Oral candidosis

June 5, 2017 | Autor: Stephen Challacombe | Categoria: Disease susceptibility, Humans, Differential Diagnosis, Risk factors, Clinical Sciences, Risk Factors
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Oral Candidosis: CAMILE S. FARAH, BDSc, PhD ROBERT B. ASHMAN, PhD, DSc STEPHEN J. CHALLACOMBE, PhD, BDS, FRCPath, FDSRCSE, FMedSci

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any Candida species are commensals of the oral mucosa. They are usually innocuous, but they can cause disease when conditions are favorable. These organisms typically colonize mucocutaneous surfaces, which can be portals of entry into deeper tissues when host defenses are compromised.1 The advent of the human immunodeficiency virus (HIV) and AIDS has resulted in a resurgence of oral Candida infections that were formerly seen mainly in immunocompromised patients, or in persons at the extreme ends of the age spectrum. In this article we review the pathogenesis, classification, clinical and histopathological presentation, and diagnosis and management of oral candidosis. We also present current research concepts relating to host defense mechanisms against oral Candida albicans infections.

Etiology and Pathogenesis Candidosis is most commonly caused by the yeast Candida albicans, and to a far lesser extent C. parapsilosis, C. tropicalis, C. glabrata, C. krusei, C. pseudotropicalis, and C. guilliermondi.2 More recently, oral candidosis has been associated with C. dubliniensis in HIV-infected individuals.3 Candida albicans is a commensal residing in the oral cavity of the majority of healthy humans.2 It is a dimorphic fungus that can exist both in a yeast phase (blastospore, blastoconidial) and a hyphal (mycelial) phase. In the yeast phase C. albicans are 2 to 8 ␮m ⫻ 3 to 14 ␮m in size, but hyphae can extend a few hundred micrometers.4 They do not undergo a sexual cycle, and they reproduce by multilateral budding. Depending on the environmental conditions, they may develop either in the mycelial form, composed of long branching septae or filaments, or as spherical or ovoid yeast cells. Dimorphism is not only relevant to the pathogenicity of the yeast, but also to the clinical problems of diagnosis and treatment.4 From the School of Dentistry, The University of Queensland, Brisbane, Australia; and Division of Oral Medicine, Pathology, Microbiology, and Immunology, Guys, Kings, and St. Thomas’ Dental Institute, Guys Hospital, London, UK. Address correspondence to Camile S. Farah, BDSc, PhD, Oral Pathology, Oral Biology and Pathology, School of Dentistry, The University of Queensland, Brisbane 4072, Queensland, Australia. © 2000 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010

It is generally accepted that host factors play an equal if not a more important role than organism virulence attributes in the pathogenesis of oral candidosis. The local intraoral environmental milieu, such as the presence of prostheses, also plays a crucial role in the disease process. Indeed, it is a combination of the microbial virulence factors, environmental factors, and host defense factors that determine the disease process and the various manifestations of infection. The classification of these is complex and is discussed later.

Epidemiology Candida albicans is the most common Candida species isolated from the oral cavity both in health and disease.5 Symptom-free oral carriage of Candida organisms has been recognized for many years. The reported prevalence in clinically normal mouths of healthy adults ranges from 3% to 48%,6 and 45% to 65% in healthy children.2 The oral carriage of yeasts is higher in hospitalized than ambulant patients, with a median carriage rate of 54.7% for all species and 38.1% for C. albicans alone.7

Factors Predisposing to Oral Candida Infections Although the transition from commensalism to disease may be associated with the virulence characteristics of the organism, it is widely accepted that host factors are of paramount importance in the development of the infection. Candida species are strictly opportunistic pathogens, which cause disease when the host defenses are defective— hence, the designation “disease of the diseased” given to Candida infections.8 The major local and systemic factors that predispose humans to candidosis have been classified by Odds2 as natural, dietary, mechanical, and iatrogenic (Table 1). The most important of these are discussed below.

Prostheses Ill-fitting denture appliances and inadequate oral hygiene represent the main chronic local irritants in the oral cavity. It is likely that the constant irritation by the prosthesis may cause local microscopic breaches in the oral mucosa, thus allowing access by the organism. Furthermore, salivary yeast counts are much higher in full-denture wearers than in dentate subjects.9 The ad0738-081X/00/$–see front matter PII S0738-081X(00)00145-0

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Table 1.

Factors That Predispose Humans to Oral Candidosis Local Factors Reduced salivary flow Epithelial changes Changes in commensal flora High carbohydrate diet Systemic Factors Altered hormone state Diabetes Hypothyroidism Hyperparathyroidism Adrenal suppression Iron or folate deficiencies Immunosuppression Drugs Immunodeficiencies Altered polymorph function

herence of C. albicans to denture-base materials in vitro is most probably related to the hydrophobicity of the organism.10 Yeasts were detected in 78% to 100% of patients with denture-induced stomatitis,11 with a 10fold increase in yeast counts in denture plaque obtained from denture-induced stomatitis patients compared with healthy controls.12 Angular cheilitis is another case in which constant maceration of the skin folds at the angles of the mouth may lead to Candida infection.13 There are a number of co-factors such as iron or folate deficiency and inadequate denture construction involved in the pathogenesis of the disease,14 although it is highly likely that the frequently cracked, macerated, thin, moist atrophic epithelium would be a key factor in predisposing the individual to Candida-induced angular cheilitis.

Drug Therapy and Radiation Therapy Patients on broad-spectrum antimicrobial therapy may be predisposed to alterations in the oral flora. Acute atrophic candidosis caused by C. albicans is well recognized.15 Topical, systemic, and aerosolized corticosteroids are all important in this respect, and excessive use of antibacterial mouthwashes can also be followed by oral yeast infection.5 Drugs with xerostomic side effects (such as psychotherapeutics) also predispose to oral candidosis.16 Xerostomia (in Sjogren’s syndrome and after radiotherapy) predisposes to marked changes in the oral microbial flora and candidosis.17 Lack of salivary flushing action and the absence of antifungal salivary constituents such as lactoferrin, lysozyme, and histatins may help explain the increased oral yeast carriage and infection seen in xerostomic patients.5 Changes in pH, content of glucose, and secretory IgA levels also play an important role in predisposing subjects to the infection.5 Longitudinal studies of patients undergoing radiation therapy to the head and neck show significant increases in the numbers of Candida species on the

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surface of the tongue, in whole saliva, and in dental plaque.18,19

Malignant Diseases Host defense mechanisms are impaired in patients with malignant disease, and also as a result of the therapeutic chemotherapy and radiotherapy involved in its treatment. This can lead to disordered numbers and dysfunction of polymorphonuclear and mononuclear phagocytes and to oral candidosis.20 It is estimated that 50% and 70% of patients undergoing radiotherapy and chemotherapy, respectively, for leukemia and solid tumors, suffer from oral candidosis.21 Acute forms of oral mycoses are prevalent in patients with myeloproliferative disease and provide potential sources for fungal septicemia.20,22

Dietary Factors A variety of nutritional factors, including deficiencies of iron, folic acid, and vitamins, and diets rich in carbohydrates, have been implicated in the pathogenesis of oral candidal infections. Cases of chronic mucocutaneous candidosis, chronic atrophic candidosis, angular stomatitis, and atrophic glossitis have been reported in association with iron-deficiency anemia, and the infection was difficult to eradicate as long as the iron deficiency remained.23,24

Endocrine Disorders Candida species are more prevalent in the oral cavity of diabetic subjects than in those of healthy nondiabetic individuals.25,26 Darwazeh et al27 have shown a significant increase in the adhesion of Candida to oral epithelial cells of diabetics when compared with a healthy population. Although oral carriage of Candida species may be increased among diabetics, symptomatic or asymptomatic candidal infection may not be significantly higher than in healthy controls.5 Chronic hyperplastic candidosis can occur as part of chronic mucocutaneous candidosis, often with identifiable immunologic or endocrine abnormalities as major factors. Endocrine disorders such as hypothyroidism, hypoparathyroidism, and adrenal insufficiency have a familial incidence and are found in children and young adults, particularly in girls. The most frequently associated endocrine manifestations include idiopathic hyperparathyroidism and hypoadrenocorticism, but candidosis follows only where there is an immune defect.16

Immunologic Disorders HIV and AIDS Fungal infections, particularly atrophic and pseudomembranous candidosis, are common in patients with HIV infection. The immunodeficiency affect-

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ing T-helper lymphocytes during HIV infection makes patients with the disease more prone to secondary infections, notably opportunistic C. albicans infections. The first patient diagnosed with AIDS presented with oral candidosis,28 and oral candidosis was a common feature in patients who eventually developed AIDS.29 Oral candidosis occurs in over 60% of HIV-infected patients,30 and more than 80% of patients diagnosed with AIDS had oral candidosis.31 Generally, one in two to one in three individuals with HIV infection will develop oral candidosis. The erythematous variant is most frequently seen in these patients, followed by the pseudomembranous, angular cheilitis, and then hyperplastic candidosis.5 Combination antiviral therapy, however, dramatically reduced the prevalence of oral opportunistic infections, including candidosis.32 A myriad of immunological abnormalities occur as a consequence of HIV infection, particularly as the disease progresses to AIDS.33 Monocytes and macrophages express CD4, and HIV can directly infect these cells.34 Other alterations to mononuclear phagocyte function have been described including alterations in phenotypic marker expression, accessory cell function, chemotaxis, cytokine production, and respiratory burst activity.35–37 Nevertheless, profound CD4⫹ T-cell depletion is the immunological hallmark of AIDS, and is the most likely factor accounting for the increased susceptibility of these patients to opportunistic infections. The role for CD4⫹ T cells in host resistance against opportunistic fungal infections is supported by the frequent occurrence of fungal infections in patients with idiopathic CD4⫹ T-cell lymphocytopenia, a condition characterized by low CD4⫹ counts in the absence of HIV infection.38 Although HIV infection is associated with dysregulation of a number of immune factors at the mucosal surface, IgA antibody titres to C. albicans are unimpaired until relatively late in infection.39

Immunodeficiencies Candidosis is a common manifestation of a variety of immunodeficiencies. Severe combined immunodeficiency syndrome (SCID) is characterized by defects in cell-mediated immune functions. As a result of depressed cell-mediated and phagocytic immunity, chronic mucocutaneous candidosis (CMC) that may disseminate to other tissues is a feature in many SCID patients.40 Chronic recalcitrant mucocutaneous candidosis is particularly common in patients with DiGeorge syndrome,41 a condition characterized by depletion of T cells in the thymus-dependent areas of lymph nodes and in peripheral blood due to thymic hypoplasia. Hereditary myeloperoxidase deficiency is a common primary immunodeficiency seen in as many as 1 in 4000 individuals.42 There is an absence of myeloperoxidase

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(MPO) from the granules of polymorphonuclear leukocytes (PMNLs) and macrophages, which corresponds with impaired killing of C. albicans.43,44 This suggests that PMNLs play a major role in protection against candidosis, and that defects in their function underlie the recurrent episodes of oral thrush or chronic mucocutaneous candidosis seen in these patients.43,45 Similarly, patients with Chediak-Higashi syndrome, an autosomal recessive disease presenting with abnormal neutrophils, neutropenia, and impaired chemotaxis,46,47 commonly suffer from candidal infections.

Classification of Oral Candidosis The classification of oral candidosis has been fraught with difficulties and complications owing to the many manifestations the disease can take, and to the multifaceted etiology of the different conditions involved. More recently, it has been suggested that oral candidosis can been arranged into two categories, based on the distribution of the lesions,48 as follows: Category I: candidal infections confined to oral and perioral tissues (primary oral candidosis) Category II: disorders where oral candidosis is a manifestation of generalized systemic mucocutaneous candidal infection (secondary oral candidosis). Various investigators49 –51 have revised the original classification of Category I infections52 as follows: Acute: pseudomembranous, erythematous Chronic: pseudomembranous, erythematous, hyperplastic (plaque-like and nodular) Candida-associated: denture stomatitis, angular cheilitis, median rhomboid glossitis. Category II lesions are divided into subgroups,48 which take into account chronic mucocutaneous candidosis, and other immune-defect disorders as follows: Subgroup 1 2 3 4 5a 5b 5c 6

Condition Familial CMC Diffuse CMC Candidosis endocrinopathy syndrome Familial mucocutaneous candidosis Severe combined immunodeficiency syndrome DiGeorge syndrome Chronic granulomatous disease Acquired immunodeficiency syndrome (AIDS)

Clinical and Histopathological Appearance Pseudomembranous Candidosis Pseudomembranous candidosis is characterized by whitish-yellowish creamy patches on the surface of the oral mucosa and tongue (Fig 1a). The lesions develop

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Figure 1. Clinical presentation of acute pseudomembranous candidosis (a), angular cheilitis (b), Candida-associated denture stomatitis (c), median rhomboid glossitis (d), chronic mucocutaneous candidosis (e), and hyperplastic candidosis (f).

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into confluent plaques that resemble milk curds and can be wiped off to reveal a raw erythematous base.2 The plaques consist of necrotic material and desquamated parakeratotic epithelium, penetrated by C. albicans yeast cells and hyphae, as well as PMNL. Hyphae can invade as far as the stratum spinosum (Fig 2b). Edema and microabscesses containing polymorphonuclear leukocytes can be found in the outer layers of epithelium. The deeper parts of the epithelium show acanthosis, and the inflammatory response in the connective tissue comprises lymphocytes, plasma cells, and PMNL.2,53 This form of the disease is most commonly found in infants, the elderly, and terminally ill,54 particularly in combination with severe underlying conditions such as leukemia, and HIV and AIDS.55–57

Erythematous Candidosis This condition is mainly associated with the use of corticosteroids or broad-spectrum antibiotics. More recently it has commonly been seen in HIV patients,58 and up to 50% of the candidosis associated with HIV infection may be of this form.30 Clinically, it is characterized by erythematous areas generally on the dorsum of the tongue, palate, or buccal mucosa, in the absence of white plaque. Lesions seen on the dorsum of the tongue classically present as depapillated areas.30 The condition is relatively rare, but in the acute form is consistently painful.59 The histopathology of acute erythematous candidosis is essentially like other forms of the disease, with pseudohyphae penetrating and extending into the superficial epithelium. The inflammatory reaction is characterized by neutrophils in the epithelium, and a lymphocytic infiltrate in the connective tissue.

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stratum spinosum. Epithelial dysplasia is more common in the nodular form.61

Candida-Associated Denture Stomatitis Classically, this condition presents as chronic erythema and edema of the denture-bearing mucosa, especially under maxillary prostheses (Fig 1c). The patient is usually symptom free but may complain of slight soreness, and angular cheilitis can be a presenting complaint. Other factors such as bacterial accumulation, reduced salivary protection, and mechanical irritation may be implicated in denture stomatitis.12 Denture stomatitis is present in approximately 50% of complete denture wearers.12 Histologic examination of the tissues beneath the dentures shows proliferative or degenerative responses63 with reduced keratinization and thinner epithelium.64 Tissue invasion by Candida does not occur as commonly as other forms of oral candidosis, and relatively few yeasts are isolated from the mucosal surface.12 There are few hyphae, and the majority of the Candida colonize the denture surface. It is possible that the condition reflects a hypersensitivity reaction to antigens of the yeast.

Angular Cheilitis Clinically, angular cheilitis presents as sore, erythematous, fissured lesions affecting the angles of the mouth, and is commonly associated with denture stomatitis (Fig 1b).23,65 As mentioned earlier, the condition can be associated with iron deficiency anemia or vitamin B12 deficiency.66 In orofacial granulomatosis, a significant number of patients have angular cheilitis,67 and it may also be seen in AIDS.56

Median Rhomboid Glossitis Hyperplastic Candidosis Hyperplastic candidal lesions are chronic, discrete raised lesions that vary from small, palpable, translucent, whitish areas to large, dense, opaque plaques (Fig 1f). The homogeneous form presents as a uniform adherent white plaque, whereas the nodular (speckled) lesion has a clinical appearance of multiple white nodules on an erythematous background.60,61 Neither lesion will rub off. Hyperplastic candidosis usually occurs on the inside surface of the cheeks, palate, and tongue.48,61 Biopsy is important, as the condition is premalignant and shows varying degrees of dysplasia.5 Histopathological examination of the lesions reveals parakeratosis showing irregular separation and epithelial hyperplasia, with Candida invasion restricted to the upper layers of epithelium.60,62 Polymorphonuclear microabscesses form in the epithelium beneath the candidal hyphae, with a poorly demarcated chronic inflammatory infiltrate of lymphocytes and plasma cells in the upper half of the corium. Mitotic activity is often increased, but restricted to the basal and suprabasal layers of the

Median rhomboid glossitis is characterized by an area of papillary atrophy that is elliptical or rhomboid-like, symmetrically placed and centered at the midline of the tongue, anterior to the circumvallate papillae (Fig 1d).48,61 Occasionally, midline glossitis presents with a hyperplastic exophytic or lobulated appearance. Histopathologically, candidal hyphae are seen invading the superficial layers of the parakeratotic epithelium with elongated hyperplastic rete ridges extending into the corium, a PMNL infiltrate occupying the epithelium, and a lymphocyte infiltration in the corium erupting into the bases of the epithelial processes.61

Chronic Mucocutaneous Candidosis (CMC) Chronic mucocutaneous candidosis is a term given to a group of heterogeneous disorders characterized by per sistent superficial candidal infection of the mouth, skin, and nail beds, sometimes producing granulomatous masses over the face and scalp (Fig 1e).2,45,68 The principal clinical features include chronic oral candidosis, chronic cutaneous candidosis, and chronic vulvovagi-

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nal candidosis.69 Oral candidosis has been noted in more than 90% of all CMC patients.2 The tongue can become enlarged, fissured, and may have hyperplastic nodules on the lateral borders (Fig 1e). Painful angular cheilitis is frequent.40 The CMC is associated with a variety of primary immunodeficiencies such as severe combined immunodeficiency syndrome (SCID), Nezelof syndrome (thymic alymphoplasia), DiGeorge syndrome (congenital thymic aplasia), hyperimmunoglobulin E syndrome, myloperoxidase deficiency, and endocrine disorders, especially Addison’s disease and hypoparathyroidism.40,70,71 Oral lesions of CMC have similar histopathological features to those of chronic candidosis.60 Occasionally, candidal infection can spread into the pharynx, larynx, or esophagus, but further visceral involvement is rare.40

Diagnosis

Figure 2. Histopathological sections of BALB/c nu/nu tongue (a) and CBA/CaH nu/nu tongue (b) and gingiva (c) from immunodeficient mice lacking T lymphocytes, infected orally with 1 ⫻ 108 C. albicans yeasts. There is heavy infiltration of Candida hyphae penetrating the superficial hyperkeratotic epithelium, and large numbers of PMNLs forming micro-abscesses in the CBA/ CaH strain (b). The sulcular and crestal gingival tissues (c) show marked disruption and destruction, with heavy aggregations of Candida plaques and intraepithelial PMNL micro-abscesses. Sections were stained with PAS.

A thorough medical and dental history and careful attention to the signs and symptoms of the presenting complaint underlie a successful diagnosis of oral candidosis. An appropriate clinical description of the lesion is paramount in the diagnostic process as the disease can assume different clinical presentations. For example, an erythematous mucosa limited to the denturebearing surface of a prosthesis makes the diagnosis of denture-related candidosis more feasible. Several clinical and laboratory techniques are used to confirm a provisional diagnosis. The presence of Candida hyphae can be confirmed with periodic acid–Schiff (PAS) staining of a cytology smear of the pseudomembrane, thus allowing for a quick and accurate diagnosis of oral candidosis. In denture-induced erythematous candidosis, cytology smears usually fail to show any hyphal elements of the fungal organism, but may reveal fungal spores. In these cases, cultures of swabs taken from the mucosal tissues and the undersurface of the denture are extremely valuable in confirming that a fungal infection is present. Quantitative determination of the fungal burden can also be a useful marker of infection. Normal carriage in 50% of the population is less than 1000 CFU/mL, whereas in infected individuals, counts range from 4000 to 20,000 CFU/mL. Differentiation between different strains of Candida requires immunohistochemical techniques, although media may differentiate several species by colony color. This is usually only required in immunocompromised patients, or if the condition fails to resolve after appropriate antifungal treatment. It is possible to determine the sensitivity of Candida to antifungal therapy, which may be useful in such circumstances. In cases of suspected chronic hyperplastic candidosis or median rhomboid glossitis, biopsy of the relevant tissues is the most accurate method to confirm the diagnosis. Tissue specimens usually exhibit hyperparakeratosis contain-

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ing variable numbers of PAS- or silver-stain-positive hyphae that invade the keratin vertically. Microabscesses containing neutrophils are commonly seen (Fig 2b, c). Some 40% of patients with any type of oral candidosis were found to have a hematological abnormality,72 and thus hematological screening is of relevance in cases of refractory disease. Screening is mandatory in patients with chronic mucocutaneous candidosis, in HIV-positive individuals, and in others with systemic disease. Patients with CMC exhibit endocrinopathies or defects in the immune system, and patients with angular cheilitis may have underlying iron or vitamin deficiencies. It is imperative to remember that oral candidosis rarely develops in the absence of compromising factors, and clinicians should always look for underlying pathology, including dentures, when encountering a patient with oral candidosis.

Differential Diagnosis Candida infections must be differentiated from other entities where a pseudomembrane or slough is clinically present, or, in the case of erythematous candidosis, other intraoral red lesions. These include chemical burns, traumatic ulceration, mucous patches of syphilis, and white keratotic lesions. Isolated red lesions such as acute atrophic candidosis should be distinguished from thermal burns, drug reactions, erosive lichen planus, discoid lupus erythematosus, pernicious anemia, and early erythema multiforme.

Management The majority of oral C. albicans infections may be simply treated with topical applications of the polyenes, nystatin and amphotericin; however, elimination of the underlying factors responsible for the development of oral candidosis may be enough to resolve the condition. Withdrawal or substitution of broad-spectrum antibiotics can usually produce resolution of the oral fungal infection. Nevertheless, nystatin oral suspension (100,000 U/mL) or nystatin pastilles (100,000 IU) four times daily for 7 to 14 days are adequate to allow the oral microflora to return to normal. Amphotericin suspension (100 mg/mL) or amphotericin lozenges (10 mg) four times daily after meals are also effective. Nystatin or amphotericin suspensions or lozenges are also effective in eliminating the yeast from the mucosal surfaces of patients with denture-induced candidosis and angular chelitis, but the patient must remove the denture while undertaking treatment to allow the active ingredient to reach all the tissues. Another option is to coat the denture-fitting surface with miconazole gel (20 mg/mL) while it is being worn, and to repeat this three times daily, until the inflammation has cleared, usually within 7 to 14 days.

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In all cases of denture-related candidosis, proper oral and denture hygiene practices are critical if the infection is to be eliminated. The patient is advised to soak the denture overnight in 0.1% hypochlorite to eliminate C. albicans from the denture base and to cease completely wearing the denture at night. Construction of new dentures might be required if the existing appliances are ill-fitting or vertical dimensions are insufficient and are contributing to angular cheilitis. Lack of response in patients with denture stomatitis may be due to poor compliance or an underlying iron deficiency. Fluconazole or itraconazole orally can be used in resistant cases, but topical treatment is often safer, less expensive, and usually satisfactory. Underlying immunodeficiencies should be suspected when appropriately treated pseudomembranous candidosis fails to resolve. In cases of chronic mucocutaneous candidosis or oral candidosis associated with immunosuppression or HIV, topical agents may not be effective. In these instances systemic administration of ketoconazole, fluconazole, or itraconazole might be required, or rarely in the case of azole-resistant candidosis, amphotericin. Topical antifungal therapy is usually ineffective in chronic mucocutaneous candidosis, or median rhomboid glossitis, unless it is very prolonged. Additional systemic azole therapy is usually necessary to resolve the infection. Quantitative assays of Candida in the oral cavity, along with cytology, can be useful in monitoring responses to antifungal therapy. Successful treatment would be expected to result in a decrease in fungal colonies from 10,000 to 20,000 cfu/mL to a few hundred.

Current Research A definite gap exists in the understanding of the hostresponse mechanisms involved in oral C. albicans infections, and most of what is known about the disease is based on clinical observations. Current research from several laboratories points to a critical role for cellmediated immunity in the host defense against oral candidosis.73,74 There is also a contribution of phagocytic cells, predominantly neutrophils and macrophages, in the containment of the invading yeast at the oral mucosal surface.75 We have established a chronic oral C. albicans infection in immunodeficient mice that lack T lymphocytes (Fig 2a– c), and have been able to show complete resolution of the infection in mice reconstituted with functional CD4⫹ T cells (Farah, unpublished data). We have also shown that CD4⫹ T cells transferred into immunodeficient mice infiltrate the oral tissues and exert their activity there. Additionally, lymphocytes isolated from the submandibular and superficial cervical lymph nodes that drain the oral cavity

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secreted high titers of IL-12 and moderate levels of IFN-␥ in mice that cleared the infection. Moreover, RNase protection assays detected the presence of macrophage migration inhibition factor (MIF) in tongue and mucosa of mice clearing an oral infection (Farah, unpublished data). Further work has shown that monoclonal antibody depletion of neutrophils, and cytotoxic inactivation of macrophages in normal mice, leads to the establishment of an acute oral candidal infection. This work establishes the importance of T lymphocytes in experimental oral candidosis, and it supports clinical observations that link oral C. albicans infections to defects in cell-mediated immunity. The data also support the role for Th1-type cytokines and protective immunity in the resolution of oral candidosis in infected mice. It would appear that the clearance of an oral C. albicans infection is dependent on CD4⫹ T-cell augmentation of monocyte and neutrophil function exerted by Th1-type cytokines such as IL-12 and IFN-␥ as well as others such as MIF. Acknowledgments We would like to thank Associate Professor William G. Young for the clinical photographs used in this review. The experimental work presented in this article was conducted in the laboratories of RBA at Oral Biology and Pathology, School of Dentistry, The University of Queensland, and was supported by grants from the National Health and Medical Research Council of Australia to C.S.F. and R.B.A.

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