oral candidosis

Oral Candidosis:CAMILE S. FARAH, BDSc, PhDROBERT B. ASHMAN, PhD, DScSTEPHEN J. CHALLACOMBE, PhD, BDS, FRCPath, FDSRCSE, FMedSci

Many Candida species are commensals of theoral mucosa. They are usually innocuous, butthey can cause disease when conditions are

favorable. These organisms typically colonize mucocu-taneous surfaces, which can be portals of entry intodeeper tissues when host defenses are compromised.1The advent of the human immunodeficiency virus(HIV) and AIDS has resulted in a resurgence of oralCandida infections that were formerly seen mainly inimmunocompromised patients, or in persons at the ex-treme ends of the age spectrum.

In this article we review the pathogenesis, classifica-tion, clinical and histopathological presentation, anddiagnosis and management of oral candidosis. We alsopresent current research concepts relating to host de-fense mechanisms against oral Candida albicans infec-tions.

Etiology and Pathogenesis

Candidosis is most commonly caused by the yeast Can-dida 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 beenassociated with C. dubliniensis in HIV-infected individ-uals.3

Candida albicans is a commensal residing in the oralcavity of the majority of healthy humans.2 It is a dimor-phic fungus that can exist both in a yeast phase (blas-tospore, blastoconidial) and a hyphal (mycelial) phase.In the yeast phase C. albicans are 2 to 8 mm 3 3 to 14 mmin size, but hyphae can extend a few hundred microme-ters.4 They do not undergo a sexual cycle, and theyreproduce by multilateral budding. Depending on theenvironmental conditions, they may develop either inthe mycelial form, composed of long branching septaeor filaments, or as spherical or ovoid yeast cells. Dimor-phism is not only relevant to the pathogenicity of theyeast, but also to the clinical problems of diagnosis andtreatment.4

It is generally accepted that host factors play anequal if not a more important role than organism viru-lence attributes in the pathogenesis of oral candidosis.The local intraoral environmental milieu, such as thepresence of prostheses, also plays a crucial role in thedisease process. Indeed, it is a combination of the mi-crobial virulence factors, environmental factors, andhost defense factors that determine the disease processand the various manifestations of infection. The classi-fication of these is complex and is discussed later.

Epidemiology

Candida albicans is the most common Candida speciesisolated from the oral cavity both in health and disease.5Symptom-free oral carriage of Candida organisms hasbeen recognized for many years. The reported preva-lence in clinically normal mouths of healthy adultsranges from 3% to 48%,6 and 45% to 65% in healthychildren.2 The oral carriage of yeasts is higher in hos-pitalized than ambulant patients, with a median car-riage 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 diseasemay be associated with the virulence characteristics ofthe organism, it is widely accepted that host factors areof paramount importance in the development of theinfection. Candida species are strictly opportunisticpathogens, which cause disease when the host defensesare defective—hence, the designation “disease of thediseased” given to Candida infections.8

The major local and systemic factors that predisposehumans to candidosis have been classified by Odds2 asnatural, dietary, mechanical, and iatrogenic (Table 1).The most important of these are discussed below.

Prostheses

Ill-fitting denture appliances and inadequate oral hy-giene represent the main chronic local irritants in theoral cavity. It is likely that the constant irritation by theprosthesis may cause local microscopic breaches in theoral mucosa, thus allowing access by the organism.Furthermore, salivary yeast counts are much higher infull-denture wearers than in dentate subjects.9 The ad-

From the School of Dentistry, The University of Queensland, Brisbane,Australia; and Division of Oral Medicine, Pathology, Microbiology, andImmunology, Guys, Kings, and St. Thomas’ Dental Institute, Guys Hospi-tal, London, UK.

Address correspondence to Camile S. Farah, BDSc, PhD, Oral Pathol-ogy, Oral Biology and Pathology, School of Dentistry, The University ofQueensland, Brisbane 4072, Queensland, Australia.

© 2000 by Elsevier Science Inc. All rights reserved. 0738-081X/00/$–see front matter655 Avenue of the Americas, New York, NY 10010 PII S0738-081X(00)00145-0

herence of C. albicans to denture-base materials in vitrois most probably related to the hydrophobicity of theorganism.10 Yeasts were detected in 78% to 100% ofpatients with denture-induced stomatitis,11 with a 10-fold increase in yeast counts in denture plaque obtainedfrom denture-induced stomatitis patients comparedwith healthy controls.12

Angular cheilitis is another case in which constantmaceration of the skin folds at the angles of the mouthmay lead to Candida infection.13 There are a number ofco-factors such as iron or folate deficiency and inade-quate denture construction involved in the pathogene-sis of the disease,14 although it is highly likely that thefrequently cracked, macerated, thin, moist atrophic ep-ithelium would be a key factor in predisposing theindividual to Candida-induced angular cheilitis.

Drug Therapy and Radiation Therapy

Patients on broad-spectrum antimicrobial therapy maybe predisposed to alterations in the oral flora. Acuteatrophic candidosis caused by C. albicans is well recog-nized.15 Topical, systemic, and aerosolized corticoste-roids are all important in this respect, and excessive useof antibacterial mouthwashes can also be followed byoral yeast infection.5

Drugs with xerostomic side effects (such as psycho-therapeutics) also predispose to oral candidosis.16 Xe-rostomia (in Sjogren’s syndrome and after radiother-apy) predisposes to marked changes in the oralmicrobial flora and candidosis.17 Lack of salivary flush-ing action and the absence of antifungal salivary con-stituents such as lactoferrin, lysozyme, and histatinsmay help explain the increased oral yeast carriage andinfection seen in xerostomic patients.5 Changes in pH,content of glucose, and secretory IgA levels also play animportant role in predisposing subjects to the infection.5

Longitudinal studies of patients undergoing radia-tion therapy to the head and neck show significantincreases in the numbers of Candida species on the

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

Malignant Diseases

Host defense mechanisms are impaired in patients withmalignant disease, and also as a result of the therapeu-tic chemotherapy and radiotherapy involved in itstreatment. This can lead to disordered numbers anddysfunction of polymorphonuclear and mononuclearphagocytes and to oral candidosis.20 It is estimated that50% and 70% of patients undergoing radiotherapy andchemotherapy, respectively, for leukemia and solid tu-mors, suffer from oral candidosis.21

Acute forms of oral mycoses are prevalent in patientswith myeloproliferative disease and provide potentialsources for fungal septicemia.20,22

Dietary Factors

A variety of nutritional factors, including deficiencies ofiron, folic acid, and vitamins, and diets rich in carbo-hydrates, have been implicated in the pathogenesis oforal candidal infections. Cases of chronic mucocutane-ous candidosis, chronic atrophic candidosis, angularstomatitis, and atrophic glossitis have been reported inassociation with iron-deficiency anemia, and the infec-tion was difficult to eradicate as long as the iron defi-ciency remained.23,24

Endocrine Disorders

Candida species are more prevalent in the oral cavity ofdiabetic subjects than in those of healthy nondiabeticindividuals.25,26 Darwazeh et al27 have shown a signif-icant increase in the adhesion of Candida to oral epithe-lial cells of diabetics when compared with a healthypopulation. Although oral carriage of Candida speciesmay be increased among diabetics, symptomatic orasymptomatic candidal infection may not be signifi-cantly higher than in healthy controls.5

Chronic hyperplastic candidosis can occur as part ofchronic mucocutaneous candidosis, often with identifi-able immunologic or endocrine abnormalities as majorfactors. Endocrine disorders such as hypothyroidism,hypoparathyroidism, and adrenal insufficiency have afamilial incidence and are found in children and youngadults, particularly in girls. The most frequently asso-ciated endocrine manifestations include idiopathic hy-perparathyroidism and hypoadrenocorticism, but can-didosis follows only where there is an immune defect.16

Immunologic Disorders

HIV and AIDS

Fungal infections, particularly atrophic andpseudomembranous candidosis, are common in pa-tients with HIV infection. The immunodeficiency affect-

Table 1. Factors That Predispose Humans to Oral Candidosis

Local FactorsReduced salivary flowEpithelial changesChanges in commensal floraHigh carbohydrate diet

Systemic FactorsAltered hormone state

DiabetesHypothyroidismHyperparathyroidismAdrenal suppression

Iron or folate deficienciesImmunosuppression

DrugsImmunodeficiencies

Altered polymorph function

554 FARAH ET AL. Clinics in Dermatology Y 2000;18:553–562

ing T-helper lymphocytes during HIV infection makespatients with the disease more prone to secondary in-fections, notably opportunistic C. albicans infections.The first patient diagnosed with AIDS presented withoral candidosis,28 and oral candidosis was a commonfeature in patients who eventually developed AIDS.29

Oral candidosis occurs in over 60% of HIV-infectedpatients,30 and more than 80% of patients diagnosedwith AIDS had oral candidosis.31 Generally, one in twoto one in three individuals with HIV infection willdevelop oral candidosis. The erythematous variant ismost frequently seen in these patients, followed by thepseudomembranous, angular cheilitis, and then hyper-plastic candidosis.5 Combination antiviral therapy,however, dramatically reduced the prevalence of oralopportunistic infections, including candidosis.32

A myriad of immunological abnormalities occur as aconsequence of HIV infection, particularly as the dis-ease progresses to AIDS.33 Monocytes and macro-phages express CD4, and HIV can directly infect thesecells.34 Other alterations to mononuclear phagocytefunction have been described including alterations inphenotypic marker expression, accessory cell function,chemotaxis, cytokine production, and respiratory burstactivity.35–37 Nevertheless, profound CD41 T-cell deple-tion is the immunological hallmark of AIDS, and is themost likely factor accounting for the increased suscep-tibility of these patients to opportunistic infections. Therole for CD41 T cells in host resistance against oppor-tunistic fungal infections is supported by the frequentoccurrence of fungal infections in patients with idio-pathic CD41 T-cell lymphocytopenia, a condition char-acterized by low CD41 counts in the absence of HIVinfection.38 Although HIV infection is associated withdysregulation of a number of immune factors at themucosal surface, IgA antibody titres to C. albicans areunimpaired until relatively late in infection.39

Immunodeficiencies

Candidosis is a common manifestation of a variety ofimmunodeficiencies. Severe combined immunodefi-ciency syndrome (SCID) is characterized by defects incell-mediated immune functions. As a result of de-pressed cell-mediated and phagocytic immunity,chronic mucocutaneous candidosis (CMC) that maydisseminate to other tissues is a feature in many SCIDpatients.40

Chronic recalcitrant mucocutaneous candidosis isparticularly common in patients with DiGeorge syn-drome,41 a condition characterized by depletion of Tcells in the thymus-dependent areas of lymph nodesand in peripheral blood due to thymic hypoplasia.

Hereditary myeloperoxidase deficiency is a commonprimary immunodeficiency seen in as many as 1 in 4000individuals.42 There is an absence of myeloperoxidase

(MPO) from the granules of polymorphonuclear leuko-cytes (PMNLs) and macrophages, which correspondswith impaired killing of C. albicans.43,44 This suggeststhat PMNLs play a major role in protection againstcandidosis, and that defects in their function underliethe recurrent episodes of oral thrush or chronic muco-cutaneous candidosis seen in these patients.43,45

Similarly, patients with Chediak-Higashi syndrome,an autosomal recessive disease presenting with abnor-mal neutrophils, neutropenia, and impaired chemotax-is,46,47 commonly suffer from candidal infections.

Classification of Oral Candidosis

The classification of oral candidosis has been fraughtwith difficulties and complications owing to the manymanifestations the disease can take, and to the multi-faceted etiology of the different conditions involved.More recently, it has been suggested that oral candido-sis can been arranged into two categories, based on thedistribution of the lesions,48 as follows:

Category I: candidal infections confined to oral andperioral tissues (primary oral candidosis)

Category II: disorders where oral candidosis is a man-ifestation of generalized systemic mucocutaneouscandidal infection (secondary oral candidosis).

Various investigators49–51 have revised the originalclassification of Category I infections52 as follows:

Acute: pseudomembranous, erythematousChronic: pseudomembranous, erythematous, hyper-

plastic (plaque-like and nodular)Candida-associated: denture stomatitis, angular cheilitis,

median rhomboid glossitis.

Category II lesions are divided into subgroups,48 whichtake into account chronic mucocutaneous candidosis,and other immune-defect disorders as follows:

Subgroup Condition1 Familial CMC2 Diffuse CMC3 Candidosis endocrinopathy syndrome4 Familial mucocutaneous candidosis

5a Severe combined immunodeficiency syn-drome

5b DiGeorge syndrome5c Chronic granulomatous disease6 Acquired immunodeficiency syndrome

(AIDS)

Clinical and Histopathological Appearance

Pseudomembranous Candidosis

Pseudomembranous candidosis is characterized bywhitish-yellowish creamy patches on the surface of theoral mucosa and tongue (Fig 1a). The lesions develop

Clinics in Dermatology Y 2000;18:553–562 ORAL CANDIDOSIS 555

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).


into confluent plaques that resemble milk curds and canbe wiped off to reveal a raw erythematous base.2 Theplaques consist of necrotic material and desquamatedparakeratotic epithelium, penetrated by C. albicans yeastcells and hyphae, as well as PMNL. Hyphae can invadeas far as the stratum spinosum (Fig 2b). Edema andmicroabscesses containing polymorphonuclear leuko-cytes can be found in the outer layers of epithelium. Thedeeper parts of the epithelium show acanthosis, and theinflammatory response in the connective tissue com-prises lymphocytes, plasma cells, and PMNL.2,53 Thisform of the disease is most commonly found in infants,the elderly, and terminally ill,54 particularly in combi-nation with severe underlying conditions such as leu-kemia, and HIV and AIDS.55–57

Erythematous Candidosis

This condition is mainly associated with the use ofcorticosteroids or broad-spectrum antibiotics. More re-cently it has commonly been seen in HIV patients,58 andup to 50% of the candidosis associated with HIV infec-tion may be of this form.30 Clinically, it is characterizedby erythematous areas generally on the dorsum of thetongue, palate, or buccal mucosa, in the absence ofwhite plaque. Lesions seen on the dorsum of the tongueclassically present as depapillated areas.30 The condi-tion is relatively rare, but in the acute form is consis-tently painful.59 The histopathology of acute erythema-tous candidosis is essentially like other forms of thedisease, with pseudohyphae penetrating and extendinginto the superficial epithelium. The inflammatory reac-tion is characterized by neutrophils in the epithelium,and a lymphocytic infiltrate in the connective tissue.

Hyperplastic Candidosis

Hyperplastic candidal lesions are chronic, discreteraised lesions that vary from small, palpable, translu-cent, whitish areas to large, dense, opaque plaques (Fig1f). The homogeneous form presents as a uniform ad-herent white plaque, whereas the nodular (speckled)lesion has a clinical appearance of multiple white nod-ules on an erythematous background.60,61 Neither lesionwill rub off. Hyperplastic candidosis usually occurs onthe inside surface of the cheeks, palate, and tongue.48,61

Biopsy is important, as the condition is premalignantand shows varying degrees of dysplasia.5 Histopatho-logical examination of the lesions reveals parakeratosisshowing irregular separation and epithelial hyperpla-sia, with Candida invasion restricted to the upper layersof epithelium.60,62 Polymorphonuclear microabscessesform in the epithelium beneath the candidal hyphae,with a poorly demarcated chronic inflammatory infil-trate of lymphocytes and plasma cells in the upper halfof the corium. Mitotic activity is often increased, butrestricted to the basal and suprabasal layers of the

stratum spinosum. Epithelial dysplasia is more com-mon in the nodular form.61

Candida-Associated Denture Stomatitis

Classically, this condition presents as chronic erythemaand edema of the denture-bearing mucosa, especiallyunder maxillary prostheses (Fig 1c). The patient is usu-ally symptom free but may complain of slight soreness,and angular cheilitis can be a presenting complaint.Other factors such as bacterial accumulation, reducedsalivary protection, and mechanical irritation may beimplicated in denture stomatitis.12 Denture stomatitis ispresent in approximately 50% of complete denturewearers.12 Histologic examination of the tissues beneaththe dentures shows proliferative or degenerative re-sponses63 with reduced keratinization and thinner epi-thelium.64 Tissue invasion by Candida does not occur ascommonly as other forms of oral candidosis, and rela-tively few yeasts are isolated from the mucosal sur-face.12 There are few hyphae, and the majority of theCandida colonize the denture surface. It is possible thatthe condition reflects a hypersensitivity reaction to an-tigens of the yeast.

Angular Cheilitis

Clinically, angular cheilitis presents as sore, erythema-tous, 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 beassociated with iron deficiency anemia or vitamin B12deficiency.66 In orofacial granulomatosis, a significantnumber of patients have angular cheilitis,67 and it mayalso be seen in AIDS.56

Median Rhomboid Glossitis

Median rhomboid glossitis is characterized by an areaof papillary atrophy that is elliptical or rhomboid-like,symmetrically placed and centered at the midline of thetongue, anterior to the circumvallate papillae (Fig1d).48,61 Occasionally, midline glossitis presents with ahyperplastic exophytic or lobulated appearance. His-topathologically, candidal hyphae are seen invading thesuperficial layers of the parakeratotic epithelium withelongated hyperplastic rete ridges extending into thecorium, a PMNL infiltrate occupying the epithelium,and a lymphocyte infiltration in the corium eruptinginto the bases of the epithelial processes.61

Chronic Mucocutaneous Candidosis (CMC)

Chronic mucocutaneous candidosis is a term given to agroup of heterogeneous disorders characterized by persistent superficial candidal infection of the mouth, skin,and nail beds, sometimes producing granulomatousmasses over the face and scalp (Fig 1e).2,45,68 The prin-cipal clinical features include chronic oral candidosis,chronic cutaneous candidosis, and chronic vulvovagi-


nal candidosis.69 Oral candidosis has been noted inmore than 90% of all CMC patients.2 The tongue canbecome enlarged, fissured, and may have hyperplasticnodules on the lateral borders (Fig 1e). Painful angularcheilitis is frequent.40 The CMC is associated with avariety of primary immunodeficiencies such as severecombined immunodeficiency syndrome (SCID),Nezelof syndrome (thymic alymphoplasia), DiGeorgesyndrome (congenital thymic aplasia), hyperimmuno-globulin E syndrome, myloperoxidase deficiency, andendocrine disorders, especially Addison’s disease andhypoparathyroidism.40,70,71 Oral lesions of CMC havesimilar histopathological features to those of chroniccandidosis.60 Occasionally, candidal infection canspread into the pharynx, larynx, or esophagus, butfurther visceral involvement is rare.40

Diagnosis

A thorough medical and dental history and carefulattention to the signs and symptoms of the presentingcomplaint underlie a successful diagnosis of oral can-didosis. An appropriate clinical description of the lesionis paramount in the diagnostic process as the diseasecan assume different clinical presentations. For exam-ple, an erythematous mucosa limited to the denture-bearing surface of a prosthesis makes the diagnosis ofdenture-related candidosis more feasible.

Several clinical and laboratory techniques are used toconfirm a provisional diagnosis. The presence of Can-dida hyphae can be confirmed with periodic acid–Schiff(PAS) staining of a cytology smear of the pseudomem-brane, thus allowing for a quick and accurate diagnosisof oral candidosis. In denture-induced erythematouscandidosis, cytology smears usually fail to show anyhyphal elements of the fungal organism, but may revealfungal spores. In these cases, cultures of swabs takenfrom the mucosal tissues and the undersurface of thedenture are extremely valuable in confirming that afungal infection is present. Quantitative determinationof the fungal burden can also be a useful marker ofinfection. Normal carriage in 50% of the population isless than 1000 CFU/mL, whereas in infected individu-als, counts range from 4000 to 20,000 CFU/mL.

Differentiation between different strains of Candidarequires immunohistochemical techniques, althoughmedia may differentiate several species by colony color.This is usually only required in immunocompromisedpatients, or if the condition fails to resolve after appro-priate antifungal treatment. It is possible to determinethe sensitivity of Candida to antifungal therapy, whichmay be useful in such circumstances. In cases of sus-pected chronic hyperplastic candidosis or medianrhomboid glossitis, biopsy of the relevant tissues is themost accurate method to confirm the diagnosis. Tissuespecimens usually exhibit hyperparakeratosis contain-

Figure 2. Histopathological sections of BALB/c nu/nu tongue(a) and CBA/CaH nu/nu tongue (b) and gingiva (c) from immu-nodeficient mice lacking T lymphocytes, infected orally with 1 3108 C. albicans yeasts. There is heavy infiltration of Candidahyphae penetrating the superficial hyperkeratotic epithelium, andlarge numbers of PMNLs forming micro-abscesses in the CBA/CaH strain (b). The sulcular and crestal gingival tissues (c) showmarked disruption and destruction, with heavy aggregations ofCandida plaques and intraepithelial PMNL micro-abscesses.Sections were stained with PAS.


ing variable numbers of PAS- or silver-stain-positivehyphae that invade the keratin vertically. Microab-scesses containing neutrophils are commonly seen (Fig2b, c).

Some 40% of patients with any type of oral candido-sis were found to have a hematological abnormality,72

and thus hematological screening is of relevance incases of refractory disease. Screening is mandatory inpatients with chronic mucocutaneous candidosis, inHIV-positive individuals, and in others with systemicdisease. Patients with CMC exhibit endocrinopathies ordefects in the immune system, and patients with angu-lar cheilitis may have underlying iron or vitamin defi-ciencies. It is imperative to remember that oral candido-sis rarely develops in the absence of compromisingfactors, and clinicians should always look for underly-ing pathology, including dentures, when encounteringa patient with oral candidosis.

Differential Diagnosis

Candida infections must be differentiated from otherentities where a pseudomembrane or slough is clini-cally present, or, in the case of erythematous candido-sis, other intraoral red lesions. These include chemicalburns, traumatic ulceration, mucous patches of syphilis,and white keratotic lesions. Isolated red lesions such asacute atrophic candidosis should be distinguished fromthermal burns, drug reactions, erosive lichen planus,discoid lupus erythematosus, pernicious anemia, andearly erythema multiforme.

Management

The majority of oral C. albicans infections may be simplytreated with topical applications of the polyenes, nys-tatin and amphotericin; however, elimination of theunderlying factors responsible for the development oforal candidosis may be enough to resolve the condition.

Withdrawal or substitution of broad-spectrum anti-biotics can usually produce resolution of the oral fungalinfection. Nevertheless, nystatin oral suspension(100,000 U/mL) or nystatin pastilles (100,000 IU) fourtimes daily for 7 to 14 days are adequate to allow theoral microflora to return to normal. Amphotericin sus-pension (100 mg/mL) or amphotericin lozenges (10 mg)four times daily after meals are also effective.

Nystatin or amphotericin suspensions or lozengesare also effective in eliminating the yeast from themucosal surfaces of patients with denture-induced can-didosis and angular chelitis, but the patient must re-move the denture while undertaking treatment to allowthe active ingredient to reach all the tissues. Anotheroption is to coat the denture-fitting surface with micon-azole gel (20 mg/mL) while it is being worn, and torepeat this three times daily, until the inflammation hascleared, usually within 7 to 14 days.

In all cases of denture-related candidosis, proper oraland denture hygiene practices are critical if the infectionis to be eliminated. The patient is advised to soak thedenture overnight in 0.1% hypochlorite to eliminate C.albicans from the denture base and to cease completelywearing the denture at night. Construction of new den-tures might be required if the existing appliances areill-fitting or vertical dimensions are insufficient and arecontributing to angular cheilitis.

Lack of response in patients with denture stomatitismay be due to poor compliance or an underlying irondeficiency. Fluconazole or itraconazole orally can beused in resistant cases, but topical treatment is oftensafer, less expensive, and usually satisfactory. Underly-ing immunodeficiencies should be suspected when ap-propriately treated pseudomembranous candidosisfails to resolve.

In cases of chronic mucocutaneous candidosis or oralcandidosis associated with immunosuppression orHIV, topical agents may not be effective. In these in-stances systemic administration of ketoconazole, flu-conazole, or itraconazole might be required, or rarely inthe case of azole-resistant candidosis, amphotericin.Topical antifungal therapy is usually ineffective inchronic mucocutaneous candidosis, or median rhom-boid glossitis, unless it is very prolonged. Additionalsystemic azole therapy is usually necessary to resolvethe infection.

Quantitative assays of Candida in the oral cavity,along with cytology, can be useful in monitoring re-sponses to antifungal therapy. Successful treatmentwould be expected to result in a decrease in fungalcolonies from 10,000 to 20,000 cfu/mL to a few hun-dred.

Current Research

A definite gap exists in the understanding of the host-response mechanisms involved in oral C. albicans infec-tions, and most of what is known about the disease isbased on clinical observations. Current research fromseveral laboratories points to a critical role for cell-mediated immunity in the host defense against oralcandidosis.73,74 There is also a contribution of phago-cytic cells, predominantly neutrophils and macro-phages, in the containment of the invading yeast at theoral mucosal surface.75 We have established a chronicoral C. albicans infection in immunodeficient mice thatlack T lymphocytes (Fig 2a–c), and have been able toshow complete resolution of the infection in mice re-constituted with functional CD41 T cells (Farah, unpub-lished data). We have also shown that CD41 T cellstransferred into immunodeficient mice infiltrate theoral tissues and exert their activity there. Additionally,lymphocytes isolated from the submandibular and su-perficial cervical lymph nodes that drain the oral cavity


secreted high titers of IL-12 and moderate levels ofIFN-g in mice that cleared the infection. Moreover,RNase protection assays detected the presence of mac-rophage migration inhibition factor (MIF) in tongueand mucosa of mice clearing an oral infection (Farah,unpublished data). Further work has shown that mono-clonal antibody depletion of neutrophils, and cytotoxicinactivation of macrophages in normal mice, leads tothe establishment of an acute oral candidal infection.

This work establishes the importance of T lympho-cytes in experimental oral candidosis, and it supportsclinical observations that link oral C. albicans infectionsto defects in cell-mediated immunity. The data alsosupport the role for Th1-type cytokines and protectiveimmunity in the resolution of oral candidosis in in-fected mice. It would appear that the clearance of anoral C. albicans infection is dependent on CD41 T-cellaugmentation of monocyte and neutrophil function ex-erted by Th1-type cytokines such as IL-12 and IFN-g aswell as others such as MIF.

Acknowledgments

We would like to thank Associate Professor William G.Young for the clinical photographs used in this review. Theexperimental work presented in this article was conducted inthe laboratories of RBA at Oral Biology and Pathology,School of Dentistry, The University of Queensland, and wassupported by grants from the National Health and MedicalResearch Council of Australia to C.S.F. and R.B.A.

References

1. Rogers TJ, Balish E. Immunity to Candida albicans. Micro-biol Rev 1980;44:660–82.

2. Odds FC. Candida and candidosis. London: Balliere Tin-dall, 1988.

3. Sullivan DJ, Westerneng TJ, Haynes KA, et al. Candidadubliniensis sp. nov.: Phenotypic and molecular characteri-sation of a novel species associated with oral candidosis inHIV-infected individuals. Microbiology 1995;141:1507–21.

4. Saltarelli CG. Candida albicans. The pathogenic fungus.New York: Hemisphere Publishing, 1989.

5. Samaranayake LP, MacFarlane TW. Oral candidosis. Lon-don: Wright, 1990.

6. Arendorf TM, Walker DM. The prevalence and intra-oraldistribution of Candida albicans in man. Arch Oral Biol1980;25:1–10.

7. Wilkieson C, Samaranayake LP, MacFarlane TW, et al.Oral candidosis in the elderly in long-term hospital care.J Oral Pathol Med 1991;20:13–6.

8. Trousseau U. Lectures on clinical medicine delivered atthe Hotel-Dieu Paris. London: New Sydenham Society,1869.

9. Parvinen T. Stimulated salivary flow rate, pH and lacto-bacillus and yeast concentrations in persons with differenttypes of dentition. Scand J Dent Res 1984;92:412–8.

10. Radford DR, Challacombe SJ, Walter JD. Denture plaqueand adherence of Candida albicans to denture-base mate-

rials in vivo and in vitro. Crit Rev Oral Biol Med 1999;10:99–116.

11. Olsen I. Denture stomatitis. Occurrence and distributionof fungi. Acta Odontol Scand 1974;32:329–33.

12. Budtz-Jorgensen E. Candida-associated denture stomatitisand angular cheilitis. In: Samaranayake LP, MacFarlaneTW, editors, Oral candidosis. London: Wright, 1990.

13. MacFarlane TW, Helnarska SJ. The microbiology of angu-lar cheilitis. Br Dent J 1976;140:403–6.

14. MacFarlane TW, Samaranayake LP. Clinical oral microbi-ology. Bristol: Wright, 1989.

15. Kennedy MJ, Volz PA. Dissemination of yeasts after gas-trointestinal inoculation in antibiotic-treated mice. Sab-ouraudia 1983;21:27–33.

16. Kostiala I, Kostiala AAI, Kahanpaa A. Oral mycoses andtheir treatment. Acta Odontol Scand 1979;37:87–101.

17. Epstein JB, Truelove EL, Izutzu KT. Oral candidiasis:Pathogenesis and host defense. Rev Infect Dis 1984;6:96–106.

18. Brown LR, Dreizen S, Handlers S, et al. The effect ofradiation-induced xerostomia on saliva and serum ly-sozyme and immunoglobulin levels. J Dent Res 1975;54:740–50.

19. Samaranayake LP, Robertson AG, MacFarlane TW, et al.The effect of chlorhexidene gluconate and benzydaminemouthwashes on mucositis induced by therapeutic irra-diation. Clin Radiol 1988;39:291–4.

20. Kostiala I. Acute fungal stomatitis in compromised hosts:Causative agents, serologic findings, topical treatment.Proc Finn Dent Soc 1986;82:1–96.

21. Regezi JA, Sciubba JJ. Oral pathology: Clinical pathologiccorrelations. Philadelphia: Saunders, 1999.

22. Dreizen S, McCredie KB, Keating MJ, et al. Oral infectionsassociated with chemotherapy in adults with acute leuke-mia. Postgrad Med 1982;71:133–46.

23. Cawson RA. Chronic oral candidosis, denture stomatitisand chronic hyperplastic candidosis. In: Winner HI, Hur-ley R, editors. Symposium on Candida infections. Edin-burgh: Livingstone, 1966:139–52.

24. Higgs JM, Wells RS. Chronic mucocutaneous candidosis:Associated abnormalities of iron metabolism. Br J Derma-tol 1972;86:88–102.

25. Wilson RM, Reeves WG. Neutrophil phagocytosis andkilling in insulin-dependent diabetes. Clin Exp Immunol1986;63:478–84.

26. Dourov N, Coremans-Pelseneer J. Experimental chroniclingual candidosis induced in streptozotocin diabetic rats.Mykosen 1987;30:175–83.

27. Darwazeh AM, Lamey PJ, Samaranayake LP, et al. Therelationship between colonisation, secretor status and in-vitro adhesion of Candida albicans to buccal epithelial cellsfrom diabetics. J Med Microbiol 1990;33:43–9.

28. Gottlieb MS, Schanker HM, Fan PT, et al. Pneumocystispneumonia–Los Angeles. MMWR Morb Mortal Wkly Rep1981;30:250–1.

29. Gottlieb MS, Schroff R, Schanker HM, et al. Pneumocystiscarinii pneumonia and mucosal candidiasis in previouslyhealthy homosexual men: Evidence of a new acquiredcellular immunodeficiency. N Eng J Med 1981;305:1425–31.

30. Palmer GD, Robinson PG, Challacombe SJ, et al. Aetio-


logical factors for oral manifestations of HIV. Oral Dis1996;2:193–7.

31. McCarthy GM, Mackie ID, Koval J, et al. Factors associ-ated with increased frequency of HIV-related oral candi-diasis. J Oral Pathol 1991;20:332–6.

32. Reichart PA. Infections of the mouth mucosa (I). HIVinfection—an epidemiological, clinical and therapeuticupdate. Mund Kiefer Gesichtschir 1999;3:236–41.

33. Fauci AS. Multifactorial nature of human immunodefi-ciency virus disease: Implications for therapy. Science1993;262:1011–8.

34. Alkhatib G, Combadiere C, Broder CC, et al. CC CKR5: ARANTES, MIP-1 alpha, MIP-1 beta receptor as a fusioncofactor for macrophage-tropic HIV-1. Science 1996;272:1955–8.

35. Ho WZ, Cherukuri R, Douglas SD. The macrophage andHIV-1. Immunol Ser 1994;60:569–87.

36. Trial J, Birdsall HH, Hallum JA, et al. Phenotypic andfunctional changes in peripheral blood moonocytes dur-ing progression of human immunodeficiency virus infec-tion. Effects of soluble immune complexes, cytokines, sub-cellular particulates from apoptotic cells, and HIV-1-encoded proteins on monocytes phagocytic function,oxidative burst, transendothelial migration, and cell sur-face phenotype. J Clin Invest 1995;95:1690–701.

37. Wahl SM, Orenstein JM, Smith PD. Macrophage functionsin HIV-1 infection. In: Gupta S, editor. Immunology ofHIV infection. New York: Plenum Press, 1996.

38. Duncan RA, von Reyn CF, Alliegro GM, et al. IdiopathicCD41 T-lymphocytopenia: Four patients with opportu-nistic infections and no evidence of HIV infection. N EnglJ Med 1993;328:393–8.

39. Challacombe SJ, Sweet SP. Salivary and mucosal immuneresponses to HIV and its co-pathogens. Oral Dis 1997;3(Suppl 1):S79–84.

40. Porter SR, Scully C. Chronic mucocutaneous candidosisand related syndromes. In: Samaranayake LP, MacFarlaneTW, editors. Oral candidosis. London: Wright, 1990.

41. Cleveland WW, Fogel BJ, Brown WT, et al. Fetal thymictransplant in a case of DiGeorge syndrome. Lancet 1968;ii:1211–4.

42. Parry MF, Root RK, Metcalf JA, et al. Myeloperoxidasedeficiency: Prevalence and clinical significance. Ann In-tern Med 1981;95:293–301.

43. Lehrer RI, Cline MJ. Leukocyte myeloperoxidase defi-ciency and disseminated candidiasis: The role of myelo-peroxidase in resistance to Candida infection. J Clin Invest1969;48:1478–88.

44. Klebanoff SJ. Myeloperoxidase: Contribution to the micro-bicidal activity of intact leukocytes. Science 1970;169:1095–7.

45. Kirkpatrick CH, Rich RR, Bennett JE. Chronic mucocuta-neous candidiasis: Model-building in cellular immunity.Ann Intern Med 1971;74:955–78.

46. Oliver C, Essner E. The formation of anomalous lyso-somes in monocytes, neutrophils, and eosinophils frombone marrow of mice with Chediak-Higashi syndrome.Lab Invest 1975;32:17–27.

47. Wolff SM, Dale DC, Clark RA, et al. The Chediak-Higashisyndrome: Studies of host defenses. Ann Intern Med 1972;76:293–306.

48. Scully C, el Kabir M, Samaranayake LP. Candida andoral candidosis: A review. Crit Rev Oral Biol Med 1994;5:125–57.

49. Samaranayake LP, Yaacob HB. Classification of oral can-didosis. In: Samaranayake LP, MacFarlane TW, editors.Oral candidosis. London: Wright, 1990.

50. Holmstrup P, Axell T. Classification and clinical manifes-tations of oral yeast infections. Acta Odontol Scand 1990;48:57–9.

51. Samaranayake LP. Superficial fungal infections. CurrOpin Dent 1991;4:415–23.

52. Lehner T. Classification and clinico-pathological featuresof Candida infections in the mouth. In: Winner H, HurleyR, editors. Symposium on Candida infections. Edinburgh:Livingstone, 1966:119–37.

53. Cawson RA. Thrush in adult out-patients. Dent Prac 1965;15:361–5.

54. Finlay IG. Oral symptoms and Candida in the terminallyill. Br Med J 1986;292:592–3.

55. Kostiala I, Kostiala AAI, Kahanpaa A. Acute fungal sto-matitis in patients with haematologic malignancies:Quantity and species of fungi. J Infect Dis 1982;146:101.

56. Samaranayake LP, Holmstrup P. Oral candidiasis andhuman immunodeficiency virus infection. J Oral PatholMed 1989;18:554–64.

57. Samaranayake LP. Oral candidosis: An old disease in newguises. Dent Update 1990;17:36–8.

58. Greenspan D, Overby G, Feigal DW, et al. Sites andrelative prevalence of hairy leukoplakia, pseudomembra-nous candidiasis and erythematous candidiasis. In: Pro-ceedings of the Fifth International Conference on AIDS.Montreal, Canada, 1989.

59. Lehner T. Oral candidosis. Dent Pract Dent Rec 1967;17:209–16.

60. Cawson RA, Lehner T. Chronic hyperplastic candidia-sis—candidal leucoplakia. Br J Dermatol 1968;80:9–16.

61. Walker DM, Arendorf TM. Candidal leukoplakia, chronicmultifocal candidosis and median rhomboid glossitis. In:Samaranayake LP, MacFarlane TW, editors. Oral candido-sis. London: Wright, 1990.

62. Daniels TE, Schwartz O, Larsen V, et al. Langerhan’s cellsin candidal leukoplakia. J Oral Pathol 1985;14:733–9.

63. Razek MK, Shaaban N. Histochemical and histopatholog-ical studies of alveolar mucosa under complete dentures.J Prosthet Dent 1978;39:29–39.

64. Watson I, MacDonald D. Oral mucosa and complete den-tures. J Prosthet Dent 1982;47:133–40.

65. Budtz-Jorgensen E. The significance of Candida albicans indenture stomatitis. Scand J Dent Res 1974;82:151–90.

66. Scully C, Cawson RA. Medical problems in dentistry.Oxford: Butterworth-Heinemann, 1998.

67. Samaranayake LP, Lamey PJ. Oral candidosis. I. Clinico-pathological aspects. Dent Update 1988;15:227–31.

68. Edwards JEJ, Lehrer RI, Stiehm ER, et al. Severe candidalinfections: Clinical perspective, immune defense mecha-nisms, and current concepts of therapy. Ann Intern Med1978;89:91–106.

69. Chilgren RA, Quie PG, Meuwissen HJ, et al. Chronicmucocutaneous candidiasis, deficiency of delayed hyper-sensitivity and selective local antibody defect. Lancet1967;ii:688–93.


70. Porter SR, Scully C. Orofacial manifestations in primaryimmunodeficiencies: T lymphocyte defects. J Oral PatholMed 1993;22:308–9.

71. Porter SR, Scully C. Orofacial manifestations in primaryimmunodeficiencies: Polymorphonuclear leukocyte de-fects. J Oral Pathol Med 1993;22:310–1.

72. Challacombe SJ. Haematological abnormalities in oral li-chen planus, candidiasis, leukoplakia and non-specificstomatitis. Int J Oral Maxillofac Surg 1986;15:72–80.

73. Lacasse M, Fortier C, Chakir J, et al. Acquired resistance

and persistence of Candida albicans following oral candi-diasis in the mouse: A model of the carrier state in hu-mans. Oral Microbiol Immunol 1993;8:313–8.

74. Chakir J, Cote L, Coulombe C, et al. Differential pattern ofinfection and immune response during experimental oralcandidiasis in BALB/c and DBA/2 (H-2d) mice. OralMicrobiol Immunol 1994;9:88–94.

75. Challacombe SJ. Immunologic aspects of oral candidiasis.Oral Surg Oral Med Oral Pathol 1994;78:202–10.


oral candidosis

Documents