Etiology and STI/HIV Coinfections Among Patients With Urethral and Vaginal Discharge Syndromes in South Africa : Sexually Transmitted Diseases

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Etiology and STI/HIV Coinfections Among Patients With Urethral and Vaginal Discharge Syndromes in South Africa

Mhlongo, Sakhile BSc*; Magooa, Precious BSc*; Müller, Etienne E. PHD*; Nel, Noel BTech; Radebe, Frans MSc*; Wasserman, Elizabeth MMed, DPhil; Lewis, David A. FRCP(UK), PHD*‡§

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Sexually Transmitted Diseases 37(9):p 566-570, September 2010. | DOI: 10.1097/OLQ.0b013e3181d877b7
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The burden of sexually transmitted infections (STI) within South Africa is high.1,2 The most common STI presentations to public healthcare clinics (PHCs) are the male urethral discharge syndrome (MUDS) and vaginal discharge syndrome (VDS) in men and women, respectively. The main STI pathogens responsible for these 2 syndromes include Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, and Mycoplasma genitalium. Bacterial vaginosis and candidiasis, which do not normally require sexual transmission, cause a proportion of the vaginal discharges observed in clinical practice.2,3

Within South Africa, STI patients are managed using the syndromic management approach in accordance with WHO recommendations.4,5 Syndromic management aims to treat the common causes of STI syndromes, through the use of treatment algorithms described in flowcharts. This approach is cost-effective, allowing nurses to treat the majority of STI patients without the need for laboratory-based diagnostics.6,7 Surveillance is a critical component of syndromic management and should generate data on clinically diagnosed STI syndromes, syndrome etiology, and antimicrobial resistance.5

This article reports, for the first time, data collected as part of South Africa's national microbiological surveillance (NMS) program for STIs. Etiological studies were undertaken for MUDS and VDS syndromes in Cape Town, Western Cape Province, and Johannesburg, Gauteng Province. The associations of MUDS/VDS pathogens with syphilis, genital herpes type 2 (HSV-2), and HIV serostatus were determined.

MATERIALS AND METHODS

Patient Recruitment

Consecutive MUSD/VDS patients were recruited in Salt River Clinic (Cape Town) and Alexandra Health Centre (Johannesburg). Symptomatic patients were only enrolled if visible urethral discharge (men) or abnormal vaginal discharge (women) was confirmed on clinical examination; symptomatic patients without such clinical signs were excluded from the survey. Genital examination included milking of the male urethra if discharge was not visible at the meatus, and speculum examination in females to visualize the vagina and cervix. Surveillance took place in 3 months in Cape Town and 4 months in Johannesburg between November 2006 and April 2007. The Human Research Ethics Committee of the University of the Witwatersrand approved the study (Protocol No. M051024).

Specimen Collection

After obtaining informed consent, genital specimens and 10 mL blood samples were collected and labeled with a unique surveillance number, not linked to any patient-identifying information. Swabs and sera were stored at −70°C until testing was undertaken. For women, one swab was taken from the lateral vaginal wall and posterior fornix for Gram staining and a second from the endocervix for molecular testing. For men, one swab was taken for molecular testing and a second for N. gonorrhoeae isolation for antimicrobial susceptibility testing, as reported previously.8

Patient Management

Patients were treated in accordance with national STI treatment guidelines. All patients received a single dose of oral ciprofloxacin (500 mg) plus 7 days of doxycycline (100 mg, 12 hourly).9 VDS patients also received metronidazole (400 mg, 12 hourly for 7 days) and, whether clinically indicated, a single clotrimazole pessary (500 mg). All patients were offered same-day HIV voluntary counseling and testing using rapid tests as per normal clinic practice, partner notification slips, and health education.

Laboratory Methodology

Gram Staining and Microscopy.

The detection of Candida in Gram-stained vaginal smears, taken from women with abnormal vaginal discharge, was used to diagnose candidiasis. Nugent scoring was used to diagnose bacterial vaginosis using the same smears.10

Molecular Detection of Pathogens Causing VDS and MUDS.

A real-time multiplex polymerase chain reaction (M-PCR) assay, developed at the Centers for Disease Control and Prevention (Atlanta, United States), was used to detect N. gonorrhoeae, C. trachomatis, T. vaginalis, and M. genitalium in DNA extracted from genital swabs. The primers and probes used targeted the N. gonorrhoeae cytosine-specific DNA methyltransferase gene, the cryptic plasmid of C. trachomatis, the T. vaginalis repeated DNA fragment, and the M. genitalium mgp gene, encoding for the MgPa adhesion protein. After incubation at 50°C (2 minutes) and Taq activation at 95°C (10 minutes), 40 cycles of denaturation (95°C, 20 seconds), and annealing/extension (60°C, 60 seconds) took place. M-PCR assays were undertaken on a Rotor-Gene 3000 platform (Corbett Research, Australia). Genomic DNA extracts prepared from the following ATCC strains were used as controls: N. gonorrhoeae (ATCC 700825), C. trachomatis (ATCC VR885), T. vaginalis (ATCC 30001), and M. genitalium (ATCC 33530).

Serological Testing for Syphilis, Herpes, and HIV.

Sera were tested with the nontreponemal rapid plasma reagin (RPR) test (Macro-Vue Biokit, Becton Dickinson and Co, Cockeysville, MD), the Treponema pallidum particle agglutination assay (Serodia TPPA, Fujirebio Inc, Tokyo, Japan), the HerpeSelect HSV-2 enzyme-linked immunosorbent assay (Focus Diagnostics, Cypress, CA), the Determine HIV-1/2 antibody test (Abbott Laboratories, Tokyo, Japan), and the Unigold HIV test (Trinity Biotech PLC, Bray, Ireland). A positive HIV serostatus was assigned for sera reactive with both HIV rapid tests.

Statistical Methods

Data were entered and analyzed using an Excel database and STATA version 9.0. A 2-tailed Fisher exact test was used to determine associations between syndrome etiology and serological diagnoses with the level of statistical significance set at P = 0.05.

RESULTS

Patient Recruitment and Specimen Collection

A total of 300 VDS (Cape Town, 94; Johannesburg, 206) and 507 MUDS (Cape Town, 290; Johannesburg, 217) were enrolled (Table 1). Six vaginal smears were lost in transit and 19 patients declined phlebotomy.

T1-8
TABLE 1:
Etiology and Seroprevalence of Syphilis, HSV-2 and HIV Among Patients With Male Urethral and Vaginal Discharge Syndromes in Cape Town and Johannesburg

Etiology of the VDS

Bacterial vaginosis was the most frequent cause, and trichomoniasis the most frequent sexually transmitted cause, of VDS in both cities (Table 1). VDS patients in Johannesburg had statistically significantly more T. vaginalis and M. genitalium than those in Cape Town; there were no statistically significant differences observed for the other infections. Even as there was no difference in STI pathogen prevalence between the survey sites, the prevalence of mixed STIs (excluding BV and/or the presence of Candida) was statistically significantly more frequent among VDS patients in Johannesburg.

Etiology of the MUDS

An overall etiology was found in approximately 90% of MUDS patients with gonorrhoea accounting for most MUDS cases at both sites (Table 1). There was a higher relative prevalence of gonococcal infections in Cape Town, whereas the opposite was true for C. trachomatis, M. genitalium, and T. vaginalis infections. As with VDS cases, there were more mixed STI infections detected among MUDS cases in Johannesburg.

Syphilis, HSV-2, and HIV Infections

A higher prevalence of RPR seropositivity was observed among VDS compared to MUDS patients (P = 0.0077) but this was not related to geographical site. The TPPA assay confirmed 32 (94%) of the 34 RPR positive cases; the 2 TPPA negative cases were HIV-infected women of unknown pregnancy status, one of whom had a genital ulcer of undetermined etiology. The seroprevalence of HSV-2 infection was higher in Johannesburg for both women and men (Table 1). A statistically significantly higher HSV-2 seroprevalence was observed among VDS compared to MUDS patients in Johannesburg (P = 0.0005) but not in Cape Town. There was a higher HIV seroprevalence among MUDS patients in Johannesburg compared to Cape Town (Table 1). The HIV seroprevalence was statistically significantly higher in VDS compared to MUDS cases in both Cape Town (43.5% vs. 23.8%, P = 0.0005) and Johannesburg (52.0% vs. 38.6%, P = 0.0072).

Associations Between HIV and Other Infections

Among all the MUDS cases, gonorrhoea was associated with a positive HIV serostatus and chlamydial infection with a negative HIV serostatus (Table 2). HIV was associated with candidiasis only in Cape Town (OR: 4.4, 95% CI: 1.33–14.55) (Table 3). A positive HSV-2 serostatus was strongly associated with HIV infection in both MUDS and VDS patients.

T2-8
TABLE 2:
Association Between HIV Serostatus and Other Infections Among 491 Men With Urethral Discharge
T3-8
TABLE 3:
Association Between HIV Serostatus and Other Infections Among 290 Women With Vaginal Discharge

DISCUSSION

South Africa is one of only a few African countries to have nationally representative data on the seroprevalence of HIV, and to a lesser extent, syphilis.2,11 There are no nationally representative community-based microbiologic studies for other STIs. The recently established NMS program for STIs, coordinated by the STI Reference Centre at the National Health Laboratory Service's National Institute for Communicable Diseases, aims to collect longitudinal data, through repeated cross-sectional surveys at the same PHC, on the etiologies of common STI syndromes for each of South Africa's 9 provinces. Prior STI surveys within South Africa have mostly been one-time cross-sectional studies and lack the longitudinal component required to study trends.2 A strength of the NMS program is that it enables monitoring of trends in the etiology of key STI syndromes over time within a national sentinel clinic-based network and can thus inform the national STI program about the appropriateness of existing STI treatment algorithms.

This article reports for the first time baseline etiological data from the South African NMS program concerning the MUDS and VDS in Johannesburg and Cape Town. These cities have different community profiles, with increased representation of black Africans in Johannesburg and colored individuals in Cape Town. The ethnic background of the black African populations also varies between the 2 cities, with predominantly more Xhosa-speaking people in Cape Town and relatively more Zulu-, Sotho-, and Tswana-speaking people in Johannesburg. Salt River is an industrial area of Cape Town with a large number of street-based commercial sex workers, whereas Alexandra, situated to the north-east of Johannesburg, is a large African township containing many immigrants.12 At the time of the study, HIV seroprevalence among antenatal clinic attendees was lower in Cape Town (16.1%) compared to Johannesburg (29.7%).11

Gonorrhoea was confirmed as the main MUDS pathogen and was more prevalent among HIV-infected men. It is therefore important to ensure that effective antigonococcal therapy is included as part of the MUDS drug regimen and those clinicians in both the public and private sector are trained adequately in STI management.5,8 Because of the recent rapid rise in the prevalence of quinolone resistant gonococci within South Africa, ciprofloxacin was replaced by single-dose cefixime as first-line syndromic therapy for presumptive gonorrhoea in 2008.4,13

It is interesting to note the low relative prevalence of chlamydial infection in comparison to that of gonorrhoea among MUDS patients in South Africa compared to MUDS patients in Europe and the United States.14,15 This may be due to number of reasons, including (i) a preferential selection for gonococcal cases because of exclusion of men with self-reported dysuria from our survey, (ii) the increased likelihood of patients with gonorrhoea to present for treatment in view of increased severity of symptoms, (iii) the possibility that South Africa may yet have to experience a chlamydial epidemic on the scale seen in Europe/United States, or (iv) that C. trachomatis is in fact so highly prevalent in South Africa that patients have rapidly repeated exposures resulting in increased immunity.16–19 The association of chlamydial infections with an HIV seronegative status in MUDS cases requires further investigation.

The prevalence of M. genitalium among both MUDS and VDS patients was higher in Johannesburg compared to Cape Town but the reasons underlying this observation are not clear. There are no previously published studies on the prevalence of M. genitalium among PHC attendees with MUDS/VDS in South Africa. A study undertaken in 1998 among miners with genital ulcers in Carletonville, Gauteng Province, demonstrated a M. genitalium prevalence of 11.1% among those with urethritis.20 Similarly, a study undertaken in West Africa between 1996 and 1997 reported a M. genitalium prevalence of 10.0% among men with MUDS.21 Studies in Europe, which usually enroll men with self-reported dysuria alone and/or with urethral discharge, have demonstrated a higher prevalence of M. genitalium.22 For women, M. genitalium is associated more with cervicitis than with vaginal discharge and studies among women with VDS in Africa are few.23 The prevalence of M. genitalium has been reported to be as high as 24.4% among West African commercial sex workers.23

There were no statistically significant site-related differences in the relative prevalence of STIs, bacterial vaginosis, and candidiasis in women with VDS. Bacterial vaginosis was the most prevalent VDS etiology, and trichomoniasis was confirmed as the leading sexually transmitted cause of the syndrome. One limitation of this study is that candidiasis was diagnosed on the basis of a combination of an abnormal vaginal discharge and the presence of Candida on microscopy. Because the detection of candidal species by microscopy may represent either infection or colonization, the prevalence of “true” candidiasis may have been overestimated.

The VDS algorithm has repeatedly been shown to have a low positive predictive value for diagnosing STIs in women, which may lead to stigmatization, relationship difficulties, and domestic violence.6 A risk assessment approach may improve the overall performance of the VDS algorithm although proxy markers for STIs cannot replace sensitive and specific diagnostic tests in achieving optimum patient management.6,24,25 As diagnosis of abnormal vaginal discharge depends on a clear patient history and a familiarity of the clinician with abnormal examination findings, the higher proportion of VDS cases without an etiological diagnosis in Cape Town may have been due to excessive enrolment of women with physiological vaginal discharge.

The statistically significant associations between HIV and HSV-2 infection add to a wealth of existing epidemiologic data on the HIV-herpetic link in Africa.26 The NMS program is unique in that all patients consent to have sera anonymously tested for HIV infection, allowing additional linking of HIV seroprevalence data to STI syndrome etiology data. This study highlights the high prevalence of HIV among STI patients in South Africa compared to contemporary findings of both the 2005 community-based national HIV survey (13.3% in women, 8.2% in men) and the 2007 national HIV prevalence survey among antenatal patients (30.3% in Gauteng, 12.6% in the Western Cape).11,27 Given the high prevalence of HIV coinfection among STI patients, it is important to ensure that HIV testing is discussed in depth during STI-related clinical consultations.4 Opt-out approaches to HIV testing, used with success in many antenatal screening programs, may enhance the proportion of STI patients who know their HIV status.28

In conclusion, this surveillance study has highlighted the importance of gonococcal infection in South Africa, demonstrated high rates of HIV coinfection among STI patients, and revealed some differences in STI syndrome etiology among STI patients in Cape Town and Johannesburg. From the public health perspective, it is important that such etiological surveys take place periodically and include linked data on HIV seroprevalence.

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