Literature review > Issue_1 > Review on Mukenge-Tshibaka et al. 

This skilled multinational team with extensive STD/HIV research experience in West Africa re-examined clinical vs. laboratory diagnosis of gonococcal or chlamydial uterine infection among FSW in Benin, adding an assessment of how failure of infected women to return promptly for laboratory test results would offset the benefits of greater sensitivity of lab tests in promptly bringing them into treatment. Interpreting comparisons of clinical vs. laboratory diagnosis requires (1) definition, accurate interpretation, and feasibility of measurement of the constellation of risk factors, symptoms, and signs that warrant a clinical (syndromic) diagnosis of uterine infection; (2) the sensitivity, specificity, and predictive values of the diagnostic laboratory tests used for the uterine infections of interests; (3) contextual factors such as populations studied and accessibility of services; and (4) the relative clinical and public health importance of infections missed by clinical diagnosis or by rapid but relatively insensitive laboratory tests, and therefore not treated (i.e., the marginal public health cost-benefit of more sensitive tests in terms of preventing transmission or complications of STI).

Regarding clinical diagnosis, this study wisely ignored symptoms, which of course correlates better with infection in women seeking care for symptoms than in FSW undergoing routine exams or in surveys of the general population [1]. The risk factors identified here (young age, short duration of prostitution, number of clients) are plausible and generalizable. Manifestations of inflammation associated with cervical infection in this study included signs of cervicitis, signs of PID, "presence of" vaginal discharge, and microscopic evidence of >10 PMN per field (level of magnification not specified) in vaginal fluid. The level of association of signs of cervicitis with laboratory diagnosis of cervical infection varies with the experience and training of the clinician performing the speculum exam [2]. The relatively strong association found in this study (OR 2.35) is consistent with the extensive experience of the research team, and may not be generalizable to all similar settings.

The clinical diagnosis of pelvic inflammatory disease was surprisingly common in this study (8.3%), but was not significantly associated with either cervicitis or with cervical gonococcal or chlamydial infection - probably indicating the non-specificity of the syndromic diagnosis of PID in this setting - as in some previous studies [3]. Although presence of vaginal discharge has been associated with cervical infection in this study and in other West African studies, vaginal discharge is "present" in many women without cervical infection, and has not been associated with cervical infection in other studies [4, 5]. Increased concentration of PMN leukocytes in vaginal fluid was also found associated with cervical infections; vaginal fluid may be easier to sample than cervical fluid, but is not considered ideal for detecting cervical infection; vaginal trichomoniasis is also a common cause of increased PMN in vaginal fluid.

In comparing laboratory diagnosis with clinical syndrome diagnosis, one must consider not only the laboratory test's performance in detecting specific pathogens of interest, but also the tests' coverage of all potential pathogens capable of causing the syndrome. We already know today that a high proportion of cases of well-defined cervicitis are not attributable to gonorrhea or chlamydial infection; herpes simplex virus, T. vaginalis, and perhaps Mycoplasma genitalium [6] represent additional causes. More remains to be learned about the causes of cervicitis. Perhaps at some future date, when more pathogens have been implicated as causes of cervicitis, STD specialists will be amused at our current efforts to achieve high predictive values of the diagnosis of cervicitis with respect to only two of the known curable causes of cervicitis. For example, if gonorrhea and chlamydial infection were to account for only half of all infectious causes of cervicitis in a given population, then the predictive value of signs of cervicitis would not be expected to exceed 50%.

Concerning contextual influences on STD diagnosis and treatment, low prevalence of cervical infection certainly lowers the predictive value of syndromic and even laboratory diagnoses. Further, the major contribution of this paper is to extend the observation of Gift, Hook, Schwebke, and others [7-9] to show clearly that in a developing country setting, positive laboratory tests may not lead to treatment if rapid tests are not used, and systems for testing or for linking non-rapid test results to treatment are inefficient, costly, or difficult for clinicians or patients to navigate [7-9]. This represents the strongest argument for developing rapid laboratory tests for the pathogens causing uterine infection - a major goal of the STI Diagnostics Initiative - so that test results could guide initiation of treatment at the same clinic visit. Even relatively insensitive rapid tests could lead not only to more timely treatment, compared to highly sensitive but not rapid tests, but also to treatment of a higher percentage of infected patients, if a sufficiently high percentage of infected patients fail to return for the highly sensitive test results.

Finally, the marginal public health benefit of highly sensitive tests compared to less sensitive rapid tests or to syndromic diagnosis, depends in part upon the relative transmissibility and risk of complications of infections detectable by highly sensitive tests but not by less sensitive tests or syndromic diagnosis - issues that remain unanswered. To the extent infections detected only by the more sensitive tests involve quantitatively less shedding of the pathogen, lower infectivity is plausible, since inoculum size is a major determinant of the efficiency of transmission for most infections. The relative transmissibility of infections detected by the more sensitive tests in the absence of local inflammation remains largely undefined, although there is evidence that the quantity of shedding of gonococci [10] and of chlamydia [11] is less in patients with less urethral or cervical inflammation.

In summary, risk assessment and the detection of inflammation at the site of genital infection (as with infection of other organ systems) can be a useful guide not only for selective testing, but also for selective treatment. In the cervix, inflammation can be detected by inspection during speculum exam, by microscopic examination of endocervical exudate, or even simply by detection of markers of inflammation using a dipstick test [12]. In the hands of trained, experienced clinicians and laboratory technologists, local inflammation predicts infection with N. gonorrhoeae and C. trachomatis, and perhaps also with M. genitalium, and potentially with other curable infectious pathogens; and hypothetically may identify the subset of infections that are most transmissible. Clinical diagnosis can guide prompt syndromic therapy. Rapid diagnostic tests would offer the same potential advantage of prompting early rapid therapy, and could offer greater specificity than clinical diagnosis for the known infections being sought.

References:

1. Garcia P, Holmes KK. Training pharmacy workers in STD recognition, management, and prevention: A randomized controlled trial. Bull WHO 2003;81(11):806-814.

2. Wi T, Mesola V, Manalastas R, Tuazon C, Mugriditchian DS, Perine P, Ghee A, Holmes KK, Whittington WL. Syndromic approach to detection of gonococcal and chlamydial infections among female sex workers in two Philippine cities. Sex Trans Infect 1998;74(Suppl 1):S118-S122.

3. Ryan CA, Zidouh A, Manhart LE, Selka R, Xia M, Moloney-Kitts M, Mahjour J, Krone M, Courtois BN, Dallabetta G, Holmes KK. Reproductive tract infections in primary health care, family planning, dermatovenereology clinics: Evaluation of syndromic management in Morocco. Sex Transm Infect 1998;74(Suppl 1):S95-105.

4. Dalabetta G, Gerbase AC, Holmes KK. Problems, solutions, and challenges in syndromic management of sexually transmitted diseases. Sex Transm Infect 1998;74(Suppl 1):S1-11.

5. Ryan CA, Courtois BN, Hawes SE, Stevens CE, Eschenbach DA, Holmes KK. Risk assessment, symptoms and signs as predictors of vulvovaginal and cervical infections in an urban US STD clinic: Implications for use of STD algorithms. Sex Transm Infect 1998;74(Suppl 1):S59-76.

6. Manhart LE, Critchlow CW, Holmes KK, Dutro SM, Eschenbach DA, Stevens CE, Totten PA. Mucopurulent cervicitis and Mycoplasma genitalium. J Infect Dis 2003 Feb 15;187(4):650-7.

7. Ryan C, Holmes KK. Approach to STD case management. In: Holmes KK, Sparling PF, Mårdh P-A, Lemon SM, Stamm WE, Wasserheit JW, eds. Sexually Transmitted Diseases, 3rd ed. New York, McGraw-Hill Book Co., 1999.

8. Schwebke JR, Sadler R, Sitton JM, Hook EW 3rd. Positive screening tests for gonorrhea and chlamydial infection fail to lead consistently to treatment of patients attending a sexually transmitted disease clinic. Sex Transm Dis 1997;24:181-4.

9. Gift TL, Pate MS, Hook EW 3rd, Kassler WJ. The rapid test paradox: when fewer cases detected lead to more cases treated: a decision analysis of tests for Chlamydia trachomatis. Sex Transm Dis. 1999 Apr;26(4):232-40.

10. Whittington WL, Holmes KK. Unique gonococcal phenotype associated with asymptomatic infection in men and with erroneous diagnosis of nongonococcal urethritis. J Infect Dis. 2000; 181:1044-8.

11. Geisler WM, Suchland RJ, Whittington WL, Stamm WE. Quantitative culture of Chlamydia trachomatis: relationship of inclusion-forming units produced in culture to clinical manifestations and acute inflammation in urogenital disease. J Infect Dis. 2001 Nov 15;184(10):1350-4.

12. Knud-Hansen CR, Dallabetta GA, Reichart C, Pabst KM, Hook EW 3rd, Wasserheit JN. Surrogate methods to diagnose gonococcal and chlamydial cervicitis: comparison of leukocyte esterase dipstick, endocervical gram stain, and culture. Sex Transm Dis. 1991 Oct-Dec;18(4):211-6

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