foregoing three major variants of
the least common of the triad of major clinical vari- oral candidiasis there are a number of other oral le-
ants. Hyperplastic candidiasis appears as chronic, sions associated with Candida, where the yeast is not
discrete raised lesions that vary from small, palpable, the sole etiologic agent.

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Oral mucosal fungal infections

Candida-associated denture stomatitis


(syn; chronic atrophic candidiasis,
denture sore mouth)
In Candida-associated denture stomatitis, the
characteristic clinical feature is chronic erythema
and edema of the mucosa in contact with the fit-
ting surface of the denture. Its primary etiology is
overgrowth of commensal Candida between the
denture surface and the palate where natural sali-
vary flow is restricted (21). The mucosa beneath the
mandibular dentures is almost never involved. Fig. 9. Papillary hyperplasia of the palate in Candida-
Apart from occasional soreness this condition is associated denture stomatitis (NewtonÕs type III) in a full-
usually symptomless. However, patients may com- denture wearer.
plain of an associated angular cheilitis and a
burning or tingling sensation beneath the denture.
Candida-associated denture stomatitis has been
Angular cheilitis
classified into three subtypes depending on the
severity of the lesion: Angular cheilitis ⁄ stomatitis is characterized by
• Type I: localized simple inflammation or pinpoint soreness, erythema and fissuring at the angles of the
hyperemia. mouth and is commonly associated with denture-
• Type II: an eythematous or generalized simple induced stomatitis (Fig. 10). Both yeasts and bacteria
type presenting as more diffuse erythema involving (especially Staphylococcus aureus) are involved as
part of, or the entire, denture-covered mucosa interacting and predisposing factors (21, 31, 128).
(Fig. 8). Angular stomatitis may present as an isolated ini-
• Type III: a granular or papillary type commonly tial feature of anemia or vitamin deficiency, such as
involving the central part of the hard palate and vitamin B12 deficiency, which will resolve once the
alveolar ridge (85) (Fig. 9). underlying disease has been treated. Iron-deficiency
It was thought that the latter papillary type of lesions anemia and other vitamin deficiencies may predis-
is essentially caused by the presence of the prosthe- pose to angular cheilitis. The lesion is a result of
ses. However, recent reports of similar lesions in HIV- maceration caused by deep, occlusive folds of the
infected individuals imply that the denture is not the skin at the angles of the mouth in individuals with
prime etiological factor for the condition (95). In reduced facial height caused by old age or ill-fitting
addition to Candida, co-factors such as bacterial dentures. However, angular stomatitis is seen in
infection, mechanical irritation, or rarely an allergic young individuals with HIV infection, possibly owing
reaction to the denture base material, have also been to impaired immunity (108). Exfoliative chelitis,
implicated in denture-induced stomatitis.

Fig. 10. Typical macerated and moist appearance of an


Fig. 8. Erythematous lesions of Candida-associated den- angular cheilitis lesion in an elderly denture wearer. These
ture stomatitis of the hard palate (NewtonÕs type II) in a lesions are typically due to mixed fungal and bacterial
full-denture wearer. (usually staphylococcal) infection.

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Samaranayake et al.

Fig. 11. Classic appearance of median rhomboid glossitis Fig. 12. Linear gingival erythema showing the ribbon-like,
in an elderly woman who also complained of burning red band circumscribing the gingival margin. Mixed can-
mouth. didal and bacterial infections are incriminated in this
disease entity observed in HIV-infected individuals.

predominantly of the lower lip, may also be associ-


ated with Candida, especially in HIV-infected pa- researchers consider it to be a progressive disease in
tients and may be considered another variant of HIV-infected individuals and a harbinger of more
candidiasis in AIDS patients (95). severe necrotizing periodontitis commonly seen with
very low CD4 counts. This condition has been
described both in HIV-infected adults and rarely
Median rhomboid glossitis in children (126). The linear gingival erythema lesions
Median rhomboid glossitis is characterized by an in three children with pediatric AIDS resolved after
area of papillary atrophy that is elliptical or rhomboid antifungal medication (126). In a recent study, Sac-
in shape, symmetrically placed centrally at the mid- charomyces cerevisiae was the only fungal species
line of the tongue, anterior to the circumvallate detected from subgingival plaque in a linear gingival
papillae (Fig. 11). Occasionally it presents with a erythema subject with high HIV load, implying that
hyperplastic, exophytic or even lobulated appear- opportunistic infections occur in a highly susceptible
ance. The relevance of Candida to the etiology of immunocompromised host (1).
median rhomboid glossitis has been controversial Candida spp. such as C. dubliniensis have also
(127) because a mixed bacterial and ⁄ or fungal flora been implicated in linear gingival erythema of AIDS
is associated with the condition (115). There are patients (126, 135). Although detailed microbiologi-
many reports of resolution of the lesion after topical cal and pathological data are currently lacking, it is
antifungal therapy, implying that, at least in some likely that linear gingival erythema is caused by
cases, the sole etiological agent is Candida. mixed bacterial and fungal opportunistic infections
superimposed on a background of generalized
immune deficiency.
Linear gingival erythema Linear gingival erythema is one of the oral mani-
Linear gingival erythema is the newest addition to the festations of HIV infection and is considered to be a
Candida-associated lesions and was first described in type of HIV-associated periodontal lesion, together
individuals infected with HIV (48, 87). The lesion is with necrotizing periodontal diseases, including nec-
defined as a nonplaque-induced gingivitis presenting rotizing ulcerative gingivitis, necrotizing ulcerative
a distinct erythematous band of at least 2 mm along periodontitis and necrotizing stomatitis (6, 25, 96, 124).
the margin of gingivae, with either diffuse or punc- It has been reported that the prevalence of linear
tuate erythema of the attached gingivae (Fig. 12). The gingival erythema ranges from 2 to 38% in subjects
amount of erythema is disproportionately intense for with HIV infection (42, 54, 60, 75, 111). Considering
the amount of plaque present, and usually no ulcer- the great variation in prevalence data, there is a
ation or pocketing ⁄ attachment loss is present (124). debate as to whether linear gingival erythema is
The lesion may be localized in the gingival margins of specific to HIV infection and what the appropriate
one or two teeth, or may be generalized. Linear gin- diagnostic guidelines for linear gingival erythema
gival erythema may or may not be accompanied by may be (124). For example, linear gingival erythema
occasional bleeding and discomfort (96). Some may be misdiagnosed as conventional gingivitis or

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Oral mucosal fungal infections

vice versa. The consensus, however, is that although topical antifungal therapy (58). In general, the more
linear gingival erythema may manifest in HIV-free severe the candidiasis, the greater the likelihood that
subjects, its prevalence is markedly greater in HIV- patients with chronic mucocutaneous candidiasis
infected individuals (124). It has recently been will exhibit immunological defects, especially in cell-
emphasized that a diagnosis of linear gingival ery- mediated immunity. Some studies suggest a defect in
thema should be assigned only to lesions that remain cytokine (interleukin-2 and gamma-interferon) pro-
resistant to plaque removal over multiple visits (124). duction in response to candidal and specific bacterial
Further well-designed clinical studies are warranted antigens, with reduced serum levels of IgG2 and IgG4
to clarify these diagnostic points. as a major cause of the infection (antigenic overload)
Clinically, treatment of linear gingival erythema (65).
consists of professional periodontal scaling and In brief, the oral lesions in these candidiasis pa-
debridement, effective plaque control at home and tients are recalcitrant and do not respond to routine
twice-daily mouth rinsing with 0.12% chlorhexidine topical antifungals, such as the polyenes, but may
gluconate for 2 weeks; antifungals are usually not respond to azole-group drugs that are systemically
needed (96). administered. However, owing to the underlying
immune deficiency, relapses are the rule following
the cessation of antifungal medication.
Secondary oral candidiases
A few patients experience chronic candidiasis from an
early age, sometimes with a definable immune defect Management of oral candidiasis
(e.g. chronic mucocutaneous candidiasis). Candidal
General
infections in these patients occur in the oral mucosa,
tongue (Fig. 13), skin and other body parts. These There have been many changes in the range and
secondary oral candidal infections have increased efficacy of medications designed to manage oral
recently because of the high prevalence of an attenu- candidiasis over the past 20 years. Treatment options
ated immune response, subsequently to diseases such vary from topical delivery of polyene agents up to four
as HIV infection, hematological malignancy and times a day, which was the sole mode, to systemic
aggressive treatment with cytotoxic agents. Here we delivery of azole agents ranging from weekly single
describe the classic, yet rare, chronic mucocutaneous doses of drugs (fluconazole) to a single dose per day
candidiasis syndrome that manifests with lesions in for a week or so (itraconazole) (Table 3). However,
the oral cavity as well as in other areas of the body. azoles, which were once considered as Ômagic bulletsÕ
for human mycoses, are gradually losing their potency
owing to the emergence of drug-resistant fungi,
Chronic mucocutaneous candidiasis
including a number of Candida spp. such as C. glab-
syndromes
rata and C. krusei. Hence, as a general rule, traditional
Chronic mucocutaneous candidiasis syndromes are a medication with the polyenes should be the first line
group of rare illnesses, in which there is persistent of treatment and the azoles should be kept as a second
mucocutaneous candidiasis that responds poorly to line of defense.
This section provides an overview of currently
available antifungal drugs for the management of oral
candidiasis and their prescribing details. In general,
antifungal drugs fall into three main categories: the
polyenes (nystatin and amphotericin B), the azoles
(miconazole, clotrimazole, ketoconazole, itraconaz-
ole and fluconazole), and newer investigational
agents that are currently undergoing clinical trials.
The anticandidal DNA analogue, 5-fluorocytosine,
mainly used for systemic candidiasis, is not discussed
in this review.

Polyene antifungals
Fig. 13. Chronic hyperplastic candidal lesions of the
dorsal tongue in a 14-year-old girl with chronic mucocu- Two polyenes – nystatin and amphotericin B – are
taneous candidiasis. commonly used for the treatment of oral candidiasis.

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