Professional Documents
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Printed in Singapore. All rights reserved Journal compilation 2009 Blackwell Munksgaard
PERIODONTOLOGY 2000
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.
40
Oral mucosal fungal infections
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.
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.
42
Oral mucosal fungal infections
43
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.
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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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