Lower genital tract infection in women
The prime target of chlamydial infection in the lower genital tract of women is the columnar epithelial cells lining the endocervical canal [lay reader: the neck of the womb]. Cervicitis is inflammation of the cervix and it may be caused by one or more pathogens. The classic signs of cervicitis include: pain in passing urine, frequency, soreness, and a cervical discharge which, on Gram staining and microscopy, shows the presence of ten or more polymorphonuclear leukocytes per high-power field. The colour and opacity of this exudate is also important [Sellors et al., 2000]. The cervix itself may be swollen [edematous] and reddened [erythematous], and may bleed easily when a sample is collected with a swab. Occasionally trachoma grading, analogous to those of trachoma, may be observed on the cervix. However as the underlying appearance of the cervix varies substantially with the menstrual cycle, type of oral contraception or pregnancy it is unwise to believe that chlamydial cervicitis can be recognized reliably from symptoms alone. Moreover, many patients are asymptomatic, attending clinics as the partners of men with urethritis [Hare & Thin, 1983].
Many cases of mucopurulent cervicitis are idiopathic [of no identified cause]. A study of archival mucopurulent cervical specimens in Seattle found Mycoplasma genitalium in 50 (7%) of 719 women. Young age, multiple recent partners, prior miscarriage, smoking, menstrual cycle, and douching were positively associated with M. genitalium infection, whereas bacterial vaginosis and cunnilingus were negatively associated. After adjustment for age, phase of menstrual cycle, and presence of known cervical pathogens, it was found that women with M. genitalium infection had a 3.3-fold greater risk of mucopurulent cervicitis, which suggests that this organism may also be a cause of cervicitis Manhart et al., 2003. [For a review of M. genitalium infection, see Taylor-Robinson, 2002]. Nevertheless the two most regularly identified causes of cervicitis are gonococci [gonorrhoea] and Chlamydia trachomatis. Gonococci and chlamydia are of particular importance as being likely to give rise to PID and its complications [Comment: The possible complications of M. genitalium infection in women are not well defined but it is associated serologically with salpingitis and with tubal factor infertility.].
Serovars of C. trachomatis causing urogenital disease
Chlamydial cervicitis is caused by C. trachomatis organisms of serovars D to K. Serovar E is particularly common. A study typing the infecting Chlamydiae among female sex workers in Senegal found that serovar E caused 46% of the infections and was less associated with visible signs of cervical inflammation than other serovars. It was suggested that the high rate of asymptomatic infection by serovar E conferred a transmission advantage in this high risk population [Sturm-Ramirez et al., 2000].
The possible relationship of recurrent chlamydial cervicitis to the infecting serovar in women was examined by Dean et al., 2000. The usual assumption is that recurrence of infection with a new chlamydial serovar indicates reinfection, whereas same-serovar recurrences may be due to persisting infection. A study of 552 women with more than three recurrent infections over 2 years found that 24% had same-serovar recurrences of which 45% were the less common subgroup C serovars; this was significant [statisticians: OR 2.4; 95% CI 1.7-3.5; P<.0001]. Further study indicated that cervical infections with C subgroup serovars particularly, may be persistent for years, perhaps because these organisms are able to adapt especially flexibly to immune pressure from the host [Dean et al., 2000].
Suchland et al., 2003 described a longitudinal study of the prevalence of C. trachomatis serovars over the period 1988 - 1996 in 7110 female and 4344 male health clinic patients in the Seattle region. Serovar E was the most prevalent (32%), followed by F (18%) and D (13%). Being female, African American, and infected with serovar B was associated with young age (P < 0.001, P < 0.001, and P = 0.09, respectively). C subgroup serovars were found in older patients (P < 0.001). From 1988 - 1996, the percentage of infections with serovars F and G increased (P = 0.007, P = 0.009), while those with I and K decreased (P < 0.001, P = 0.008), and B, D, D-, E, H, Ia, and J remained stable. The age of those with positive C. trachomatis cultures decreased over the period (P < 0.001). It was concluded that in this population, the major serovars were relatively stable but significant changes in the distribution of minor serovars, especially G, were observed over time [Suchland et al., 2003].
The same group also examined the relationship of serovar to the clinical presentation of chlamydial urogenital disease in a cross sectional study of 480 women and 700 heterosexual men [Geisler et al., 2003]. Allowing for the fact that 89% of women and 86% of men were infected predominately with serovars D, E, F, Ia, or J, it was found that, after controlling for age and race, women who reported abdominal pain and/or dyspareunia were more often infected with serovar F (P= 0.048).d No association of specific clinical manifestations with serovars was detected in men. Overall it was concluded that the clinical manifestations of urogenital infection are not strongly influenced by the infecting serovar. However there is a positive relationship between the number of chlamydiae present in the genital tract and the presence of mucopus, the character of the discharge and the likelihood of a diagnosis of pelvic inflammatory disease [Geisler et al., 2001].
It is also important to distinguish between gonococcal and chlamydial infection as they require different antibiotic therapy. Unfortunately, the diagnosis of chlamydial cervicitis can only reliably be made using diagnostic kits [see: labtests Diagnostics Intro]. Although excellent diagnostic kits for chlamydial infection are available, for financial reasons, they are often not available locally, even in developed countries.
In resource poor areas of the world there is usually no option but to manage and treat lower genital tract infections on the basis of clinical signs alone [syndromic treatment]. When compared against proper laboratory testing this has generally been found to be unsatisfactory for chlamydial genital tract infections [Chandeying et al., 1996; Sellors et al., 1998], partly because a high proportion of chlamydial genital tract infections are symptomless, and partly because of confounding by other infections. In one study presumptive diagnosis of chlamydial cervicitis based on mucopurulent endocervical discharge and 10 or more polymorphs per high-power microscope field had a sensitivity of 18.9% and a positive predictive value of only 29.2% [Sellors et al., 1998]. In a large Seattle-based study, the positive predictive value of inflammation as detected by endocervical Gram stain was too low to be used for directing treatment in the absence of mucopurulent cervicitis [Marrazzo et al., 2002]. Statistically, mucopurulent cervicitis is nevertheless a marker for endometritis, salpingitis, and adverse pregnancy outcomes [Nyirjesy, 2001]. In developing countries, where the prevalence of lower genital tract chlamydial infection in sexually active women may be of the order of 26% [Tiwara et al., 1996] the challenge is to develop cheap and reliable diagnostic tests for chlamydial infection.
Various algorithms have been produced to help the clinician identify risk factors and markers for sexually transmitted disease in order to inform control programs [Morrison et al., 1999]. In one important study, urine samples from 13,204 new female U.S. Army recruits were screened for C. trachomatis infection by a sensitive nucleic acid based test [LCR]. The overall prevalence of chlamydial infection in this population was high at 9.2%. Risk factors independently associated with chlamydial infection included: having ever had vaginal sex [Odds ratio OR= 5.9], being less or equal to 25 years old [OR 3.0], more than one sex partner in the previous 90 days [OR 1.4]; a new partner in the previous 90 days [OR 1.3] having had a partner in the previous 90 days who did not always use condoms [OR 1.4], and having ever had a sexually transmitted disease [OR 1.2] [Gaydos et al., 1998]. Vaginal douching is also a significant risk factor [OR 2.29] for chlamydial genital tract infection [see: Genital tract prevention]. Distinguishing those with upper genital tract involvement [endometritis] from those with lower genital tract infection only is difficult unless an endometrial biopsy is performed [see: Genital tract PID]. One study reported that women with upper genital tract involvement tend to be older and were 7.1 times [95% CI = 2.2-23.0] more likely to report abdominal pain than women with a lower genital tract infection alone [Nelson et al., 1998; see also PID complications].
The US recommended treatment options for chlamydial cervicitis are as follows [CDC STI Guidelines 2002]:
The IUSTI additionally include, as alternative regimens:* *
labtests Treatment Macrolides 1 gram orally in a single dose
Doxycyclin 100 mg twice a day for 7 days.
Erythromycin base 500 mg orally four times a day for 7 days,
Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days,
Ofloxacin 300 mg orally twice a day for 7 days
Levofloxacin 500 mg orally for 7 days.
labtests Treatment Macrolides 150mg orally twice a day for 7 days* *
labtests Treatment Macrolides 250mg orally twice a day for 7 days.
A metanalysis of 12 published clinical trials of azithromycin (1 gram once) versus doxycycline (100 mg twice daily for 7 days) for the treatment of genital tract infections found no statistical difference on cure rates or adverse reactions between the two drugs [Lau & Qureshi, 2002]. Doxycycline is cheaper, but azithromycin has a clear advantage where patient compliance is an issue, as it can be given as a supervised single dose. Both are likely to treat M. genitalium infection.
Erythromycin was considered less efficacious than either azithromycin or doxycycline. Moreover gastrointestinal side effects frequently dissuade patients from complying with this regimen. Ofloxacin was considered similar in efficacy to doxycycline and azithromycin, but is more expensive to use and offers no advantage with regard to dosage. Levofloxacin has not been fully evaluated, but the guidelines considered that, from its pharmacology and anti chlamydial activity in vitro it was a reasonable alternative choice. Other quinolones were either ineffective or had not been sufficiently evaluated. The first dose of antibiotic should preferably be given under supervision in the clinic and patients should be asked to abstain from sexual intercourse for 7 days after single-dose therapy or until completion of a 7 day course, whichever is appropriate. Sexual partners should also be treated to prevent reinfection. Tests for microbiological cure are not normally necessary unless symptoms persist unexpectedly [CDC STI Guidelines 2002]. Moreover the detection of chlamydial antigen or nucleic acid by sensitive diagnostic tests following a course of treatment does not necessarily indicate continuing presence of viable Chlamydiae, as it takes two to three weeks for dead organisms to be eliminated. In a large Seattle-based study, empirical treatment for chlamydial infection based on mucopurulent cervicitis was probably not indicated in women aged 25 years or older [Marrazzo et al., 2002].
[MEW] September 2003
NEXT: Cervical Cancer
CDC STI Treatment guidelines, May 2002 CDC Atlanta [For clinicians] * *
Chandeying, V., Skov, S., Kemapunmanus, M., Law, M., Geater, A. & Rowe P. (1998). Evaluation of two clinical protocols for the management of women with vaginal discharge in southern Thailand. Sexually Transmitted Infections 74, 194 - 201.
Dean, D., Suchland, R. J., Stamm, W. E. (2000). Evidence for long-term cervical persistence of Chlamydia trachomatis by omp1 genotyping. Journal of Infectious Diseases 182, 909 - 916.
Gaydos, C. A., Howell, M. R., Pare, B., Clark, K. L., Ellis, D. A., Hendrix, R. M., Gaydos, J. C., McKee, K. T. Jr. & Quinn, T. C. (1998). Chlamydia trachomatis infections in female military recruits. New England Journal of Medicine 339, 739 - 744.
Geisler, W. M., Suchland, R. J., Whittington, W. L. & Stamm, W. E. (2001). Quantitative culture of Chlamydia trachomatis: relationship of inclusion-forming units produced in culture to clinical manifestations and acute inflammation in urogenital disease. Journal of Infectious Diseases 184, 1350 - 1354.
Geisler, W. M., Suchland, R. J., Whittington, W. L. & Stamm, W. E. (2003). The relationship of serovar to clinical manifestations of urogenital Chlamydia trachomatis infection. Sexually Transmitted Diseases 30, 160 - 165.
Hare M. J. & Thin, R. N. (1983). Chlamydial infection of the lower genital tract of women. British Medical Bulletin 39, 138 - 144.
Jones, B. R., Collier, L. H. & Smith, C. H. (1959). Isolation of virus from inclusion blenorrhoea. Lancet i, 902 - 905.
Lau, C. Y. & Qureshi, A. K. (2002). Azithromycin versus doxycycline for genital chlamydial infections: a meta-analysis of randomized clinical trials. Sexually Transmitted Diseases 29, 497 - 502.
Manhart, L. E., Critchlow, C. W., Holmes, K. K., Dutro, S. M., Eschenbach, D. A., Stevens, C. E. & Totten, P. A. (2003). Mucopurulent cervicitis and Mycoplasma genitalium. Journal of infectious diseases 187, 650 - 657.
Marrazzo, J. M,, Handsfield, H. H. & Whittington, W. L. (2002). Predicting chlamydial and gonococcal cervical infection: implications for management of cervicitis. Obstetrics and Gynecology 100, 579 - 584.
Morrison, C. S., Sekadde-Kigondu, C., Miller, W. C., Weiner, D. H. & Sinei, S. K. (1999). Use of sexually transmitted disease risk assessment algorithms for selection of intrauterine device candidates. Contraception. 59, 97 - 106.
Nelson, D. B., Ness, R. B., Peipert, J. F., Soper, D. E., Amortegui, A. J., Gluck, J., Wiesenfeld, H. & Rice, P. A. (1998). Factors predicting upper genital tract inflammation among women with lower genital tract infection. Journal of Women's Health 7, 1033 - 1040.
Nyirjesy P. (2001). Nongonococcal and Nonchlamydial Cervicitis. Current Infectious Disease Reports 3, 540 - 545.
Scholes, D., Stergachis, A., Ichikawa, L. E., Heidrich, F. E., Holmes, K. K. & Stamm WE. (1998). Vaginal douching as a risk factor for cervical Chlamydia trachomatis infection. Obstetrics and Gynecology 91, 993 - 997.
Sellors, J. W., Walter, S. D. & Howard M. (2000). A new visual indicator of chlamydial cervicitis? Sexually Transmitted Infections 76, 46-8.
Sellors J, Howard M, Pickard L, Jang D, Mahony J, Chernesky M. (1998). Chlamydial cervicitis: testing the practice guidelines for presumptive diagnosis. Canadian Medical Association Journal 158, 41 - 46.
Sturm-Ramirez, K., Brumblay, H., Diop, K., Gueye-Ndiaye, A., Sankale, J. L., Thior, I., N'Doye, I., Hsieh, C. C., Mboup, S. & Kanki, P. J. (2000). Molecular epidemiology of genital Chlamydia trachomatis infection in high-risk women in Senegal, West Africa. Journal of Clinical Microbiology 38, 138 - 145. Full article
Suchland, R. J., Eckert, L. O., Hawes, S. E. & Stamm, W. E. (2003). Longitudinal Assessment of Infecting Serovars of Chlamydia trachomatis in Seattle Public Health Clinics: 1988-1996. Sexually Transmissible Diseases *30, 357-361.
Taylor-Robinson, D. (2002). Mycoplasma genitalium - an update. International Journal of STD and AIDS 13, 145 - 151. [A useful review by the discoverer of this organism].
Tiwara, S., Passey, M., Clegg, A., Mgone, C., Lupiwa, S., Suve, N. & Lupiwa, T. (1996). High prevalence of trichomonal vaginitis and chlamydial cervicitis among a rural population in the highlands of Papua New Guinea. Papua New Guinea Medical Journal 39, 234 - 238.