Title Candida and oral candidosis: A review

Author(s) Scully, C; EiKabir, M; Samaranayake, LP

Citation Critical Reviews In Oral Biology And Medicine, 1994, v. 5 n. 2, p.125-157

Issued Date 1994

URL http://hdl.handle.net/10722/53261

Rights This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Critical Reviews in Oral Biology and Medicine, 5(2):125-157 (1994)

Candida and Oral Candidosis: A Review

C. Scully and M. El-KabirEastman Dental Institute for Oral Healthcare Sciences, 256 Gray's Inn Road, London, England

Lakshman P. Samaranayake*Oral Biology Unit, Faculty of Dentistry, The University of Hong Kong, Prince Philip Dental Hospital,34, Hospital Road, Hong Kong

* Author to whom all correspondence should be addressed.

ABSTRACT: Candida species are the most common fungal pathogens isolated from the oral cavity. Their oralexistence both as a commensal and an opportunist pathogen has intrigued clinicians and scientists for many

decades, and recent investigations have revealed many attributes of this fungus contributing to its pathogenicity.In addition, the advent of the human immunodeficiency virus infection and AIDS has resulted in a resurgence oforal Candida infections. Clinicians are witnessing not only classic forms of the diseases but also newer clinicalvariants such as erythematous candidosis, rarely described hithertofore. Therefore, this review is an attempt atdetailing the current knowledge on Candida and oral candidoses together with the newer therapeutic regimesemployed in treating these mycoses.

KEY WORDS: Candida, oral candidosis.

1. INTRODUCTION

The advent of the human immunodeficiencyvirus infection and AIDS has resulted in a resur-

gence of oral Candida infections that are usuallyseen in the very young, the very old, and the verysick. Candida albicans is the most common Can-dida species isolated from the oral cavity both inhealth and disease, while other species such as

C. glabrata, C. tropicalis, and C. guilliermondiiare infrequently but consistently isolated (Sam-aranayake, 1990a). C. albicans is a dimorphicfungus existing both in the blastospore phase (syn.yeast phase, blastoconidial phase) and the hyphalor mycelial phase. Although these organisms typi-cally colonize mucocutaneous surfaces, the lattercan be portals of entry into deeper tissues whenhost defenses are compromised (Rogers andBalish, 1980).

An excellent account of systemic candidosiscan be found in monographs by Odds (1988) andTumbay et al. (1991), while the subject of oral

candidosis has been addressed recently in detailby Samaranayake and MacFarlane (1990).

I. TAXONOMY AND TYPING OFCANDIDA

The genus Candida is a collection of some150 asporogenous yeast species. Because of theirinability to form a sexual stage, they are mostoften classified among the fungi imperfecti in theclass Deuteromycetes (Lodder, 1970). SevenCandida species are ofmajor medical importance,and of these C. albicans, C. tropicalis, andC. glabrata are the most frequently isolated (morethan 80%) from medical specimens. The otherpathogenic Candida species are C. parapsilosis,C. stellatoidea, C. guilliermnondii, C. krusei, andC. pseudotropicalis. Candida stellatoidea is dif-ferentiated from Candida albicans by its inabilityto assimilate sucrose. However, the high DNAhomology between the two yeasts led Meyer et al.

1045-441 1/94/$5.00© 1994 by Begell House, Inc.

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(1984) to classify C. stellatoidea as a sucrose-negative variant of C. albicans.

Within the class Deuteromycetes, the distin-guishing feature of the Candida species is theirability to form pseudohyphae, the only exceptionbeing C. glabrata (Lodder, 1970). A number oftechniques have been used over the years to dif-ferentiate Candida isolates either belonging todifferent species or belonging to the same spe-cies. These are annotated below.

A. DNA Base Composition

The base composition of nuclear and mito-chondrial DNA in yeasts is expressed as the mo-lar percentages of guanine plus cytosine (G+C)(Kurtzman and Phaff, 1987). The G+C contentamong species within a genus often varies within10%, but differences much above 10% may suggestthat the genus in which the organisms have beenplaced is composed of several genera (Olsen, 1990).

B. Typing and Mapping of DNA

DNA typing methods based on digestion andelectrophoresis ofDNA fragments appear to offerimportant potential advantages over phenotypicmethods in taxonomy. Such methods provide abasis for the development of cloned probes forstudies on DNA homology (Scherer and Stevens,1987; Fox et al., 1989).

C. DNA-DNA Homology

DNA-DNA complimentarity experimentsmeasure the fidelity of complementary base pair-ing of denatured DNA strands from test pairs(Leth and Stenderup, 1969).

D. Ribosomal RNA

Ribosomal RNA (rRNA)-DNA homologystudies have been made with species of relativelyfew genera. The data suggest that intragenericrelationships established with this method are notusually meaningful, owing to the high degree ofconservation of the DNA sequences coding forrRNA (Phaff, 1984).

E. Enzymes

The amino acid sequence of enzymes such asglutamine synthetase and superoxide dismutasedetermined with quantitative microcomplementfixation may help evaluate the relationship be-tween yeasts (Kurtzman and Phaff, 1987).Alloenzyme electrophoresis is based on the ideathat genetic diversity develops over time. Thisimplies that genetically distant organisms showmajor differences in protein composition, and thatmore closely related organisms show a high de-gree of similarity in protein composition.Alloenzyme analysis is even more sensitive forstudying intraspecific variation among yeasts thanDNA-DNA sequence complementarity (Kurtzmanand Phaff, 1987; Odds, 1988).

F. Cellular Protein/polypeptide Profiles

Autoradiographic analysis of (35S) methion-ine-labeled cellular proteins separated by sodiumdodecyl sulfate-polyacrylamide gel electrophore-sis shows that different Candida species and otheryeast species produce distinct patterns (Shen et al.,1988).

G. Killer Systems

Killer toxins of yeast may be useful for differ-entiating strain types among the pathogenic spe-cies for surveillance studies (Morace et al., 1983)and to determine their geographic distribution(Young, 1987).

H. Carbohydrates

Capsular and cell wall polysaccharides havebeen used in taxonomic studies, particularly at thegeneric level (Weijman and Rodriguez DeMiranda, 1988). Differentiation between yeastshas also been made from the absence or presenceof glucuronic acid or D-xylose in the cell walls(Phaff, 1984).

1. Other Typing Methods

Other typing methods that use less sophisti-cated technology and commercially availablemedia include resistogram method, API ZYM,

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API 20C, and boric acid resistance assay, andcolony morphotyping (Silverman et al., 1990).

III. CANDIDA CARRIAGE IN THE ORALCAVITY

A. Prevalence Data

Symptom-free oral carriage of Candida or-ganisms has been recognized for many years.Figures obtained on the frequency of yeast car-riage in the oral cavity are dependent on isolationtechniques and time of sampling (Odds, 1988).

The reported prevalence in clinically normalmouths of healthy adults ranges from 3 to 48%(Arendorf and Walker, 1980), and in 45 to 65% ofhealthy children (Odds, 1988).

Odds (1988) has analyzed a large number ofpapers on oral carriage from the literature (Table1). From 32 papers on yeast isolation from theoral cavity in "normals", the median carriage fre-quency was 34.4% for all yeasts and 17% forC. albicans alone. In children there was a peak incarriage between the age of 1 week and 18 months.C. albicans is the most dominant species, fol-lowed by C. tropicalis, C. glabrata, C. parapsilosis,and C. krusei. Other Candida species and genera

TABLE 1Carriage of Oral Candida

Published carriage frequencies(%)

Sample detailsNo. ofpapers

Yeast isolations - "normals"Oral/pharyngeal swabSaliva/mouthwashImprint cultureOverallc

Yeast isolations - patientsOral/pharyngeal swabSaliva/mouthwashImprint cultureOverallc

C. albicans isolation - "normals"Oral/pharyngeal swabSaliva/mouthwashOverallc

C. albicans isolations - patientsOral/pharyngeal swabSaliva/mouthwashImprint cultureOverallc

Yeast carriage at different agesdNeonates up to 7 dInfants aged 1 week-18 monthsChildren >18 monthsAdults

20103

32

2392

34

165

20

2162

32

53

38

2.0-69.125.0-71.339.4-50.02.0-71.3

12.7-76.235.0-75.034.0-66.012.7-76.2

1.9-41.44.3-62.31.9-62.3

6.0-69.615.4-42.043.4-60.06.0-69.6

16.941.146.825.5

42.152.3

47.0

16.329.517.7

35.933.5

40.6

7.1-31.7 16.340.6-54.2 44.1

3.4-36.02.0-69.1

8.720.3

a Weighted by number of cases in study.b That is, arithmetic mean of frequencies quoted.c Including "not stated", etc.d Based on swab samples only to minimize bias because of sampling method.

From Odds, F. C.: Candida and Candidosis: A Review and Bibliography, 2nd ed., Balliere Tindall,London (1988).

127

Weighted SimpleRange meana meanb Median

27.736.844.434.4

48.355.4

54.7

17.623.117.0

36.636.3

38.1

16.044.0

6.024.5

24.840.544.631.5

45.356.2

50.2

17.924.219.4

36.833.5

37.5

17.346.3

15.125.1

(Rhodotorula, Saccharomyces, etc.) are rare andtransient (Stenderup, 1990).

B. Factors Affecting Candida Carriage

Carriage is more frequent in females thanmales, and during the summer months (Barlowand Chattaway, 1969). The similarities betweencarriers and noncarriers of C. albicans with re-spect to age, caries experience, periodontal status,and intraoral temperature indicate that many fac-tors do not significantly influence candidal car-riage (Arendorf and Walker, 1979). Some factorsthat do influence carriage, however include:

1. Salivary Factors

The quality and the quantity of saliva and itsconstituents play a critical role in modulating yeastcell populations in the oral cavity. Lack of sali-vary flushing action and the absence of antifungalsalivary constituents such as lactoferrin andlysozyme may help explain the increased oralyeast carriage and infection seen in xerostomicpatients (MacFarlane, 1990) and in animal mod-els (Jorge et al., 1983). The correlation betweenCandida carrier status and pH on the surface ofthe tongue shows that the carriage of yeast ishigher in acidic salivas (Arendorf and Walker,1979).

2. Temporal Variations

Candida counts increase during sleep but arereduced by taking a meal and by toothbrushing.Generally, counts are highest early in the morn-ing, and, furthermore, where counts are low, theorganisms cannot be isolated except in the earlymorning. The early morning saliva sample is alsothe most dependable for making a comparison ofthe Candida population within and between indi-viduals (MacFarlane, 1990).

Despite the above observations, early morn-ing saliva specimens from edentulous subjectsnot wearing dentures are consistently low inC. albicans. This has been attributed to sleepingwithout dentures and the consequent alteration inthe oral environment. Davenport (1970) has found

larger numbers of Candida in smears from den-tures than from mucosa. When dentures are wornat night, the early morning saliva Candida countis high; when dentures are not worn at night, theearly morning count is the lowest. The increasedCandida count following reinsertion of the den-tures suggests that plaque on the dentures harborsC. albicans (Budtz-Jorgensen, 1990).

The increase in both the frequency of carriageand the density of candidal colonization in den-ture wearers compared with dentate subjects sug-gests that prostheses encourage the presence andgrowth of candidal species (Arendorfand Walker,1979).

3. Smoking

Some studies have suggested that smokingdoes not affect Candida carriage significantly(Bastiaan and Reade, 1982; Oliver and Shillitoe,1984), while others have reported that smokingsignificantly increased carriage by 30 to 70%(Arendorf and Walker, 1980).

It has been suggested that cigarette smokingmight lead to localized epithelial alterations thatallow colonization by Candida (Arendorf andWalker, 1980). An alternative hypothesis is thatcigarette smoke provides nutrition for C. albicans.The related species of C. tropicalis, C. guillier-mondii, and C. pulcherrima have inducible en-zyme systems that would allow them to replicateusing polycyclic aromatic hydrocarbons as theirsource of carbon and energy (Takagi et al., 1980).This relationship between cigarette smoke andCandida is particularly important, as the enzymesystem in question can increase the carcinogenicactivity of the hydrocarbon and candidalleukoplakia might have a higher potential formalignant changes than other leukoplakias(Cawson and Binnie, 1980, also see below).

4. Oral Topography

C. albicans colonizes mainly the posteriordorsum ofthe tongue (Arendorf and Walker, 1980,Oliver and Shillitoe, 1984). It may be relevantthat this is the site at which median rhomboidglossitis occurs, a condition that is usually, if notalways, associated with proliferation of candidal

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hyphae (Walker and Arendorf, 1990). In denturewearers, the fitting surface of the denture is themain reservoir of the yeasts (Budtz-Jorgensen,1990).

5. Immune Status

Carriage of Candida has been shown to begreater in persons ofblood group0 and nonsecre-tors of blood group antigens in saliva (Masonet al., 1988) possibly mediated by an effect onC. albicans adhesion to epithelia (Blackwell et al.,1986). Specific antibodies to C. albicans(Vudhichamnong et al., 1982) and decreasingT-lymphocyte helper-to-suppressor ratios (Melbyeet al., 1985) may also influence carriage.

6. Oral Microflora

A number of studies have indicated that Can-dida can be isolated from the oral cavity withgreater prevalence and in greater numbers duringtetracycline therapy (McGoven et al., 1953). Ani-mal studies have shown that suppression of thecommensal oral flora by diets containing broadspectrum antimicrobials (e.g., tetracyclines) are aprerequisite to initiate and establish oral infection(Fisker et al., 1982), although other studies indi-cate that antibiotics are not essential for initiationof oral candidosis in murine models (Allen andBeck, 1983).

7. Candida Carriage in HospitalizedPatients

The oral carriage of yeasts is higher in hospi-talized than ambulant patients (Table 1), with amedian carriage rate of 54.7% for all species anda median of 38.1% for C. albicans alone.C glabrata is often found in significant numbers,with the highest frequency in denture wearers andthose with denture-induced stomatitis (Odds,1988). In one study of denture wearers withoutstomatitis, C. glabrata was found in 48% andC. albicans in 84%, with an association of the twospecies in 41%. High carriage frequencies (up to78%) are also found in the hospitalized elderly(Cumming et al., 1990; Wilkieson et al., 1991).

Thus, a consequence of hospitalization is anincrease in carrier rates, but high counts alone donot necessarily mean that the patient will haveclinical symptoms of candidosis (Mitchell et al.,1982).

IV. HOST ORAL DEFENSES AGAINSTCANDIDA INFECTION

The host defenses against Candida have beenreviewed recently (Greenfield, 1992). The oralepithelium acts as a physical barrier, and epithe-lial turnover per se contributes to defense.

A. Microbial Interactions

Competition and inhibition by the oral floraare also important in limiting the establishmentand overgrowth of fungi (Epstein et al., 1984).Microbial interactions include nutritional compe-tition, alteration in the microenvironment, andelaboration of toxic and metabolic byproducts.The indigenous bacterial flora can decrease colo-nization by C. albicans by competing for adher-ence sites on epithelial cells (Samaranayake, 1990).

In contrast, Candida may also maintain syn-ergistic relationships with pathogenic flora. Thus,synergism between C. albicans and Staphylococ-cus aureus has been observed (MacFarlane, 1990).Noteworthy in this context is the co-infection byCandida spp. and S. aureus in angular stomatitis(Warnakulasuriya, Samaranayake, and Peiris,1990).

Alterations in the microbial flora associatedwith systemic illness, hormonal changes, and useof medications (corticosteroids and antibiotics)may be significant in predisposing to candidosis(Rogers and Balish, 1980). For example, an in-creased prevalence of C. albicans in saliva hasbeen shown in patients treated with antibioticsand corticosteroids and in diabetic patients (Knightand Fletcher, 1971).

B. Salivary Nonimmune Factors

1. Iron

Iron is an essential nutrient of both bacteriaand fungi, and Weinberg (1974) noted evidencethat increased susceptibility to infectious agents

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was associated with elevated levels of iron inserum. In contrast, the iron-binding proteins, in-cluding lactoferrin, have been shown to inhibitgrowth or kill C. albicans (Nikawa et al., 1993).Samaranayake (1986) has reviewed the role ofiron in oral candidosis.

2. Lysozyme

Lysozyme (muramidase) is a low-molecular-weight protein present in relatively high concen-tration in the oral cavity, saliva, gingival crevicularfluid, and polymorphonuclear leukocytes (Brownet al., 1975). Lysozyme can, by increasing per-meability, damage Candida; C. albicans andC. glabrata are the least sensitive to lysozyme,whereas C. krusei is the most sensitive (Tobgietal., 1988).

Lysozyme has also been shown to stimulatephagocytosis in association with IgA. The hydro-lytic action of lysozyme on cell wall structuralproteins, injury to cytoplasmic membranes, ag-glutination of Candida species, and stimulationof phagocytosis indicate a significant role forlysozyme in host defense in oral candidosis (Hilland Porter, 1974).

3. Salivary Histidine-Rich Polypeptides

Salivary histidine-rich polypeptides (HRPs),together with antimicrobial proteins such aslysozyme, are antifungal and in healthy individu-als suppress Candida levels (Rayhan et al., 1992).

4. Lactoferrin

Lactoferrin is found in parotid and subman-dibular saliva and in polymorphonuclear leuko-cytes, and concentrations in saliva increasedramatically during inflammation of the oralmucosa and parotid gland (Tabak et al., 1978). Itsantifungal activity is believed to be because ofbinding of iron (Soukka et al., 1992). Lactoferrinhas also been postulated to enhance the antibacte-rial activity of lysozyme by attenuating the in-hibitory effect of iron on this enzyme (Massonand Heremans, 1971). Furthermore, as withlysozyme, there appear to be interspecies and in-traspecies variations in the sensitivity of Candidato lactoferrin (Nikawa et al., 1993). The lattergroup has demonstrated that lactoferrin may con-

fer structural changes on the cell walls of Can-dida and have demonstrated bleb-like cell wallmodifications in lactoferrin-treated yeasts.

5. Lactoperoxidase

The lactoperoxidase (LPO) system in themouth possesses antimicrobial activity (Tenovuoet al., 1977) involving multiple factors (H202 andhalides) and modes of action, including halogena-tion of microbial proteins, aldehyde formation,and oxidation of lipid sulfydryl groups (Klebanoff,1974). Significant candidacidal activity was dem-onstrated when Candida organisms were incu-bated with a conjugate oflactoperoxidase, xanthineoxidase, and specific antibody against Candida(Okuda et al., 1980).

6. Salivary Glycoproteins

Salivary glycoproteins antigenically similarto host cell surface antigens (blood group anti-gens) affect competition and prevent surface ad-herence of microbes to the mucosal surface; thisresults in augmentation of the cleansing action ofsaliva (MacFarlane, 1990; also see below).

C. Immune Factors in Host DefenseAgainst Candida

1. Granulocytes

Bone marrow-derived cells, probably neutro-phils, are crucial to the natural resistance toC. albicans (Ashman and Papadimitriou, 1990).Individual granulocytes can phagocytose up to 10yeasts (Pereira and Hosking, 1984), but the pro-portion killed remains constant at about 20 to30% regardless of the number ingested. Themyeloperoxidase (MPO)-hydrogen peroxide-ha-lide system appears to play a major role in theintracellular killing of Candida (Lehrer and Cline,1969). Susceptibility to candidal and staphylo-coccal infection has been the chief problem re-sulting from MPO deficiency (Lehrer and Cline,1969). Okuda et al. (1991) reported a case ofalveolar pyogenic granuloma in the maxilla causedby infection with C. albicans in a patient withMPO deficiency.

130

The candidacidal activity of human neutro-phils has been shown to be enhanced indepen-dently by immune interferon (IFN-a) and tumornecrosis factor (TNF) (Djeu et al., 1986). In thepresence of suboptimal levels of IFN-a, TNF actssynergistically to increase neutrophil effector func-tion. Cytokines such as granulocyte colony-stimu-lating factor (G-CSF) can increase production ofneutrophils by bone marrow and increase resis-tance to C. albicans (Matsumoto et al., 1987).Granulocytes can also kill the mycelial elementsof Candida, and the capacity to bind and to gen-erate microbicidal oxidants is augmented by se-rum opsonins (Diamond, 1988).

2. Cell-Mediated Immunity

Although phagocytosis represents the primemechanism by which C. albicans is controlled,the intrinsic candidacidal abilities of both granu-locytes and macrophages are quite limited, andfull expression of their effect is dependent onaugmentation by cytokines sythesized or inducedby T cells (Ashman and Papadimitriou, 1990).Candida infections are consistently seen whencell-mediated immunity is depressed (Valder et al.,1987). Lymphokine production by T cells is ini-tiated by an antigen-specific interaction. This pro-cess involves antigen processing and presentationby macrophages or other accessory cells that carryappropriate (compatible) class I and class 2 MHCantigens on their surface. In this context, it issignificant that human Candida-specific T cellsrequire HLA-DR-compatible macrophages fortheir activation (Jose et al., 1981), and that Can-dida infection markedly increases the expressionofHLA-DR and HLA-DQ antigens on the surfacemembranes of epithelial cells (Jontell et al., 1986).

Activation of T cells produces a wide rangeof lymphokines that can, in turn, modulate thefunctions of macrophages and other leukocytes.Interferon-gamma (IFN-,y) is the only lymphok-ine known to increase the microbicidal activitiesof macrophages: it also initiates TNF synthesis bythem (Papadimitriou and Ashman, 1989). In thepresence of suboptimal levels of IFN-y, Candidakilling by neutrophils is markedly enhanced byTNF. Unfortunately, the cytokines produced as aresult of T cell/macrophage interactions have thepotential to exacerbate symptoms of illness as

well as enhancing clearance of the infection(Ashman and Papadimitriou, 1990).

Polysaccharide antigens of C. albicans maygenerate a complex series of interactions thatsuppress both T- and B-cell responses (Piccalella,Lombardi, and Morelli, 1981). These effects mayeventually block the synthesis of both interleukin2 (IL-2) and IFN-y, as well as the expression ofthe Tac antigen (the IL-2 receptor) by normal Tcells (Lombardi et al., 1986); antigen presenta-tion and interleukin 1 (IL-1) production by mono-cytes may also be affected (Lombardi et al.,1985).

3. Humoral Immunity

Serum antibodies can affect the growth ofC. albicans (Grappel and Calderone, 1976). Themajor specific immunologic factor in saliva issIgA, which may be a primary defense againstoral candidosis by aggregating the organisms andby preventing their adherence to mucosal epithe-lium (Epstein et al., 1982).

Humoral- and cell-mediated immunity toC. albicans may comprise a second line of de-fense when penetration of mucosa or systemicinfection occurs. Wilton and Lehner (1980) re-ported that both mucocutaneous and systemiccandidosis are typically associated with defects inthe cell-mediated immune response. These can becaused by deliberate immunosuppression (as intransplant patients) or in cancer patients treatedwith cytotoxic drugs; they can be associated withsome underlying disease, such as the human im-munodeficiency virus (HIV) infection, or theymay reflect specific deficiencies in the cell-medi-ated immune response, as in chronic mucocutane-ous candidosis (Kirkpatrick, 1988).

4. The Relationship Between C. AlbicansAnd Heat Shock Protein 90

Prokaryotic and eukaryotic cells respond tothe stress of sudden rise in temperature by in-creasing the rate of synthesis of so-called "heatshock proteins" (HSPs) (Lindquist and Craig,1988). HSP90, together with its breakdown prod-ucts, is now recognized as an immunodominantantigen in fungal infections, and seroconversion

131

to it is associated with recovery from systemiccandidosis (Burnie and Matthews, 1991).

Sera from patients with culture-confirmedsystemic candidosis contain detectable antibodiesagainst C. albicans, but whereas survivors pro-duce a major antibody response to the 47-kDaantigen of Candida, fatal cases produce little orno antibody (Matthews et al., 1987). The 47-kDaantigen is a heat-stable breakdown product of thelarger 92-kDa antigen that circulates in the sera ofthese patients (Matthews et al., 1987). The 92-kDaantigen is a heat shock protein HSP90 (Matthews,1992). Antibody to the 47-kDa antigen is alsopresent in patients with chronic mucocutaneouscandidosis (CMC) and in those with AIDS(Matthews, 1992; Burford-Mason, et al., 1987).If the antibody to the 47-kDa antigen is protec-tive, this would help explain the rarity with whichsuch patients develop systemic candidosis, despitesevere superficial candidal infections (Matthews,1992). Indeed, in a neonate with Candida menin-gitis, who recovered, antibody to the 47-kDa an-tigen was the first antibody to appear in thecerebrospinal fluid (Burnie et al., 1986).

C. albicans HSP90 shows >50% direct ho-mology with human HSP90. Most of the antibod-ies produced by infected patients were directedagainst highly conserved epitopes shared withhuman HSP90. Therefore, autoreactive antibod-ies are produced commonly in patients recoveringfrom systemic candidosis without any clinicalevidence of autoimmune sequelae (Matthews,1992).

Human HSP90 is essentially intracellular,whereas candidal HSP90 circulates in the plasmain large amounts (Matthews, 1992). A pathogeniceffect resulting from candidal HSP90 might bethe disseminated intravascular coagulation some-times associated with systemic candidosis (Rebbeet al., 1987). Antibody to HSP90 would then beprotective because it neutralizes the activity oftheextracellular fungal HSP90. The possible role ofHSP90 in candidosis is discussed fully elsewhere(Matthews, 1992).

V. PATHOGENICITY OF CANDIDASPECIES

The factors involved in the pathogenicity ofC. albicans have been reviewed recently (Krempl-

Lamprecht, 1991). The pathogenesis of differentbiotypes and strains of C. albicans varies (Allenand Beck, 1983).

A. Enzymes of Candida

It has been suggested that C. albicans pro-duces an "endotoxin" (Dobias, 1964), but the lev-els ofendotoxin found in vivo may not be sufficientto produce toxic effects (Cutler et al, 1972). Al-ternatively, the organisms may produce enzymesthat facilitate penetration of the mucous mem-branes (Arendorf and Walker, 1979). Candidacertainly has the ability to produce phospholi-pases and Pugh and Cawson (1977) have shownthat the phospholipases are concentrated at thetips of fungal hyphae and localized in the vicinityof host cellular compartments where active inva-sion is occurring. These enzyme activities werefound in most C. albicans strains but not in or-ganisms known to be less virulent than C. albicans(Samaranayake et al., 1984b), such as C. glabrata,C. tropicalis, and C. parapsilosis.

Extracellular proteinases have also been im-plicated in the pathogenicity of C. albicans(MacDonald and Odds, 1980). Proteinase-defi-cient strains are noninvasive (MacDonald andOdds, 1983), and the pattern of adherence alsoreflects the expression of secretory proteinase(Borg and Ruchel, 1988). Salivary proteins, in-cluding IgA, can be almost completely degradedby acidic proteinases of Candida especially underlow pH conditions (Samaranayake et al., 1993).Recently, it has been shown that parotid saliva ismore resistant to the proteolytic action of Can-dida proteinase when compared with mixed sa-liva (Samaranayake et al., 1993). Acid proteinase(aspartyl proteinase) production is increased byC. albicans isolated from later stages of HIV in-fection and may contribute to candidosis. Therole of alkaline proteinase in the oral cavity is notclear yet.

B. Temperature Variations

The virulence of C. albicans can also be in-fluenced by the temperature at which it is grown(Hazen and Hazen, 1987). Virulence is associatedwith increased germ tube production by yeast

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grown at the lower temperature. These, in turn,display enhanced adherence characteristics com-pared with the parent yeasts mainly in the blas-tospore phase (Tronchin et al., 1988). Yeastsgrown at room temperature are more resistant tokilling by polymorphonuclear leukocytes (Antleyand Hazen, 1988). The clinical implications ofthese phenomena, if any, is not known.

C. Adhesion of Candida

There is a vast literature on this topic, whichis excellently reviewed by Kennedy (1988). Arelationship has been suggested between the ad-herence of C. albicans to surfaces and its abilityto colonize and cause disease (Odds, 1988). Animportant aspect of the pathogenicity ofC. albicans may be its nonspecific affinity andbinding to acrylic resin (Candida-associated den-ture stomatitis) and other plastics (catheter-re-lated candidosis) (Shepherd et al., 1985). Themechanism of attachment is believed to involvethe interaction of cell wall components ofC. albicans with the target surface (McCourtieand Douglas, 1984).

The initial yeast to epithelium contact may bedue to nonspecific adhesion followed by specificadhesion (Sandin, 1987). Modification of bothhost and yeast cells have been observed onceC. albicans is attached. It may be that the Can-dida cells "bump" into epithelial cells, initiallybinding reversibly and then physiological changesstrengthen the adhesion. These changes couldmodify the epithelium to the extent that more, ordifferent, receptors are exposed that stabilize andstrengthen adhesion (Tronchin et al., 1984). It hasalso been suggested that the adhesion ofC. albicans to oral mucosal cells might entail in-teractions involving divalent cations (Kennedy,1988). The adsorption of macromolecules ontoepithelial cells is believed to occur via electro-static interactions involving calcium ions and otherionic groups. Candida cells might also attach bysimilar mechanisms.

The extent and strength of the adhesion de-pends on the initial surface properties of both theorganisms and substratum involved and can beinfluenced by several factors (Rutter, 1984). Theseare listed in Table 2.

The cell surface structures promoting adhe-sion are highly dependent on the culture condi-

TABLE 2Factors Affecting Adhesion of Yeasts

Factors related to yeast cellsMedium/cultivationPhenotypeGerm tubes/hyphaeExtra-cellular polymeric material (EP)Floccular/fibrillar surface layersMannanChitinHydrophobicityCellular lipids

Factors related to host cellsCell sourceMucosal cell size and viabilityFibronectinFibrinSex hormonesYeast carriers vs. patients with overt candidosis

Environmental factors affecting adhesionCationspHSugarsSalivaHumoral antibody and serumAntibacterial drugsBacteriaLectins

tions of the yeast. Optimal adhesive activity ofC. albicans is seen only when the cells are grownin defined media at 250C (Kennedy, 1988). It hasalso been observed that the phenotypic variant,"white" cells of Candida are significantly moreadhesive to buccal epithelial cells than are"opaque" cells (Kennedy et al., 1988). The adher-ence of the hyphal phase of C. albicans to cells issignificantly greater than that of the blastosporephase cells (Samaranayake and MacFarlane,1982; Tronchin et al., 1988) so that conditionsconducive to germ tube formation result in sig-nificantly greater adherence (Sobel et al., 1981).It is not clear why viable germ tubes enhanceadherence, but it has been suggested that theremay be changes in surface components such asadhesins that could account for the increasedadherence (Kimura and Pearsall, 1978; Tronchinet al., 1988). Further, germ tubes promote clump-ing of yeast cells and binding of adjacent fila-ments, thus bringing a larger number of Candidaorganisms into contact with epithelial cells (Sobeletal., 1981).

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It is possible that sterols may be involved inadhesion mechanisms; the role of lipids is re-viewed elsewhere (Mishra et al., 1992).

The extracellular polymeric material (EP)originating from the yeast cell surface appearsimportant in facilitating adhesion. EP originatingfrom the cell surface of C. albicans contains sur-face glycoproteins responsible for yeast adhesion,and it is thought that the protein portion of themannoprotein is probably more important thanthe carbohydrate moiety (Critchley and Douglas,1987).

There are at least two surface types of Can-dida adhesin: floccular and flbrillar (Kennedy,1988). Whereas the floccular layer mediates ad-hesion to oral mucosal epithelium, isolates thatare able to synthesize a fibrillar surface layerdemonstrate increased adhesion to epithelial cells(McCourtie and Douglas, 1984).

The interaction of bacteria and fungi on epi-thelial surfaces has aroused clinical interest forsome time. The indigenous oral flora may inter-fere with adherence and colonization by Candidaorganisms. It has been observed that the normalresident bacterial flora suppresses fungal coloni-zation, whereas alteration and reduction in sur-face bacteria, such as is seen after antibiotictherapy, are associated with fungal colonizationand often symptomatic disease (Saigh et al., 1978).

Adherence is temperature dependent and canoccur at pH values consistent with those of thevaginal (pH 5.0) and oral mucosal surfaces(pH 7.0) (Samaranayake and MacFarlane, 1982).However, at low pH conditions, pH 3 to 4, theadherence of Candida to both epithelial and acrylicsurfaces is significantly increased (Samaranayakeet al., 1980).

Secretory immunoglobulin A (sIgA) can in-hibit the adherence of C. albicans to human oralepithelial cells (Vudhichamnong et al., 1982).Chitin derivatives can inhibit the adherence ofC. albicans to acrylic (Segal et al., 1992). Theeffect of blood group secretor status is discussedbelow.

D. Switching Phenomena

C. albicans frequently exhibits variant colo-nial forms when grown in vitro. For instance, a

smooth colony-forming yeast when inoculatedonto an agar surface may produce a proportion ofcolonies with rough surfaces (smooth to roughswitching). It is known that switching can betriggered by low doses of UV radiation, and oncetriggered into the high-frequency switching modeC. albicans exhibits high rates of alterations incolony morphology (Soll, 1992). Thus, C. albicanshas the capacity to switch frequently and revers-ibly between several variants, heritable, pheno-types (Soll, 1992). Switching is associated withchanges in micromorphology and physiologicproperties as well as a number of putative viru-lence traits. One switching system, "white-opaque"transition, has been examined for the capabilitiesof the two phenotypes to adhere to oral epithelialcells. "White" cells were shown to be signifi-cantly more adhesive than were "opaque" cells(Kennedy et al., 1988), and there may be differ-ences in hyphae and antigenic pattern (Soll, 1992).

It has been postulated that the switchingmechanisms of Candida may help potentiate itspathogenic features (1) during invasion of differ-ent body environments, (2) by eluding the im-mune system by altering its surface antigenicity,and (3) by escaping the action of antifungals. (Fora recent review of this phenomenon see Soll, 1992.)

VI. FACTORS PREDISPOSING TO ORALCANDIDA INFECTIONS

The major local and systemic factors thatpredispose humans to candidosis have been clas-sified by Odds (1988) as natural factors, dietaryfactors, mechanical factors, and iatrogenic fac-tors. Oksala (1990), in a review of literature of thefactors predisposing to oral candidal infection,listed those shown in Table 3. These are discussedbelow.

A. Prostheses

As far as chronic local irritants, ill-fittingappliances, and inadequate hygiene are concerned,high salivary yeast counts are much more com-mon in full-denture wearers than in dentate sub-jects (Parvinen, 1984). Yeasts are demonstrablein 78 to 100% of patients with denture-induced

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TABLE 3Factors Predisposing to Oral Candidosis

Chronic local irritantsIII-fitting appliancesInadequate care of appliancesDisturbed oral ecology or marked changes in theoral microbial flora by antibiotics, corticosteroids,xerostomiaDietary factorsImmunological and endocrine disordersMalignant and chronic diseasesSevere blood dyscrasiasRadiation to the head neckAbnormal nutritionAgeHospitalizationOral epithelial dysplasiaHeavy smoking

From Odds, 1988; Kostiala, Kostiala and Kahanpaa,1979; Petersen, 1984; Oksala, 1990.

stomatitis (Olsen, 1974). However, in microbio-logical studies of patients with denture-inducedstomatitis, yeast counts usually constituted lessthan 1% of the total microbial counts. Nonethe-less, there was a 10-fold increase in the yeastcounts in denture plaque obtained from denture-induced stomatitis patients when compared withhealthy controls (Budtz-Jorgensen, 1990).

B. Drug Therapy and Radiation Therapy

It is well known that patients on broad spec-trum antimicrobial therapy may be predisposed toalterations in the oral flora. Postantibioticstomatitis or glossitis caused by C. albicans arewell recognized (Kennedy and Volz, 1983;Midtvedt, 1990). Topical, systemic, and aero-solized corticosteroids are all important in thisrespect, and excessive use of antibacterial mouth-washes can also be followed by oral yeast infec-tion (Samaranayake, 1990).

Drugs with xerostomic side effects (such aspsychopharmaceuticals) also predispose to oralcandidosis (Kostiala et al., 1979). Xerostomia (inSjogren' s syndrome and after radiotherapy) pre-disposes to marked changes in the oral microbialflora and candidosis (Epstein et al., 1984).

Xerostomia can, in animal models, predispose tocandidosis (Jorge et al., 1993).

Longitudinal studies of patients undergoingradiation therapy to the head and neck show sig-nificant increases in the numbers of Candida spe-cies on the surface of the tongue, in whole saliva,and in dental plaque (Brown et al., 1975;Samaranayake et al., 1988).

C. Dietary Factors

A variety of nutritional factors, includingdeficiencies of iron, folic acid, vitamins and dietsrich in carbohydrates, have been implicated in thepathogenesis of oral candidal infections. Cawson(1966) was the first to describe an apparent rela-tionship between iron deficiency and oralcandidosis. Cases of chronic mucocutaneouscandidosis, chronic atrophic candidosis, angularstomatitis, and atrophic glossitis were reportedwith iron-defieciency anemia, and the infectionwas difficult to eradicate as long as the iron defi-ciency remained (Higgs and Wells, 1972). Theiron-dependent in vitro growth stimulation ofCandida is thought to be due to the blocking ofthe fungistatic property of transferrin, the iron-binding protein present in serum (Esterly et al.,1967). Moreover, iron may also affect the localhost defenses via its modulating role in the activ-ity of lysozyme and lactoferrin (Samaranayake,1990).

Iron deficiency may produce an impairmentof iron-dependent enzyme systems, thereby af-fecting the metabolism and, hence, the kinetics ofthe rapidly dividing oral epithelial cells (Rennie,MacDonald, and Dagg, 1984). Such alterationsmay result in an epithelial surface more condu-cive for the adhesion, growth, and invasion ofCandida (Jacobs and Lord, 1961). Joynson et al.(1972) demonstrated impaired cell-mediated im-munity to C. albicans in iron-deficient subjectsboth in vivo and in vitro, which were restoredonce the iron levels returned to normal. Othergeneral effects of iron deficiency that may bear arelationship to oral candidosis include deficientphagocytosis and antibody production (Wilton andLehner, 1981).

Growth of Candida either in saliva or nutrientmedia supplemented with dietary carbohydrates

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is accompanied by acid production and a signifi-cant concomitant reduction in pH to very lowlevels (Samaranayake et al., 1983a, 1984a, 1986a;Shepherd and Sullivan, 1976). The reduced pHlevels may potentiate candidal virulence by en-hancing its growth, multiplication, and adherenceto host tissues, while activating the acidic pro-teases and phospholipases of the yeast. Further-more, the direct cytotoxic effect of the acidicmetabolites may exacerbate the host inflamma-tory response (Samaranayake and MacFarlane,1985).

D. ImmunologiclEndocrine Disorders

Studies show that Candida species are moreprevalent in the oral cavity of diabetic patientsthan in those of healthy nondiabetic individuals.A study by Lamey et al. (1988) found no signifi-cant difference in the prevalence of oral candidalcarriage and infection in diabetic patients vs.nondiabetics in relation to the ability or inabilityto secrete blood group antigens. Other possiblefactors such as the ability of Candida to adhere tothe oral tissue rather than inherited ability to se-crete blood group substances may determine thoseparameters in diabetics. For instance, Darwazehet al. (1990) have recently shown a significantincrease in the adhesion of Candida to oral epi-thelial cells of diabetics when compared with ahealthy population.

Fungal infections, particularly pseudomem-braneous and atrophic candidosis, are common inpatients with HIV infection and other secondaryimmunodeficiencies. As a result ofdepressed cell-mediated immunity or phagocytic immunity,chronic mucocutaneous candidosis (CMC) canalso be a feature of primary immune defects suchas severe combined immune deficiency syndrome(SCID) (Porter and Scully, 1990). This is fullydiscussed below.

Chronic hyperplastic candidosis may occuras part of chronic mucocutaneous candidosis, of-ten with identifiable immunologic or endocrineabnormalities as major factors. Endocrine disor-ders have a familial incidence and are found inchildren and young adults, particularly in girls.The most frequently associated endocrine mani-festations include idiopathic hyperparathyroidismand hypoadrenocorticism, but candidosis follows

only where there is an immune defect (Kostialaetal., 1979).

E. Malignant Diseases

Host defense mechanisms are impaired bythe malignant process and its chemotherapy, whichin turn can lead to disordered numbers and dys-function of polymorphonuclear and mononuclearphagocytes and to oral candidosis (Petersen, 1984;Kostiala, 1986).

Acute forms of oral mycoses are frequent inpatients with myeloproliferative disease and pro-vide potential sources for fungal septicaemia(Kostiala, 1986; Dreizen et al., 1982). C. albicansis isolated in virtually all episodes of fungalstomatitis (Kostiala, 1986).

F. Secretory Status

Correlations between blood groups and vul-nerability to infectious diseases, including mycoticinfections, are well documented (Bird and Tovey,1982). Blood group antigens are present on mu-cosal epithelial cells (Bird and Tovey, 1982) andare found in saliva, gastric secretions, and otherbody fluids of most individuals (secretors). It hasbeen suggested that the nonsecretion of bloodgroup substances is associated with an increasedsusceptibility to oral infection with C. albicans(Blackwell et al., 1986). The highly significantexcess ofboth blood group0 antigen nonsecretionamong C. albicans carriers suggests it contributesto the oral carriage in healthy subjects. Blackwellet al. (1986) found a greater proportion of non-secretors in patients with oral C. albicans infec-tions. Mason, Weber, and Willoughby (1988) alsofound an excess of nonsecretors among healthyC. albicans carriers. The blood group H antigenfunctions as a C. albicans receptor, and, there-fore, subjects of blood group 0 (who possesslarge quantities of the H antigen on their cellsurfaces) are likely to be the most susceptible tocandidal colonization and subsequent infection(Mason, Weber, and Willoughby, 1988). In addi-tion, Lewis blood group antigen, found predomi-nantly on the cells of nonsecretors, might act as areceptor for Candida species (May, Blackwell,and Weir, 1989).

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In a study by Lamey et al. (1991), it wassuggested that secretor status may be an impor-tant factor in the development of chronichyperplastic candidosis.

VIl. CLASSIFICATION AND CLINICALMANIFESTATIONS OF ORAL CANDIDAINFECTIONS

All forms of oral candidosis are consideredopportunistic, and the epithet "disease of the dis-eased" has been applied to these infections. Nev-ertheless, it is often difficult to identify the exactpredisposing factor despite intensive investiga-tions (Samaranayake and Lamey, 1988). This,together with the varied clinical presentation oforal Candida infections, has made the task ofdisease classification somewhat difficult and com-plicated.

A. Classification

By tradition, the most frequently adoptedclassificaion of oral candidosis has been acutepseudomembranous candidosis (thrush), acuteatrophic candidosis, chronic hyperplasticcandidosis, and chronic atrophic candidosis.

Chronic hyperplastic candidosis was furthersubdivided into four groups based on localizationpatterns and endocrine involvement as chronicoral candidosis (candidal leukoplakia), endocrinecandidosis syndrome, chronic localized mucocu-taneous candidosis, and chronic diffuse candidosis.

Samaranayake and Yaacob (1990) noted thatthe last subdivision of chronic hyperplasticcandidosis generates some confusion, particularlybecause it lumps together hyperplasias that arelocalized in the oral cavity alone as well ashyperplasias related to oral manifestations ofmucocutaneous candidoses. However, a dichoto-mous classification that highlights and catego-rizes candidosis confined to oral and perioraltissues (primary oral candidosis) into one group,and candidal lesions distributed in other parts ofthe body as well as the oral cavity in another(secondary oral candidosis) may be less confusing.

Basically oral candidosis can be categorized as:

Category L: candidal infections confined to oraland perioral tissues (primary oral candidoses)(Table 4)

Category II: disorders where oral candidosis is amanifestation of generalized systemic muco-cutaneous candidal infection (secondary oralcandidoses) (Table 5);

Cheilo-candidosis and chronic multifocalcandidosis are two further clinical entities that donot fall exactly into any ofthe candidosis categories.

Cheilo-candidosis presents as a chronic, ul-cerative granulating lesion of the vermilion areaof the lower lip; chronic multifocal candidosishas been described as causing chronic, eryth-ematous plaque-like lesions in at least two of thefollowing sites: mouth, palate, and dorsum oftongue (Holmstrup and Besserman, 1983;Samaranayake and Lamey, 1988).

Following is a brief account of the clinicalvariants that comprise primary oral candidoses.Pseudomembranous, erythematous, and hyper-plastic candidoses are described first, while Can-dida-associated lesions such as denture-inducedstomatitis, angular cheilitis, and median rhom-boid glossitis, with a possible fungal and/or bac-terial etiology, are described subsequently, Finally,a note on multifocal oral candidosis and systemicCandida infections with oral manifestations (i.e.,secondary oral candidoses) is given.

A. Pseudomembranous Candidosis

Oral candidosis in the form of thrush is clas-sically an acute infection, but it may recur formany months or even years in patients using cortico-steroids topically or by aerosol, in HIV-infectedindividuals, and in other immunocompromisedpatients. The term chronic pseudomembranouscandidosis has been used for chronic recurrenceof the disease, although this term is not widelyaccepted (Proceedings of the Second World Work-shop in Oral Medicine, Chicago, 1993, in press).

Thrush may be seen in neonates and amongterminally ill patients (Finlay, 1986), particularlyin association with serious underlying conditionssuch as leukemia and other malignancies, and isincreasingly seen in HIV disease (Kostiala et al.,1982; Samaranayake, 1990b; Scully, 1988).

Thrush is characterized by white patches onthe surface of the oral mucosa, tongue, and else-where. The lesions develop and form confluentplaques that resemble milk curds and can be wiped

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TABLE 4Classification of Oral Candidosis

Human Candida mycoses

... Systemic candidoses

Superficial candidoses

... Genital infections (e.g., vulvovaginal)

... Dermal infections (skin and nails)

... Aural and ocular infections

Oral candidoses

Primary oral candidoses(Group I)

AcutePseudomembranousErythematous

Secondary oral candidosesa(Group 11)

Oral manifestations of systemicmucocutaneous candidoses (due todiseases such as thymic aplasia andcandidosis endocnnopathy syndrome)

ChronicPseudomembranousErythematousHyperplasticPlaque-likenodular

Candida-associated lesionsDenture stomatitisAngular cheilitisMedian rhomboid glossitis

a See Table 5.

From Samaranayake and Yaacob, 1990; Holmstrup and Axell, 1990; Samaranayake,1991.

off to reveal a raw, erythematous and sometimesbleeding base (Odds, 1988). The plaques in oralthrush are made up of necrotic material and desqua-mated parakeratotic epithelia, penetrated byC. albicans yeast cells and hyphae that invade asfar as the stratum spinosum. Edema andmicroabscesses containing polymorphonuclearleukocytes (PMNL) are found in the outer layersof epithelium. The deeper parts of the epitheliumshow acanthosis, and the inflammatory response

in the connective tissue comprises lymphocytes,plasma cells, and PMNL (Cawson, 1965; Odds,1988).

A possible complication of oropharyngealtrush is the involvement of the adjacent mucosa,particularly those of the upper respiratory tractand the esophagus. The combination of oral andesophageal candidosis is particularly preva-lent in HIV-infected patients (Holmstrup andSamaranayake, 1990).

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TABLE 5Classification of Oral Candidosis

Subgroup Condition OnsetAffected sites andclinical features

Familial chronicmucocutaneouscandidosis

Diffuse chronicmucocutaneouscandidosisCandidosisendocrinopathysyndrome

FamilialmucocutaneouscandosisSevere combinedimmunodeficiency

Di George'ssyndrome

Chronicgranulomatousdisease

Acquiredimmunodeficiencysyndrome (AIDS)

First decade of life

Before 5 years ofage

By second decade

In the first yearof life

Childhood

Any age

Mouth, nails, skin, mainlychronic hyperplastic lesions

Mouth, nails, skin, eyes,pharynx and larynx:chronic hyperplastic lesionsMouth: associated withhypoparathyroidism,hyppothyroidism,hypoadrenocorticism anddiabetes mellitus; chronichyperplastic lesions

Mouth, nails, scalp,flexures; chronichyperplastic lesions

Oral mucosa, skin, nails;pseudomembraneous orhyperplastic lesions

Oral mucosa, esophagus;may manifest aspseudomembraneous,erythematous, orhyperplastic lesions

Note: Group I: These are rare disorders (except Subgroup 6), where candidosisremains superficial; patients usually do not die from disseminated candidosis.

B. Erythematous (Atrophic) Candidosis

Erythematous or atrophic candidosis is an

uncommon and poorly understood condition as-

sociated with corticosteroids and topical or sys-

temic broad spectrum antibiotics or HIV disease.It may arise as a consequence of persistent acutepseudomembranous candidosis when the pseudo-membranes are shed, may develop de novo

(Lehner, 1967), or in HIV infection may precedepseudomembranous candidosis (Pindborg andNielsen, 1989).

The clinical presentation is characterized byerythematous areas generally on the dorsum ofthe tongue, palate, or buccal mucosa. Lesions on

the dorsum of the tongue present as depapillatedareas. Red areas are often seen in the palate in

HIV disease. There can be an associated angularstomatitis (Kostiala et al., 1979).

Holmstrup and Axell (1990) noted that theterm "atrophic" used to describe the red areas

could be a misnomer, as redness may be causednot only by reduced epithelial thickness atro-phy but also by increased vascularity. Hence,they suggested that the term "atrophic candidosis"should be replaced by "erythematous candidosis"in a new classification of oral candidosis(Holmstrup and Axell, 1990).

C. Hyperplastic Candidosis (CandidaLeukoplakia)

Candida leukplakias are chronic, discreteraised lesions that vary from small, palpable, trans-

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1

2

3

4

5a

5b

5c

6

lucent, whitish areas to large, dense, opaqueplaques, hard and rough to the touch (plaque-likelesions). Homogeneous areas or speckled areascan be seen, which do not rub off (nodular le-sions). Speckled leukoplakia counts for 3 to 50%of all candidal leukoplakias, and they are oftensymptomatic. Candida leukoplakias usually oc-cur on the inside surface of one or both cheeks,less often on the tongue (Cawson and Lehner,1968; Arendorf et al., 1983). Biopsy is important,as the condition is premalignant and shows vary-ing degrees of dysplasia (Samaranayake, 1990a;Daftary et al., 1972). Oral cancer supervenes in 9to 40% of candidal leukoplakias compared withthe 2 to 6% risk of malignant transformation citedfor leukoplakias in general (Banoczy, 1977). Therisk of carcinoma developing in candidalleukoplakia will depend on whether the lesion isspeckled or homogeneous, the presence and de-gree of epithelial dysplasia, and the managementadopted (Field et al., 1989).

The histopathology of candidal leukoplakiaincludes parakeratosis and epithelial hyperplasiaand Candida invasion restricted to the upper lay-ers of epithelium (Arendorf et al., 1983; Danielset al., 1985). In a minority of cases, the conditionhas been associated with iron and folate deficien-cies and with defective cell-mediated immunity(Jenkins et al., 1977; Walker and Arendorf, 1990).

D. Candida-Associated DentureStomatitis (Denture-induced Stomatitis,Denture Sore Mouth, Chronic AtrophicCandidosis)

The characteristic presenting signs of den-ture-induced stomatitis are chronic erythema andedema of the mucosa that contacts the fittingsurface of the denture. The mucosa below lowerdentures is hardly ever involved.

The patient may occasionally experience slightsoreness but is usually free of symptoms. Theonly presenting complaint may be an associatedanglular stomatitis (Scully, 1986). Dorey andBlasberg (1985) found that 28% of patients wereaware of a burning or tingling sensation underdentures, but the remainder were asymptomatic.

Newton (1962) classified denture-inducedstomatitis into three clinical types: type I, a local-

ized simple inflammation or a pinpoint hyper-aemia; type II, an erythematous or generalizedsimple type presenting as more diffuse erythemainvolving a part of, or the entire, denture-coveredmucosa, and type III, a granular type (inflamma-tory papillary hyperplasia) commonly involvingthe central part of the hard palate and the alveolarridge.

Histologic examination of the soft tissue be-neath dentures has shown proliferative or degen-erative responses (Razek and Shaaban, 1978) withreduced keratinization and thinner epithelium(Watson and MacDonald, 1982). Dentures canalso produce other changes: the oral flora may bealtered and plaque collects between the mucosalsurface of the denture and the palate. In addition,the saliva that is present between the maxillarydenture and the mucosa may have a lower pHthan usual (Burket, 1977).

The generalized simple and the granular typesof denture-induced stomatitis are most oftencaused by the accumulation of microbial plaque(bacteria or yeasts) on and in the fitting surface ofthe denture and the underlying mucosa (Arendorfand Walker, 1979; Budtz-Jorgensen, 1974). WhenCandida is involved, the more common terms"Candida-associated denture stomatitis", "den-ture-induced candidosis", or "chronic atrophiccandidosis" are used. Denture-induced stomatitisis not exclusively associated with Candida, how-ever, and, occasionally, other factors such as bac-terial infection, mechanical irritation, or an allergicreaction to the denture base material may be im-plicated (Budtz-Jorgensen, 1990). Nonetheless,there are no clinical criteria that can reliably dis-tinguish between a Candida-associated, a bacte-rial-induced, a trauma-induced denture stomatitis,or an allergic reaction to the denture base material(Budtz-Jorgensen, 1990). The high proportion ofwomen to men sufferers is more likely because ofthe higher incidence of edentulism among womenand because of the tendency for women to seekdental treatment more often than men (Dorey andBlasberg, 1985).

Patients with denture-induced stomatitis donot have any serious cell-mediated immune de-fects, but they may be deficient in migration-inhibition factor and may have overactivesuppressor T cells or other T-lymphocyte/phago-cyte defects (Iacopino and Wathen, 1992).

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E. Angular Stomatitis (Perleche, AngularCheilitis)

This is a clinical diagnosis of lesions thataffect the angles of the mouth, characterized bysoreness, erythema, and fissuring, and is com-

monly associated with denture-induced stomatitis(Cawson, 1966; Budtz-Jorgensen, 1990). Bothyeasts and bacteria (especially Staphylococcusaureus) are involved, as interacting, predisposingfactors (Cawson, 1966; Budtz-Jorgensen, 1974;Warnakulasuriya, Samaranayake and Peiris, 1991).However, angular stomatitis is, very occasion-ally, an isolated initial sign of anemia or vitamindeficiency, such as vitamin B 12 deficiency, andresolves when the underlying disease has beentreated (Scully and Cawson, 1987). Iron defi-ciency anemia and other vitamin deficiencieshave been cited as other predisposing factors(Samaranayake, 1986). In uncommon condi-tions, such as orofacial granulomatosis, up to20% of individuals have angular stomatitis, al-though Candida species are not often isolated(Samaranayake and Lamey, 1988). Angularstomatitis may also be seen in HIV disease(Samaranayake and Holmstrup, 1989).

Few authors consider that the lesion resultssolely from maceration due to deep, occlusivefolds of skin at the mouth angles in individualswith facial height reduced by old age or edentia(Chernosky, 1966).

F. Median Rhomboid Glossitis

Midline glossitis, or glossal central papillaryatrophy, is characterized by an area of papillaryatrophy that is elliptical or rhomboid in shape,symmetrically placed centrally at the midline ofthe tongue, anterior to the circumvallate papillae.Occasionally, median rhomboid glossitis presentswith a hyperplastic exophytic or even lobulatedappearance. The relevance of Candida to the con-dition has been controversial, with some authorsclaiming that the Candida causes the condition,particularly the papillary atrophy (Tapper-Joneset al., 1980). Histopathologically, candidal hy-phae infiltrate the superficial layers of theparakeratotic epithelium and a polymorphonuclearleukocyte infiltrate occupies the epithelium, with

elongated hyperplastic rete ridges and a lympho-cyte infiltration in the corium (Walker andArendorf, 1990). However, it has been demon-strated that the condition frequently shows a mixedbacterial/fungal microflora (Escobar, Farman, andArm, 1984).

G. Chronic Multifocal Oral Candidosis

This term has been given to chronic candidalinfection that may be seen in multiple oral sites,with various combinations, including (1) angularstomatitis that is unilateral or bilateral and en-countered mainly in denture wearers, (2)retrocommissural leukoplakia that is the mostconstant component of the tetrad, (3) median rhom-boid glossitis, and (4) palatal lesions (Cernea et al.,1965; Holmstrup and Besserman, 1983). Holm-strup and Bessermann (1983) applied the addi-tional criteria: (1) lesions of more than 1 monthduration; (2) an absence of predisposing medicalconditions; (3) patients who had received radio-therapy or drugs of the following types were alsoexcluded: antibiotics, antiinflammatory or immu-nosuppressive drugs, and cytotoxic or psy-chotropic agents.

Most patients are adult males and tobaccosmokers in their fifth or sixth decade at presenta-tion (Cernea et al., 1965; Pindborg, 1980). Anti-fungal therapy will clear the infection and produceclinical improvement, but recurrence is common,unless smoking can be reduced (Holmstrup andBessermann, 1983).

H. Oral Candidosis Associated withSystemic Infections

Candidosis is usually restricted to the skinand mucous membranes but may occasionallyspread. Systemic forms of candidosis may affectonly one organ or be disseminated (Candidasepticaemia) hematogenously (Odds, 1988).Whereas the candidoses included in Table 4(Group I) are limited mainly to the oral cavity, itis important to recognize that oral candidal infec-tion can occasionally manifest as a result of sys-temic complications (Group II or secondary oralcandidoses, Table 5) (Bodey and Anaissie, 1989).

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In immunocompromised patients, however, itis clear that the majority of patients withcandidaemia have evidence of invasive infection.For example, up to 30% of all patients with acuteleukemia die with systemic Candida infections(Carpentier, Kiehn, and Armstrong, 1981). Theusual presentation is a patient with persistent fe-ver unresponsive to broad-spectrum antibacterialantibiotics (Odds, 1988).

Vil. CANDIDOSIS ANDIMMUNOCOMPROMISED HOSTS

A few patients have chronic candidosis froman early age, sometimes with a defineable immunedefect (e.g., chronic mucocutaneous candidosis).The number of patients immunocompromised bydiseases such as HIV infection, hematologicalmalignancy, and treatment protocols, includingaggressive cytotoxic therapy, however, has in-creased during recent years and comprises by farthe largest such group.

A. Chronic Mucocutaneous Candidosis(CMC)

CMC is the term given to the group of raresyndromes, sometimes with a defineable immunedefect, in which there is persistent mucocutane-ous candidosis that responds poorly to topicaltreatment. In general the more severe the

candidosis, the greater the likelihood that immu-nological defects (particularly of cell-mediatedimmunity) can be identified (Scully, 1988). Themain types of these rare disorders and their fea-tures are shown in Table 6 (Scully and Cawson,1987). Further details are given elsewhere (Porterand Scully, 1990; Scully and Cawson, 1987).

B. HIV-Related Oral Candidosis

Candida infections, with oral thrush andesophagitis as frequent clinical manifestations,are the most common opportunistic infectionsencountered in AIDS (Klein et al., 1984;Holmberg and Meyer, 1986; Samaranayake andScully, 1989). Ever since the first clinical defini-tion of AIDS (1981), the CDC/WHO have recog-nized candidosis of the mouth, oesophagus,trachea, bronchi, and lungs as "major" opportu-nistic infections and important indicator diseases.

Subsequently, in 1986 the Walter Reed ArmyInstitute of Research (Redfield et al., 1986)adopted a staging classification of HIV infection,applicable to adults only, based on HIV-antibod-ies and virus isolation, chronic lymphadenopathy,T-helper cells/mm3, delayed hypersensitivity, ap-pearance of thrush, and other opportunistic infec-tions (Drouhet and Dupont, 1991).

Also, it has been shown in prospective studiesof HIV-infected patients that the occurrence of anotherwise unexpected mycosis (typically oralcandidosis) in an HIV-infected individual can be

TABLE 6Chronic Mucocutaneous Candidosis Syndromes

Type Clinical features

Familial CMC

Diffuse CMC (Candida granuloma)

Candidosis-endocrinopathy syndrome

Candidosis thymoma syndrome

Persistent oral candidosisIron deficiencySevere chronic candidosisSusceptibility to bacterial infectionsMild chronic candidosisHypoparathyroidismHypoadrenocorticismChronic candidosisMyasthenia gravisHematological disorders

From Scully, C. and R. Cawson, 1987.

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predictive of the subsequent development of full-blown AIDS (Klein et al., 1984; Sabin et al.,1992).

Retrospective studies have shown that at least58 to 81% of all AIDS patients contract a fungalinfection at some time, and 10 to 20% die as adirect consequence (Holmberg and Myer, 1986).Clearly, Candida infections appear to be the mostcommon fungal infection, occurring in at least75% of HIV-infected patients (Scully et al., 1990).McCarthy et al. (1991) have shown that 92% ofpatients with a diagnosis of AIDS had oralcandidosis, compared with only 24% of HIV-infected patients who had not developed AIDS.

1. Factors Associated with IncreasedFrequency of HIV-Related OralCandidosis

The main cause of infection in HIV disease isthe immune impairment, but candidosis is foundapproximately three times more frequently inpatients who also have xerostomia (McCarthyetal., 1991).

Recent studies have shown that oral Langer-hans cells are infected by HIV (Braathen et al.,1987) and may also play a role in candidosis.Candida itself may also induce immunosuppres-sion, and this can influence the prognosis of HIVinfection (Odds, 1988).

2. Clinical Variants of Oral Candidosisin HIV Infection

The manifestations of candidal infections inHIV infection are usually restricted to superficialcandidosis with varying degrees of severity. Al-though not life-threatening, these infections arepersistent and debilitating (Holmberg and Meyer,1986). The major clinical variants of oralcandidosis, namely pseudomembranous, eryth-ematous, and hyperplastic candidoses, have allbeen described in HIV-infected individuals, andit should be stressed that their clinical presenta-tion is similar to those who are not infected withHIV.

Thrush (pseudomembranous candidosis), themost immediately clinically obvious type of

candidosis, may involve any area of the oral mu-cosa, but most frequently the tongue, hard andsoft palate, and buccal mucosa. Oral thrush canmanifest for a variable time period prior to thedevelopment of Kaposi's sarcoma or other life-threatening opportunistic infections (Scully et al.,1990; Holberg and Meyer, 1986).

The erythematous (atrophic) type of oralcandidosis is found predominantly in the palatalmucosa and dorsum of the tongue (Scully et al.,1990; Samaranayake and Holmstrup, 1989). Somehave suggested that erythematous candidosis is asserious a prognostic indicator as pseudo-membranous candidosis, because the erythematousform is more difficult to recognize and, hence, isunderdiagnosed (Dodd et al., 1991).

Esophageal candidosis in a person with noother known cause for diminished resistance tothe disease is also considered indicative of AIDS(Centers for Disease Control/Classification, 1985).Esophageal candidosis is notable for its persis-tence, but dissemination does not appear to re-sult (Armstrong et al., 1985). Esophagealcandidosis gives rise to dysphagia andretrosternal discomfort and, in some, tender-ness on pressing on the sternum. Lack of esoph-ageal symptoms in a patient with AIDS andoral candidosis does not, however, excludeesophageal involvement (Holmberg and Meyer,1986), which can be diagnosed by endoscopy(Tavitian et al., 1986).

Also, candidosis presenting as median rhom-boid glossitis is not uncommon in HIV disease.Angular stomatitis is not infrequent and its ap-pearance in a nondenture wearer, particularly if ina high-risk group or if it is recalcitrant to treat-ment, now raises the suspicion of the presence ofHIV or other immune defects (Scully et al., 1990;Samaranayake, 1990b).

Oral candidosis appears also to be a frequentsign of HIV infection in children. Most childrenwith perinatal HIV infection develop mucocuta-neous candidosis in the first year of life, as op-posed to a small percentage of children who arediagnosed after this period as having AIDS. There-fore, in the young infants with HIV infection,chronic mucocutaneous candidosis may act as awarning sign for early and severe morbidity (Selik,Strarcher, and Curran, 1988; Samaranayake,1990b).

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Histologically, oral candidal infection in HIV-infected patients frequently shows a remarkablyweak inflammatory reaction; the epithelium maybe invaded by numerous hyphae or pseudohyphaewithout the ususal characteristic massive infil-trate of polymorphonuclear leukocytes. Likewise,the subepithelial inflammatory reaction is sparseand contains few or no leukocytes (Greenspanetal., 1986).

IX. THE POSSIBLE ROLE OF CANDIDAIN ORAL CARCINOGENESIS

Candida-involved leukoplakias (keratoses) areoften of the nonhomogeneous types (Roed-Peterson et al., 1970) and untreated, 5 to 10%may develop into carcinomas (Pindborg, 1980).However, although the epithelium of theleukoplakias is invaded by Candida it is unclearwhether the yeasts are causally involved in thedevelopment or transformation of leukoplakia.

Candida albicans is, by far, the species mostcommonly isolated, and the biotypes associatedwith leukoplakias differ from those isolated fromnormal oral cavities (Jepsen and Winther, 1965;Krogh et al., 1987; Krogh, 1990). Candida typesfrom nonhomogeneous leukoplakia have highernitrosation potentials than others, which mightindicate a possible role of specific types in thetransformation of some leukoplakias (Krogh,1990). Candida species may be involved incarcinogenesis by elaborating nitrosamine com-pounds (Blank et al., 1968; Krogh et al., 1987),which act either directly on the oral mucosa orinteract with other chemical carcinogens to acti-vate specified protooncogenes and thereby ini-tiate oral neoplasia (Field et al., 1989).

Candida leukoplakia is characterized histo-logically by chronic intraepithelial inflammationwith fungal hyphae invading the superficial lay-ers of the epithelium (Cawson and Lehner, 1968).The cellular changes often include hyperplasia,cellular atypia, mild or severe dysplasia, and in situor invasive carcinoma (Cawson and Lehner, 1968;Pindborg, 1971; Roed-Petersen et al., 1970).

Candida may produce preneoplastic changesin the oral mucosa in animal models (Franklinand Martin, 1986) and can act as a tumor pro-moter (O'Grady and Reade, 1992).

X. LABORATORY DIAGNOSIS OF ORALCANDIDOSIS

Systems for identification of yeasts may rangefrom a few simple tests useful in speciatingC. albicans to a large battery of tests that enablesdifferentiation of all yeasts of medical and dentalimportance. Identification is best accomplishedby using a combination of morphologic featuresand biochemical characteristics.

A. Microbiology

Any kind of clinical material (swab, sputum,etc.) for microscopy or culture should be exam-ined as quickly as possible, because drying mayimpair the viability of yeasts. As quantitative as-sessment is an important factor in the differentia-tion between carriers and infected patients,specimens must be dealt with immediately, orkept in transport medium and stored in a refrig-erator, for a maximum period of 24 h. When theclinical material is received in the laboratory, it isplated on a suitable culture medium. Frequently,Sabouraud's dextrose agar is used as a primaryculture medium, although it rarely permits dis-tinction between different yeast species (Silvermanet al., 1990). For the latter purpose, Pagano-Levinmedium is useful (Samaranayake, MacFarlane,and Williamson, 1987).

1. Smears

Detection of yeasts in a clinical specimenshould start with direct microscopic examinationof smears from the lesion. After fixation, oneslide is stained by the Gram stain and the other bythe periodic acid Schiff (PAS) technique. Yeastcells appear dark blue after Gram staining and redor purple in PAS preparations (Silverman et al.,1990).

2. Swab

Rubbing a sterile cotton-tipped swab over thelesional tissue or all surfaces irrespective of theclinical signs is a useful assay for the presence or

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absence of Candida, but it cannot provide a quan-titative estimate (Silverman et al., 1990).

3. Imprint Culture Technique

This technique uses a sterile plastic foam padof known size (typically 2.5 x 2.5 cm) dipped inSabouraud's broth and placed on the suspectmucosal surface for 60 s. Then the plastic foam isplaced directly on Sabouraud's or Pagano-Levinagar. Candida density at each site is determinedby a Gallenkamp colony counter and expressed ascolony-forming units per mm2 (CFU mm2)(Arendorf and Walker, 1979). Arendorf andWalker (1979), using the imprint culture tech-nique, surmized that the technique could also beused to discriminate between the carrier state andoral candidosis. Thus, according to these work-ers, colony counts in excess of 30 CFU cm2 ofmucosa in the dentate and 49 CFU cm2 in denturewearers suggested a candidal infection.

4. Paper Points

C. albicans has been detected previously inhigh numbers in the subgingival flora (Slots et al.,1988) or in the gingival tissues of acute periodon-tal abscesses (Peterson et al., 1987). An absor-bent sterile paper point is inserted to the depth ofthe pocket and then transferred to a transportmedium (Olsen, 1990). The latter is thenwhirlimixed thoroughly, in the laboratory andplated out on appropriate media.

5. Salivary Culture Technique

This involves requesting the patient to expec-torate about 2 ml of mixed unstimulated salivainto a sterile, universal container. The number ofCandida expressed as CFU per milliliter of salivais estimated by counting the resultant growth onSabouraud's agar (Silverman et al., 1990).

Epstein, Pearsall, and Truelove (1980) haveshown that the quantitative culture of saliva is auseful adjunct in diagnosis of oral candidosis.They demonstrated that carriers and patients withoral Candida can be distinguished reliably (with

95% confidence limits) on the basis of quantita-tive culture. Patients with clinical candidosis har-bor greater than 400 CFU of Candida per milliliterof saliva (Epstein, Pearsall, and Truelove, 1980).

6. Oral Rinse Technique

This consists of requesting the patient to rinsethe mouth for 60 s with 10 ml of sterile phos-phate-buffered saline (PBS, pH 7.2) or sterilewater. The patient then returns the oral rinse tothe universal container. If the patient wears adenture, this should be removed prior to sam-pling. The oral rinse is centrifuged at 1700 x g for10 min, and the deposit resuspended in 1 ml ofsterile PBS. The concentrated oral rinse is nowinoculated on appropriate media to assess CFUper milliliter of rinse sample using a Spiral Platerprior to incubation. The CFU (estimated using aGallenkamp colony counter) is multiplied by thedilution factor to yield the CFU per milliliter oforiginal oral rinse sample (Samaranayake et al.,1986b).

The concentrated oral rinse culture techniquehas a number of advantages over the imprint tech-nique. It is simple to perform as it does not in-volve the clinician in judgement of the samplingsite. In addition to Candida species, a single rinsesample can be used for quantitation of other or-ganisms such as coliforms (Samaranayake et al.,1986b).

7. Commercial Systems

A rapid commercial system (Microstix-Can-dida and Oricult-N) for diagnosing oral candidosisis useful for screening patients in the clinicalsetting, particularly when microbiology laborato-ries are not within easy access (Silverman et al.,1990).

B. Histopathology

Although swabs and smears are essential fora micobiological diagnosis of a number of typesof oral candidosis when candidal leukoplakia(chronic hyperplastic candidosis) is suspected, a

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biopsy specimen should be taken. Because Can-dida species stain poorly by hematoxylin andeosin, staining with periodic acid Schiff (PAS) orGridley's or Gomori's methenamine silver (GMS)stains are used. In both Gridley's and the PASprocedure, the fungi appear a pinkish-red. TheGMS technique stains yeast cell walls brown-black because of deposition of reduced silver.The presence of blastospores and characteristicpseudohyphae or hypae in the superficial epithe-lial tissues identifies the fungus as a species ofCandida. However, as the speciation of the or-ganism cannot be performed by this means alone,cultural studies should also be used (Silvermanet al., 1990).

Blastospores similar to those of Candida spe-cies may be seen in histoplasmosis or crypto-coccosis, both of which are becoming increasinglyimportant and may manifest orally with increas-ing frequency in AIDS patients (Greenspan et al.,1986). Therefore, if only blastospores of Candidaare seen in tissue sections of suspect patients,serial sections should be carefully searched forpseudohyphae or hyphae of Candida species(Silverman et al., 1990).

C. Immunologic Tests

Immunity in superficial candidosis and in oralcandidosis is predominantly cell mediated (Budtz-Jorgensen, 1990). Cell-mediated immunity toC. albicans antigens can be demonstrated in mosthuman subjects both by the appearance of de-layed skin hypersensitivy to Candida antigensand by in vitro tests of cellular immunity such asinhibition of leukocyte migration or stimulationof lymphocyte transformation to Candida anti-gens (Odds, 1988).

As tests of humoral immunity, the Candidaagglutinin test, the Candida complement fixationtest, the Candida precipitin test, immunofluores-cence, and ELISA tests have been used. In theserological tests, four principal types of Candidaantigens have been used, namely, whole nonvi-able yeast cells, Candida culture filtrates, cellwall polysaccharides or glycoproteins, and cyto-plasmic antigens from mechanically disruptedyeast cells. Serologic tests for Candida, however,are not diagnostic tools, as the diagnosis can beachieved more readily by clinical evaluation and

by smear or culture (Odds, 1988; Jeganathan andChan, 1992).

D. Hematologic Investigations

Because oral candidosis is associated fre-quently with predisposing factors such as nutri-tional deficiencies, blood dyscrasias or HIVdisease, estimates ofhemoglobin, lymphocyte andwhite blood cell counts, corrected whole bloodfolate, vitamin B 12 and serum ferritin can beimportant (Scully and Cawson, 1987).

Tests such as lymphocyte function, serumimmunoglobulins, calcium status, or parathyroidhormone levels are unnecessary except in chronicmucocutaneous candidosis. Because some endo-crine disorders may be associated with oralcandidosis, tests of thyroid or adrenocortical func-tion are warranted in selected individuals (Lameyand Samaranayake, 1988).

Xi. PROPHYLAXIS OF ORALCANDIDOSIS

Those at greatest risk of fungal infection arepatients with HIV disease, receiving cancer che-motherapy, immunosuppressive therapy, or pro-longed antibiotic therapy.

Often in the treatment of fungal infection at-tention to the underlying cause will avoid theneed for prolonged or repeated courses of treat-ment. If antibiotics or corticosteroids (oral or in-haled) are the probable cause, reducing the doseor changing the treatment may help. Intermittentor prolonged topical treatment may be necessarywhere the underlying cause is unavoidable or in-curable (Drug and Therapeutics Bulletin, 1990).

In patients with severe immunosuppression,prevention of colonization and infection is thegoal because the oropharyngeal region may be theprimary source of initial colonization and allowsubsequent spread of the infection. In HIV infec-tion, topical agents will often control the infectioninitially until the increasing immune defect ne-cessitates systemic agents (Epstein, 1990).

Topical antifungal agents are available asrinses, tablets, vaginal tablets, and creams. Oralrinses are useful for patients with dry mouth whomay have difficulty in dissolving tablets. How-

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ever, some oral products are sweetened with sugar,thus predisposing to dental caries (Epstein, 1990).

Denture plaque often contains Candida spe-cies. Therefore, to prevent denture-inducedstomatitis, denture cleansing that includes removalof Candida is a necessary and important factor(Olsen, 1974; Budtz-Jorgensen, 1974). Cleanserscan be divided into groups according to theirmain components: alkaline peroxides, alkalinehypochlorites, acids, disinfectants, and enzymes(Budtz-Jorgensen, 1990).

Yeast lytic enzymes and proteolytic enzymesare found to be the most effective against candida(Tamamato et al., 1985). Denture soak solutioncontaining benzoic acid completely eradicatesC. albicans from the denture surface as it is takenup into the acrylic resin and eliminates the organ-ism from the internal surface of the prosthesis(lacopino and Wathen, 1992). Kamalakshi et al.(1992) have shown the effectiveness of an oralrinse containing 0.12% chlorhexidine gluconatein complete elimination of C. albicans from theacrylic resin surface of the denture, and in reduc-tion of palatal inflammation. A protease-contain-ing denture soak (alcalase protease) is also aneffective way of removing denture plaque, espe-cially when combined with brushing (Odman,1992).

XII. TREATMENT OF ORAL CANDIDOSIS

Antifungal chemotherapy has been reviewedrecently (van den Bossche, 1991; Graybill, 1992;Rinaldi, 1992).

A. Polyene Antifungal Agents

The polyene agents are derived from Strepto-myces species; they include nystatin andamphotericin (Epstein, 1990; Lewis et al., 1991).

1. Nystatin

Nystatin was the first specific polyene anti-fungal agent effective in the treatment ofcandidosis. Nystatin, if swallowed, may lead oc-casionally to gastrointestinal side effects such asnausea, vomiting, and diarrhea (Epstein, 1990;

Lewis et al., 1991; Drug and Therapeutics Bulle-tin, 1990). However, when given parenterally, thetoxicity and insolubility have limited it to topicaluse in a rinse form, oral and vaginal tablets orcreams. The medications have to be applied fourtimes daily, 500,000 units for adults and 100,000for children. Higher doses may be required inimmunocompromised patients.

2. Amphotericin

Amphotericin binds to the membrane sterolsof fungal cells, causing impairment of their bar-rier function and loss of cell constituents(Warnock, 1991). It has a broad spectrum of ac-tion that includes most of the major fungal patho-gens of man.

The use of amphotericin for oral infections isusually limited to topical application (oral sus-pension 100 mg/ml, lozenges 10 mg) (Epstein,1990; Lewis et al., 1991; Drug and TherpeuticsBulletin, 1990). Occasional strains of C. albicansresistant to amphotericin are now being reported(Conly et al., 1992).

Amphotericin is not absorbed from the gut,and although it can be given intravenously (forsystemic candidosis) there is a considerable riskof toxicity, which may manifest as fever, vomit-ing, and renal, bone marrow, cardiovascular, andneurological toxicity.

B. Azole Agents

These synthetic antifungals, subdivided intoimidazoles and triazoles, are the first broad spec-trum agents active against a number of yeasts.Their fungistatic property is due to the changes inthe permeability of the yeast cell cytoplasmicmembranes. The currently available imidazolesare clotrimazole, miconazole, econazole, andketoconazole, while fluconazole and itraconazoleare the more recently introduced triazoles (Epstein,1990; Bodey, 1992).

1. Clotrimazole

Clotrimazole may be the most potent topicalagent in this class of antifungals but is used as a

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topical agent only because of its gastrointestinaland neurological toxicity (Odds, 1988).

2. Miconazole

Miconazole is used mainly for topical treat-ment of candidosis. It is available for parenteraluse against systemic mycoses, but the injectioncontains polyethoxylate castor oil, which mayprovoke allergic reactions (Bodey, 1992).

3. Ketoconazole

Ketoconazole was the first of the imidazoleagents shown to be capable of achieving thera-peutic blood levels when given orally. This led tothe drug being used in the treatment ofCMC andcandidosis in immunocompromised patients, butadverse effects, including nausea, rashes, pruritus,and hepatotoxicity, have restricted its use (Brassetal., 1982).

4. Fluconazole

Fluconazole is a recently introduced bis-triazole antifungal that acts by inhibiting fungalergosterol production essential in cell wall forma-tion (Bammer et al., 1990). Fluconazole inhibitsthe cytochrome c-dependent demethylation stepin the formation of ergosterol in the cell mem-brane. Fluconazole has little affinity for mamma-lian cytochromes, which is thought to explain itsapparently low toxicity (Hay, 1990a, 1990b).

Adhesion of Candida to epithelial cells, widelyrecognized as the essential step in the process ofcandidal colonization and subsequent infection(Kennedy, 1988) is also significantly inhibited byfluconazole (Darwazeh et al., 1991). Becausefluconazole is secreted in saliva in high concen-tration, it is tempting to speculate that fluconazolemay interfere with the synthesis or structure ofCandida receptors on buccal epithelial cells (Far-row, 1987).

Oral absorption of fluconazole is rapid andnearly complete within 2 h (Washton, 1989). In-travenous preparations are available for patientswho cannot take medication by mouth. Flucon-azole appears to undergo relatively little metabo-

lism in the body, elimination being predominantlyrenal (Brammer et al., 1990; Hay, 1990). Withnormal renal function, the serum half-life is ap-proximately 30 h. The concentration of drug inthe CSF is estimated to be between 50 to 90%plasma concentration. All this suggests thatfluconazole is best given once daily and will pen-etrate into CSF and urine in high concentration(Humphrey et al., 1985).

Oral fluconazole has generally been well tol-erated and, with usual doses, does not appear tosuppress the synthesis of corticosteroid hormones.Elevated plasma concentration of tolbutamide,phenytoin, and warfarin have been observed afterfluconazole administration, but without signifi-cant effects (Breckenridge, 1992). Although seri-ous cutaneous reactions and hepatitis haveoccurred in a few patients receiving fluconazole,these reactions appear to be infrequent and maynot be related to the fluconazole at all (Galgiani,1990), although in a study by Franklin et al. (1990),jaundice and abnormal liver function tests wereseen in some patients treated with fluconazole forHIV-related oral candidal infection. Wells andLever (1992) reported a patient with AIDS-re-lated oropharyngeal candidosis treated withfluconazole who developed a dose-related liverdysfunction.

In patients with chronic atrophic oralcandidosis, fluconazole is effective, particularlywhen administered concurrently with an oral an-tiseptic such as chlorhexidine (Hay, 1990b). Inpatients with chronic mucocutaneous candidosisin whom relapses after initial remission are ex-pected, fluconazole in a dose of 50 mg producedbeneficial clinical and mycological responses in amean period of 10 d (Hay, 1990b).

The efficacy and toxicity offluconazole 50 mgdaily was compared with ketoconazole 200 mgdaily in a randomized prospective, double-blindevaluation of patients with either AIDS or AIDS-related complex. Infection was eradicated in allpatients treated with fluconazole, but in only 75%of the patients who were given ketoconazole(de Wit et al., 1989). It would seem that the re-gime of 50 mg per day (single dose therapy) offluconazole for a period of 2 to 3 weeks may beadequate to prevent or suppress candidosis in HIV-infected patients. Indeed, 50 mg per day is thedose recommended by the drug manufacturers forthe treatment of oral candidosis. Nevertheless,

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either maintenance therapy or intermittent therapywith fluconazole is essential to prevent relapseafter cessation of treatment (Lewis et al., 1991).

AIDS patients treated with fluconazole200 mg/d orally for approximately 3 weeks hadrecurrence of oral and pharyngeal candidosis af-ter the therapy was stopped. When the fluconazoletherapy was started again at the same dosage asbefore, the patients had an incomplete response(Lucatorto et al., 1991).

Patients undergoing therapy for metastaticmalignancy were randomly assigned to receivefluconazole or placebo as antifungal prophylaxis.Oropharyngeal candidosis developed in only 2%of patients receiving fluconazole but in 28% ofpatients receiving placebo. The favorable resultsfrom this study indicate that fluconazole shouldbe evaluated as antifungal prophylaxis in patientsat greatest risk of developing serious fungal infec-tions, such as transplant patients or those receiv-ing chemotherapy for malignant diseases (Bodeyet al., 1990).

AIDS, and when treating infections at criticalsites, such as candidal meningitis and failures torespond to triazoles such as fluconazole (Siegman-Igra and Raban, 1992). None of the azoles areentirely benign and they are expensive. Hepato-toxicity may be common to all of them, and thepotential for endocrine toxicities exists, particu-larly at high doses. Furthermore, as with any newagent, novel toxicities may yet be discovered(Graybill, 1989).

The introduction of any new antimicrobial isalmost always associated with the emergence ofresistant flora (Ayliffe, 1979). As far as triazolesand Candida species are concerned, there are dis-concerting reports that indicate that some yeastsmay have either developed or are developing re-sistance (Evans et al., 1991; Smith et al., 1991 a;Johnson et al., 1993).

The development of cross-resistance ofC. albicans to different imidazoles during treat-ment with a single azole derivative has been de-scribed (Holt and Azmi, 1978; Johnson et al.,1984).

5. Itraconazole

This is an orally active bis-triazole, similar tofluconazole, which inhibits ergosterol biosynthe-sis in the fungal cell. It has a long half-life andfewer side effects than ketoconazole but is expen-sive (Jansen et al., 1991) and is eliminatedhepatically. Its use is contraindicated in liver dis-ease. It is available in 50 and 100 mg capsules and10 mg/ml oral solution. For a period of 2 weeks100 to 200 mg/d gives good clinical and labora-tory results compared with ketoconazole andclotrimazole (Smith et al., 1991b; Blatchford,1990).

The availability of an oral solution may offeradvantages over capsules because it will be easierto swallow for patients with oral candidosis andfor administration by nasogastric tube (Blatchford,1990).

6. Drawbacks of the Azoles

All the azoles (i.e., the imidazoles andtriazoles) are fungistatic, not fungicidal. This isan important consideration when treating thechronically immunosuppressed, such as those with

C. DNA Analogues

1. Flucytosine (5-Fluorocytosine)

This DNA analogue, which interferes withnucleic acid synthesis of the yeast cells, may beuseful as oral therapy for systemic fungal infec-tions in a dose of 50 to 150 mg/kg/d in divideddoses four times daily. Toxicity is due to meta-bolic effects on rapidly dividing host cells such asbone marrow cells. Other side effects are nausea,vomiting, and hepatic dysfunction (Epstein, 1990).

XiII. CONDLUDING REMARKS

Although considerable progress has been madein the understanding of Candida and oralcandidosis during the last few decades, much re-mains to be done. The precise nature of determi-nants of virulence of Candida, and the responseof host tissues to them, are still unclear, althoughour knowledge on these and other aspects ofCandida pathogenicity has advanced consider-ably due to recent applications of molecular bio-logical techniques to investigate phenomena such

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as phenotypic switching. The increasing preva-lence of oral Candida infections in HIV-infectedpatients and the emergence of antifungal resis-tance to the newer azoles has in addition renewedthe vigor and impetus of Candida research. Be-cause of a combination of recent knowledge andincreasingly sophisticated technology, the futurefor Candida research will doubtless be fruitful,exciting, and highly rewarding.

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