MYCOPLASMA GENITALIUM WAS FIRST ISOLATED from the male urethra in 1981.1 Currently, this bacterium is considered one of the most common causes of nongonococcal urethritis.2–7 More recently, M. genitalium has been identified as a potential genitourinary tract pathogen in women. Specifically, M. genitalium has been associated with mucopurulent cervicitis, plasma cell endometritis, pelvic inflammatory disease (PID), and tubal factor infertility using either polymerase chain reaction analysis of genital specimens or serologic methods.8–13
Most evidence supports the sexual transmission of M. genitalium. 4–6,14–17 The highest prevalence of M. genitalium is found in high-risk sexual populations such as female sex workers and sexually transmitted disease clinic attendees.12,14,17,18 Nevertheless, to our knowledge, no published accounts have reported longitudinally collected data to determine risk factors for incident M. genitalium infection and the persistence of M. genitalium in the female genital tract.
In 2004, 4.9 million individuals were newly infected with HIV, 50% of whom were women with 25.4 million prevalent cases of HIV in sub-Saharan Africa alone.19 Several sexually transmitted infections (STIs) such as those caused by herpes simplex virus type 2, bacterial vaginosis, and Haemophilus ducreyi increase the risk of HIV transmission 2- to 10-fold.20,21 In prior studies, M. genitalium has been positively associated with HIV-infection and/or stage C3 AIDS10,17 and perhaps to transmission of HIV among HIV-discordant couples.22 Whether M. genitalium is a marker for high-risk sexual behavior, an opportunistic infection among HIV-infected individuals, or increases transmission of HIV cannot be elucidated from earlier cross-sectional investigations.
The objectives of the current study were to determine the incidence, risk factors, and persistence in the female genital tract for M. genitalium and to assess the role of HIV infection on the risk of acquiring M. genitalium in a high-risk population of female sex workers in Nairobi, Kenya.
A cohort of 299 female sex workers, 18 to 35 years of age, was recruited from May 2000 to study the epidemiology and immunobiology of STIs at the Kariobangi Nairobi City Council Clinic in Nairobi, Kenya.23 Women were counseled on the hazards of commercial sex and encouraged to seek alternate employment. They were also counseled on how to reduce harm and were provided free condoms and given treatment for bacterial STIs. After written informed consent was obtained, demographic and clinical history information was obtained, a general physical and pelvic examination was performed, and women were asked to return for evaluation of incident STI every 2 months. At the initial visit, cervical specimens were obtained for M. genitalium, Chlamydia trachomatis, and Neisseria gonorrhoeae molecular detection, and blood was collected for HIV and syphilis serologies and CD4 and CD8 T-lymphocyte enumeration. Endometrial biopsies were collected by use of an endometrial Pipelle (Unimar Inc., CT) at enrollment, approximately every 6 months for the first year of follow up and if clinically diagnosed with PID. At each follow-up visit, interval clinical and sexual histories and symptoms related to STI were ascertained. Women were examined for evidence of STIs, including molecular testing for M. genitalium, C. trachomatis, and N. gonorrhoeae. At 6-month intervals, blood for HIV and syphilis serology and CD4 T-cell lymphocyte counts were repeated. Women were asked to return to the study clinic within 4 days to receive the results of STI testing. Those found infected with C. trachomatis and N. gonorrhoeae received 100 mg doxycycline twice daily for 7 days or a single dose of 500 mg ciprofloxacin, respectively.
Cervical and endometrial samples were collected in a dry tube and 800 to 1,000 μL of 2SP buffer (0.2 mol/L sucrose in phosphate buffer, pH 7.5) was added and frozen at −20°C until testing for C. trachomatis and N. gonorrhoeae by polymerase chain reaction (PCR) (AMPLICOR; Roche Diagnostic Systems, Branchburg, NJ) in Kenya. Subsequently, the frozen specimens were shipped to Seattle and analyzed for M. genitalium using the MgPA-IMW PCR assay24 after purification of DNA using the MasterPure DNA Purification Kit (Epicentre, Madison, WI). All PCR assays were performed with an equivalent amount of preprocessed sample (12.5 μL). All positive specimens were repurified and reanalyzed by PCR to control for any possible tube mislabeling or PCR contamination. Only those positive in both assays were considered true-positives.
Serum was tested for HIV antibodies by enzyme-linked immunosorbent assay (ELISA) (Detect HIV; BioChem ImmunoSystems, Montreal, Canada) with positive results confirmed by a second ELISA (Recombigen; Cambridge Biotech, Ireland). CD4 cells from peripheral blood were enumerated using a FACSCAN (Becton-Dickinson, Baltimore, MD). Serologic testing for syphilis was performed using rapid plasma reagin (Becton-Dickinson) for screening and Treponema pallidum hemagglutination assay (TPHA, Biotech Laboratories, U.K.) for confirmation.
A modification of the strain typing method of Jensen et al25,26 was used to identify and differentiate M. genitalium strains identified in the cervical samples from 7 persistently infected women. After PCR amplification using primers MgPa-1 and MgPa-3 as described,25,26 PCR products were concentrated using the MinElute PCR Purification Kit (Qiagen, Valencia, CA), ligated into the pCR 2.1-Topo vector (Invitrogen, Carlsbad, CA) and then transformed into TOP10 competent Escherichia coli (Invitrogen). E. coli transformants with recombinant plasmids containing PCR products were selected on L-agar plates containing 100 μg/mL ampicillin and 40 μg/mL X-gal inoculated into L-broth with 100 μg/mL ampicillin and then incubated overnight at 37°C shaking. Three recombinant plasmids derived from each cervical sample were subsequently isolated using the QIAprep Spin Miniprep kit (Qiagen) and sequenced at the University of Washington Biochemistry DNA Sequencing Facility (http://depts.washington.edu/biowww/dna/) using the M13F or M13R primer provided in the Topo cloning kit (Invitrogen). The ClustalW program (http://www.ch.embnet.org/software/ClustalW.html) was used to align resulting sequences, which were then manually adjusted to correct for sequencing and/or alignment errors.
SAS for Windows 9.1 (SAS, Cary, NC) was used for analyses. Tests for associations with continuous measures included correlation coefficients and Mann-Whitney U tests. For categorical variables, χ2 tests were performed. Graphic examination aided in determining the form of each measure’s association with M. genitalium infection, e.g., linearly, quadratically, or through a step function. Survival analysis on recurrent events (of the same type) was performed to assess factors related to M. genitalium infection. Subjects were considered to be at risk for new infections from the time the previous infection cleared, defined as ≥1 negative M. genitalium PCR test. Some potential risk factors were measured only at baseline (e.g., duration of prostitution, marital status, and age at menarche), whereas others were repeated (e.g., condom use practices, STI, and STI symptoms). Therefore, Cox regression was performed using time-independent and time-dependent covariates; this allowed maximum opportunity to observe the effect of current risk factors on acquisition of M. genitalium.
Table 1 summarizes the sociodemographic, sexual history, and laboratory findings of the 299 women in the cohort at enrollment; cervical specimens were available for M. genitalium testing from 255 subjects at baseline and from an additional 44 women at other time points during study follow up. On average, the women were 23.9 ± 5.3 years old, had worked as sex workers 3.9 ± 3.2 years, and had on average 11.7 ± 7.6 partners per week. At enrollment, 40 of 255 (16%), 24 of 296 (8%), and 18 of 295 (6%) were infected with M. genitalium, C. trachomatis, and N. gonorrhoeae, respectively (Table 1). HIV infection was detected in 87 (30%) participants.
Correlates and Characteristics of Incident Mycoplasma genitalium Infection
Women infected with M. genitalium at the first evaluable visit were included in the computation of incidence if they were observed to be susceptible, i.e., had at least one intervening M. genitalium-negative visit at any time and contributed additional M. genitalium samples. Thus, a total of 244 women contributed data to calculate the incidence of M. genitalium infection and were included in the survival analysis presented in Table 1. Among the 244 women, 77 M. genitalium incident infections were detected during 339.9 woman-years giving an annual incidence of 22.7 per 100 women-years. Twelve (16%) of the 77 incident infections occurred in women infected at enrollment with a single intervening negative sample before a presumed new M. genitalium infection during follow up. Thus, if the negative M. genitalium PCR was the result of a false-negative result, the 12 presumed incident infections could represent persistent rather than new infections. The remaining 65 primary M. genitalium infections were used to calculate a more conservative estimate of incidence (19.1 per 100 woman-years). Because we think that the false-negative M. genitalium test result rate was exceedingly small, we used the total of 77 primary incident cases for the remaining analyses. The survival curve for incident M. genitalium infection with up to 33 months of follow up (Fig. 1) shows the percent infected and number of women available for analysis at each follow-up visit. One or more additional infections occurred during study follow up in 22 subjects for a total of 107 incident infections.
The incidence rate of 22.7 M. genitalium infections per 100 women-years was calculated by defining the time of infection as the midpoint between a woman’s last recorded negative and first recorded positive visits. Any missed visits occurring before the last recorded negative were assumed to be also negative for M. genitalium, an assumption that probably underestimates the true rate of infection. As a comparative approach, we repeated the calculations censoring individuals after they had missed a single follow-up visit. This method left 21 cases of M. genitalium with 72.5 women-years of observation yielding an annual incidence of 29.0%, which most likely overestimates the rate of new infections.
In the 46 subjects in which M. genitalium was detected in a cervical specimen and who had an endometrial biopsy collected at the same visit for M. genitalium PCR testing, 24 (52%) were also positive in the endometrium. No women were positive in endometrial and not in cervical specimens.
Persistence of Mycoplasma genitalium Infections
Fifty-six (52%), 18 (17%), 10 (9%), and 23 (21%) M. genitalium infections persisted for 1, 3, 5, and ≥7 months, respectively, based on positive M. genitalium PCR results over successive visits (Fig. 2). To determine if these persistently infected women were infected with the same strain throughout the successive visits, we used an established system of strain typing with high discriminatory index between strains.25,26 This system is based on single nucleotide polymorphisms that occur within the first 500 bases of mgpB, a region of this gene that is present in a single copy in the genome and thus is relatively well conserved. Among a convenience sample of 7 women apparently persistently infected with M. genitalium for 10 months or more (median, 14.4 months; minimum, 10.5 months; maximum, 21.1 months), 5 different strains were detected, all of which were clearly different from G-37, the type strain, and divergent in bases previously shown to vary between strains25,26 (Fig. 3). In contrast to the sequence diversity observed between samples from different women, the M. genitalium strain typing sequences were identical among samples taken from the same woman at different time points.
Risk Factors for Incident Mycoplasma genitalium
Table 1 demonstrates the univariate analyses of factors associated with incident M. genitalium infection. Both incident C. trachomatis (hazard ratio [HR] = 2.4; 95% confidence interval [CI] = 1.5–4.0) and N. gonorrhoeae (HR = 2.0; 95% CI = 1.2–3.5) were associated with an increased risk of M. genitalium. Women who were single had an increased risk of M. genitalium (HR = 1.7; 95% CI = 1.03–2.9), whereas those who were ≥25 years (HR = 0.4; 95% CI = 0.3–0.8), charged more than 150 Ksh (approximately $2 US) (HR = 0.6; 95% CI = 0.4–0.9), and used an antibiotic at the current visit (HR = 0.6; 95% CI = 0.4–0.99) had a reduced risk of M. genitalium (Table 1). HIV-infected women had a borderline increased risk of M. genitalium (HR = 1.7; 95% CI = 0.99–2.7). Signs and symptoms consistent with genital tract infection (e.g., cervicitis, cervical friability, abnormal vaginal discharge) did not correlate with M. genitalium infection (Table 2) nor with C. trachomatis infection (data not shown). Furthermore, bacterial vaginosis, T. vaginalis, and clinical PID were not associated with M. genitalium.
In Cox regression multivariate analysis, after controlling for factors associated with M. genitalium in univariate analyses, age ≥25 years (adjusted [A]HR = 0.36; 95% CI = 0.19–0.67), and longer residence in Nairobi (AHR = 0.97 per year; 95% CI = 0.94–0.99) correlated with decreased risk of M. genitalium. HIV-infected women had a 2.17-fold increased risk (95% CI = 1.17–3.71) of incident M. genitalium infection after adjustment for potential confounders (Table 2). However, degree of immunosuppression, as measured by CD4 count, was not associated with risk of M. genitalium.
Although condom use was not associated with incident M. genitalium infection, report of consistent condom use (≥75% of the time) relative to less consistent condom use at the enrollment visit correlated with a decreased odds of M. genitalium detection at baseline (9% vs. 20%, P <0.02). In part, this may be explained by the increased use of condoms reported over the course of the study from 41% at baseline to 67% at the time of incident M. genitalium infection or censoring.
Of the 107 new infections of M. genitalium, 104 (96%) were from women who were taking antibiotics at some point during follow up. Of the 2,158 visits with M. genitalium results and antibiotic data, and excluding infections prevalent at enrollment, 1,112 (52%) included the prescription of antibiotics. The proportion of visits M. genitalium-positive was similar for visits involving prescription of antibiotics (119 [11%] of 1,112 visits) and those in which no antibiotics were prescribed (124 [11%] of 1,043 visits). Furthermore, the use of specific antibiotics, including doxycycline, erythromycin, and metronidazole alone and ciprofloxacin, doxycycline, and metronidazole used in combination to treat clinical PID either at the current or prior visit was not associated with the proportion of visits positive for M. genitalium (data not shown).
This study is one of the first to explore the incidence, risk factors, and persistence of M. genitalium in women. M. genitalium had a greater incidence (22.7 per 100 women-years) than that for both C. trachomatis (14%) and N. gonorrhoeae (8%) was associated with common STI risk factors such as concurrent STI and younger age, persisted for ≥7 months in 19% of subjects, was detected in specimens collected from the endometrium and was positively correlated with HIV infection. Furthermore, M. genitalium was associated with persistent infection (≥3 months in approximately 50% of women) despite the high prevalence of antibiotic use among this study population.
Several investigations have found a high prevalence of M. genitalium in high-risk female populations.5,9,12,18 The design of our investigation enabled us to prospectively assess the association of potential risk factors with the incidence of M. genitalium. In a prior cross-sectional study, common risk factors for STIs among sex workers, for example, lower average charge per sex act, single marital status, and coinfection with other STIs was associated with prevalent M. genitalium infection.12,18 In multivariate analysis in the current study, older women whether resulting from altered levels of exposure, higher levels of innate resistance, acquisition of immunity, or all 3 were at decreased risk of M. genitalium infection. Similar findings have been demonstrated for C. trachomatis in which recently acquired immunity correlated with protection against subsequent infection.23
Unlike prior cross-sectional investigations of women,11,12,14,18M. genitalium infection was not associated with common STI signs and symptoms. However, this finding was not surprising because M. genitalium has been previously detected in asymptomatic high-risk women.15 In addition, even in women with symptomatic disease, this organism appears to cause mild symptoms and signs and low levels of inflammation9 and, similar to C. trachomatis, was not associated with STI signs and symptoms in the same cohort. Alternatively, the lack of an association with cervicitis and M. genitalium may in part be the result of the different diagnostic measures used in our investigation in comparison to others. For example, to diagnosis cervicitis, we relied on clinical criteria that included cervical erythema and mucopurulent discharge and did not perform a cervical Gram stain as others have done to show the association between C. trachomatis and M. genitalium with cervicitis.11,27 Even among studies relying on cervical Gram stain to assess association with other STI pathogens, various criteria have been used making the comparison across studies difficult.27 Nevertheless, the lack of an association among cervicitis, vaginal discharge, and PID in the current study does not rule out that M. genitalium can cause these syndromes and their sequelae. For example, 70% to 75% of C. trachomatis genital tract infections in women are asymptomatic and yet C. trachomatis is accepted as a major known cause of these clinical syndromes, including tubal factor infertility.28
One of the most interesting findings of our study was the greater than 2-fold increased risk of M. genitalium infection among subjects who were HIV-infected even after controlling for other risk factors. Although prior investigations have found a correlation between HIV and M. genitalium, they were unable to ascertain the temporality of the association as a result of the cross-sectional nature of the investigations.17,23 Our study suggests that HIV may reduce resistance to M. genitalium infection or that HIV-infected women have certain behavioral risk characteristics, which increase their risk of M. genitalium infection, factors that we attempted to control for in multivariate analysis. On the other hand, it is known that HIV, independent of the degree of immunosuppression, causes T-cell and other immune cell dysfunction, which could alter immunity and susceptibility to M. genitalium infection.29
Several investigators have reported M. genitalium to be more commonly detected both serologically and directly in persons with AIDS when compared with asymptomatic HIV-infected persons.29,30 It is possible that M. genitalium might opportunistically infect immunocompromised individuals, or equally plausible, that it might colonize persons with AIDS as a result of their high consumption of broad-spectrum antibiotics to which M. genitalium may be resistant. In our investigation, 96% of the women who had an episode of M. genitalium infection took antibiotics at some point during the study, some of which were broad spectrum, although ever and recent use of antibiotics during follow up was not associated with an altered risk of M. genitalium infection.
Persistence of M. genitalium infection was commonly detected in our cohort with 48% of infections lasting ≥3 months. Of course reinfection of this highly exposed cohort in which antibiotic use was common rather than persistence might account for our findings. Therefore, to further assess whether these women were persistently infected or infected with another M. genitalium strain, we performed molecular strain typing analysis25 on cervical specimens from 7 women persistently infected with this organism for up to 21 months. In this analysis, all specimens tested both early and late during infection from the same woman contained M. genitalium of the same strain type consistent with persistent infection with a single organism. Although specific treatment for M. genitalium was not provided, one might have expected that natural immunity would make persistence a less common event. One explanation for this persistence might be that variations of the antigenic MgPa protein encoded by the mgpB gene may occur, which lead to immune evasion.31,32 Although reinfection with the same strain cannot be ruled out, these results are consistent with persistent infection of these women with the same M. genitalium strain as opposed to reinfection with another strain during follow up. These observations support M. genitalium’s ability to establish chronic, long-term infection in the genital tract of women the clinical significance of which requires further exploration.
The high incidence of M. genitalium infection along with its association with HIV raises important concerns about the importance of M. genitalium as a significant STI. Growing evidence suggests that M. genitalium causes genital tract disease in both women and men, ascends in to the endometrium, and that it is commonly sexually transmitted.5,6,9–12 Future studies should further explore the association between M. genitalium and HIV infection, factors related to the persistence of M. genitalium infection, and factors associated with upper tract infection and sequelae. Such investigations should help elucidate factors associated with immunity against M. genitalium infection and depending on these findings lead to vaccine development. Furthermore, in light of these and other data, routine screening and treatment of high-risk populations should be considered.
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