Sihavong, Amphoy MD, MMedSc*†; Phouthavane, Traykhouane DMM‡; Lundborg, Cecilia Stålsby PhD*∥**; Sayabounthavong, Khanthanouvieng MD, MS§; Syhakhang, Lamphone PhD¶; WahlstrÖm, Rolf MD, PhD*
THE GLOBAL DISEASE BURDEN of reproductive tract infections (RTI), including sexually transmitted infections (STI), is a major public health concern, particularly in developing countries.1 WHO estimated that 151 million new cases of STI occurred in South and Southeast Asia in 1999, representing nearly 44% of all new STI cases estimated to occur worldwide.2 RTI/STI impose a burden of morbidity and mortality most particularly on women and children, resulting in serious economic, social, and psychological consequences.3 The presence of an untreated or incorrectly treated STI can increase the risk of both acquisition and transmission of human immunodeficiency virus (HIV).4 Improved treatment services of STI can reduce the incidence of HIV infection in populations with a high prevalence of curable STI and high-risk sexual behavior, particularly in the early phases of an HIV epidemic.5
Laos, with a population of 5.5 million,6 is one of the least developed countries, low on health indicators.7 Although high HIV prevalence has been reported in neighboring countries (such as Cambodia, Thailand, and Myanmar),8–10 the little data available from Laos showed low HIV prevalence, 0.05% among the 15- to 49-year-old population.11 However, in the last decade, after opening its borders to foreign investments and visitors that resulted in massive economic expansion and social changes, Laos is facing the challenges of an increase in domestic and cross-border migration, number of sex workers, unsafe sexual behavior through informal sexual services, and illicit drug use, especially among the youth.12 Sentinel surveillance in 2001 showed that HIV prevalence rate was 0.9% among high-risk groups such as service women (any woman who worked in a small drink shop, nightclub, or guesthouse and had direct contact with customers),13 and that infection rates of certain STI among service women were high, 32% for chlamydia and 14% for gonorrhea.13 Behavioral surveillance showed that one-third of truck drivers reported paying for sex in the past year.12 Few of the truck drivers reported a current STI symptom, but 11% had a symptom of STI in the past year.13 Community-based surveys showed that 38% of those reporting more than 3 sexual partners had never used condoms.14 A substantial prevalence of lower genital tract infections has been reported among antenatal care clinic patients in Vientiane.15 A study of young men revealed sexual behaviors that could lead to accelerated HIV transmission.16 Self-treatment for RTI/STI is widespread17 and may contribute to the increase in antimicrobial resistance, which increasingly precipitates chemotherapeutic failure.18 Thus, appropriate management of RTI/STI, including prompt and correct treatment of RTI/STI in combination with health education, is of major public health importance.
Data on the etiology and prevalence of RTI/STI is very limited in Laos but is highly relevant to the development, planning, and management of STI services throughout the country as a response to awareness of the country's vulnerability to HIV/AIDS epidemic and to the continuing increase in antimicrobial resistance. It is important to know the prevalence of RTI/STI to best apply WHO's syndromic case management approach, a cost-effective RTI/STI control strategy, especially in resource-poor settings.19
The objectives of this study were to clinically and microbiologically identify RTI including STI, and to monitor the antibiotic susceptibility of N. gonorrhoeae (NG) among women attending a gynecology outpatient department (OPD) in Vientiane to provide essential information for future interventions to contribute to quality improvement of RTI/STI management.
Materials and Methods
Study Setting and Population
This clinical and laboratory-based cross-sectional study was conducted from July 2000 to December 2001 at the Sethathirath Hospital, a university and referral hospital in Vientiane, the capital of Laos (population 531,800). The hospital has about 300 daily outpatient visits, including approximately 70 daily obstetrics/gynecology visits of which, on average, 5 are first-time visits for gynecology. Inclusion criteria were all women aged 15 to 49 years attending for a first visit to the gynecology OPD of Sethathirath Hospital during the study period and agreeing to participate. Exclusion criteria included menstruation, heavy vaginal bleeding, pregnancy, hysterectomy, and antibiotic use in the preceding 2 weeks, all based on self-report.
Data Collection Procedures
Standardization of gynecological examination, specimen collection, transport and storage, and relevant laboratory procedures was ensured by appropriate training of all involved staff before starting the study. A nurse-receptionist screened all attendees using a checklist of inclusion and exclusion criteria. After the purpose of the study had been explained, all eligible women were asked if they would be willing to participate in the study, and no one refused. Informed consent was obtained, emphasizing that refusing to participate or leaving the study at any time would not adversely affect the care provided. A clinician obtained a standardized history including sociodemographic data and details of current symptoms related to RTI/STI, followed by gynecological examination. After a careful examination of the vulva, perineum, and perianal areas, a sterile, nonlubricated Cusco speculum was introduced. Any abnormalities were noted, and specimens for laboratory testing were collected from the posterior vaginal fornix and endocervical canal. Finally, a bimanual pelvic examination was made. All tests in this study were free of charge. Routine laboratory tests for syphilis and HIV were not included.
The specimens were immediately transported to the adjacent hospital laboratory for etiological diagnosis. The tests consisted of vaginal wet mount (vaginal secretions diluted with normal saline solution) with Gram stain for the microscopical detection of Candida species, Trichomonas vaginalis (TV) and bacterial vaginosis (BV), and endocervical Gram stain and culture for NG. Gen-Probe test was used for Chlamydia trachomatis (CT) on endocervical material using 2 Dacron-tipped swabs. Antibiotic susceptibility for gonorrhea was determined at the hospital laboratory and confirmed at the Centre of Laboratory and Epidemiology on NG subcultures. The Centre of Laboratory and Epidemiology performed quality control reviewing 10% of randomly selected negative slides and all positive gonorrhea identified by Gram stain and/or subcultures. The results of the clinical examinations were not known to the laboratory staff.
Definitions and Clinical Diagnosis
Syndromic case management means that the diagnosis and management are based on the identification of syndromes, which are combinations of symptoms and signs, and the recommended treatment for these syndromes.
In this study, the clinical diagnosis was based on reported symptoms and clinical signs from the speculum and bimanual examinations as follows:
Vaginitis: Inflammatory appearance of the vagina or abnormal vaginal discharge, or both.
Cervicitis: Inflammatory appearance of the cervix or cervical erosion or cervical bleeding at touching or abnormal discharge from cervical os, or combinations.
Vaginitis Plus Cervicitis: Combination of signs of cervicitis and vaginitis.
Pelvic Inflammatory Disease (PID): Purulent or muco-purulent discharge from the cervical os combined with lower abdominal or adnexal tenderness or cervical motion tenderness.
Candidiasis was diagnosed by the visualization of budding yeasts or pseudohyphae on microscopy of vaginal wet mount and/or Gram stain TV by the visualization of motile trichomonads on microscopy of vaginal wet mount, BV by Nugent's Gram stain score20 of 7 to 10, NG by a positive intracellular Gram-negative diplococci on microscopy of endocervical Gram stain and confirmed by a positive culture by inoculation on modified Thayer-Martin medium followed by inoculation at 37°C in 10% carbon dioxide. Antimicrobial susceptibility for ceftriaxone, ciprofloxacin, spectinomycin, penicillin, and tetracycline was determined by E test (Biodisk, Stockholm, Sweden) on NG subcultures. CT was diagnosed by a positive result of a nucleic acid hybridization test (Gen-Probe Pace-2 System, C. trachomatis, Gen-Probe, San Diego, CA) on endocervical smears.
Management of RTI/STI
Clinicians based the initial treatment on WHO21 and national22 guidelines on syndromic RTI/STI case management. The recommended drugs for the treatment of vaginal discharge and lower abdominal pain syndromes include metronidazole orally in single dose or daily for 7 days for BV or trichomoniasis, clotrimazole cream or vaginal suppository for candidiasis, ceftriaxone or cefixime or spectinomycin in single dose for gonorrhea, and doxycycline or tetracycline or erythromycin for 7 days orally for chlamydia. A follow-up appointment was arranged 1 week later for any further treatment of RTI/STI subsequently detected by laboratory tests. All treatment options should be given together with the “4 Cs”: counseling/education, correct condom use, contact tracing, and compliance with the treatment regimen prescribed.22
Data entry and analysis was done by Epi Info version 6.04 (Centers for Disease Control and Prevention, Atlanta, GA) and SPSS version 10 (Chicago, IL). The frequencies, means, standard deviations, and proportions were used for the data analysis. The 95% confidence intervals and the χ2 test were used to compare differences between age groups. The sensitivity, specificity, and positive predictive value (PPV) of RTI/STI clinical diagnosis were determined using laboratory test results as the reference.
The research project was approved by the Laos Ministry of Health and the European Union STI project, and the National Committee for the Control of AIDS Bureau, Ministry of Health, Lao PDR. A verbal consent was obtained from each participant after each was informed of the purpose of the study and assured that all collected information would remain confidential. All study personnel were trained in the importance of strict confidentiality of information and data, and all personality-identifying data were kept in a private place under lock and key until the end of the study. No names and identifying information were used in the analysis to ensure confidentiality of the information.
Demographic Characteristics of Study Participants
In total, 1125 women participated in the study. The mean age of the study participants was 31.2 years (SD 7.4 years) and nearly half (44%) were aged <30 years. Background information is shown in Table 1. The majority of women (87%) came from different districts of Vientiane capital and 13% from other nearby provinces.
Prevalence of Clinical and Laboratory Findings of RTI
The most common symptoms reported by the women during the interview were vaginal discharge (67%), followed by lower abdominal pain (30%) (Table 1). Of these, 6.5% reported both vaginal discharge and lower abdominal pain. In total, 922 (82%) presented clinically with an RTI syndrome, including possible STI (Table 2). However, laboratory testing verified an infection in 719 women (64%), including 121 women (10.8%) with an STI (NG, CT, or TV). Fifty-two percent of all women had a single infection, and 12% had 2 or more infections.
The total prevalence among all participants of any kind of RTI was 76%, including 12% for STI (NG, CT, and TV) (Table 3). The most common endogenous infection was candidiasis (40%), followed by BV (25%). Of the STI, CT was found in 4.1%, NG and TV both in 3.7%. Five women (0.5%) had coinfection with NG and CT, and 1 (0.1%) with NG and TV, whereas 1 (0.1%) had simultaneous infections with NG, CT, and TV. The prevalence of NG and CT cases was higher among women under 30 years of age (P < 0.05).
For the 749 women who reported vaginal discharge (Table 1), the prevalence was 3.5% (26 cases) for NG, 3.6% (27 cases) for CT, 3.7% (28 cases) for TV, 26.8% (201 cases) for BV, and 43.5% (326 cases) for candidiasis. Of those women, 67% had a single infection, and 0.4% had 2 infections.
All 41 isolates of NG were fully sensitive to ceftriaxone and spectinomycin, but 8 isolates (20%) were resistant to ciprofloxacin, 40 (98%) resistant to penicillin, and all 41 (100%) resistant to tetracycline. Forty isolates (98%) were resistant to more than 1 drug.
Efficacy of Clinical Diagnosis of RTI
The sensitivity, specificity, and PPV for the treatment of vaginitis for candidiasis were 69%, 82%, and 71%, respectively, whereas for the treatment of vaginitis for TV and/or BV they were 70%, 74%, and 52%, respectively. For the syndromic approach that recommends drugs against both gonorrhea and chlamydia for the treatment of vaginitis plus cervicitis and/or PID syndrome, the sensitivity was high (98%) but the specificity was lower (81%), and the PPV only 30%. For every woman receiving correct treatment for either gonorrhea or chlamydia, 2 others were treated unnecessarily. If the treatment is based only on symptoms (Table 1), the PPV for treating vaginal discharge as a potential STI (NG, CT, or TV), would be only 10.4%, thus involving unnecessarily treatment of 8 women to each correct case.
We found that among women attending a first visit to a gynecology OPD in the capital of Laos, 2 of 3 had an etiologically diagnosed RTI, and 1 of 8 had an STI with chlamydia, gonorrhea, or trichomoniasis. Two of 5 women had candidiasis, and 1 of 4 had BV. Resistance of N. gonorrhoeae was nearly total to some drugs commonly used for RTI/STI.
Endogenous infections (candidiasis 40% and BV 25%) were found to be the most prevalent in this study as in other studies.15,23,24 For STI, the prevalence of trichomoniasis and gonorrhea (3.7% for each) were higher than those reported among antenatal care clinic patients at the same study site (1.8% and 0.8%, respectively),15 but the rate of chlamydia was much lower (4.1% vs. 10.2%).15 Such high proportions are not unexpected among gynecology outpatients, as those women mostly got symptoms of vaginal discharge or lower abdominal pain before seeking care. However, it is not clear why the rate of chlamydia was lower than among pregnant women. It might be due to the known fact that women of younger age have a higher rate of chlamydia, as pregnant women had a lower mean age (25.7 years vs. 31.2 years). The significant number of disease cases of public health importance found in this study, especially in younger women, raises concerns that it is important to promptly and effectively treat these infections along with implementing partner notification for prevention of reinfection and complications (e.g., PID and infertility) arising from these infections, and that promotion of condoms should be one priority in the health education activities for protection against HIV and RTI/STI.25
Treatment regimens must be tailored to the prevalence of antimicrobial resistance in each setting.2 Antibacterial susceptibility studies for gonorrhea in the WHO–Western Pacific Region and in Sweden have shown high resistance to quinolones (63% in the Philippines and 52% in Sweden).26,27 In our study, 20% of the isolates were resistant to ciprofloxacin, indicating the necessity to consider another first-line treatment.2 All isolates remained fully sensitive to ceftriaxone and spectinomycin. This may be because these drugs were rarely used in Laos at the time of the study, mainly due to their high cost. On the other hand, we found high resistance to penicillin and total resistance to tetracycline. These 2 drugs were among the most common drugs used for RTI/STI in Laos.17 This is consistent with other reports in developing countries.28 However, the number of isolates in our study was only 41, and further work is required before definitive guidance can be given. It is also important to repeatedly monitor resistance patterns to guide treatment in cases where treatment, because of patients' unwillingness or inability to pay for expensive laboratory investigations, is mainly based on clinical symptoms and signs.
It is noteworthy that all 41 cases of gonorrhea and 44 of the 46 cases of chlamydia would have been included as cases using a syndromic approach, based on clinical examination for vaginitis plus cervicitis and PID syndrome. However, for each woman treated correctly for either gonorrhea or chlamydia, 2 more women would be treated unnecessarily. Without clinical examination, 8 more women would receive unnecessary treatment of vaginal discharge as a potential STI. The additional cost of overtreatment includes treatment costs, possible adverse effects of antibiotics, and the emerging problem of antibiotic resistance. STIs cannot be diagnosed accurately on clinical grounds alone, and their complications and late results are serious, particularly for women. Hence, concurrent with syndromic case management, periodic evaluations of etiological diagnosis should be available in referral settings to ensure adequacy of the treatment algorithms and prescribed medications.
It is not clear that having etiological diagnosis available for women in this clinic improves the public health outcome because laboratory diagnoses would not be available at the time women visit. This delay may lead to patients not returning for treatment and further disease transmission.29 Studies on STI clinic populations have shown that up to 20% of patients with positive chlamydia or gonorrhea tests fail to return for treatment within 30 days, and 30% fail to return 2 weeks after test results.30 This can lead to the spread of the disease and ultimately may result in increased cases of PID in women.29 Another major challenge for laboratory diagnoses of gonorrhea and chlamydia in Laos is that in practice their high costs and technical requirements make their routine use difficult and would not be feasible on a large scale for the whole country. The results provide another compelling argument about the need for simple, affordable, and rapid point-of-care STI diagnosis. It has been reported that rapid point-of-care diagnostic tests can be important tools for STI control in women.31 However, it is not known whether this clinic and other health care services in Laos will be able to afford even inexpensive and rapid diagnostic tests and appropriate treatment. There is a need for local research to assess the cost-effectiveness of rapid point-of-care tests in STI diagnosis and treatment in this resource-poor setting.
The limitations of the study include: (1) the use of culture for gonorrhea and Gen-Probe test for chlamydia that have been reported to have lower sensitivity when compared with nucleic acid amplification tests (e.g., polymerase chain reaction)32,33; (2) because this was the first clinical and laboratory-based study on RTI/STI conducted in Laos, data on sexual behavior of women and their partners were not included in the questionnaire because of concern about acceptance of the study; and (3) the study was limited to one geographical location in a hospital setting in the capital of Laos, and thus it cannot be considered nationally representative. Nevertheless, this study could provide useful information to support use of the national algorithm. Also, the study could provide important epidemiologic data on RTI/STI for future risk behavior and population-based studies, as well as to guide planning and resource allocation of decision makers for future interventions. This could contribute to improved quality of RTI/STI management.
In conclusion, this study demonstrates that it is feasible to provide syndromic and etiological case management for RTI, including STI, in a gynecology OPD. The number of women treated unnecessarily can be reduced still further by strengthening the clinical diagnostic capacity and following correct RTI/STI treatment where laboratory testing is not available or used. Concurrent with syndromic case management, periodic evaluations of etiological diagnosis should be available to ensure adequacy of the treatment algorithms and prescribed medications.
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