Oral Candidiasis

Oral candidiasis is the most prevalent opportunistic infection

affecting the oral mucosa. In the vast majority of cases, the
lesions are caused by Candida albicans. The pathogenesis is
not fully understood, but a number of predisposing factors
have been shown to convert C. albicans from the normal
commensal flora (saprophytic stage) to a pathogenic organism
(parasitic stage). C. albicans is usually a weak pathogen,
and candidiasis is said to affect the very young, the very
old, and the very sick.1 Most candidal infections only affect
mucosal linings, but rare systemic manifestations may have
a fatal course.
Oral candidiasis is divided into primary and secondary
infections (Table 5-1).1 The primary infections are restricted
to the oral and perioral sites, whereas secondary infections
are accompanied by systemic mucocutaneous manifestations.
Etiology and Pathogenesis
C. albicans, C. tropicalis, and C. glabrata comprise together
over 80% of the species isolated from human candidal infections.
1 To invade the mucosal lining, the microorganisms
must adhere to the epithelial surface; therefore, candidal
strains with better adhesion potential are more virulent than
strains with poorer adhesion ability. The yeasts’ penetration of
the epithelial cells is facilitated by their production of lipases,
and for the yeasts to remain within the epithelium, they must
overcome constant desquamation of surface epithelial cells.
There is an apparent association between oral candidiasis
and the influence of local and general predisposing factors.
The local predisposing factors (Table 5-2) are able to promote
growth of the yeast or to affect the immune response
of the oral mucosa. General predisposing factors are often
related to an individual’s immune status and endocrine status
(see Table 5-2). Drugs as well as diseases, which suppress
the adaptive or the innate immune system can affect the
susceptibility of the mucosal lining. Pseudomembranous
candidiasis is also associated with fungal infections in young
children, who neither have a fully developed immune system
nor a fully developed oral microflora.
Denture stomatitis, angular cheilitis, and median
rhomboid glossitis are referred to as Candida-associated
infections as bacteria may also cause these infections.2
Angular Cheilitis
Angular cheilitis presents as infected fissures of the commissures
of the mouth, often surrounded by erythema
(Figure 5-6).14,15 The lesions are frequently coinfected with
both Candida albicans and Staphylococcus aureus. VitaminB12
deficiency, iron deficiencies, and loss of vertical dimension
have been associated with this disorder. Atopy has also been
associated with the formation of angular cheilitis.16 Dry skin
may promote the development of fissures in the commissures,
allowing invasion by the microorganisms. Thirty percent of
patients with denture stomatitis also have angular cheilitis,
but this infection is only seen in 10% of denture-wearing
patients without denture stomatitis.17
Clinical Manifestations
Secondary oral candidiasis (see Table 5-1) is accompanied
by systemic mucocutaneous candidiasis and other immune
deficiencies.20 Chronic mucocutaneous candidiasis (CMC)
embraces a heterogeneous group of disorders, which, in addition
to oral candidiasis, also affect the skin, typically the nail bed
and other mucosal linings, such as the genital mucosa.21 The
face and scalp may be involved, and granulomatous masses can
be seen at these sites. Approximately 90% of the patients with
CMC also present with oral candidiasis. The oral manifestations
may involve the tongue, and white plaque-like lesions are seen
in conjunction with fissures. CMC can occur as part of endocrine
disorders, including hyperparathyroidism and Addison’s
disease. Impaired phagocytic function by neutrophilic granulocytes
and macrophages caused by myeloperoxidase deficiency
have also been associated with CMC. Chediak-Higashi syndrome,
an inherited disease with a reduced and impaired
number of neutrophilic granulocytes, lends further support
to the role of the phagocytic system in candidal infections as
these patients frequently develop candidiasis. Severe combined
immunodeficiency (SCID) syndrome is characterized by a
defect in the function of the cell-mediated arm of the immune
system. Patients with this disorder frequently contract disseminated
candidal infections. Thymoma is a neoplasm of thymic
epithelial cells that also entails systemic candidiasis. Thus, both
the native and adaptive immune systems are critical to prevent
development of systemic mucocutaneous candidiasis.
Diagnosis and Laboratory Findings
The presence of candidal microorganisms as a member of the
commensal flora complicates the discrimination of the normal
state from infection. It is imperative that both clinical
findings and laboratory data (Table 5-3) are balanced in order
to arrive at a correct diagnosis. Sometimes antifungal treatment
has to be initiated to assist in the diagnostic process.
Smear from the infected area comprising epithelial cells,
creates opportunities for detection of the yeasts. The material
is fixed in isopropyl alcohol and air-dried before staining with
periodic acid–Schiff (PAS). The detection of yeast organisms
in the form of hyphae- or pseudohyphae-like structures is
usually considered a sign of infection although these structures
have also been identified in normal oral mucosa.22
This technique is particularly useful when pseudomembranous
oral candidiasis and angular cheilitis are suspected. To
increase the sensitivity, a second scrape can be transferred to
a transport medium followed by cultivation on Sabouraud
agar. To discriminate between different candidal species, an
additional examination can be performed on Pagano-Levin
agar. Imprint culture technique can also be used where sterile
plastic foam pads (2.5 × 2.5 cm) are submerged in Sabouraud
broth and placed on the infected surface for 60 seconds. The
pad is then firmly pressed onto Sabouraud agar, which will
be cultivated at 37°C. The result is expressed as colony forming
units per cubic millimeter (CFU/mm2). This method is
a valuable adjunct in the diagnostic process of erythematous
candidiasis and denture stomatitis as these infections consist
of fairly homogeneous erythematous lesions. Salivary
culture techniques are primarily used in parallel with other
diagnostic methods to obtain an adequate quantification of
candidal organisms. Patients who display clinical signs of
oral candidiasis usually have more than 400 CFU/mL.23
In chronic plaque-type and nodular candidiasis, cultivation
techniques have to be supplemented by a histopathologic
examination. This examination is primarily performed
to identify the presence of epithelial dysplasia and to identify
invading candidal organisms by PAS staining. However, for
the latter, there is a definitive risk of false-negative results.

Management
Treatment for fungal infections, which usually include antifungal
regimens, will not always be successful unless the
clinician addresses predisposing factors that may cause recurrence.
Local factors are often easy to identify but sometimes
not possible to reduce or eradicate. Antifungal drugs have a
primary role in such cases. In smokers, cessation of the habit
may result in disappearance of the infection even without
antifungal treatment (Figure 5-9A and B). The most commonly
used antifungal drugs belong to the groups of polyenes
or azoles (Table 5-4). Polyenes such as nystatin and amphotericin
B are usually the first choices in treatment of primary
oral candidiasis and are both well tolerated. Polyenes are not
absorbed from the gastrointestinal tract and are not associated
with development of resistance.24 They exert the action
through a negative effect on the production of ergosterol,
which is critical for the yeast’s cell membrane integrity.
Polyenes can also affect the adherence of the fungi.25
Whenever possible, elimination or reduction of predisposing
factors should always be the first goal for treatment of
denture stomatitis as well as other opportunistic infections.
This involves improved denture hygiene and a recommendation
not to use the denture while sleeping. The denture
hygiene is important to remove nutrients, including
desquamated epithelial cells, which may serve as a source
of nitrogen, which is essential for the growth of the yeasts.
Denture cleaning also disturbs the maturity of a microbial
environment established under the denture. As porosities in
the denture can harbor microorganisms, which may not be
removed by physical cleaning, the denture should be stored
in antimicrobial solutions during the night. Different solutions,
including alkaline peroxides, alkaline hypochlorites,
acids, disinfectants, and enzymes, have been suggested.14
The latter seems to be most effective against candidal strains.
Chlorhexidine may also be used but can discolor the denture
and also counteracts the effect of nystatin.
Type III denture stomatitis may be treated with surgical
excision in an attempt to eradicate microorganisms present
in the deeper fissures of the granular tissue. If this is not sufficient,
continuous treatment with topical antifungal drugs
should be considered. Patients with no symptoms are rarely
motivated for treatment, and the infection often persists
without the patients being aware of its presence. However,
the chronic inflammation may result in increased resorption
of the denture-bearing bone.
Topical treatment with azoles such as miconazole is the
treatment of choice for angular cheilitis 27 often infected by both
S. aureus and candidal strains. This drug has a biostatic effect
on S. aureus in addition to the fungistatic effect. Retapamulin
can be used as a complement to the antifungal drugs. If angular
cheilitis comprises an erythema surrounding the fissure, a
mild steroid ointment may be required to suppress the inflammation.
To prevent recurrences, patients have to apply a moisturizing
cream, which may prevent new fissure formation.28
Systemic azoles may be used for deeply seated primary
candidiasis, such as chronic hyperplastic candidiasis,
denture stomatitis, and median rhomboid glossitis with a
granular appearance, and for therapy-resistant infections,
mostly related to compliance failure. There are several disadvantages
with the use of azoles. They are known to interact
with warfarin, leading to an increased bleeding propensity.
This adverse effect may also be present with topical application
as the azoles are fully or partly resorbed from the
gastrointestinal tract. Development of resistance is particularly
compelling for fluconazole in individuals with HIV
disease.29 In such cases, ketoconazole and itraconazole have
been recommended as alternatives. However, cross-resistance
has been reported between fluconazole on the one hand
and ketoconazole, miconazole, and itraconazole on the other.
The azoles are also used in the treatment of secondary oral
candidiasis associated with systemic predisposing factors and
for systemic candidiasis.