Systematic Review: Noninvasive Testing for Chlamydia trachomatis and Neisseria gonorrhoeae

Context Can nucleic acid amplification tests on urine samples replace cervical and urethral samples to screen for chlamydia and gonorrhea? Contribution Pooled data from 29 studies showed that 3 commercially available nucleic acid amplification tests had high specificity (>95%) for detecting chlamydia and gonorrhea. Sensitivity was reasonably high (approximately 80% to 93%), except for polymerase chain reaction (PCR) for gonococcal infections in women (approximately 56%). Limitations Few studies tested transcription-mediated amplification and strand displacement amplification assays. Implications Nucleic acid amplification tests are easily obtainable non-invasive tests on urine samples that detect chlamydia and gonorrhea reasonably well. However, negative results on PCR assays on urine samples are not useful to rule out gonococcal infections in women. The Editors Chlamydia trachomatis and Neisseria gonorrhoeae infections are among the most common bacterial sexually transmitted infections worldwide (1). In the United States, experts estimate an annual incidence of 2.8 million new chlamydial infections and 720000 new gonococcal infections, the majority of which are asymptomatic (2). Nearly every major U.S. public health organization now recommends routine screening of sexually active young women for chlamydial infection (3-5). Screening young women for chlamydia has been shown to be a cost-effective method of preventing pelvic inflammatory disease, which is a major cause of infertility and chronic pelvic pain (6). Although the proportion of women who are screened appears to be increasing, 60% or fewer women at risk undergo screening (7, 8). In many settings, the prevalence of chlamydial infection in asymptomatic young men is around 3% to 5% (9-11). The screening of young men may be needed as part of a strategy to prevent chlamydial infection in young women, but little evidence is available to support recommendations for or against screening of men. Nonetheless, in both men and women, chlamydial and gonococcal infections are associated with a 3-fold to 6-fold increase in the risk for transmission or acquisition of HIV (12). Traditional methods of screening for chlamydial infection require a speculum examination in women and insertion of 1 or more swabs into the urethra in men. Not only are these screening methods embarrassing and uncomfortable, but they also require a clinic visit and use of an examination room, sterile equipment, gowns, and trained clinicians. Noninvasive screening options, such as urine testing or self-collected vaginal swabs, could eliminate some of the barriers to screening for chlamydial infection. Noninvasive methods are clearly preferred by patients (13, 14) and could substantially increase the acceptability and convenience of screening in a variety of settings. Urine-based screening has been used to identify infections in young women in primary care settings who are not receiving pelvic examinations (15) and can increase the proportion of sexually active young persons who receive chlamydial screening in clinical practices (16). Therefore, replacing invasive screening procedures with noninvasive screening procedures might improve adherence with screening guidelines. Several newly developed nucleic acid amplification tests that use noninvasive samples have been evaluated. Previous reviews of various types of tests for chlamydia concluded that nucleic acid amplification tests have superior sensitivity (17-19) but did not specifically address the question of whether tests on noninvasively obtained samples are as accurate as those obtained with cervical or urethral samples. No widely accepted guidelines exist for screening for gonorrhea. However, each of the commercially available nucleic acid amplification tests can evaluate for C. trachomatis and N. gonorrhoeae in the same specimen. This combination testing option makes it convenient for many clinicians to test for chlamydial infection and gonorrhea simultaneously. The literature on these assays can be confusing because the study samples and reference standards used differ greatly. We conducted a systematic review of the literature on the sensitivity and specificity of urine-based nucleic acid amplification tests for C. trachomatis and N. gonorrhoeae. We specifically sought to compare the results obtained with urine samples to those obtained with cervical and urethral samples and to further analyze the results according to type of assay, sample characteristics, and reference standard used. Methods We based our review strategy on several articles that outline procedures for conducting systematic reviews and meta-analyses, including the QUORUM guidelines for reporting of meta-analyses (20) and general guidelines for systematic reviews of diagnostic tests (21-24). Literature Search We searched the MEDLINE database for articles published from 1 January 1991 to 31 December 2004. We specifically sought articles that contained the Medical Subject Headings Chlamydia trachomatis, chlamydial infections (not pneumoniae), or Neisseria gonorrhoeae and also included the terms nucleic acid amplification techniques or polymerase chain reaction or the text words strand displacement, transcription-mediated, or polymerase. Additional articles were identified through references of relevant articles and a hand search through January 2005 of the 3 journals in which articles on these topics most commonly appeared (Journal of Clinical Microbiology, Sexually Transmitted Diseases, and Sexually Transmitted Infections). Study Selection We selected studies that evaluated 1 of 3 commercially available nucleic acid amplification tests, presented data separately by sex, included data obtained from the same assay on both a urine sample and a traditional sample (obtained from the cervix or urethra), and used an appropriate reference standard. We excluded studies that used a nucleic acid amplification test that is not commercially available, including studies that evaluated the ligase chain reaction assay (which was removed from the commercial market in 2002). We also excluded some studies in which data were obtained from urine samples only because one of our main objectives was to determine whether such results were similar to those obtained from cervical or urethral samples. The choice of an appropriate reference standard is complicated because the nucleic acid amplification tests under evaluation are generally more sensitive than the other diagnostic methods that could be used for reference standards. The choice is also complicated by the fact that both C. trachomatis and N. gonorrhoeae can simultaneously infect multiple anatomic sites. In some women, chlamydia can be detected only in the cervix. In others, it can be detected only in the urethra or urine. The diagnostic test must therefore be able to detect the maximum number of infected persons who require treatment. In evaluating reference standards, we included studies in which 2 conditions were met. First, samples must have been collected from at least 2 anatomic sites, including the cervix in women or the urethra in men. In addition, the reference standard required confirmation by culture (which most experts consider to be 100% specific) or by at least 1 additional nucleic acid amplification test that differed from the test under evaluation (to ensure acceptable sensitivity of the reference standard). Examples of reference standards that did not meet our site and test criteria included urine tests that were compared only with other urine tests, nucleic acid amplification tests that were compared only with culture or other less-sensitive assays, and nucleic acid amplification tests that were confirmed by the same test under evaluation but at a different anatomic site. Data Extraction and Validity Assessment Two of the authors independently read each eligible article and extracted detailed information on the study sample, test characteristics, reference standard, and results. If a study included results from both symptomatic and asymptomatic patients, we included both sets of results. If a study presented data obtained by using more than 1 reference standard, we selected the results that were most consistent with the reference standard criteria outlined earlier. Several guidelines suggest criteria to evaluate validity and report results of diagnostic test studies, although there is no consensus on which criteria are most important for study validity (21-24). We abstracted information that was consistently noted in these reports, including whether the study sample was clearly defined and not already known to have the condition, whether the reference standard tests were conducted without knowledge of the test under evaluation, whether all participants received the same diagnostic evaluation, and whether the reference standard was clearly defined. For each study, we calculated 95% CIs for sensitivity and specificity by using the binomial distribution. We calculated positive likelihood ratios by using the following formula: sensitivity/(1corresponding specificity). We calculated negative likelihood ratios by using the following formula: (1sensitivity)/specificity. To calculate likelihood ratios, we converted sensitivities or specificities of 1.0 to 0.9999. Data Synthesis Studies were assessed qualitatively and quantitatively. The qualitative assessment identified potential sources of heterogeneity, which included different types of assays, sex of study participants, and presence or absence of symptoms in the sample. We therefore aimed to stratify studies into groups with clinically similar tests, participants, and infections (25). Our initial intent was to synthesize study results by constructing a summary receiver-operating characteristic curve (26, 27). This method is a particularly robust way of synthesizing diagnostic test information across studies because it is relatively insensitive to the particular test threshold t