Oral mycoses in HIV infection Lakshman P. Samaranayake, THE PRINCE PHILIP

DENTAL

BDS, DDS, MIBiol,

MRCPath,a Hong Kong

HOSPITAL

Oral mycoses in human immunodeficiency virus (HIV) infection are becoming increasingly common. Of these, oral candidiasis is by far the most prevalent; fewer than 10 cases of cryptococcosis, histoplasmosis, and geotrichosis have thus far been reported. Oral candidiasis is one of the earliest premonitory signs of HIV infection and may present as erythematous, pseudomembranous, hyperplastic, or papillary variants, or as angular cheilitis. Cumulative data from 23 surveys (incorporating 3387 adults) suggest that in general, oral candidiasis may develop in one third to half of HIV-seropositive persons. Almost equal numbers of cases manifest with either erythematous or pseudomembranous variants. These and related concepts pertainktg to oral mycoses in HIV infection are reviewed. (ORAL SURG ORAL MED ORAL.PATHOL 1992;73:171-80)

F ungi are ubiquitous

organislms. They live in soil, water, and on animals and human beings. In human beings they can inhabit a variety of habitats such as the skin and thje mucosae and generally live as innocuous commensals. However, when the body defenses are weak, particularly the cellular limb of the immune response, these commensals transform into parasitic pathogens. Hence it is not surprising that in human immunodeficiency virus (HIV) infection mycoses are commonly encountered and are indeed the earliest premonitory signs of this relentless disease process. Of the mycoses encountered in HIV infection, candidiasis and cryptoc80ccosis are the most common, whereas a number of other infections, including histoplasmosis and aspergilhosis, have also been described.* These infections can be both superficial and/or systemic. In the oral cavity, at least four types of mycoses can manifest as a result of HIV infection, namely candidiasis, cryptococcosis, histoplasmosis, and geotrichosis.2 Candidiasis comprises by far the majority of infections, whereas the rest are encountered rarely, with only a handful of reports in the literature. Hence in this report oral candidiasis in HIV infection is reviewed in depth with only a brief mention of the other mycoses. ORAL. CANDIDIASIS

A number of clinical variants of oral candidiasis are now recognized. Traditionally the disease was classiaFormerly Consultant Senior Lecturer in Oral Medicine and Pathology; now Reader in Oral Biology, Oral Biology Unit, Prince Philip Dental Hospital, Hong Kong. 7/12/31470

fied as acute pseudomembranous (thrush), acute atrophic, chronic atrophic, and chronic hyperplastic varieties, with the subsequent addition of Candidaassociated angu1a.r cheilitis.3 However, there has been a need to revise this classification in the light of newer findings, particularly with respect to oral candidiasis in acquired immunodeficiency syndrome (AIDS).4-6 The variety of clinical types of oral or systemic candidiasis is matched by a variety of causative yeast species. Candida albicans is the best known and by far the most common pathogen of the group, although several other species such as Candida glabrata and Candida tropicalis are infrequently isolated from oral lesions.7 To understand the pathogenesis of oral candidiasis, it is important to realize the commensal existence of this fungus intraorally in some 20% to 50% of healthy persons.* The commensal nature of this organism implies (1) that the vast majority of oral candidiases are endogenous in origin and (2) that total eradication of the organism from the human host by antifungal therapy is difficult. The latter has obvious implications in the management of oral candidiases, because maintenance therapy must be used to keep the infection at bay, particularly in immunocompromised patients. Epidemiology

From the earliest periods of the AIDS epidemic, oral candidiasis was recognized as an important sign of the disease process and its progression. For instance, the first documented patient with AIDS had oral candidiasisg whereas unexplained oral candidiasis was prominently featured in persons in whom 171

172 Samaranayake Table

QRAL Sum ORAL Mm tku. PATH~L February 1992

I. Prevalence of oral candidiasis in adult population groups with HIV-1 infection* I

/ Authov (yr)

Homosexual men Homosexual men, heterosexuals Seropositives 76% homosexual, bisexual men, others US veterans Homosexual men, bisexuals 76% IVDA; 17% homosexual men and others Seropositives

Lozada et ali7 (1983) Phelan et alI8 (1987) Kenard et ak3* (1987) Reichart et alz9 (1987)

California N.Y. Copenhagen Berlin

Adelson et al.“’ (1988) Engelman et al.?’ (1988)

us

Ficarra et a1.23(1988)

Florence

Korting et al.“” (1988)

Munich

Melnick et a1.15(1988) Sinicoo et a1.18(1988)

Seattie, Wash Turin, Italy

Casariego et ai.3’ (1989) Coleman et a12* (1989) Feigal et all2 (1989)

Buenos Aires Dublin Calif.

Likimani

Abidjan, Ivory Coast

et a13@(1989)

California

Loeb et a13’ (1989)

Brussels

Mugaruka et al.33 (1989) Porter et al.” (1989) Schulten et a1.27(1989)

Kinshasa, Zaire Bristol, UK Amsterdam

Wanzala et a1.39(1989) Barone et al.“’ (1990)

Nairobi Florence

Kissinger et akA2 (1990) Schi$dt et a140 (1990)

Port-au-Prince, Haiti Dar es Salaam, Tanzania Kinshasa, Zaire

Tukutuku

et akd3 (1990)

Source

Geogmphic location

--__

nRC, AIDS-relate&complex; IVB.4,

Homosexual men IVDA (68%) and others Seropositives Seropositives 83% homosexuals, 17% IVDA Hospitalized seropositives 39% homosexuals, 35% African, 14% IVDA 10% heterosexuals and others Hospitalized Africans Seropositives 79% Homosexuals and others Female prostitutes 65% IVDA and others Seropositives Medical and dental patients Hospitalized Africans

Disease state

I

n

j Candidiasis / (S)

AIDS AIDS Seropositive All stages

53 103 23 110

51 93 48 35

All stages Seropositive

60 125

43 17

AIDS, ARC, seropositive AIDS, ARC, seropositive Seropositive Seropositive

217

57

84

73

120 321

13 13

Seropositive Seropositive Seropositive

105 30 315

64 96 12

Seropositive (HIV-l,HIV-2) Seropositive

130

49

700

22

Seropositive AIDS and seropositive AIDS and seropositive

!OO 44 75

62 36 52

Seropositive Seropositive

269 217

12 73

Seropositive AIDS Seropositive

29 43 83

93

intravenous drug abuser.

‘Reports with less than 20 subjects are excluded.

AIDS eventually developed.‘O-l’ Thus Klein et al.,” early in the AIDS epidemic, focused the attention of clinicians worldwide on this disease entity by demonstrating its value as a predictor of full-biown AIDS in adults. A substantial body of epidemiologic data now emphasize its high prevalence in HIV-infected persons.16-43The frequency of Candida isolation and clinical signs of oral candidiasis increases with advancing HIV infection.“4%44 In one study of 62 HIVinfected patients,24 microbiologic recovery of oral C. albicans isolates was 57.5% for Centers for Disease Control stage I patients; 76.5% for stage II patients, and 87.5% for stage III patients. Table I lists the prevalence of oral candidiasis in adults infected with HIV. In 22 reported investigations in a total of 3387

adults, the prevalence ranges from I 1% to 96%. The mean frequency of oral candidiasis weighted according to the number of subjects in each study (Le., weighted mean) is 36.5%, whereas the figures for simple mean and median are 47.7% and 43%, respectively, indicating that, in general, oral candidiasis may develop in one third to half of HIV-infected persons. The prevalence rates of candidiasis vary substantially among surveys cited in Table I, perhaps for many reasons. Patient selection is obviously one cause of variation in epidemiologic studies. Although most workers defined the selection criteria, particularly the disease state, others failed to mention this and categorized all persons as IIIV seropositive. Second, the clinical parameters used in the diagnosis may have

Oral mycoses in HIV infection

Volume 73 Number 2

Table II. Prevalence of oral candidiasis in children with HIV-l Author (yr)

infection

’ Geographic location

Mastrucci et al.3” (1988) Davachi et ak3’ (1988)

California Kinshasa, Zaire

Silvia et al.36 (1989)

N.Y. US Florida

Leggott et al.37 (1990)

173

Seropositives Hospitalized infants and children (I mo- 12 yr) Pediatric AIDS Seropositives

been different from ‘one country or center to another. Finally, the microbiologic sampling method used may play a critical role in the diagnostic decision making process (discussed later). Replorts by Davachi et a1.35 from Zaire, and Mastrucci et a1.,34Silvia et a1.,36and Leggott et a1.37 from the United Sta.tes indicate that oral candidiasis is a frequent sign of HIV infection in children (Table II). Cumulative data from the latter studies in 384 children demonstrate a weighted mean frequency of 37.9% (simple mean 34.4%) for oral candidiasis in children with HIV infection. Furthermore, Silvia et a1.36found that 50% of 42 children with perinatal HIV infection or pediatric AIDS had oral and cutaneous candidiasis in the first year of life, as opposed to 10% of 20 children in whom AIDS was diagnosed after this period. They concluded that in very young infants with HIV infection chronic mucocutaneous candidiasis may act as a warning sign for early and severe morbidity. Furthermore, in a longitudinal study of two cohorts of 159 children, Leggott et a1.37found the most common oral lesions to be oral candidiasis and parotid enlargement. Other investigators have also found Candida-induced thrush, esophagitis, pneumonia, endocarditis, and disseminated infection in children who died of AIDS.45 Oral candidiasis, particularly the pseudomembranous variety of thrush, is not uncommon among otherwise healthy infants, and surveys suggest an incidence not excee:ding 7% and usually less than 5%.46-49 This is generally acknowledged to be due to the immature defense mechanisms in the newborn infant, and it is thought that the latter, together with HIV infection, may act in concert in precipitating the severe morbidity, including oral candidiasis associated with HIV infection. It is therefore surprising that the weighted mean prevalence of oral candidiasis in adults (33.5%) and children (37.9%) are somewhat similar. Further, Wanzala et a1.50found in an African population of infants (mean age 25 weeks) born to seropositive (56 infants) and seronegative (106 infants) mothers the occurrence of oral candidiasis was not HIV specific. The overall prevalence of the disease was 7% to 8% in both groups of infants. However,

AIDS

24 196

33 42

AIDS in 1st yr AIDS after 2nd yr Seropositive

42 20 100

50 10 35

Seropositive Symptomatic

these authors do not mention the HIV seropositivity of either group of infants. To conclude from the meager data available, it seems that in general, prevalence of oral candidiasis in seropositive adults and children are not dissimilar. Clinical

variants

With the increasing frequency of oral candidiasis in HIV infection it has become evident that the disease may present as four distinct clinical variants, namely (1) pseudomembranous variant, (2) erythematous (atrophic) variant, (3) hyperplastic variant, and (4) angular cheilitis.2 The classic nomenculature, where the term atrophic is used to describe a red mucosal surface, has received much criticism recently,5 because the redness of the mucosa may be caused by increased vascularity with or without reduced thickness of the epithelium. Hence the term “erythematous candidiasis” in preference to “atrophic candidiasis” has been adopted for this condition and is now widely used. The four clinical variants occur with varying frequency in patients with AIDS, AIDS-related complex, and healthy seropositive patients and therefore it is important to distinguish among these types.51>s2 Recent data* pertaining to the prevalence of these clinical variants are shown in Tables III and IV. From the available information it appears that (1) erythematous candidiasis is equally if not more frequent than the pseudomembranous variety, (2) one fifth to one fourth of patients appear to have these variants, and (3) angular cheilitis and hyperplastic candidiasis are -the least common variants. Another noteworthy feature of oral candidiasis in HIV infection is the presentation of the disease in mulliple oral sites. This phenomenon has infrequently been documented in HIV-negative persons as chronic multifocal oral candidiasis.4 However, in HIV infection, involvement of multiple oral foci appears to be common, Thus Cahn et a1.54noted multiple foci in 62% of 105 HIV-positive Argentinian patients with erythematous candidiasis, and Mastrucci et a1.34 *References 23, 26, 21, 29, 32, 33, 38, 39, 42, 53.

I 74

Samaranayake

ORALSURGORAL

Table II!. Prevalence rates of clinica! variants of oral candidiasis in different population

Mm QRALPATHOL February 1992

groups with HIV-l

infection (includes seropositive, ARC, and AIDS patients)

Reichart et al.*a (1987) Ficarra et aLZ3 (1988) Langford et aLs3 (1988) Mugaruka et a1.33(1989) Porter et a1.26(1989) Schulten et a1.27(1989) Casariego et aL3* (1989) Wanzala et a1.39 (1989) Schi#dt et al!O (1990) Ceggott et al.”

Berlin Florence Berlin Kinshasa, Zaire Bristol, UK Amsterdam Buenos Aires Nairobi Dar es Salaam, Tanzania Fla.

(1990)

44 15 105 269 56

35 51 NA 62 36 52 64 12 43

40 13 32 31 69 6 8.5 0.4 23

37 31 15 30 5.5 26 96 10.5 21

37 NA 20 2 5.5 5 3.8 0.4 NA

13 NA NA NA 19.4 23 20 1.5 NA

100

NA

35

25

NA

NA

110 211 260 100

Some patients had more than one clinical variant. ARC, AIDS-related complex; NA, no data available. “As a percentage of those with oral candidiasis.

Table IV. Summary statistics related to oral candidiasis in HIV-infection* j Prevalence frequencies

Disease state Oral candidiasis Erythematous candidiasis Pseudomembranous candidiasis Hyperplastic candidiasis Angular cheilitis

(%)

No. of paper4 abstracts

Range

Weighted7 mean

Simpleimean

23 10

1 l-96 lo-96

36.5 27.4s

47.1 29.75

10

0.4-69

20.3

26.0

7

0.4-20

11.0

10.5

5

1.5-23

10.8

15.4

*Data from Tables I and III. TWeighted by overail number of patients with oral candidiasis in each study. fArithmetic mean of frequencies quoted. §As a percentage of those with oral candidiasis.

found this in four of eight California children with HIV infection. However, in an African study of 269 seropositive women,39 only two patients had multifocal presentations of the disease. It should be noted that the term “multifocal candidiasis” is loosely applied for either the presentation of a single clinical variant or diRerent clinical variants at two or more sites. Clinical

features

The erythematous or atrophic form of oral candidiasis appears clinically as a red lesion. The sites most frequently affected are the palate and the dorsum of the tongue, with associated depapillation. In one study 55 the lesion was present on the hard palate in 60%, on the soft palate in 17%, and on the dorsum of the tongue in 57% of 66 patients with erythematous candidiasis, and in another study54 49% of 105

patients had this lesion on the hard palate, 42% in the soft palate, and 12% on the buccal mucosa. In another African survey 39the lesions of the tongue and palate were reported in 63% and 50%, respectively, of 31 HIV-positive women. Before the AIDS era, erythematous candidiasis, then called acute atrophic candidiasis, was infrequently observed in patients after broad-spectrum antibiotic therapy or rarely during corticosteroid therapy. 56 The erythematous appearance was believed to be a secondary consequence of shedding of the plaque of pseudomembranous candidiasis, which was the primary event. 57On the contrary, in HIV infection the erythematous type appears to precede the pseudomembranous variety,51, 58 although prospective surveillance studies are warranted to confirm this observation. Pseudomembranous candidiasis classically presents as semiadherent, whitish yellow, soft: creamy, droplike or sometimes confluent membranes. The latter can be removed from the mucosa by wiping with a gauze swab, which leaves a red and slightly bleeding surface. The disease is usually acute, but in HIV-infected patients it may, if untreated, persist for several months during which the course of the infection appears to be chronic rather than acute. Pseudomembranous lesions may involve any area of the oral mucosa, most frequently the tongue, hard and soft palate, and buccal mucosa.*, 59 In a study of IO6 AIDS patients with this condition, 48% and 42% of the lesions were seen on the dorsum and lateral surface of the tongue, respectively: 20% on the hard palate, 19% on the soft palate, and 15% on the buccal mucosa.55 The hyperplastic form of candidiasis in HTVinfected patients is most often seen bilaterally on the buccal mucosa and rarely in the retrocommissural

Volun ” 73 Number 2

area, which is the classic pres,entation site in HIVnegative persons. The lesions are characterized by irremovable whitish yellow patches, and the lesions have been related to tobacco smoking.2 This form and angular cheilitis each constitute approximately 10% of oral candidiases seen in HIV infection. The chronic hyperplastic candidal variant in HIVpositive or AIDS patients should be clearly distinguished from hairy leukoplakia lesions.60 Indeed, on histobpathologic examination candidal hyphae can be demonstrated within the superficial epithelium of hairy leukoplakia lesions and Candida species can be recovered from its surface.2 However, close examination of the epithelium should enable its differentiation from. hyperplastic candidiasis due to the characteristic histopathologic features (e.g., presence of koil.ocytes).2 Angular cheilitis (angular stomatitis) is a disease of multifactorial etiology, and it may be infective or noninfective in origin. AIDS and HIV infection should now be:added to the list of causative factors of angular cheilitis, because cumulative data from a number of studies26T27,32,38 indicate that one in 10 patients with HIV infection may have angular cheilitis. Before the advent of HIV infection, these lesions were most commonly seen in elderly persons as a complication of denture-induced stomatitis (chronic atrophic candidiasis) and the disease was relatively rare among younger age groups. Clinically the lesions manifest as red, fissured crusts with or without ulceration and could be accompanied by subjective symptoms of soreness, tenderness, burning, or pain. 61Although the infection is generally caused by Candida species and/or Staphylococcus aureus,62 the extent of involvement of the latter organisrms in HIV-induced angular cheilitis remains to be determined. Another type of oral candidiasis, the papillary variant, has also been described by some workers.29, 53 Characteristically manifesting in the hard palate, they appear as erythematous papillary nodules similar to those observed in denture-induced papillomatosis. In two German studies this variant was found in 6% and 11% of 262 and 110 HIV-positive and AIDS patients, resplectively.29, 53 Histologically, candidal infection in HIV-infected patients frequently shows a rernarkably weak inflammatory reaction. The epithelium may be invaded by numerous hyphae or pseudohyphae without the characteristic massive infiltrate of polymorphonuclear leukocytes. Likewise, subepithelial inflammation is mild.2 Pathogenesis

Rielatively few details of the pathogenesis of AIDSassociated oral candidiasis are known. The prevalence

Oral mycoses in HIV infection

175

of oral colonization with C. albicans has been studied in 225 homosexual men (99 of whom had antibodies to HIV-l) and 175 heterosexual men.44 Carriage of Candida was most prevalent (77.8%) among HIVseropositive homosexual men. Whereas a heavy growth of C. albicans in culture and findings of pseudomycelial elements in oral smears correlated well with HIV-seropositivity, half of patients with positive smears had no clinical signs of oral candidiasis. Furthermore, on reexamining the latter group 12 to 18 months later similar results were obtained, implying a higher incidence of nonpathologic colonization in this high-risk group. Although candidiasis of the esophagus is one of the opportunistic infections included as definitive diagnostic criteria for AIDS oral candidiasis is not among these criteria. However, oral candidiasis in many patients becomes clinically apparent in the prodromal stages of AIDS and among patients at risk. In addition, it may be predictive for future development of full-blown AIDS.r5, 63,64 Klein et a1.15were the first to draw attention to this phenomenon. In 22 previously healthy adults with unexplained oral candidiasis, 19 persons had a reversed T4/T8 ratio and 20 had generalized lym.phadenopathy when compared with 20 similar patients with a reversed T4/T8 ratio and generalized lymphadenopathy who did not have oral candidiasis. Of the 22 patients with oral candidiasis, 13 (59%) acquired a major opportunistic infection or Kaposi’s sarcoma at a median interval of 3 months, as compared with none of the 20 patients with generalized lymphadenopathy and immunodeficiency but without candidiasis, who were studied for a median of 12 months. AIDS developed in 12 of 15 patients with candidiasis and T4/T8 ratios less than or equal to 0.5 1, as compared with none of four with ratios equal to or greater than 0.60.15 Two reports have described a possible correlation between frequency of oral C. albicans carriage and number of suppressor T cells in a group of white homosexual men and in an African population.65, 66Recently, Plettenberg et al. 67 also demonstrated a statistically significant correlation between alteration of immunologic markers, oral candidiasis, and progression to AIDS. However, one study failed to correlate increasing number of suppressor T cells with increased frequency of Candida carriage or positive smears when patients were separated into groups on the basis of occurrence of HIV antibodies.44 Foci of oral candidiasis may act as potential reservoirs of organisms for local spread of the disease in the immunocompromised host, although the mode and the sequence of spread is unknown. In a study of 20 consecutive patients with AIDS and oral candidiasis, Tavitian et a1.68showed that oral candidiasis might in

176

Samaranayake

ORAL SURG ORAL Mm

ORAL Pamor.

February 1992 Table V. Specimens required for the laboratory investigation of oral candidiasis Disease variant

-

Swab

Smear

Biopsy

Candida species

+

+

-

+

ir

-

+ +

* +

+ -

+

+

-

C. albicans C. glabrata C. stellatoidea lreclassijed as C. albicans) C. paratropicalis (reclassified as C. tropicalis) C. famata C. kefyr C. tropicalis C. krusei C. rugosa C. guilliermondii

.4cutepseudomembranous candidiasis Acute atrophic (erythematous) candidiasis Chronic hyperplasticcandidiasis Chronic atrophic (erythematous) candidiasis Angular cheilitis f, Useful; t , may be useful; -, inappropriate.

fact be an indication of esophageal candidiasis. Thus early treatment of oral candidiasis should be mandatory to prevent further spread of infection. Laboratory

Table VI. Candida species and other fungal isolates from oral cavities of HIV-infected patients* :

Uncommon fungi Saccharomyces cerevisiae Rhodotorula rubra Rhodotorula pijiminae Fonsecaea pedrosoi Prototheca stagnura Trichosporon pullulans Cryptococcus albidus Cryptococcus neoformans Histoplasma rapsulatum Ceotrichum candidum

*References 73-76.

diagnosis

Because of a variety of clinical forms of candidiasis, a number of differing specimens such as smears, swabs, imprint samples, salivary samples, oral rinse samples, and biopsy specimens have been used for the laboratory diagnosis of oral candidiasis. The sensitivity of these techniques varies widely and therefore has obvious implications in the short term with regard to diagnosis of the disease and in the long term on global prevalence data. A plea has therefore been made emphasizing the importance of international standardization and calibration of data obtained from persons with HIV infection.52 Hence all clinicians dealing with tbese patient groups should be aware of the relative sensitivities of the diagnostic techniques that they routinely employ. Table V shows the sampling techniques easily available to the clinician that are necessary to confirm the presence or absence of a specific clinical variant of oral candidiasis. Although these are the traditional sampling techniques when clinical evidence of disease is observed, other techniques such as the quantitative culture of undiluted saliva69 and the oral rinse70 technique appear to be sensitive in assessing overall oral candidal carriage when no focus of infection is visible. In addition to saliva’j9 and oral rinse cultures,7a the technique of imprint cultures,71 where square foam pads are applied to several mucosal surfaces and the imprints of the pads are subsequently cultured on Sabouraud’s medium for the growth of yeast species, is useful in quantitative estimation of Candida per unit area of the mucosa. Each of the previously mentioned techniques has merits in specific clinical situations. For instance, swabs and smears as time-honored tools should be used in most situations where lesions are clinically

apparent and a semiquantitative estimate of yeast numbers is to be made. Other methods such as imprint and rinse samples are particularly useful for estimating quantitative candidal carriage; the former yields yeasts per unit mucosal surface and the latter yeasts per milliliter of rinse. The reader is referred to Silverman et a1.72for a comprehensive review of the laboratory diagnosis of oral candidiasis. Candida

species

and biotypes

Consideration has been given so far to the prevalence of yeasts as a group in various clinical studies. A few reports are available of the relative proportions of different yeast species isolated from HIV-positive persons. C. albicans is undoubtedly the most common Candida species isolated intraorally in both HIVpositive and healthy carriers.73-76 Data from three reports73-75 yield a mean figure of 77.6% (range 56% to 84%) of total yeast isolates to be C. albicans in HIV-positivecarriers compared with 69.6% in healthy (HIV-negative) carriers.7 Other Candida species and rare fungal strains isolated from HIV-positive patients are shown in Table VI. The extent to which species identification can be relied on is always an unknown factor. Detailed methods of yeast identification may differ between laboratories, and hence it is hoped that standardized instruments of identification are used globally to yield comparable data. The current confusion among yeast taxonomists is another confounding variable.77 In addition to the intraoral carriage of different species of Candida, it appears that different biotypes of C. albicans exist in persons infected with HIV. Thus Korting et a1.24and Franker et al.74 found that 21% and 19% of isolates, respectively, from HIV-pos-

Oral mycoses in HIV infection

Volume 73 Number 2

itive patients did not belong to Candida biotypes of HIV-free persons, with the use of a typing system described by Williamson et aL7* Rrawner and CZutler,79 using a serotyping technique, found that immunocompromised persons, including those with AIDS, are at least twice as likely to be infected by serotype B than serotype A strains as opposed to immunocompetent persons, who were equally likely to carry serotypes A and B. Further, a change in biotype or serotype pattern on repeated evaluation of the same patient has also been noted. These studies underline the importance of a reliable, standardized biotyping system for Candida isolates from HIV-infected patients, for (1) the evaluation and localization of sources of infection, (2) the determination of frequency of change of biotype patterns and particularly selection of biotypes during therapy, and (3) the differentiation between therapeutic failure and reinfection in cases of recalcitrant oral candidiasis. Whereas simple biotyping systems that use standardized, quality-controlled, commercially available media have been described,sO the advent of the more sophisticated DNA. fingerprintjing methods of Candidas should help clarify the importance of strain variations in the pathogenesis of HIV-related oral candidiasis. It is worth commenting on the controversial subject of the pathogenic significance of the hyphal phase of C. albicans. Many reports state or imply that only the hyphal phase of Candida is invasive or pathogenic whereas yeast cells or blastospores are merely harmless commensals (for a review see Oddss2). The corollary of this is that the presence of yeast cells in a specimen is harmless whereas “hyphae” implies a pathogenic process or an active infection. Thus some workers8”, 84 found a positive correlation between hyphae and oral candidiasis whereas others7’, 85 have been unable to do so. Torssander et a1.,44for instance, found mycelial elements in half of HIV-infected patients with oral candidiasis, although positive “hyphal” smears were also found in several subjects without any evidence of immune deficiency. When the subjects with positive hyphal smears were reexamined after 12 to 18 months, they still yielded hyphal elements in the absence of any symptoms. Hence it seems, at least intraorally, that hyphal and mycelial findings represent a variant of commensal colonization. Of related interest is the inability of species such as C. glabrata and Candida krusei, whose pathogenic status is well established, to form hyphae and/or mycelia either in vitro or in vivo.86 To conclude, the pathogenic role of candidal hyphae should. not be overemphasized until more evidence is available to confirm or refute a morphologic demarcation, if any, betwleen health and disease.

177

Management

The standard antifungal drug regimen for oral candidiasis consists of topical administration of either polyenes (nystatin or amphotericin) or imidazoles (clotrimazole). 87 In HIV-infected persons the response to treatment with polyenes or clotrimazole is transient and relapses are very common. Such failures are caused mainly by the underlying immunodeficiency, although poor patient compliance as a result of frequent administration, gastrointestinal upsets, unpalatable taste, and intolerance may also play a role. For these reasons systemic antifungals have been advocated for HIV-related oral candidiases, and two groups of drugs: ketoconazole, a derivative of the imidazole group, and the newer fluconazole and itroconazole, belonging to the bis-triazole group are being used for this purpose. 88 A number of reviews are available on the management of HIV-related oral candidiases,59, x9,9oand the reader is referred to these and to the current symposium proceedings of Scully et al. (pp. 215-225) for information on this topic. ORAL CRYPTOCOCCOSIS

Cryptococcosis is a chronic fungal disease involving primarily the lungs, although the central nervous system and occasionally the skin and mouth may also be affected.91 The disease occurs worldwide, and the causative agent is the yeast Cryptococcus neoformans, found in bird droppings. The disseminated form of the disease may occur in compromised hosts such as patients with leukemia, persons receiving steroid therapy, and patients with HIV infection. The face, scalp, and neck are the common sites of cutaneous lesions, which may present as papules, acneiform pustules, abscesses, ulcers, superficial granulomas, or sinus tracts. Intraorally the lesions have been described on the gingiva, the hard and soft palate, pharynx, buccal mucosa, and tonsillar pillars appearing as swellings, ulcers, or nodules of granulation tissue. 92 In patients with AIDS cryptococcosis is a major opportunistic infection and hence an increased number of patients with oral cryptococcosis can be expected. Clinical

features

in HIV infection

At least three cases of oral cryptococcosis,93-95 all from the United States, have been described in HIV infection. The first case was in a 41 -year-old Hispanic homosexual man who had a persistent ulcer of the tongue and concurrent oral candidiasis.93 The lingual ulcer was confirmed to be due to C. neoformans. The second patient was a 25-year-old black man who had an ulcer on the midposterior hard palate as an initial

17% Samaranayake

manifestation of disseminated cryptococcosis.94The third patient was a 66-year-old white man who had a nonhealing ulcer of the right maxilla that on microbiologic and pathologic examination was found to be due to cryptococcosis.95 Laboratory

diagnosis

The yeast CXneoformans is round or elliptic, and it is morphologically differentiated from Candida species by its narrow-based budding and thick carminophilic capsule.91Scraping or pus from lesions are examined in potassium hydroxide wet mounts, whereas macerated biopsy material or direct contact smears can be examined with nigrosin or india ink as negative stains when the capsule can be clearly visualized. Alternatively the capsule in biopsy specimenscan be stained with periodic acid-Schiff, mucicarmine, or methenamine-silver. Samples can be cultured in Sabouraud’s medium and incubated at 37” C for up to 2 to 4 weeks, when the yeasts appear as glistening, mucoid, tan to brown colonies. Several serologic tests for cryptococcosis are available, but false-positive and -negative results occur. The complement fixation test to measure antibody in serum appears to be the most specific.91 anagement

Amphotericin B is the drug of choice, and maintenance therapy may be required.88991 ORAL HISTOPLASMOSIS

Histoplasmosis is a deep mycosis caused by Histoplasma capsulatum. It is a dimorphic fungus with a mold form and a yeast form. The latter is the parasitic form and appears as budding yeasts similar to Candida. The clinical presentation of the diseasecan vary from acute to chronic respiratory illness, with dissemination to a chronic mucocutaneous form often manifesting as ulceration of the oropharynx.91 The lesions have been described in almost every part of the oral mucosa; the tongue, palate, and buccal mucosa are the most common. About 30% to 50% of patients with disseminated histoplasmosis have oral lesions, frequently presenting as the initial sign.92 Clinical

features

in HIV infection

Thus far three caseshave been reported in the literature on oral histoplasmosis in HIV infection. The first was in a 41-year-old homosexual man with an ulcerated lesion in the anterior of the floor of mouth (also see Greenspan et aL2). The second patient was a 26-year-old white woman, an intravenous drug abuser, who had a palatal perforation caused by histoplasmosis and concurrent candidiasis.96 The last case was of a disseminated histoplasmosis in a male

ORAL SURG ORAL MED ORAL PATHOL February 1992

AIDS patient and was diagnosed by biopsy of a palatal lesion.97 Laboratory

diagnosis

Diagnosis of oral histoplasmosis is mainly on histologic grounds. Specific immunofluorescence tests can be used to identify Histoplasma cells in sections or smears.91They grow slowly in Sabouraud’s medium as white or tan, velvety colonies; a long incubation period of some 12 weeks is required. A rising titer to histoplasmin antigen with a complement fixation or immunodiffusion test are important for diagnosis 91,92

Management

Amphotericin B is the drug of choice, with ketoconazole as an alternative.88,91 ORAL GEOTRlCHOSlS

Geotrichum candidum is a yeastlike fungus that produces geotrichosis, an infection of bronchi, lungs, and mucosae.91In sputum the organism appears as rectangular arthrospores or thick-walled ovoid yeast cells. The natural habitat of the fungus is not known, and in the mouth they usually produce thrushlike lesions. Clinical

features

in HIV infection

A single HIV-infected patient with oral geotrichosis has been mentioned in the literature (Greenspan D, personal communication, quoted by Pindborg JJ52). REFERENCES 1. Mawr H, Shelhamer J, Kovacs JA, Parillo JE, Ognibene F. Infectious complications of AIDS. In: De Vita VJ, Hellman S, Rosenberg SA, eds. AIDS etiology, diagnosis, treatment and prevention. Philadelphia: JB Lippincott, 198§:161-84. 2. Greenspan D, Greenspan JS, Pindborg JJ, Schiddt M. AIDS and the mouth. Copenhagen: Munksgaard, 199b. 3. MacFarlane TW. Samaranavake LP. Clinical oral microbiology. Bristol: Wright, 1989:125. 4. Holmstrup P, Besserman M. Clinical, therapeutic and pathogenic aspects of chronic oral multifocal candidosis. ORAL SURG ORAL MED ORAL PATHOL 1983;56:388-95. 5. Samaranayake LP, Yaacob H. Classification of oral candidosis. In: Samaranayake LP, MacFarlane TW, eds. Oral candidosis. Bristol: Wright, 1990:124-32. 6. Holmstrup P, Axe11 T. Classification and clinical manifestations of oral yeast infections. Acta Odontol Stand 1990; 48:57-60. 7. MacFarlane TW. Ecology and epidemiology of Candida. In: Samaranayake LP, MacFarlane TW. Oral candidosis. London: Wright, 1990:21-46. 8. Samaranayake LP. Oral candidosis: predisposing factors and pathogenesis. In: Derrick DD, ed. Dental annual 1989. Bristol: Wright, 219-35. 9. Gottlieb MS, Schanker HM, Fan PT, Saxon A, Weisman JO, Pozalski I. Pneumocystis pneumonia-Los Angeles. MMWR 1981;30:250-1. 10. Follansbee SE, Busch DF, Wolfsy CB, et al. An outbreak of

Oral mycoses in HIV infection

Volume 73 Number 2

11,

12.

13.

14.

15.

16. 17.

Pneumocystis carinii pneumonia in homosexual men. Ann Intern Med 1982;96:705-13. Masur H, Michelis MA, Wormser GP, et al. Opportunistic infection in previously healthy women: initial manifestations of a community-acquired cellular immunodeficiency. Ann Intern Med 1982;97,533-9. Gottlieb MS, Schroff R, Schranker HM, et al. Pneumocystis carinii pneurnonia and mucosal candidiasis in previously healthy homolsexual men: evidence of a new acquired cellular immunodeficiency. N Engl J Med 1981;305:142531. Small CB, Kelin RS, Friedland GH, Mall B, Emeson EE, Spigland I. Community-acquired opportunistic infections and defective cellular immunity in heterosexual drug abusers and homosexual men. Am J Med 1983;74:433-41. Masur H, Michelis MA, Greene JB, et al. An outbreak of community acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction. N Engl J Med 1981;305:1431-8. Klein RS, Harris CA, Small CB, Moll B, Lesser M, Friedland GH. Oral candidiasis in high risk patients as the initial manifestation of the acquired immunodeficiency syndrome. N Engl J Med 1984;311:354-7. Samaranayake LP, Scully C. Oral candidosis in HIV infection. Lancet 1989;2:1491-2. Lozada F, Silverman S Jr, Migliorati CA, Conant MA, Volberding PA. Oral manifestations of tumour and opportunistic infections in theacquired immunodeficiency syndrome (AIDS): findings in 53 homosexual men with Kaposi’s sarcoma. ORAL SURF ORAL MED ORAL PATHOL

1983;56:491-4.

31.

32.

33.

34.

35.

36.

37.

38.

18. Phelan JA, Salzman BR, Friedland GH, Klein RS. Oral findings in patients with acquired immunodeficiency syndrome. ORAL SURG ORAL MED ORAL PATHOL

1987;64:50-6.

19. Adelson R, Kleinman D, Rhyne R, et al. Oral health component of a national surveillance program of HIV-infected veterans: a pilot study [Abstract]. Presented at Fourth International Conference on AIDS; 1988; Stockholn 20. Coleman D, Russell R, Harwood M, Mulachy F, Shanley D. Clinical and microbiological analysis of oral candidiasis in HIV-positive patients. J Dent Res 1989;68:893. 21. Engelman J, Greenspan D, Lifson R, et al. Oral manifestations of HIV infection in a cohort of homosexual and bisexual men [Abstract]. Presented at Fourth International Conference on AIDS; 1988; Stockholm. 22. Feigal DW, Overby GL, Greenspan D, et al. Oral lesions and immune functions with and without HIV infection. J Dent Res 1989;68:190. 23. Ficarra G, Gaglioti D, Barone R, et al. Oral candidiasis and hairy leukoplakia among HIV-infected IV drug abusers [Abstract]. Presented at Fourth International Conference on AIDS; 1988; Stockholm. 24. Korting HC, Ollert M, Georgii A, Froschl M. In vitro susceptibilities and biotypes of Cundida albicans isolates from the oral cavities of patients infected with human immunodeficiency virus. J Clin Microbial 19&9;26:2626-31. 25. Melnick S, Engel D, Truelove E, et al. Oral disease and HIV infection [Ab’stract]. Presented at Fourth International Conference on AIDS; 1988; Stockholm. 26. Porter SR, Luker J, Scully C, Glover S, Griffiths MJ. Orofacial manifestations of a group of British patients infected with HIV-l. J Oral Path01 Med 1989;18:47-8. 27. Schulten EA.JM, Ten Kate RW, Van Der Waal I. Oral manifestations of HIV infection in 75 Dutch patients. J Oral Path01 Med 1989;18:42-6. 28. Sinicco A, Mloniaci D, Greco D, Raiteri R, Giacometti E. Oral lesions in 327 anti-HIV positive subjects [Abstract]. Presented at Fourth International Conference on AIDS; 1988; Stockholm. 29. Reichart PA, Gelderblom HR, Becker Kuntz A. AIDS and the oral cavity: the HIV-infection-virology, etiology, origin, immunology precautions and clinical observations in 110 patients. Int J Oral Maxillofac Surg 1987;16:129-53. 30. Likimani S, IDe Cock KM, Green TL, et al. Oral manifesta-

39.

40.

179

tions of HIV infection in Abidjan, Cote d’Ivoire [Abstract]. Presented at Fifth International Conference on AIDS; 1989; Montreal. Loeb I, Prieels F, De Wit S, Clumeck N. Occurrence of oral pathology among different risk groups of HIV infected patients [Abstract]. Presented at Fifth International Conference on AIDS; 1989; Montreal. Casariego Z, Cahn P, Perez H, et al. Oral pathology in 105 HIV-reactive patients in Buenos Aires [Abstract]. Presented at Fifth International Conference on AIDS; 1989; Montreal. Mugaruka Z, Perriens J, Ngaly B, Baende E, Kahotwa J, Rapita B. Oral manifestations of HIV infection in African patients [Abstract]. Presented at Fifth International Conference on AIDS; 1989; Montreal. Mastrucci MT, Scot GB, Leggott PJ, Greenspan D, Greenspan J. Oral manifestations of HIV infection in children [Abstract]. Presented at Fourth International Conference on AIDS; 1988; Stockholm. Davachi F, Mayemba N, Kabongo L, et al. Incidence of opportunistic infection in 196 children with symptomatic AIDS in Kinshasa [Abstract]. Presented at Fifth International Conference on AIDS; 1989; Montreal. Silvia A, Iosub S, Baniji M, Stone RK, Gromisch DS, Wasserman E. Chronic mucocutaneous candidosis in paediatric AIDS [Abstract]. Presented at Fifth International Conference on AIDS, 1989; Montreal. Leggott PJ, Mastrucci MT, MacPhail, et al. Oral lesions in children with HIV infection [Abstract]. Presented at Sixth International Conference on AIDS, 1990; San Francisco. Kenard B, Rindum JL, Pindborg JJ. Oral findings in 23 patients with antibodies against HIV. Tandlagebladet 1987;91:100-2. Wanzala P, Manji F, Pindborg JJ, Plummer F. Low prevalence of oral mucosal lesions in HIV-l seropositive African women. J Oral Path01 Med 1989;18:416-8. Schiddt M, Bakilan PB, Hiza JFR, et al. Oral candidiasis and hairy leukoplakia correlate with HIV infection in Tanzania. ORAL SURG ORAL MED ORAL PATHOL

1990;69:591-6.

41 Barone A, Ficarra G, Gaglioti D, Orsi A, Mazzotta F. Prevalence of oral lesions among HIV infected intravenous drug abusers and other risk groups. ORAL SURG ORAL MED ORAL PATHOL

1990;69:169-73.

42 Kissinger P, Adrien M, Bolos R, et al. Predictability of HIV status in Haitian adults [Abstract]. Presented at Sixth International Conference on AIDS; 1990; San Francisco. L, Kayembe K, Odio W, 43 Tukutuku K, Muyembe-Tamfum Kandi K, Ntumba M. Oral manifestations of AIDS in a heterosexual population in a Zaire hospital. J Oral Path01 Med 1990;19:232-4. L, Biberfeld G, Karlsson A, 44. Torssander J, Morfeldt-Manson Putkonen PD, Wasserman J. Oral Candida albicans in HIV infection. Stand J Infect Dis 1987;19:291-5. 45. Ross LA, Wong VK, Gomperts ED, Ricalde AL, Church JA. Spectrum of infections identified at autopsy in paediatric AIDS [Abstract]. Presented at Fifth International Conference on AIDS; 1989; Montreal. 46. Dunn P. Thrush in the newborn. Br Med J 1962;1:256-7. 47. Kaloyannides TM. Oral moniliasis in the newborn. J Can Dent Assoc 1968;34:496-7. 48. Kaul KK, Shah PM, Pohowalla JN. Oral moniliasis in the newborn and neonatal morbidity. Indian J Paediatr 1960; 27:115-24. 49. Shrand H. Thrush in the newborn. Br Med J 1961;2:1530-3. 50. Wanzala P, Datta P, Temmerman M, Pindborg J, Kisumbi N, Kariuki H. Oral mucosal lesions in infants of HIV-oositive and HIV-negative mothers [Abstract]. Presented at Fifth International Conference on AIDS; 1989; Montreal. 51. Pindborg JJ. Oral candidosis in HIV infection. In: Robertson PB, Greenspan JS, eds. Perspectives in oral manifestations of HIV infection. Littleton, Mass: PSB Publishing, 1988:28-37. 52. Pindborg JJ. Classification of oral lesions associated with HIV infection. ORAL SURG ORAL MED ORAL PATHOL 1989;67: 292-5.

f 80

Samaranayake

53. Langford AA, Reichart P, Pohle HD. Oral manifestations associated with HIV infection [Abstract]. Presented at Fourth International Conference on AIDS; 1988; Stockholm. 54. Cahn P, Casariego Z, Perez H, et al. Erythematous candidiasis: early clinical manifestation in HIV-reactive patients [Abstract]. Presented at Fifth International Conference on AIDS; 1989; Montreal. 55. Greenspan D, Overby G, Feigal DW, MacPhail L, Miyasaki S, Greenspan JS. Sites and relative prevalence of hairy leukoplakia, pseudomembranous candidiasis and erythematous candidiasis [Abstract]. Presented at Fifth International Conference on AIDS; 1989; Montreal. 56. Lehner T, Ward RG. Iatrogenic oral candidosis. Br J Dermato1 1970;83:161-6. 57. Cawson RA. Essentials of dental surgery and pathology. 3rd ed. Edinburgh: Churchill, 1978:288. 58. Pindborg JJ: Nielsen H. Significance of oral lesions: oral candidosis. J Dent Res 1989;68:859. 59. Holmstrup P, Samaranayake LP. Acute and AIDS-related oral candidoses. In: Samaranayake LP, MacFarlane TW, eds. Oral candidosis, London: Wright, 1990:133-55. 60. Samaranayake LP, Pindborg JJ. Hairy leucoplakia [Editorial]. Br Med J 1989;4298:270-1. 61. Ohman SC, Dahlen G, Moller A, Ohman A. Angular cheilitis: a clinical and microbial study. J Oral Path01 1985;15:213-7. 62. MacFarlane TW, Helnarska SJ. The microbiology of angular cheilitis. Br Dent J 1976;140:403-6. 63. Chandrasekar PH, Molinari JA. Oral candidiasis: forerunner of acquired immunodeficiency syndrome (AIDS)? ORAL SURF ORAL MED ORAL PATHOL 1985;60:532-4. 64. Murrav HW. Hillman JK. Rubin BY. et al. Patients at risk for AIDS-ielated opportunistic infections. N Engl J Med 1985;313:1504-10. 65. Schonheyder H, Melbye M, Biggar RJ, Ebbesen P, Neuland CY, Stenderup A. Oral yeast flora and antibodies to Cundidn al&cans in homosexual men. Mykosen 1984;27:539-44. 66. Melbye M, Schonheyder H, Kestens L, et al. Carriage of oral Candida albicans associated with a high number ofcirculatine supuressor T lvmnhocvtes. J Infect Dis 1985:152:1356-7. 67. Plittenberg A, Reisinger ‘R, Lenzner U, Ernst ‘M, Kern P, Meigel W, Oral candidiasis determined by a quantitative method-correlation to marker of the immunologic system [Abstract]. Presented at Fifth International Conference on AIDS; 1989; Montreal. 68. Tavitian A, Raufman JP, Rosenthal LE. Oral candidiasis as a marker for esophageal candidiasis in the acquired immunodeficiency syndrome. Ann Intern Med 1986;104:54-5. 69. Epstein JB; Pearsall NN, Truelove EL. Quantitative relationship between Candidu albicans in saliva and the clinical status of human subjects. J Clin Microbial 1?80;12:475-6. 70. Samaranayalte LP, MacFarlane TW, Lamey PJ, Ferguson MM. A comparison of oral rinse and imprint sampling techniques for the detection of yeast, coliform and Staphylococcus au&us carriage in theoral cavity. J Oral Path01 1986;15:25 1-4. 71. Arendorf TM. Walker DM. Oral candidal oooulations in health and disease. Br Dent J 1979;147:267-72. ’ 72. Silverman S, Migliorati CA, Epstein JB, Samaranayake LP. Laboratory diagnosis of oral candidosis. In: Samaranayake LP, MacFarlane TW, eds. Oral candidosis. London: Wright, 1990:213-37. 73. Silverman S, Luangjarmekorn L, Gallo J, Migliorati C. Findings and management of 50 HIV-infected patients with positive oral Candida cultures [Abstract], Presented at Sixth International Conference on AIDS; 1990; San Francisco. 74. Franker CK, Lucartorto FM, Johnson BS, Jacobson JJ. Characterization of the mycoflora from oral mucosal surfaces of some HIV-infected patients. ORAL SURF ORAL MED ORAL PATHOL 1990;69:683-7. 75. Pires MFC, Costa CR, Berman E, Orozco B. Study of fungi of the oral microbiota of HIV sero-positive patients [Abstract]. Presented at Fifth International Congress of the Academy of Oral Pathology; 1990; Tokyo.

ORAL SLRG ORAL MED ORAL P.I\THOL February 1992 76. Wray D: Felix DH, Cumming CG. Aiteration of humoral responsesroCundiduinHIVinfection.BrDentJ 1990;168:326-8. 77. Barnet JA, Payne RW: Yarrow D. Yeasts: characteristics and Identification. Cambridge: Cambridge University Press, 1983. 78. Williamson MI? Samaranayake LP, MacFarlane TW. Biotypes of Cundida albicans using the API 20C system. FEMS Microbial Lett 1986;37:27-9. 79. Brawner DL, Cutler JE. Oral Cundida albicans from nonhospitalized normal carriers, immunocompetent hospitalized patients and immunocompromised patients with or without acquired immunodeficiency syndrome. J Clin Microbial 1989;27:1335-41. 80. Williamson MI, Samaranayake LP, MacFarlane TW. A new simple method for biotyping Candida albicans. Microbios 1987;51:159-67. 81. Matthews R, Burnie J. Assessment of DNA fingerprinting for rapid identification of outbreaks of systemic candidiasis. Br Med J 1989;298:345-7. 82. Odds FC. Morphogenesis in Cundida albicans. Crit Rev Microbiol 1985;12:45-93. 83. Kozinn PJ, Taschdjian CL. Enteric candidiasis: diagnosis and clinical considerations. Paediatrics 1962;30:71-85. 84. Budtz-Jorgensen E, Stenderup A, Grabowski M. An epidemiologic study of yeasts in elderly denture wearers. Community Dent Oral Epidemiol 1975;3:115-9. occurrence 85. Olsen I, Birkeland JM. Denture stomatitis-yeast and pH of saliva and denture plaque. Stand J Dent Res 1977;85:130-4. 86. Odd FC. Candida and candidosis. London: Balliere Tindall, 1988. 87. Lamey PJ, Samaranayake LP. Oral candidosis: 2. Diagnosis and management. Dent Update 1988;15:328-31. 88. Glatt AE; Chirgwin K; Landesmann SH. Treatment of infections associated with human immunodeficiency virus. N Engl J Med 1988;318:1439-48. 89. Samaranayake LP, Holmstrup P. Oral candidiasis and human immunodeficiency virus infection. J Oral Path01 Med 1989;18:554-64. 90. Hay RJ. Overview of studies of Ruconazole in oropharyngeal candidiasis. Rev Infect Dis 1990;12:S334-7. 91. Rippon JW. Medical mycology. 2nd ed. Philadelphia: WB Saunders, 1982. 92. MacFarlane TW, Samaranayake LP. Systemic infections. In: Johns JH, Mason DK, eds. Oral manifestations of systemic disease. 2nd ed. London: Ball&e Tindall, 1990:339-86. 93. Lynch DP, Naftolin LZ. Oral Cryptococcus neoformans infection in AIDS. ORAL SI!RG OKAL MED ORAL PATHOS 1987;64:449-53. 94. Glick M: Cohen SG, Cheney RT, Crooks GW. Greenberg MS. Oral manifestations of disseminated Cryptococcus neoformans in a patient with acquired immunodeficiency syndrome. ORAL SURG ORAL MED ORAL PATHOL

1987;64:454-9.

95. Dobson TB, Perrott DH, Leonard MS. Nonhealing ulceration of oral mucosa. J Oral Maxillofac Surg 1984;47:849-52. 96. Fowler CB, Nelson JF, Henley DW. Smith RB. Acquired immunodeficiency syndrome presenting as a palatal perforation, ORAL SURG ORAL MED ORAL PATHCIL

1989;67:313-8.

97. Rosana DB, Neves MAS, Neves FD. Study clinic-therapeutic pathologic of 10 cases of disseminated histoplasmosis and AIDS in Sao Paulo, Brazil [Abstract]. Presented at Sixth International Conference on AIDS; 1990; San Francisco. Reprint requests: L. P. Samaranayake, BDS, DDS, MIBiol, Oral Biology Unit Prince Philip Dental Hospital University of Hong Kong 34 Hospital Rd. Sai Ying Pun, Hong Kong

MRCPath