ORAL CANDIDIASIS : Etiology and pathogenesis, epidemiology, clinical findings, clinical manifestations, diagnosis, laboratory findings, management

1, Etiology and Pathogenesis

C.albicans, C.tropicalis, and C.glabrata comprise together over 80% of the species isolated from human Candida infection. to invade the mucosal lining, the microorganisms must adhere to the epithelial surface; therefore, strains of candida with better adhesion potential are more pathogenic than strains with poorer adhesion. 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 in uence of local and general predisposing factors. The local predisposing factors are able to promote growth of Candida or to affect the immune response of the oral mucosa. General predisposing factors are often related to the patient’s immune and endocrine status

The immune status can be affected by drugs as well as a dis- ease, which suppresses the adaptive or the innate immune system. Pseudomembranous candidiasis is also associated with fungal infections in young children, who do not have a fully developed immune system.

Denture stomatitis, angular cheilitis, and median rhom- boid glossitis are referred to as Candida-associated infections as these lesions may, in addition to Candida, be caused by bacteria.

2. Epidemiology

The prevalence of Candida, as part of the normal oral  ora, shows large geographic variations, but an average  gure of 35% has been calculated from several studies. With improved detection techniques, a prevalence as high as 90% has been proposed. Candida is more frequently isolated from women, and seasonal variations have been observed, with an increase during the summer months. Hospitalized patients have a higher prevalence of Candida.4 In healthy subjects, blood group O and nonsecretion of blood group antigens are separate and cumulative risk factors for oral carriage of C. albicans.

In denture-wearers, the prevalence of denture stomatitis varies, but in population studies, it has been reported to be approximately 50%.

3. Clinical Findings

Pseudomembranous Candidiasis. The acute form of pseu- domembranous candidiasis (thrush) is grouped with the primary oral candidiasis and is recognized as the classic Candida infection. The infection pre- dominantly affects patients medicated with antibiotics, immunosuppressant drugs, or a disease that suppresses the immune system.

The infection typically presents with loosely attached membranes comprising fungal organisms and cellular debris, which leaves an in amed, sometimes bleeding area if the pseudomembrane is removed. Less pronounced infections sometimes have clinical features that are dif cult to discri- minate from food debris. The clinical presentations of acute and chronic pseudomembranous candidiasis are indis- tinguishable. The chronic form emerged as a result of human immunode ciency virus (HIV) infections as patients with this disease may be affected by a pseudomembranous Candida infection for a long period of time. However, patients treated with steroid inhalers may also acquire pseudomembranous lesions of a chronic nature. Patients infrequently report symp- toms from their lesions, although some discomfort may be experienced from the presence of the pseudomembranes.

Erythematous Candidiasis. The erythematous form of candidiasis was previously referred to as atrophic oral candidiasis. An erythematous surface may not just re ect atrophy but can also be explained by increased vasculari- zation. The lesion has a diffuse border, which helps distinguish it from erythroplakia, which has a sharper demarcation. Erythematous candidiasis may be considered a successor to pseudomembranous candidiasis but may also emerge de novo.1 The infection is predominantly encountered in the palate and the dorsum of the tongue of patients who are using inhalation steroids. Other predisposing factors that can cause erythematous candidiasis are smoking and treat- ment with broad-spectrum antibiotics. The acute and chronic forms present with identical clinical features.

Chronic Plaque-Type and Nodular Candidiasis. The chronic plaque type of oral candidiasis replaces the older term, candidal leukoplakia. The typical clinical presentation is characterized by a white plaque, which may be indistinguish- able from an oral leukoplakia.

A positive correlation between oral candidiasis and moderate to severe epithelial dysplasia has been observed, and both the chronic plaque-type and nodular candidiasis have been associated with malignant transforma- tion, but the probable role of yeasts in oral carcinogenesis is unclear. It has been hypothesized that it acts through its capacity to catalyze nitrosamine production.

Denture Stomatitis. The most prevalent site for denture stomatitis is the denture-bearing palatal mucosa. It is unusual for the mandibular mucosa to be involved. Denture stomatitis is classi ed into three different types.12 Type I is localized to minor erythematous sites caused by trauma from the denture. Type II affects a major part of the denture- covered mucosa. In addition to the features of type II, type III has a granular mucosa in the central part of the palate. The denture serves as a vehicle that protects the microorganisms from physical in uences such as salivary  ow. The micro ora is complex and contains, in addition to Candida, bacteria from several genera, such as Streptococcus, Veillonella, Lactobacillus, Prevotella (formerly Bacteroides), and Actinomyces. It is not known to what extent these bacteria participate in the pathogenesis of denture stomatitis.

Angular Cheilitis. Angular cheilitis is infected  ssures of the commissures of the mouth, often surrounded by erythema. The lesions are frequently coinfected with both Candida and Staphylococcus aureus. Vitamin B12, iron de - ciencies, and loss of vertical dimension have been associated with this disorder. Atopy has also been associated with the for- mation of angular cheilitis. Dry skin may promote the devel- opment of  ssures in the commissures, allowing invasion by the microorganisms. Thirty percent of patients with denture stomatitis also have angular cheilitis, which only affects 10% of denture-wearing patients without denture stomatitis.

Median Rhomboid Glossitis. Median rhomboid glossitis is clinically characterized by an erythematous lesion in the center of the posterior part of the dorsum of the tongue. As the name indicates, the lesion has an oval con guration. This area of erythema resulting from atrophy of the  liform papillae and the surface may be lobulated. The etiology is not fully clari ed, but the lesion frequently shows a mixed bacterial/fungal micro ora. Biopsies yield Candida hyphea in more than 85% of the lesions. Smokers and denture-wearers have an increased risk of developing median rhomboid glos- sitis as well as patients using inhalation steroids. Sometimes a concurrent erythematous lesion may be observed in the palatal mucosa (kissing lesions). Median rhomboid glossitis is asymptomatic, and management is restricted to a reduction in predisposing factors. The lesion does not entail any increased risk for malignant transformation.

Oral Candidiasis Associated with HIV. More than 90% of acquired immune de ciency syndrome (AIDS) patients have had oral candidiasis during the course of their HIV infection, and the infection is considered a portent of AIDS development. The most common types of oral candidiasis in conjunction with HIV are pseudomembranous candidiasis, erythematous candidiasis, angular cheilitis, and chronic hyperplastic candidiasis. As a result of the highly active antiretroviral therapy (HAART), the prevalence of oral candidiasis has decreased substantially. 

4. Clinical Manifestations

Secondary oral candidiasis is accompanied by systemic mucocutaneous candidiasis and other immune de - ciencies. Chronic mucocutaneous candidiasis (CMC) embraces a heterogeneous group of disorders, which, in addi- tion to oral candidiasis, also affect the skin, typically the nail bed and other mucosal linings, such as the genital mucosa. 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 affections may involve the tongue, and white hyperplastic lesions are seen in conjunction with  ssures. CMC can occur as part of endocrine disorders as hyperparathyroidism and Addison’s disease. Impaired phagocytic function by neutro- philic granulocytes and macrophages caused by myeloper- oxidase deficiency has also been associated with CMC. Chediak-Higashi syndrome, an inherited disease with a reduced number of impaired neutrophilic granulocytes, lends further support to the role of the phagocytic system in Candida infections as these patients frequently develop candidiasis. Severe combined immunode ciency syndrome is character- ized by a defect in the function of the cell-mediated arm of the immune system. Patients with this disorder frequently con- tract disseminated Candida infections. Thymoma is a neo- plasm of thymic epithelial cells that also entails systemic can- didiasis. Thus, both the native and adaptive immune systems are critical to prevent development of systemic mucocutaneous candidiasis.

4. Diagnosis and Laboratory Findings 

The presence of Candida as a member of the commensal  ora complicates the discrimination of the normal state from infec- tion. It is imperative that both clinical  ndings and laboratory data are balanced in order to arrive at a correct diagnosis. Sometimes antifungal treatment has to be launched to assist in the diagnostic process.

Smear from the infected area, which comprises epithelial cells, creates opportunities for detection of the yeasts. The material obtained is  xed in isopropyl alcohol and air-dried before staining with periodic acid–Schiff (PAS). The detection of yeast organisms is considered a sign of infection. This tech- nique 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 dis- criminate between different Candida species, an additional examination can be performed on Pagano-Levin agar. Imprint culture technique can also be used where sterile plastic foam pads (2.5x2.5 cm) are submerged in Sabouraud broth and placed on the infected surface for 60 seconds. The pad is then  rmly 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 tech- niques are primarily used in parallel with other diagnostic methods to get an adequate quanti cation of Candida. Patients who display clinical signs of oral candidiasis usually have more than 400 CFU/mL.

In chronic plaque-type and nodular candidiasis, cul- tivation techniques have to be supplemented by a histo- pathologic examination. This examination is primarily performed to identify the possible presence of epithelial dysplasia and to identify invading Candida organisms by PAS staining. However, for the latter, there is a de nitive risk of false-negative results.

5. Management 

Before starting antifungal medication, it is necessary to iden- tify any predisposing factor. Local factors are often easy to identify but sometimes not possible to reduce or eradicate. Antifungal drugs have a primary role in such cases. The most commonly used antifungal drugs belong to the groups of polyenes or azoles. Polyenes such as nystatin and amphotericin B are the  rst alternatives in treatment of pri- mary oral candidiasis and are well tolerated. Polyenes are not absorbed from the gastrointestinal tract and are not associated with development of resistance. They exert the action through a negative effect on the production of ergosterol, which is critical for the Candida cell membrane integrity. Polyenes can also affect the adherence of the fungi.

Although rarely realistic, permanent removal of the den- ture is an effective treatment for denture stomatitis. However, elimination or reduction of predisposing factors should always be the  rst goal for treatment of denture stomatitis as well as other opportunistic infections. This involves improved den- ture 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. Denture cleaning also disturbs the maturity of a microbial environment beneath the denture. As porosities in the denture harbour microorganisms that may not be accessible to physical cleaning, the denture should be stored in antimicrobial solutions. Different solutions, including alkaline peroxides, alkaline hypochlorites, acids, disinfectants, and enzymes, have been suggested. The latter seems to be most effective against Candida. Chlorhexidine may be used but can discolor the denture and counteracts the effect of nystatin.

Type III denture stomatitis may be treated with surgical excision if it is necessary to eradicate microorganisms present in the deeper  ssures of the granular tissue. If this is not suf-  cient, 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 patient being aware of its presence. However, the chronic in ammation may result in increased resorption of the denture-bearing bone.

Topical treatment with azoles such as miconazole is the treatment of choice in angular cheilitis often infected by both S. aureus and Candida. This drug has a biostatic effect on S. aureus in addition to the fungistatic effect to Candida. Fusidic acid (2%) can be used as a complement to the anti- fungal drugs. If angular cheilitis comprises an erythema sur- rounding the  ssure, a mild steroid ointment may be required to suppress the in ammation. To prevent recurrences, patients have to apply a moisturizing cream, which will prevent new  ssure formation.

Systemic azoles may be used for deeply seated primary candidiasis, such as as chronic hyperplastic candidiasis, den- ture 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 war- farin, leading to an increased bleeding propensity. The adverse effect is also valid for topical application as the azoles are fully or partly resorbed form the gastrointestinal tract. Development of resistance is particularly compelling for  uconazole in HIV patients. In such cases, ketoconazole and itraconazole have been recommended as alternatives. However, cross-resistance has been reported between  uconazole 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.

The prognosis of oral candidiasis is good given that pre- disposing factors associated with the infection are reduced or eliminated. Persistent chronic plaque-type and nodular candi- diasis have been suggested to entail an increased risk for malignant transformation compared with leukoplakias not allied with a Candida infection. Patients with primary candidiasis are also at risk if systemic predisposing factors arise. For example, patients with severe immunosuppression as seen in conjunction with leukemia and AIDS may encounter disseminating candidiasis with a fatal course.

Source : 

Burket's Oral Medicine. Eleventh Edition.2008.