Mucosal Candidal Colonization and Candidiasis in ...

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Mucosal Candidal Colonization and Candidiasis in Women with or at Risk for Human Immunodeficiency Virus Infection Paula Schuman, Jack D. Sobel, Suzanne E. Ohmit, Kenneth H. Mayer, Charles C. J. Carpenter, Anne Rompalo, Ann Duerr, Dawn K. Smith, Dora Warren, and Robert S. Klein, for the HIV Epidemiology Research Study (HERS) Group*

From the Division of Infectious Diseases, Department of Medicine, Wayne State University School of Medicine, Detroit, Michigan; the Division of Infectious Diseases, Department of Medicine, the Miriam Hospital and Brown University School of Medicine, Providence, Rhode Island; the Division of Infectious Diseases, Department of Medicine, and the Department of Epidemiology and Social Medicine, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York; the School of Medicine, Johns Hopkins University, Baltimore, Maryland; and the Centers for Disease Control and Prevention, Atlanta, Georgia

Mucosal candidiasis, including oropharyngeal, esophageal, and vaginal candidiasis, is the most common opportunistic fungal infection among persons infected with HIV [1 – 10]. Colonization of oral mucosal surfaces and symptomatic disease are closely related to the development and severity of cellular immunodeficiency [1, 4, 5, 11 – 15]. Mucosal candidiasis, although rarely lethal, contributes significantly to the morbidity and cost of treating HIV disease [10, 16]. Although most studies of mucosal candidiasis have focused on HIV-infected men who have sex with men [1, 7, 11, 14, 16], it was recognized early in the epidemic that mucosal candidiasis was prevalent among HIV-seropositive women [17 – 20]. In addition, mucosal candidiasis was noted to occur in a hierar-

Received 9 December 1997; revised 17 June 1998. This research was supported by cooperative agreements (U64/CCU106795, U64/CCU200714, U64/CCU306802, and U64/CCU506831) with the Centers for Disease Control and Prevention. Informed consent was obtained from study participants prior to enrollment. All study protocols were approved by institutional review boards at each study site and carried out according to their guidelines. * Members of the HERS group are listed at the end of text. Reprints or correspondence: Dr. Paula Schuman, Division of Infectious Diseases, Wayne State University School of Medicine, 4160 John R, Suite 2140, Detroit, Michigan 48201. Clinical Infectious Diseases 1998;27:1161–7 q 1998 by the Infectious Diseases Society of America. All rights reserved. 1058–4838/98/2705–0008$03.00

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chical pattern, in which oral and esophageal candidiasis occurred in women with severe to profound immunocompromise, while vaginal candidiasis occurred frequently and appeared to be unrelated to immunosuppression [19]. More problematic were early observations that vaginal candidiasis in HIV-seropositive women was often recurrent and unresponsive to conventional therapy [17] and that new onset or increased frequency of vaginal candidiasis may represent the earliest manifestation of HIV infection [19, 21]. The difficulties with clarifying the relationship between vaginal candidiasis and HIV infection are complicated by the fact that vaginal candidiasis is a common condition among women of reproductive age, regardless of HIV serostatus [22 – 24]. There is a paucity of information on the behavioral and biological risk factors that predispose women to become colonized with Candida species and develop candidiasis. A higher risk of vaginal candidiasis has been found among women using oral contraceptives, hormone replacement therapy, corticosteroids, and antibiotics [23, 25, 26]. Hyperglycemia and pregnancy are also believed to predispose to vaginal candidiasis. The prevalence of candidiasis is higher among sexually active women than among women who remain abstinent, and various sexual practices have been shown to transmit specific strains of Candida from one partner to another [24, 27]. Data on use of illicit substances and mucosal candidiasis are not available. We report findings at baseline from the HIV Epidemiology Research Study (HERS), a multicenter, longitudinal cohort

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The epidemiology of mucosal candidal colonization and candidiasis was studied in a multicenter cohort of 871 human immunodeficiency virus (HIV)-seropositive and 439 demographically and behaviorally similar HIV-seronegative women. Cross-sectional analyses at baseline revealed that oropharyngeal colonization with Candida species was more prevalent among seropositive women and among women reporting recent cigarette smoking and injection drug use. Oropharyngeal candidiasis was also more prevalent among seropositive women. Both oropharyngeal colonization and candidiasis were significantly associated with a lower median CD4 lymphocyte count among seropositive women. Vaginal candidal colonization was more prevalent among seropositive women and among those reporting recent injection drug use and current insulin or oral antihyperglycemic therapy. Vaginal candidiasis was equally likely to be diagnosed in seropositive and seronegative women and was not significantly related to recent sexual contact. Neither vaginal colonization nor candidiasis was significantly related to a lower median CD4 lymphocyte count among seropositive women. Baseline evaluation indicated differences in the epidemiology of oropharyngeal and vaginal candidal colonization and candidiasis in HIV-seropositive women and suggested possible variation in pathogenesis of candidal infection at these two mucosal sites.

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study of HIV disease course and determinants of disease progression in women in the United States [28]. Our objectives were (1) to compare the frequencies of oropharyngeal and vaginal candidal colonization and candidiasis among HIV-seropositive and demographically and behaviorally similar seronegative women and (2) to determine the associations of mucosal colonization and candidiasis with immunosuppression, with risk activities, and with reported medications. The distributions of Candida species among isolates and the factors associated with these distributions were also considered.

CID 1998;27 (November)

abnormal vaginal discharge and either vaginal erythema or edema were present on examination. Statistical tests for association were carried out with x2, Wilcoxon’s rank sum, and logistic regression analyses in the SAS-PC and EGRET statistical packages [29, 30]. The associations of oropharyngeal and vaginal candidal colonization and candidiasis with HIV serostatus, CD4 lymphocyte count or category (õ200, 200 – 499, and §500 cells/mm3), risk activities, and current medications were evaluated. Significant bivariate associations were simultaneously considered in logistic regression models. Findings were considered statistically significant at the P õ .05 level, and all tests were two-tailed.

Methods

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Results Population Characteristics

Among the 1,310 women enrolled in the HERS, 871 (67%) were HIV-seropositive and 439 (33%) were HIV-seronegative; 1,304 had oropharyngeal examination data and 1,288 had gynecologic examination data available from the baseline visit for analysis. HIV infection risk activity was identified as IDU by 52% of the women and as sexual contact by 48%; enrollment risk activities were equally distributed by HIV serostatus by study design. The median age of seropositive women at enrollment (35.1 years) did not significantly differ from that of seronegative women (34.5 years). More than 58% of participants were identified as black, 24% as white, and 16% as Latina. Although 57% of participants had graduated from high school, only 18% reported employment. Seventeen percent of seropositive women had CD4 lymphocyte counts of õ200/mm3, and 51% had counts between 200/mm3 and 499/mm3 (median, 377/mm3). Seropositive women were more likely than seronegative women to report a history of oral yeast infection (ever: 25% vs. 1%, P õ .001; recently [prior 6 months]: 18% vs. 1%, P õ .001). Similarly, seropositive women were more likely to report a history of vaginal yeast infection (ever: 84% vs. 77%, P Å .002; recently: 45% vs. 33%, P õ .001). Among women reporting recent vaginal yeast infections, seropositive women were more likely to report that their recent infections were more frequent than in previous months (80% vs. 71%, P Å .037), but seropositive and seronegative women were equally likely to report that their recent infections were more severe than in previous months (76% vs. 72%, P Å .480). Seropositive women were more likely than seronegative women to report current antibiotic therapy (30% vs. 10%, P õ .001). Use of trimethoprim-sulfamethoxazole or dapsone as prophylaxis for Pneumocystis carinii pneumonia (PCP) was reported by 20% of seropositive women; 6% of these women reported current use of additional antibiotics. Antifungal therapy, including that with topical and oral agents, was reported by 10% of seropositive and 1% of seronegative women (P õ .001). Current use of hormone replacement therapy, hormonal contraceptives, corticosteroid therapy, spermicides, and

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Investigators at HERS sites in the Bronx (New York), Detroit, Baltimore, and Providence (Rhode Island) began enrolling women in April 1993 and completed enrollment in January 1995. At two study sites (Detroit and Providence) women were recruited primarily from medical care settings; at the other two sites (Bronx and Baltimore) they were recruited from community sources. Participants were predominantly urban residents infected with or at risk of infection with HIV through injection drug use (IDU) or sexual contact. Eligible women were aged 16 – 55 years, were fluent in either English or Spanish, were able to give informed consent, and (for HIV-seropositive women) had had no prior AIDS-defining illness. Seropositive and seronegative women were enrolled at a ratio of 2:1. Participants were interviewed regarding sociodemographics, medical history, and risk activities, including substance use and sexual activity. Oral and gynecologic examinations were performed by clinicians who received centralized training in diagnosis of oropharyngeal and genital tract conditions. Specimens for fungal culture from the oropharynx and vagina were collected and processed to identify those women colonized with Candida species. Microscopic evaluations of vaginal secretions for Candida hyphae or blastospores, with use of 10% potassium hydroxide (KOH) preparations, were also performed. Candidal colonization was defined as the presence of organisms at a mucosal site, as determined by culture on Sabouraud dextrose agar incubated at 307C. Positive isolates were shipped to the Candida reference laboratory at Wayne State University in Detroit for identification of the species. Candida species were identified among isolates by means of germ-tube formation in human serum, chlamydospore production, and the API 20C yeast identification system (Analytab Products, Plainview, NY). Specimens of cervicovaginal secretions were also routinely obtained and evaluated for bacterial vaginosis, trichomoniasis, and other pathogens. Blood was collected and processed for lymphocyte subsets by dual-color flow cytometry. Women with oropharyngeal candidal colonization were considered to have oropharyngeal candidiasis if one or more of pseudomembranous, erythematous, or angular cheilitis oral lesions were clinically diagnosed. Women with vaginal candidal colonization were considered to have vaginal candidiasis if


Candidal Colonization and Candidiasis

Table 1. Frequency distributions for oropharyngeal and vaginal candidal colonization and candidiasis, as related to HIV serostatus at baseline, among women participating in the HIV Epidemiologic Research Study (HERS). No. (%) of women with indicated HIV status Variable

Seropositive

Seronegative

P value

518 (60.4) (87.3)

207 (47.5) (85.8)

õ.001 NS

116 (22.4)

7 (3.4)

õ.001

318 (37.4) (73.8) 27 (8.5)

91 (21.0) (61.2) 8 (8.8)

õ.001 .024 NS

Oropharyngeal candidal colonization (n Å 1,293) With C. albicans (%) Oropharyngeal candidiasis (n Å 725) Vaginal candidal colonization (n Å 1,284) With C. albicans (%) Vaginal candidiasis (n Å 409)

Oropharyngeal Candidal Colonization

Culture results for oropharyngeal candidal colonization were available for 1,293 participants (99%). Oropharyngeal colonization was identified in 518 (60%) of the HIV-seropositive women and 207 (48%) of the seronegative women (P õ .001).

Women reporting a history of oral yeast infection (ever, P õ .001; recently, P õ .001) were more likely to have colonization at baseline. The median CD4 lymphocyte count for seropositive women with oropharyngeal candidal colonization was significantly lower than for seropositive women without oropharyngeal colonization (363/mm3 vs. 405/mm3, P Å .004). Oropharyngeal candidal colonization was greatest among older women (P Å .002) and among those reporting current antibiotic therapy (P Å .013), recent cigarette smoking (P õ .001), and IDU (P õ .001). Among seropositive women, oropharyngeal colonization was increased among those reporting use of medications as prophylaxis for PCP (P Å .042). In a multivariate logistic regression model, recent cigarette smoking and IDU remained significantly associated with oropharyngeal candidal colonization after adjustment for the effects of age at enrollment, HIV serostatus, CD4 lymphocyte category, and HERS site (table 3). Results of Candida species identification were available for 686 (95%) of the positive oral fungal cultures. Candida albicans was most commonly identified (87%), followed by Candida glabrata (13%); Candida tropicalis (8%); Candida parapsilosis (2%); Candida krusei (1%); and Candida stellatoidea, Saccharomyces cerevisiae, Candida kefyr, Rhodotorula rubra, Candida paratropicalis, and Candida rugosa (each õ1%) (table 4). Eleven percent of cultures yielded more than one identified Candida species; this finding did not significantly vary by HIV serostatus. The likelihood of isolation of C. albicans vs. another Candida species did not significantly vary by HIV serostatus or by median CD4 lymphocyte count for seropositive women. Current antifungal use was associated with increased likelihood of oropharyngeal colonization with a non – C. albicans species (P Å .012). Oropharyngeal Candidiasis

Among the 725 women with oropharyngeal candidal colonization, 116 (22%) of the HIV-seropositive and 7 (3%) of the

Table 2. Frequency distributions for oropharyngeal and vaginal candidal colonization and candidiasis, as related to CD4 lymphocyte category at baseline, in 843 HIV-seropositive HERS participants. No. (%) of women per indicated CD4 lymphocyte category Variable Oropharyngeal candidal colonization (n Å 831) With C. albicans (%) Oropharyngeal candidiasis (n Å 499) Vaginal candidal colonization (n Å 826) With C. albicans (%) Vaginal candidiasis (n Å 309)

õ200/mm3

200 – 499/mm3

§500/mm3

P value

96 (68.1) (88.9) 38 (39.6)

263 (61.9) (85.4) 57 (21.7)

140 (52.8) (89.1) 17 (12.1)

.006 NS õ.001

54 (38.6) (69.4) 3 (5.6)

170 (40.3) (73.4) 17 (10.0)

85 (32.2) (77.2) 7 (8.2)

NS NS NS

NOTE. Values for CD4 lymphocyte counts were unavailable for 28 seropositive women. HERS Å HIV Epidemiology Research Study.

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insulin or oral antihyperglycemic agents did not differ by serostatus. Seropositive and seronegative women were equally likely to report recent (in prior 6 months) IDU, cigarette smoking, and alcohol use. Significantly more seronegative women reported recent crack cocaine use, marijuana or hashish use, heterosexual contact/vaginal sex, and lesbian contact. The frequency distributions for oropharyngeal and vaginal colonization and candidiasis by HIV serostatus and CD4 lymphocyte category (HIV seropositive women only) are presented in tables 1 and 2.

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Table 3. Results of logistic regression analysis to evaluate factors associated with oral candidal colonization at baseline in HIV-seropositive and HIV-seronegative women participating in the HIV Epidemiology Research Study (HERS).

Table 5. Results of logistic regression analysis to evaluate factors associated with oral candidiasis at baseline in Candida-colonized HIV-seropositive and HIV-seronegative women participating in the HIV Epidemiology Research Study (HERS).

Factor

Factor

OR (95% CI)

HIV seropositive Increased age (per year) CD4 lymphocyte category õ200/mm3 200 – 499/mm3 §500/mm3 Antibiotic use Cigarette smoking Injection drug use

P value

1.27 (.93 – 1.74) 1.02 (1.00 – 1.04)

.13 .021

. . .* (.47 – 1.12) (.30 – .77) (.76 – 1.40) (1.35 – 2.35) (1.28 – 2.34)

.15 .002 .83 õ.001 õ.001

.73 .48 1.03 1.78 1.73

OR (95% CI)

HIV seropositive Increased age (per year) CD4 lymphocyte category õ200/mm3 200 – 499/mm3 §500/mm3 Antibiotic use

3.92 (1.58 – 9.67) 1.00 (.97 – 1.04) . . .* .49 (.28 – .85) .27 (.13 – .54) 1.34 (.82 – 2.19)

P value .003 .90

.012 õ.001 .24

NOTE. Analyses were adjusted for HERS site. * Reference value.


Table 4. Distribution of the predominant Candida species among isolates from HERS participants with oral or vaginal candidal colonization and oral or vaginal candidiasis. No. (%) of women with colonization Candida species C. C. C. C.

albicans glabrata tropicalis parapsilosis

Oral (n Å 686) 597 91 56 11

(87) (13) (8) (2)

Vaginal (n Å 373) 263 89 12 7

(71) (24) (3) (2)

No. (%) of women with candidiasis Oral (n Å 113) 97 17 9 2

(86) (15) (8) (2)

Vaginal (n Å 33) 28 6 0 0

(85) (18) (0) (0)

NOTE. Additional species accounted for õ2% of isolates. In some Candida-positive cultures, more than one species was identified. HERS Å HIV Epidemiology Research Study.

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Vaginal Candidal Colonization

Results of cultures for isolation of Candida from vaginal specimens were available for 1,284 participants (98%). Vaginal colonization was identified in 318 (37%) of the HIV-seropositive women and in 91 (21%) of the seronegative women (P õ .001). Women who reported a vaginal yeast infection (ever or recently) were not more likely than women who did not report infection to have vaginal colonization identified at baseline. Black women, regardless of HIV serostatus, were more likely than other participants to have vaginal colonization (P Å .009). Median CD4 lymphocyte counts for seropositive women with and without vaginal colonization did not significantly differ (372/mm3 vs. 389/mm3, P Å .11). Vaginal colonization was increased among women reporting current antibiotic therapy (P Å .001), insulin or oral antihyperglycemic use (P Å .048), or recent IDU (P Å .029). Other risk activities, including sexual activities, were not significantly related to the likelihood of vaginal colonization. Seropositive women reporting current use of PCP prophylaxis were not more likely to have vaginal colonization. In a multivariate logistic regression model, recent IDU and insulin or oral antihyperglycemic therapy remained significantly associated with vaginal candidal colonization after adjustment for the effects of age at enrollment, HIV serostatus, CD4 lymphocyte category, HERS site, and black race (table 6). Candida species identifications were available for 373 (91%) of the positive vaginal fungal cultures. C. albicans was most commonly identified (71%), followed by C. glabrata (24%); C. tropicalis (3%); C. parapsilosis (2%); Trichosporon beigelii

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seronegative women (P õ .001) had one or more pseudomembranous (76%), erythematous (20%), or angular cheilitis (28%) oral lesions clinically diagnosed [31]. Women with a history of oral yeast infection (ever, P õ .001; recently, P õ .001) were more likely to have oropharyngeal candidiasis diagnosed at baseline. Among seropositive women with oropharyngeal colonization, the median CD4 lymphocyte count was significantly lower for those with oropharyngeal candidiasis (271/mm3 vs. 390/mm3, P õ .001). The likelihood of oropharyngeal candidiasis was increased among colonized participants reporting current antibiotic therapy (P õ .001) and among colonized seropositive women reporting current use of prophylaxis for PCP (P Å .001). In a multivariate logistic regression model, current antibiotic therapy was no longer significantly associated with oral candidiasis after adjustment for the effects of age at enrollment, HIV serostatus, CD4 lymphocyte category, and HERS site (table 5). Among the 123 women with oral colonization and clinical candidiasis, 113 (92%) had their Candida species isolates iden-

tified. C. albicans was most commonly identified (86%), followed by C. glabrata (15%), C. tropicalis (8%), C. parapsilosis (2%), and S. cerevisiae (1%) (table 4). Eleven percent of cultures had more than one Candida species identified. Women with oral candidiasis and women with colonization only were equally likely to be colonized with C. albicans.



Table 6. Results of logistic regression analysis to evaluate factors associated with vaginal candidal colonization at baseline in HIVseropositive and HIV-seronegative women participating in the HIV Epidemiology Research Study (HERS). Factor HIV seropositive Increased age (per year) CD4 lymphocyte category õ200/mm3 200 – 499/mm3 §500/mm3 African American race Antibiotic use Insulin use Injection drug use

OR (95% CI)

P value

1.81 (1.28 – 2.57) .98 (.96 – .99)

õ.001 .01

1.12 .77 1.17 1.26 4.28 1.35

. . .* (.74 – 1.69) (.49 – 1.22) (.85 – 1.60) (.93 – 1.70) (1.28 – 14.36) (1.04 – 1.84)

.60 .27 .34 .14 .019 .046


Vaginal Candidiasis

Among the 409 women with vaginal candidal colonization, 27 seropositive women (9%) and 8 seronegative women (9%) (P Å .93) were considered to have vaginal candidiasis, defined as presence of abnormal discharge and vaginal erythema or edema on examination. Twenty-five (71%) of the women with vaginal candidiasis, diagnosed on the basis of positive culture and signs of inflammation, had positive KOH smears on microscopic evaluation. Five (14%) of the women with vaginal candidiasis had coexisting trichomoniasis identified by saline wet mount. Among seropositive women with vaginal colonization, median CD4 lymphocyte counts did not significantly differ for those with and without vaginal candidiasis (P Å .72). No significant associations of vaginal candidiasis with serostatus or CD4 lymphocyte count were demonstrated when all women in the HERS cohort were considered or after controlling for current antifungal use. Current medications, including antibiotics and contraceptives, and risk activities, including sexual activities, were not significantly associated with the likelihood of vaginal candidiasis. Women reporting a history of vaginal candidiasis (ever, P Å .09; recently, P Å .50) were not significantly more likely

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to have vaginal candidiasis diagnosed at baseline, nor were those women who reported more frequent (P Å .73) or more severe (P Å .08) recent vaginal yeast infections. Among the 35 women with vaginal candidiasis, Candida species identifications were available for 33 isolates (94%). C. albicans was most frequently identified (85%), followed by C. glabrata (18%) and T. beigelii (3%) (table 4); two cultures (6%) had more than one species identified. Among women with vaginal colonization, those with vaginal candidiasis were more likely to be colonized with C. albicans than those without vaginal candidiasis, although not significantly so (P Å .058). Discussion The HERS cohort mirrors the demographics and risk activities of women in the United States with HIV/AIDS and thus affords a unique opportunity to study mucosal candidiasis and its relationship to HIV infection in women. As seropositive women were enrolled prior to the diagnosis of AIDS, the natural history of mucosal candidiasis throughout the course of HIV infection can be studied. The present report is limited to data collected at baseline visits; thus, candidal esophagitis, an AIDS-defining illness, was not seen but will be studied as it occurs during follow-up. Oropharyngeal colonization with Candida species was prevalent among all women in the cohort, but significantly more so among HIV-seropositive women. As expected, seropositive women were more likely to have oropharyngeal candidiasis, an opportunistic infection that rarely occurs among healthy adults. Among seropositive women, the prevalence of oropharyngeal colonization and candidiasis increased as the CD4 lymphocyte count declined. The clinical spectrum observed was similar to that previously reported in predominantly male populations [32, 33]. Women reporting prior oral yeast infection were more likely to be colonized with Candida species and to have oropharyngeal candidiasis on the baseline examination. Candida species isolated from colonized women and from women with oropharyngeal candidiasis were similar, a finding confirming published reports [34 – 37]. C. albicans and C. glabrata were the species most frequently identified. Fourteen percent of women with oropharyngeal candidiasis were colonized with only non – C. albicans species. In previous reports of oropharyngeal candidiasis in patients with HIV infection, oral disease was attributed exclusively to C. albicans, and non – C. albicans species were deemed nonpathogenic or ‘‘innocent bystanders’’ [1]. Vaginal colonization by Candida species was more commonly detected in seropositive women; however, the prevalence among seropositive women did not increase with immunosuppression. Non – C. albicans species were more frequently identified in vaginal vs. oral isolations (especially C. glabrata) but were not recovered more from seropositive women or women reporting current use of antifungal agents. Fifteen percent of women with vaginal candidiasis were colonized with only non – C. albicans species. Our results differ from those of

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(1%); and C. stellatoidea, Candida lusitaniae, C. krusei, C. paratropicalis, and Rhodotorula glutinis (each õ1%) (table 4). For 4% of cultures, more than one Candida species was identified. Seronegative women were more likely than seropositive ones to be colonized with a non – C. albicans isolate (P Å .024). The likelihood of a C. albicans isolate vs. other species did not significantly vary by median CD4 lymphocyte count among seropositive women. Current antifungal therapy was not significantly associated with isolation of a non – C. albicans species.

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Thus, longitudinal evaluation of the epidemiology of mucosal candidiasis in the HERS cohort will provide additional data on the relationship of vaginal candidiasis and progressive HIV infection. Because HERS visits are not symptom-driven and may not capture episodes of vaginal candidiasis, especially those that are self-diagnosed and treated with over-the-counter antifungal agents, studies with alternative designs and followup strategies may be helpful. If longitudinal data confirm that there is little difference in the frequency of vaginal candidiasis between HIV-seropositive and HIV-seronegative women, the recommendation of the Centers for Disease Control and Prevention that frequent vaginal candidal infections should prompt HIV testing would need to be reconsidered [21]. In summary, cross-sectional analysis of HERS baseline data revealed an increased prevalence of mucosal candidal colonization of the oropharynx and vagina among HIV-seropositive women. Oral colonization and candidiasis were associated with progressive immunodeficiency. Vaginal candidiasis was equally prevalent among seropositive and seronegative women and was not associated with immunocompromise. The differences between oropharyngeal and vaginal colonization frequency and patterns of mucosal disease suggest variation in the pathogenesis of candidiasis at these two mucosal sites. Identification of the species of Candida isolates revealed a higher-than-expected occurrence of non-albicans Candida species, which may be causally associated with the pathogenesis of mucositis. Continued longitudinal assessment of this cohort will be useful in determining the natural history of mucosal candidiasis in HIV-seropositive women and at-risk seronegative women.

Acknowledgments

The authors thank the study staff at each site and all of the women who participated in the HERS.

Members of the HERS Group

The HERS Group consists of the authors and the following persons: Ellie E. Schoenbaum, M.D., Robert D. Burk, M.D., Barbara Greenberg, Ph.D., and Penelope Demas, Ph.D. (Albert Einstein College of Medicine); Carl Christensen, M.D., William Brown, M.D., Wayne D. Lancaster, Ph.D., and Ann Eyler, M.D., M.P.H. (Wayne State University School of Medicine); Liza Solomon, Dr.P.H., Jean Anderson, M.D., Alvaro Munoz, Ph.D., Kenrad Nelson, M.D., Joseph Margolick, M.D., Ph.D., Keerti Shah, Ph.D., Alice Gleghorn, Ph.D., Neil Graham, M.D., M.P.H., and David Vlahov, Ph.D. (Johns Hopkins University School of Hygiene and Public Health); Timothy Flanigan, M.D., Susan Cu-Uvin, M.D., Maria Mileno, M.D., Robert Boland, M.D., Jeffrey Peipert, M.D., Michael Stein, M.D., and Josiah Rich, M.D. (Brown University School of Medicine); Janet Moore, Ph.D., Bert Peterson, M.D., and Scott Holmberg, M.D., M.P.H. (Centers for Disease Control and Prevention); Lewis K. Schrager, M.D., Beth Unger, M.D., and Sandra L. Melnick, Dr.P.H. (National Institute of Allergy and Infectious Diseases); and Sonja McKinlay, Ph.D., Herman Mitch-

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Spinillo et al., who reported finding a higher proportion of non-albicans Candida species in HIV-seropositive women with vaginal candidiasis [20]. Noteworthy was the infrequency with which vaginal candidiasis was observed in contrast to oropharyngeal candidiasis among HIV-seropositive women. Vaginal candidiasis was not more prevalent in seropositive women with low CD4 lymphocyte counts or in women with a self-reported history of vaginal candidiasis, including those reporting a recent increase in frequency and severity of vaginal candidiasis. The absence of highly prevalent vaginal candidiasis among HIV-seropositive women in our study contrasts with earlier reports suggesting increased frequency and severity of vaginal candidiasis among seropositive women [17 – 20]. These discrepancies in part reflect the design of the present study, which was not intended to measure incident vaginal candidiasis, but rather allowed detection of coincidental symptomatic vaginitis during scheduled baseline examinations. Results presented here are consistent with findings from the Women’s Fungal Study conducted by the Terry Beirn Community Program for Clinical Research on AIDS, a randomized clinical trial of weekly fluconazole vs. placebo for the prevention of mucosal candidiasis in women with late HIV infection [38]. In that study women were followed for the development of vaginal or oral/esophageal candidiasis and underwent standardized diagnostic evaluations. Oropharyngeal candidiasis occurred more frequently than vaginal candidiasis during followup. C. albicans and C. glabrata were the Candida species most frequently identified among mucosal site isolates, and antifungal use was associated with increased likelihood of colonization with a non – C. albicans species. Analysis of candidiasis events among women in the placebo arm of the study revealed that women reporting a history of oropharyngeal candidiasis were more likely to have incident oral events during follow-up, as were those with lower CD4 lymphocyte counts [39]. Vaginal candidiasis during follow-up was not more likely among those with a prior AIDS diagnosis or those with lower CD4 lymphocyte counts at baseline; however, a history of two or more episodes of vaginal candidiasis was predictive of subsequent disease. The relationship between HIV, immunocompromise, and vaginal candidiasis remains controversial. Duerr et al. recently reported a greater prevalence of vaginal candidal colonization and vaginal candidiasis among HIV-seropositive women with CD4 lymphocyte counts of õ200/mm3 than among either seropositive women with counts of ú500/mm3 or seronegative women [40]. Differences in study design, including participant recruitment, methodology, study populations, data analysis, and definitions of vaginal candidiasis, may account for these varying results. Duerr et al. used a definition of vaginal candidiasis based on self-reported symptoms and positive culture. Our definition included positive culture plus the presence of signs of vaginal inflammation on pelvic examination. We did not collect baseline data on self-reported symptoms of vaginitis; however, these data will be available from follow-up visits.




ell, Ph.D., Les Kalish, D.Sc., Susan Barkin, Ph.D., Alvaro Tinajero, M.D., Debra Jones, Ph.D., and Susan Alperin, M.P.H. (New England Research Institute).

References

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