TITLE: Urine Based Testing for Gonorrhea and Chlamydia: A Review of Diagnostic Accuracy, Cost-Effectiveness, and Compliance

Transcription

1 TITLE: Urine Based Testing for Gonorrhea and Chlamydia: A Review of Diagnostic Accuracy, Cost-Effectiveness, and Compliance DATE: 30 November 2009 CONTEXT AND POLICY ISSUES: There are two main ways to obtain specimens for gonorrhea and chlamydia testing: 1) swabs from the infected area, and 2) urine. 1 For urogenital infection in women, vulvovaginal and urethral swabs can be collected by patients or by a clinician, while the endocervical swabs are collected by a clinician during pelvic examination. For urogenital infection in men, urethral swab can be self-collected. 2 In addition to the traditional method of testing, which involves cell cultures of collected samples from the cervix or urethra, the alternative is nucleic acid amplification tests (NAATs) that can be performed on urine or swab specimens. 3,4 Three types of NAATs that are commercially available are polymerase chain reaction (PCR), transcriptional-mediated amplification (TMA), and strand displacement amplification (SDA). 4 The test performance and acceptability with respect to types of specimen collection in the screening and diagnosis of gonorrhea and chlamydia infections are questions. This review assesses the performance, costeffectiveness, compliance (by means of acceptability), and stability (during transport) of urinebased testing versus swab testing for gonorrhea and chlamydia. RESEARCH QUESTIONS: 1. What is the comparative diagnostic accuracy of urine-based testing versus swab testing for gonorrhea and chlamydia? 2. What is the cost-effectiveness of urine-based testing versus swab testing for gonorrhea and chlamydia? 3. What is the compliance with urine-based testing versus swab testing for gonorrhea and chlamydia and what are the factors that affect compliance? 4. What is the evidence regarding the stability of urine samples for gonorrhea and chlamydia testing during transport? Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 METHODS: A limited literature search was conducted on key health technology assessment resources, including PubMed, the Cochrane Library (Issue 3, 2009), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI, EuroScan, international health technology agencies, and a focused Internet search. The search was limited to English language articles published between 2004 and October Filters were applied to limit the retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, controlled clinical trials, observational studies, economic studies, and guidelines. SUMMARY OF FINDINGS: Three systematic reviews and meta-analyses, 12 observational studies, two economic evaluations and four guidelines were identified. HTIS reports are organized so that the higher quality evidence is presented first. Therefore, systematic reviews and meta-analyses are presented first. These are followed by observational studies, economic evaluations, and evidence-based guidelines. Systematic reviews and meta-analyses Marrazzo & Scholes, performed a systematic review to assess the acceptability and uptake of urine testing for chlamydia among asymptomatic men. Studies were categorized as 1) those of testing in established venues (2 studies), 2) those of home-based testing (6 studies), and those assessing attitudes towards or experience with testing (3 studies). When the test was offered in non sexually transmitted disease clinics venues, acceptability and uptake of testing by men was in the mid-60% range. Acceptance of home-based testing, including mailing of test kits, was lower. Barriers affecting the acceptability of testing included low self-perception of risk for asymptomatic infection, and inconvenience of providing test specimens. The limited evidence owing to this relatively new topic and the diversity of both methods and study populations in the available studies contributed to the limitations of this review. The authors concluded that urine testing for chlamydia among asymptomatic men in established community and clinic settings is likely to yield relatively high acceptance rates than in the home-based settings. Pavlin et al., systematically reviewed the literature to document the views, attitudes, and opinions of women about being screened, tested, and diagnosed with chlamydia. Twenty-five studies were included. Women were more likely to accept testing/screening of chlamydia if they understood the seriousness of the infection and were aware that the infection can be asymptomatic. They preferred a wide range of options including urine tests, self-collected swabs, pelvic exams, and clinician-collected swabs, home-testing and community-based testing. Tests should be free, easy, and quick. Women wanted support, assistance, and maintenance of confidentiality, and felt the diagnosis should be normalized and de-stigmatized. Overall, the issues regarding chlamydia screening, testing and diagnosis among women include need for knowledge and information, choice and support, concerns about confidentiality, cost, fear, anxiety and stigma. This review was limited to studies written in English and 98% of the included studies dealt with the views of women from USA and UK. Cook et al., reviewed studies that assessed the sensitivity and specificity of three NAATs, namely PCR, TMA, and SDA assays for gonorrhea and chlamydia in urine (men and women) Urine Based Testing for Gonorrhea and Chlamydia 2

3 specimens, and cervical (women) or urethral (men) swab specimens. A total of 29 studies were included. A mixture of symptomatic and asymptomatic participants was included in most studies, and few studies separated symptomatic from asymptomatic results. The numbers of included studies (in parentheses), and the pooled sensitivities and specificities for each type of NAAT are shown in Table 1. The reference standard varied among the included studies. For both chlamydia and gonorrhea testing in women, the pooled specificities of each of the 3 assays exceeded 97% for both urine and cervical swab samples. The pooled sensitivities of PCR and TMA on urine samples were nearly identical to those obtained on cervical swab samples for chlamydia testing in women. For gonorrhea testing in women, the sensitivity of urine PCR was lower than cervical swab PCR. Also, the sensitivities of SDA on urine samples were slightly lower than those on cervical swabs, for both chlamydia and gonorrhea tests in women. For chlamydia testing in men, the pooled sensitivities and specificities of each of the 3 assays on urine samples were similar to those obtained on urethral swab samples. For gonorrhea in men, the pooled sensitivities and specificities of urine PCR were comparable to those of urethral PCR. Evidence regarding the other two assays (TMA and SDA) for gonorrhea in men was not available. One of the limitations of this review is that there were few studies on TMA and SDA. The authors concluded that all three commercially available NAATs have excellent sensitivity and specificity for detection of chlamydia in urine samples. The results of urine samples from both men and women are comparable to those from cervical or urethral swab samples. In women, urine samples were not suitable for detection of gonorrhea by PCR method. Data on effectiveness of NAATs on urine samples to screen for gonorrhea in asymptomatic men were limited. Table 1: Sensitivity and Specificity of NAATs for Chlamydia and Gonorrhea in Cook et al. 7 Tests Women Urine PCR (N=14) Cervical swab PCR (N=14) Urine TMA (N=4) Cervical swab TMA (N=4) Urine SDA (N=2) Cervical swab SDA (N=2) Chlamydia Sensitivity 83.3% ( ) 85.5% ( ) 92.5% ( ) 96.7% ( ) 79.9% ( ) 93.6% ( ) Specificity 99.5% ( ) 99.6% ( ) 98.6% ( ) 99.1% ( ) 99.1% ( ) 97.9% ( ) Tests Urine PCR (N=4) Cervical swab PCR (N=4) Urine TMA (N=1) Cervical swab TMA (N=1) Urine SDA (N=1) Cervical swab SDA (N=1) Gonorrhea Sensitivity 55.6% ( ) 94.2% ( ) 91.3% ( ) 99.2% ( ) 84.9% ( ) 96.5% ( ) Specificity 98.7% ( ) 99.2% ( ) 99.3% ( ) 98.7% ( ) 99.4% ( ) 99.5% ( ) Urine Based Testing for Gonorrhea and Chlamydia 3

4 Tests Men Urine PCR (N=12) Urethral swab PCR (N=12) Urine TMA (N=2) Urethral swab TMA (N=2) Urine SDA (N=2) Urethral swab SDA (N=2) Chlamydia Sensitivity 84.0% ( ) 87.5% ( ) 87.7% ( ) 95.9% ( ) 93.1% ( ) 92.4% ( ) Specificity 99.3% ( ) 99.2% ( ) 99.4% ( ) 99.4% ( ) 93.8% ( ) 96.3% ( ) Tests Gonorrhea Sensitivity Specificity Urine PCR (N=4) 90.4% ( ) 99.7% ( ) Urethral 96.1% 99.0% swab PCR ( ) ( ) (N=4) Urine TMA NA NA Urethral swab TMA NA NA Urine SDA NA NA Urethral swab SDA CI: confidence interval; N: number of studies; NA: not available; NAATs: nucleic acid amplification tests; PCR: polymerase chain reaction; SDA: strand displacement amplification; TMA: transcription-mediated amplification Observational studies Twelve observational studies were identified covering test performance (9 studies 8-16 ) and acceptability (4 studies 10,17-19 ). One study 10 reported both test performance and acceptability. Table 2 presents the summary of the characteristics and findings from the included studies. Details on test performance and acceptability of individual studies are in Appendix 1. NA NA Table 2: Characteristics and Findings from Included Studies Study; Population; setting country A. Test performance Skidmore et Women (n=2,745; al., 2006; 8 age years); UK community Renton et al., 2006; 9 UK Logan et al., 2005; 10 UK Women presenting for termination of pregnancy (n=863; age years); clinic Women with bleeding in early pregnancy (n=209; mean age: 29.3 years); hospital Specimen types Vaginal swab, urine Endocervical and vaginal swabs, urine Endocervical and vaginal swabs, urine Test types (infection) PCR, SDA (chlamydia) LCR, DFA (chlamydia) Amplified DNA assay (chlamydia) Main findings Both vaginal swab and urine specimen are suitable substrates for NAATs The sensitivity of both tests for urine specimen was less than that of endocervical or vaginal swab. Amplified DNA assay had a lower performance with urine samples than with endocervical or vaginal swab Urine Based Testing for Gonorrhea and Chlamydia 4

5 Study; country Chandeying et al., 2004; 11 Thailand Jensen et al., 2004; 12 Denmark Kellogg et al., 2004; 13 USA Sturm et al., 2004; 14 South Africa Shrier et al., 2004; 15 USA Peng & Kang, 2004; 16 China B. Acceptability Hoebe et al., 2006; 17 The Netherlands Logan et al., 2005; 10 UK Population; setting Women (523 sex workers; age years; 430 outpatient; age years); clinic 1856 men and 753 women (age not restricted); STD clinic Girls (n=229; age 6-20 years) suspected child sexual abuse; sexual abuse specialty clinic Pregnant women (n=185; mean age 25 years); first-time antenatal clinic attendees Asymptomatic women (n=139; age years); clinic Men (n=852; age not reported); STD clinic Women (n=413; age years); STD clinic Women with bleeding in early pregnancy (n=209; mean age: 29.3 years); hospital Specimen types Vaginal swab, tampon, urine Urethral swab, urine Vaginal swab, urine Endocervical swab, tampon, urine Self-collected vaginal swabs, and urine; clinician collected urethral, vaginal, and endocervical swabs Urethral swab, urine Self-taken vaginal swab, urine Endocervical and vaginal swabs, urine Test types (infection) PCR (chlamydia) PCR (chlamydia) LCR, PCR, and culture (chlamydia, gonorrhea) SDA, culture (chlamydia, gonorrhea) PCR, LCR, culture (chlamydia) LCR, culture (chlamydia) Amplified DNA assay (chlamydia, gonorrhea) Amplified DNA assay (chlamydia) Main findings PCR had higher positivity with tampon and vaginal swab than with urine Urine is better than urethral swab for chlamydia detection by PCR LCR is better than PCR and culture. Both LCR and PCR had better performance with vaginal swab than with urine specimens. Tampon SDA identified more infections than assays on endocervical swab and urine Urine gave lowest sensitivity compared to endocervical, vaginal and urethral swabs The sensitivity of urine LCR was significantly higher than that of urethral swab culture (P<0.001) The vast majority of participants (over 90%) were positive about selfcollection of urine samples and vaginal swabs Urine was most preferable choice compared with vaginal and endocervical methods. Vaginal was preferred over endocervical method. Urine Based Testing for Gonorrhea and Chlamydia 5

6 Study; country Population; setting Specimen types Test types (infection) Chernesky Women (n=1509; Self-taken Type of test et al., average age 26.6 vaginal swab, not reported 2005; 18 years); clinics urine; (chlamydia, Canada and physiciancollected gonorrhea) USA vaginal and cervical swab Tebb et al., Young women Home test Type of test (n=98, age (urine), clinicbased not reported years); follow-up (urine), (Sexually survey 9 months clinic-based transmitted after initial clinic visit vaginal swab, infections) clinic-based pelvic examination DFA: direct fluorescent antibody; LCR: ligase chain reaction; n: number of participants; NAATs: nucleic acid amplification tests; PCR: polymerase chain reaction; SDA: strand displacement amplification; STD: sexually transmitted disease; TMA: transcription-mediated amplification Main findings Self-collected vaginal swabs were preferred over urine and cervical swabs Home urine test was the first choice over clinic-based vaginal swab and clinicbased pelvic examination The findings of these observational studies showed that, in most women, self-collected urine or vaginal swab was preferred over cervical swab. Compared to vaginal and endocervical swabs, urine gave lower sensitivity to different NAATs for detection of chlamydia and gonorrhea infections. When compared with urethral swab in one study, urine was a better specimen for PCR to detect chlamydia in both men and women. Economic evaluations Blake et al., evaluated the cost-effectiveness of screening strategies for Chlamydia trachomatis using cervical swabs, urine, and self-obtained vaginal swabs in a sexually transmitted disease (STD) clinic setting. A decision analysis was modeled for a hypothetical cohort of 10,000 women per year attending STD clinics. Incremental cost-effectiveness of four chlamydia screening strategies were compared: 1) Endocervical DNA Probe (PACE2, Gen- Probe), 2) Endocervical AC2 (Aptima Combo 2, Gen-Probe), 3) Self-obtained Vaginal AC2, and 4) Urine AC2. The AC2 test is among a new generation of tests that use nucleic acid amplification and is FDA-approved for use on endocervical, urine, and vaginal specimens. Strategies 1 and 2 required a speculum examination; strategies 3 and 4 required a speculum examination for symptomatic patients or those due for Pap smear. The primary outcome measure was number of cases of pelvic inflammatory disease (PID). Secondary outcome measures were infertility, ectopic pregnancy, and chronic pelvic pain. The time horizon was 10 years. The analyses were conducted from the public health care perspective and included only direct medical costs. The analyses showed that the urine AC2 and endocervical AC2 were not cost-effective strategies. Self-obtained vaginal AC2 strategy was the least expensive and most cost-effective strategy compared with either the urine or endocervical AC2 tests in preventing PID. Although the cost to process AC2 is the same regardless of specimen used, the cost to obtain urine or endocervical sample is more than the cost to obtain a vaginal sample. In this study, the Urine Based Testing for Gonorrhea and Chlamydia 6

7 sensitivity of the vaginal AC2 is higher than the sensitivity of either the urine or endocervical AC2. Furthermore, of the three sampling techniques, over 80% of women preferred vaginal sampling as it was easy to perform. The authors concluded that the use of vaginal swab to detect Chlamydia in an STD clinic setting is cost-saving and cost-effective. Aledort et al., assessed the cost-effectiveness of gonorrhea screening in women ages 15 to 29 years, seeking care in urban emergency departments (ED) using non-invasive or rapid point-of-care tests. A state-transition Markov model was developed to compare the net lifetime health consequences, costs, and cost-effectiveness of routine ED care (no screening) to gonorrhea screening using 1 of 5 detection methods: gram-stained smear of endocervical swab specimens, urine-based NAATs, NAATs performed on endocervical swabs, rapid immunochromotographic strip test (RIS) performed on clinician-collected vaginal swabs, and RIS on patient-collected vaginal swabs. Screening women between 15 and 29 years with urine-based NAAT strategy was less costly and more effective than no screening and was therefore cost saving (i.e., lowest costundominated strategy). RIS using clinician-obtained vaginal swabs was the next most costeffective strategy after the urine-based test. Screening with RIS on patient-obtained specimen, with Gram stain, and with NAATs on cervical specimen were less effective and cost more per person compared with the previous strategies (i.e., dominated). The authors concluded that screening females aged 15 to 29 years for gonorrhea in some EDs with rapid, point-of-care tests is cost-effective compared with other well-accepted preventive interventions. Guidelines and recommendations Four guidelines that offer specific clinical guidance as to what type of testing should be used were included. Definitions of the levels of evidence and recommendations are in Appendix 2. The Canadian Guidelines on Sexually Transmitted Infections, were developed and updated by the Expert Working Group, which includes sexually transmitted infection (STI) experts in the fields of medicine, nursing, laboratory, public health, and research. These experts were authors and reviewers of the guidelines, and made evidence-based recommendations for the prevention, diagnosis, treatment, and management of STIs in Canada. No recommendation grade was provided. The guidelines have recommendations regarding laboratory diagnosis of gonococcal and chlamydial infections. Urine and swab (urethral and cervical) specimens were recommended for NAAT detection of chlamydia and gonorrhea infections (Table 3). Urine Based Testing for Gonorrhea and Chlamydia 7

8 Table 3: Laboratory Diagnosis of Specific Infections Chlamydia trachomatis NAATs are the most sensitive and specific and should be used whenever possible for urine, urethral and cervical specimens; blood and mucous can affect NAAT performance. 3 Non-invasive specimens such as urine can be used in NAATs, making test more acceptable to patients. 10 Both C. trachomatis and N. gonorrhea can be detected from a single specimen in some NAATs. 11 (p6) 22 Neisseria gonorrhea NAATs are approved for cervical and urethral swabs and urine; some NAATs are also approved for vaginal swabs. 11 Urine and vaginal swabs are convenient specimens for women without a cervix, and urine may be most convenient for those who may not readily submit a pelvic examination. Urine is a preferred specimen for men if a NAAT is performed. (p7) 22 NAATs: nucleic acid amplification tests The guideline from the New York State Department of Health, has recommendations regarding annual screening of patients for gonoccocal and chlamydial infection. No recommendation grade was provided. Information on the development of the guideline was not reported. In this guideline, urine and swab specimens for NAAT were recommended for the detection of gonorrhea and chlamydia in both men and women presenting with or without symptoms. The swab specimens were also recommended for culture in the detection of those infections. The UK National Screening and Testing Guidelines, have been developed following the methodological framework of the Appraisal of Guidelines Research and Evaluation instrument (AGREE). The key features include Scope and Purpose, Stakeholder Involvement, Rigour of Development, Presentation, Applicability and Editorial Independence. These guidelines provided recommendations for testing of sexually transmitted infections including gonorrhea and chlamydia. Samples taken from urethra, rectum, and oropharynx are done by swabbing. Urine is collected after patient has held urine for at least an hour. Both urine and swab specimens were recommended for culture or NAAT in the detection of gonorrhea and chlamydia in different types of populations. The Queensland Management Guidelines for the Detection and treatment of sexually Transmissible and other Genital infections, version III, was adapted through a process of consultation with sexual health practitioners across Queensland, Australia. These guidelines have recommendations for specimen collection and testing for gonorrhea and chlamydia. Both urine and swab specimens were recommended for PCR in the detection of gonorrhea and chlamydia infections in both men and women (Table 4). No recommendation grade was provided. Urine Based Testing for Gonorrhea and Chlamydia 8

9 Table 4: Recommended Investigations Gonorrhea Women Endocervical swab for Gram-stained smear A Gram-stained urethral smear may be useful in women who have urethral symptoms, or women at risk who have had a hysterectomy. 25 Endocervical swab for culture. This should be sent promptly to the laboratory at room temperature in Amies or charcoalcontaining Stuart s transport medium. 25 First-catch urine gonorrhea by PCR appropriate during screening programs or where patients are asymptomatic. 25 Pharyngeal and anorectal swabs for culture if symptoms or sexual history suggest infection at these sites. Gramstained smears should be taken via proctoscopy if there are symptoms after unprotected anal intercourse. 25 Men Chlamydia Endocervical swab for Chlamydia trachomatis PCR 25 PCR is the main test used to identify chlamydia. 25 First-catch urine chlamydial test for PCR or self obtained low vaginal swab for chlamydial PCR 25 Pharyngeal and anorectal swabs for PCR. If there is a history of patient performing unprotected fellatio or being the receptive partner in unprotected anal sex 25 Although PCR is not validated 25 for specimen obtained from vagina, rectum and throat, this is still the recommended test for Chlamydia. 25 Swab of urethral discharge for Gramstained smear will confirm the diagnosis 25 First-catch urine chlamydial test for PCR is the standard test for screening males rather than urethral PCR swab 25 Swab of urethral discharge for gonococcal culture should be sent to the laboratory at room temperature in Amies or charcoalcontaining Stuart s medium. Gonococci survive poorly in plain Stuart s medium. 25 First-catch urine gonorrhoea test by PCR appropriate during screening programs or where patients are asymptomatic 25 Pharyngeal and anorectal swabs for culture if the sexual history suggest infection at these sites. Gram-stained smears should be taken via proctoscopy if there are symptoms, if there is a history of unprotected receptive anal intercourse 25 PCR: polymerase chain reaction Limitations First-catch urine chlamydial test for PCR external urethral swab. 25 If urethral discharge is present. Pharyngeal and anorectal swabs for PCR. If there is a history of patient performing unprotected fellatio or being the receptive partner in unprotected anal sex 25 Although PCR is not validated 25 for specimen obtained from vagina, rectum and throat, this is still the recommended test for Chlamydia. 25 There was only one meta-analytic review comparing the performance of NAATs on urine versus cervical swab in women, and urine versus urethral swab in men. No randomized controlled trials or controlled trials were identified. The acceptability (or uptake) was used as an indirect indication for compliance. Evidence regarding the cost-effectiveness of urine-based versus swab testing was limited. Urine Based Testing for Gonorrhea and Chlamydia 9

10 The three systematic reviews identified included information from observational studies, and no randomized controlled trials were identified. Observational studies do not control for potential selection bias. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING: Overall, the identified literature reported that urine-based testing is either comparable or less sensitive than swab-based testing for detection of gonorrhea and chlamydia in men and women, depending on the types of test and types of specimen collection being compared. A self-obtained vaginal swab NAAT strategy in the detection of chlamydia was found least expensive and most cost-effective compared with urine or endocervical tests. For screening of gonorrhea in women, there was no clear evidence regarding cost-effectiveness comparing urine-based testing and swab-based testing. Evidence regarding cost-effectiveness of urinebased testing versus swab-based testing for detection of gonorrhea and chlamydia in men was lacking. Self-taken specimen such as vaginal swab and urine in women was reported to be the preferred method over clinician-collected approach. Fear of being stigmatized and inconvenience of providing test specimens are factors that might affect the acceptability of the test in women. No information was found with respect to other factors including client vulnerability, gender, immigrant status, addictions, and homeless that might affect compliance. For screening and diagnosis of gonorrhea and chlamydia, the identified guidelines have made recommendations regarding the types of test and types of specimen collection according to specific populations. No study regarding the stability of swab-based versus urine-based specimen during transportation or storage could be found. PREPARED BY: Khai Tran, MSc, PhD, Research Officer Emmanuel Nkansah, MLS, MA, Information Specialist Health Technology Inquiry Service htis@cadth.ca Tel: Urine Based Testing for Gonorrhea and Chlamydia 10

11 REFERENCES: 1. Evans J. Gonorrhea and chlamydia tests [Internet]. Ann Arbor (MI): University of Michigan Health System; 2009 Jan 14. [cited 2009 Nov 17]. Available from: 2. Chernesky MA, Chong S, Smieja M, Ewert R, Hayhoe B, Jang D. Young men collect their own urethral swab for the diagnosis of chlamydia trachomatis and neisseria gonorrhoeae by the APTIMA Combo 2 assay [Internet]. Abstract presented at: Beyond the Hidden Epidermic: Evolution or Revolution? 2006 National STD Prevention Conference; 2006 May 8; Jacksonville (FL). [cited 2009 Nov 19]. Available from: 3. Spigarelli MG. Urine gonococcal/chlamydia testing in adolescents. Curr Opin Obstet Gynecol Oct;18(5): Lin K. How reliable is urine testing for gonorrhea and chlamydia? Am Fam Physician [Internet] Dec 1 [cited 2009 Nov 17];72(11). Available from: 5. Marrazzo JM, Scholes D. Acceptability of urine-based screening for Chlamydia trachomatis in asymptomatic young men: a systematic review. Sex Transm Dis Nov;35(11 Suppl):S28-S Pavlin NL, Gunn JM, Parker R, Fairley CK, Hocking J. Implementing chlamydia screening: what do women think? A systematic review of the literature. BMC Public Health [Internet] [cited 2009 Nov 3];6:221. Available from: 7. Cook RL, Hutchison SL, Ostergaard L, Braithwaite RS, Ness RB. Systematic review: noninvasive testing for Chlamydia trachomatis and Neisseria gonorrhoeae. Ann Intern Med Jun 7;142(11): Skidmore S, Horner P, Herring A, Sell J, Paul I, Thomas J, et al. Vulvovaginal-swab or first-catch urine specimen to detect Chlamydia trachomatis in women in a community setting? J Clin Microbiol [Internet] Dec [cited 2009 Nov 3];44(12): Renton A, Thomas BM, Gill S, Lowndes C, Taylor-Robinson D, Patterson K. Chlamydia trachomatis in cervical and vaginal swabs and urine specimens from women undergoing termination of pregnancy. Int J STD AIDS Jul;17(7): Logan S, Browne J, McKenzie H, Templeton A, Bhattacharya S. Evaluation of endocervical, first-void urine and self-administered vulval swabs for the detection of Chlamydia trachomatis in a miscarriage population. BJOG [Internet] Jan [cited 2009 Nov 3];112(1): Available from: Urine Based Testing for Gonorrhea and Chlamydia 11

12 11. Chandeying V, Lamlertkittikul S, Skov S. A comparison of first-void urine, selfadministered low vaginal swab, self-inserted tampon, and endocervical swab using PCR tests for the detection of infection with Chlamydia trachomatis. Sex Health. 2004;1(1): Jensen JS, Bjornelius E, Dohn B, Lidbrink P. Comparison of first void urine and urogenital swab specimens for detection of Mycoplasma genitalium and Chlamydia trachomatis by polymerase chain reaction in patients attending a sexually transmitted disease clinic. Sex Transm Dis Aug;31(8): Kellogg ND, Baillargeon J, Lukefahr JL, Lawless K, Menard SW. Comparison of nucleic acid amplification tests and culture techniques in the detection of Neisseria gonorrhoeae and Chlamydia trachomatis in victims of suspected child sexual abuse. J Pediatr Adolesc Gynecol Oct;17(5): Sturm PD, Connolly C, Khan N, Ebrahim S, Sturm AW. Vaginal tampons as specimen collection device for the molecular diagnosis of non-ulcerative sexually transmitted infections in antenatal clinic attendees. Int J STD AIDS Feb;15(2): Shrier LA, Dean D, Klein E, Harter K, Rice PA. Limitations of screening tests for the detection of Chlamydia trachomatis in asymptomatic adolescent and young adult women. Am J Obstet Gynecol Mar;190(3): Peng XB, Zeng K. Ligase chain reaction for Chlamydia trachomatis detection in urine specimens from symptomatic and asymptomatic men. Di Yi Jun Yi Da Xue Xue Bao May;24(5): Hoebe CJ, Rademaker CW, Brouwers EE, ter Waarbeek HL, van Bergen JE. Acceptability of self-taken vaginal swabs and first-catch urine samples for the diagnosis of urogenital Chlamydia trachomatis and Neisseria gonorrhoeae with an amplified DNA assay in young women attending a public health sexually transmitted disease clinic. Sex Transm Dis Aug;33(8): Chernesky MA, Hook EW, III, Martin DH, Lane J, Johnson R, Jordan JA, et al. Women find it easy and prefer to collect their own vaginal swabs to diagnose Chlamydia trachomatis or Neisseria gonorrhoeae infections. Sex Transm Dis Dec;32(12): Tebb KP, Paukku MH, Pai-Dhungat MR, Gyamfi AA, Shafer MA. Home STI testing: the adolescent female's opinion. J Adolesc Health Dec;35(6): Blake DR, Maldeis N, Barnes MR, Hardick A, Quinn TC, Gaydos CA. Cost-effectiveness of screening strategies for Chlamydia trachomatis using cervical swabs, urine, and selfobtained vaginal swabs in a sexually transmitted disease clinic setting. Sex Transm Dis Jul;35(7): Aledort JE, Hook EW, III, Weinstein MC, Goldie SJ. The cost effectiveness of gonorrhea screening in urban emergency departments. Sex Transm Dis Jul;32(7): Urine Based Testing for Gonorrhea and Chlamydia 12

13 22. Updates to the Canadian guidelines on sexually transmitted infections edition. Ottawa: Public Health Agency of Canada; 2008 Jan. [cited 2009 Nov 12]. Available from: National Guideline Clearinghouse. Rockville (MD): National Guideline Clearinghouse; c Gonococcal and chlamydial infections; 2007 Oct 7 [cited 2009 Nov 12]. Available from: Ross J, Ison C, Carder C, Lewis D, Mercey D, Young H. Sexually transmitted infections: UK national screening and testing guidelines [Internet]. London: British Association for Sexual Health and HIV (BASHH); 2006 Aug. [cited 2009 Nov 12]. Available from: Queensland management guidelines for the detection and treatment of sexually transmissible diseases and genital infections. Version III. Brisbane (Australia): Queensland Health, Queensland Government; 2006 Jan. [cited 2009 Nov 12]. Available from: Urine Based Testing for Gonorrhea and Chlamydia 13

14 APPENDIX 1: Descriptions of Individual Observational Studies on Test Performance and Acceptability A. Test Performance 1. Skidmore et al., evaluated the performance of two NAATs (PCR and SDA) for detecting Chlamydia in self-collected vulvovaginal-swab and first-catch urine specimens from women in a community setting. This Chlamydia screening study involved 2,745 women (aged 16 to 39 years) sending paired vulvovaginal-swab and first-catch urine specimens to two laboratories in the UK. There were 146 true positive results. Combined results of both NAATs showed that using vulvovaginal-swab specimens correctly identified 142/146 true-positive specimens (relative sensitivity, 97.3%; 95% CI, 93.1 to 99.2%), compared with 134/146 identified using urine specimens (relative sensitivity, 91.8%; 95% CI, 86.1 to 95.7%). The relative specificity for both specimen types was 99.6% or higher. The authors concluded that, in community settings, both vulvovaginal-swab and first-catch urine specimens from women are suitable substrates for NAATs. 2. Renton et al., assessed the prevalence of Chlamydia in endocervical and vaginal swabs and first pass urine specimens from women presenting for termination of pregnancy using either the LCR or the direct fluorescent antibody (DFA) test. Of the 940 women presenting for termination of pregnancy at a Center family planning clinic in west London, UK, 863 women (15 to 48 years) were recruited for the study. The median gestation time was 8 weeks (range: 1-22 weeks). The overall prevalence of Chlamydia was 8.54% (95% CI: %). The sensitivity of the LCR test for cervical, vaginal, and urine specimens was 97% (93-99%); 94% (88-99%), and 83% (75-92%), respectively. The sensitivity of the DFA test for cervical, vaginal, and urine specimens was 93% (87-99%); 92% (86-99%), and 78% (68-88%), respectively. The authors concluded that NAATs such as LCR are appropriate for screening women seeking termination of pregnancy and women in early pregnancy. The sensitivity of the both tests for urine specimens was less. 3. Logan et al., compared, in parallel, different approaches of opportunistically screening women with bleeding in early pregnancy for Chlamydia infection. A study population consisted of 209 women (mean age 29.3 years) with a history of vaginal bleeding and less than 24 weeks of gestation, admitted to an early pregnancy assessment unit. Each woman provided two or more of the following specimens: self-obtained vulval swab, first-void urine, and/or endocervical swab. An amplified DNA assay (BD Probe Tec) was used. The overall prevalence was 3.9% ( %). The positivity for endocervical swab, self-collected vulval swab, and first-void urine was 75%, 100%, and 38%, respectively. Thus, an amplified DNA assay had a lower performance with urine samples than with endocervical or vulval swabs obtained from pregnant women with history of vaginal bleeding. 4. Chandeying et al., compared first-void urine, self-administered low vaginal swab, selfinserted tampon, and endocervical swab using PCR for the detection of Chlamydia infection in Thai women. Of the 1011 women interviewed, 523 sex workers (age 16 to 52 years) and 430 Urine Based Testing for Gonorrhea and Chlamydia 14

15 outpatient women (15 to 47 years) participated in the study took place in a hospital outpatient clinic. The prevalence of positive detection among the sex workers/outpatient women was 17.6%/7.2%, 15.6%/5.4%, 12.8%/4.2%, and 11.6%/5.7% using tampons, vaginal swab, urine, and endocervical swab. Significantly more women were willing to use tampons (sex workers) or vaginal swab (outpatient women) for repeat specimen collection. The authors concluded that tampon and vaginal self-collected methods are acceptable to women in Thailand and are good alternative method for detection of Chlamydia. 5. Jensen et al., compared urethral swab specimens and first void urine (FVU) specimens from male and female patients (age not restricted) at a sexually transmitted disease clinic for the detection of Chlamydia infection using an in-house, inhibitor-controlled PCR. Urethral swabs and FVU were collected from 1856 men and 753 women who also had cervical swabs collected. A positive diagnosis was made if any one of the specimens tested positive and was confirmed in a second PCR assay targeting independent genes. For Chlamydia in men, the relative sensitivity for urine was 98.4% as compared with a urethral swab sensitivity of 89.4% (P<0.0001). For Chlamydia in women, FVU was also found to be the most sensitive diagnostic specimen, but for optimal sensitivity, it should be supplemented with a cervical specimen. The authors concluded that urine appears to be a better diagnostic specimen than urethral swab for Chlamydia detection by PCR in a cohort of sexually transmitted disease clinic attendees. 6. Kellogg et al., compared the performance of three test methods LCR, PCR, and culture) on vaginal swab and urine specimens for detection of Gonorrhea and Chlamydia from victims of suspected child sexual abuse. The participants included 229 girls between age 6 and 20 who reported at a specialized sexual abuse clinic in San Antonio, Texas, USA. Table A1: Positivity Across Tests Vaginal LCR (%) Urine LCR (%) Vaginal PCR (%) Urine PCR (%) Culture (%) Chlamydia Gonorrhea LCR: ligase chain reaction; PCR: polymerase chain reaction Table A1 presents the percentage of positive results of each of the methods used to test for Chlamydia and Gonorrhea positivity. Only participants who were administered all tests (n=122) were included in the analysis. The results showed that LCR techniques detected more patients with Chlamydia and Gonorrhea than the PCR and culture techniques. The LCR vaginal swab detected more patients with Chlamydia and Gonorrhea than the LCR urine samples. 7. Sturm et al., evaluated the use of tampons, urine, and vaginal swabs to detect Chlamydia and Gonorrhea from first-time antenatal clinic attendees in South Africa, with and without genital discharge. Two techniques (culture and SDA) were used for Gonorrhea while SDA was used for Chlamydia. Mean age of 185 women included was 25 years (SD ± 5.97) and mean gestational age 23 weeks (SD ± 5.84). Urine Based Testing for Gonorrhea and Chlamydia 15

16 Table A2: Test Parameters (%) of Different Diagnostic Tests for Gonorrhea and Chlamydia Sensitivity Specificity PPV NPV Gonorrhea Culture endocervical swab 64 (36-86) SDA endocervical swab 57 (30-81) SDA tampon 79 (49-94) SDA urine 43 (19-70) Chlamydia SDA endocervical swab 84 (63-95) SDA tampon 92 (73-99) SDA urine 84 (63-95) CI: confidence interval; NPV: negative predictive value; PPV: positive predictive value; SDA: strand displacement assay Table A2 presents the parameters of different diagnostic tests. The results showed that the use of SDA on tampon specimens for detection of Gonorrhea and Chlamydia identified more infections than assays on endocervical swabs and urines. The performances of SDA on urine and endocervical swab specimens were comparable. 8. Shrier et al., assessed the performance of different test types, specimen sources, and collection methods for screening of genital Chlamydia infection in young women. Asymptomatic women (N=139) 16 to 25 years collected their own vaginal swabs and a first-voided urine specimen; a clinician collected urethral, vaginal, and endocervical swabs for culture and NAATs (PCR and LCR). Table A3: Test Parameters (%) of Different Diagnostic Tests for Chlamydia Sensitivity Specificity PPV NPV Urethral Culture 22 (10-41) PCR 56 (36-73) Vaginal Self-collected PCR 52 (32-71) Clinician-collected PCR 56 (36-73) Endocervical Culture 37 (20-57) PCR 52 (32-71) LCR 63 (43-80) Urine PCR 44 (27-64) LCR 63 (43-80) CI: confidence interval; LCR: ligase chain reaction; PCR: polymerase chain reaction Urine Based Testing for Gonorrhea and Chlamydia 16

17 Table A3 presents the test parameters of different diagnostic tests for Chlamydia in asymptomatic female adolescents and young adults. The prevalence was 22%. Urine LCR was comparable to endocervical LCR. However, when using PCR, urine gave lowest sensitivity compared to endocervical, vaginal, and urethral swabs. Multiple tests on multiple specimen types were analyzed to maximize the likelihood of detection (data not shown). The authors pointed out that the limitations of the use of a single test to identify Chlamydia infection should be considered when test type, specimen source, and collection method for screening young women is being considered. 9. Peng & Kang, compared the performance of urine LCR and urethral swab culture for detection of Chlamydia from symptomatic and asymptomatic men in China. Of the 852 participants (age not reported) who visited the Outpatient Department for STDs, 608 had symptoms of urethritis and 244 were asymptomatic. Before first-void urine collection, a urethral swab specimen for cell culture was collected in each case. The overall sensitivity and specificity was 98.6% and 99.4% with urine LCR, respectively, and was 77.4% and 99.5% with urethral swab culture. The sensitivity of urine LCR was significantly higher than that of urethral swab culture (P<0.001). The authors concluded that urine LCR can be used for non-invading diagnosis and screening of the infection in men. B. Acceptability 10. Hoebe et al., assessed the acceptability of self-taken vaginal swabs and first-catch urine samples for the diagnosis of urogenital Chlamydia and Gonorrhea with amplified DNA assay in young women attending a public health STD clinic. This cross-sectional survey involved 413 women (16 to 35 years) who underwent STD testing at a public health clinic. Most common reasons for their clinic visit were prior risk behavior (56%), new sexual relation (21%), possible STD symptoms (20%), risk behavior partner (17%) and fear for possible acquired STD (9%). All participants filled out a questionnaire. Self-collection of vaginal swabs was reported as easy to perform (95%). Similar results were obtained for collection of urine sample (92%). For repeat testing if necessary, 90% would choose self-collected vaginal swab and 94% would choose urine collection. Self-collected urine samples and vaginal swabs were preferred (77%) above a gynecologic examination; 23% did not voice a preference. Thus, the vast majority was positive about self-collection of urine samples and vaginal swabs. 11. Logan et al., compared, in parallel, different approaches of opportunistically screening women with bleeding in early pregnancy for Chlamydia infection. A study population consisted of 209 women (mean age 29.3 years) with a history of vaginal bleeding and less than 24 weeks of gestation. Each woman provided two or more of the following specimens: selfobtained vulval swab, first-void urine, and/or endocervical swab. Following screening, each completed a semi-questionnaire assessing the acceptability of each method undertaken. When asked to state their preferred method for screening, 3%, 30%, and 70% women chose the endocervical, vulval, and urine method, respectively. Urine was significantly preferred compared with vulval (P<0.0001) and endocervical (P<0.0001) methods, and the vulval method was significantly preferred when compared with endocervical swab (P<0.0001). Urine Based Testing for Gonorrhea and Chlamydia 17

18 Five reasons for declining of endocervical swab method: a) physically negative aspects (unpleasant, irritating, and uncomfortable); b) positive aspect of non-invasive testing (prefer selfcollected method, straight forward and simple); c) not wish to have repeated internal examination; d) felt psychologically unable to cope with the procedure; e) concern the pregnancy would be affected with the procedure. 12. Chernesky et al., surveyed women s opinion on ease and preferences as to sampling after collecting their own vaginal swab and urine and a physician collection of vaginal and cervical swabs for detection of Chlamydia and Gonorrhea infections. A total of 1509 women (average, 26.6 years; range, 15 to 71 years) were enrolled in a diagnostic study from clinics for family planning, STDs, teenagers, and student health from 8 centers in Canada and USA. A total of 1090 completed the questionnaire concerning ease and preference of collection. The results showed that 89.6% found that it was very easy to collect their own vaginal swab. Sampling preference showed that 76% preferred a vaginal swab over pelvic examination and 60% over a urine collection. Over 90% of the participants reported that handling the swabs and tubes was very easy. When asked would you test yourself more often for a sexually transmitted infection if the self-collected vaginal swab was available? 94% answered yes. The authors concluded that self-collected vaginal swabs were easy to collect and patients preferred them over urine and cervical swabs. 13. Tebb et al., assessed sexually active adolescent females attitudes of home tests for sexually transmitted infections (STI). This was a follow-up study nine months after their initial clinic visit to re-assess their attitudes and preferences regarding the specimen collections, their knowledge about STI, their recent sexual history and attitudes about STI testing methods. Ninety eight ethnically diverse adolescents (13 to 20 years old) participated in the study. The home STI testing was the preferred method over clinic-based testing for first-void urine specimen (52% versus 30% at first choice). Home urine testing was preferred over clinic-based self-administered vaginal swab and clinic-based pelvic examination (endocervical swab collected by a clinician). The authors concluded that young women in this study preferred home STI testing and the pelvic examination experience might influence their attitudes and preferences. Urine Based Testing for Gonorrhea and Chlamydia 18

19 APPENDIX 2: Definitions of the Levels of Evidence and Recommendations Levels of evidence Ia Ib IIa IIb III IV evidence obtained from meta-analysis of randomized controlled trials evidence obtained from at least one randomized controlled trial evidence obtained from at least one well designed controlled study without randomization evidence obtained from at least one other type of well designed quasi-experimental study evidence obtained from well designed non-experimental descriptive studies evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities Grading of recommendation A B C evidence at level Ia or Ib evidence at level IIa, IIb or III evidence at level IV Urine Based Testing for Gonorrhea and Chlamydia 19