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Women with pelvic inflammatory disease (PID) often present with a spectrum of symptoms. The characteristics of nongonococcal, nonchlamydial PID have not been well described. Our objective was to examine the characteristics of Mycoplasma genitalium infection among women with clinically suspected PID.
We evaluated 722 women who were enrolled in the PID Evaluation and Clinical Health study. Women with M. genitalium monoinfection were compared with women with Neisseria gonorrhoeae monoinfection or Chlamydia trachomatis monoinfection.
Compared with women with gonococcal PID, women with M. genitalium infection were less likely to have elevated systemic inflammatory markers, including an erythrocyte sedimentation rate >15 mm/h (5 [22.7%] of 22 patients vs. 45 [60.8%] of 74 patients; P = .002), a white blood cell count >10,000 cells/mL (4 [28.6%] of 14 patients vs. 42 [64.6%] of 65 patients; P = .018), and an oral temperature ≥38.3°C (0 [0.0%] of 22 patients vs. 10 [13.9%] of 72 patients; P = .085). In addition, they were less likely to present with mucopurulent cervicitis (9 [47.4%] of 19 patients vs. 60 [83.3%] of 72 patients; P = .001), elevated vaginal pH (P = .018), and high pelvic pain score (P = .014). In contrast, women with chlamydial PID had signs and symptoms that were similar to those in women with M. genitalium infection.
Because symptoms might be mild, women with M. genitalium infection might not seek PID treatment. Further studies are needed to assess the potential reproductive tract sequelae of M. genitalium infection of the upper genital tract.
Pelvic inflammatory disease (PID), which is an inflammation of the female upper genital tract that is caused by the ascension of organisms from the lower genital tract, affects ~8% of reproductive-age women in the United States at some time in their lives . Serious sequelae, including recurrent PID, tubal factor infertility, ectopic pregnancy, and chronic pelvic pain, are common sequelae of PID . The sexually transmitted pathogens Chlamydia trachomatis and Neisseria gonorrhoeae cause 30%–50% of PID cases [3-5]. Although the etiology of PID is unknown in the majority of cases, it has been epidemiologically linked to bacterial vaginosis .
Mycoplasma genitalium has been identified as a possible etiologic agent of nongonococcal, nonchlamydial PID [7-9]. It has also been detected in cervical and salpingeal samples obtained from women with laparoscopically confirmed salpingitis  and in cervical and endometrial specimens obtained from women with endometritis . Because M. genitalium is extremely difficult to culture, epidemiologic studies that assess the role of this organism in reproductive diseases among women are dependent on the development and application of PCR-based assays. Although little is known about the clinical characteristics of M. genitalium PID, evidence suggests that, as is the case in women with chlamydia, lower genital tract infections tend to be asymptomatic [11, 12].
At presentation, the characteristics of women with PID vary, and they may include pelvic pain, abnormal vaginal discharge, bleeding, itching, and/or odor. Although the most common symptom of PID is pelvic pain, many women with PID may have mild pain or no pain, despite evidence of infection and inflammation [13, 14]. The presence and severity of PID symptoms vary by microbiologic etiology, with women who have chlamydial PID being more likely than women who have gonococcal PID to be asymptomatic [15-18].
The purpose of our study was to describe the clinical features of women with lower and/or upper genital tract infection due to M. genitalium in a population of women who presented with clinically suspected PID. We hypothesized that clinical characteristics, symptoms, and pelvic pain at presentation would be less frequent and less severe among women with M. genitalium or C. trachomatis infection than they would be among women with gonococcal PID.
We used data from the baseline interview of the PID Evaluation and Clinical Health (PEACH) study, which is described in detail elsewhere . In brief, the PEACH study evaluated the effectiveness of inpatient versus outpatient treatment of PID in preventing infertility. From March 1996 through February 1999, nonpregnant women 14–36 years of age were recruited from emergency departments and outpatient facilities (obstetrics and gynecology clinics, sexually transmitted disease clinics, and private practices) from 7 primary sites (Atlanta, GA; Birmingham, AL; Charleston, SC; Detroit, MI; Philadelphia, PA; Pittsburgh, PA; and Providence, RI) and 6 secondary sites in the United States. Women were eligible to participate if they had clinically suspected PID, as defined by the following characteristics: (1) complaints of acute pain (<30 days in duration); (2) a clinical finding of pelvic tenderness; and (3) evidence of lower genital tract inflammation. Women were excluded from the study if they had severe disease that required inpatient management; could not tolerate an outpatient regimen because of vomiting; had an allergy to antibiotics; experienced a delivery, abortion, or gynecologic surgical procedure within the previous 45 days; had a previous hysterectomy, bilateral salpingectomy, or bilateral tubal ligation; had a tuboovarian abscess documented by ultrasound or laparoscope; and/or had appendicitis, hemorrhagic ovarian cyst, or another condition requiring surgery documented by ultrasound or laparoscopy. Informed consent was obtained from eligible women, and 831 participants were enrolled into the PEACH study. Institutional review board approval was obtained for the parent PEACH study, as well as for subsequent PCR testing of stored specimens for M. genitalium. For this analysis, stored cervical and endometrial specimens and M. genitalium PCR assay results were available for a subset of 722 women. The demographic, behavioral, and clinical characteristics of the 111 women who did not have M. genitalium PCR assays performed did not differ significantly from those of the women who were included in our analyses.
Baseline data were collected by trained research staff at each study center using standardized interview, examination, and specimen collection techniques. Information was collected on demographic characteristics; medical, gynecologic, and sexual histories; presenting complaints; substance use; current medications; and contraception. Cervical and vaginal swab samples, endometrial biopsy samples, and serum and urine samples were obtained from the participants.
Previously collected cervical and endometrial samples that had been stored at −70°C were tested for M. genitalium with use of the MgPa-IMW PCR assay targeting the MgPa gene . This assay has an analytical sensitivity of 15 genomes  and a high clinical sensitivity and specificity relative to transcription-mediated amplification, another M. genitalium nucleic acid amplification assay . For all samples with positive test results, a second MgPa PCR assay  was performed using another aliquot of the sample to rule out PCR product contamination or cross contamination; all of the samples with initial positive test results were verified to be M. genitalium positive by this confirmatory test.
Baseline cervical and endometrial samples were assessed at a central laboratory for N. gonorrhoeae by culture and for C. trachomatis by PCR, as described elsewhere .
The following baseline signs and symptoms were evaluated as potential characteristics of M. genitalium infection: elevated oral temperature (≥38.3°C), elevated WBC count (>10,000 cells/mL), elevated erythrocyte sedimentation rate (>15 mm/h), elevated C-reactive protein level (≥5 mg/dL), bilateral adnexal tenderness, mucopurulent cervicitis, and bacterial vaginosis (BV), defined using Gram stain  and Amsel's criteria . Mucopurulent cervicitis was defined as the presence of a grossly yellow or green exudate observed on a swab specimen obtained from the cervix. Symptoms at presentation that were evaluated as potential characteristics of M. genitalium infection included the following: nausea or vomiting, nonmenstrual vaginal bleeding or spotting, more-prolonged or heavier menstrual bleeding than usual, vaginal bleeding during or after sex, abnormal vaginal discharge, increased frequency of urination, and overall self-rated pelvic pain. A pelvic pain score was calculated as the mean of scores for pain at worst, on average, and within the previous 24 h, measured on a Likert scale and multiplied by 10 (range, 0–100).
The χ2 test, Fisher's exact test, and analysis of variance were used to evaluate baseline characteristics and symptoms at presentation. Women with M. genitalium identified in the cervix and/or endometrium who had test results that were negative for both N. gonorrhoeae and C. trachomatis were compared with women who had test results that were positive only for N. gonorrhoeae in the cervix and/or endometrium and with women who had test results that were positive only for C. trachomatis in the cervix and/or endometrium. Women who had test results that were positive only for N. gonorrhoeae were also compared with women with M. genitalium and N. gonorrhoeae coinfection. Similarly, women with test results that were positive only for C. trachomatis were compared with women with M. genitalium and C. trachomatis coinfection. We also examined the differences between women with gonococcal PID and women with chlamydial PID. All data were analyzed using SAS, version 9.1 (SAS). P values <.05 were considered to be statistically significant.
Compared with women with gonococcal PID, women with M. genitalium infection were generally less likely to have elevated systemic inflammatory markers, including erythrocyte sedimentation rates >15 mm/h (5 [22.7%] of 22 patients vs. 45 [60.8%] of 74 patients; P = .002), WBC counts >10,000 cells/mL (4 [28.6%] of 14 patients vs. 42 [64.6%] of 65 patients; P = .018), and oral temperatures ≥38.3°C (0 [0.0%] of 22 patients vs. 10 [13.9%] of 72 patients; P = .085) (table 1). Women with M. genitalium infection were also significantly less likely to present with mucopurulent cervicitis (9 [47.4%] of 19 patients vs. 60 [83.3%] of 72 patients; P = .001). In addition, they had significantly lower mean composite pain scores at baseline (P = .014). The clinical characteristics of women with test results positive for only N. gonorrhoeae did not differ from those of women with test results positive for N. gonorrhoeae and M. genitalium. After adjustment for BV status (normal or intermediate vs. BV flora), all results remained the same (data not shown).
In contrast with women with N. gonorrhoeae infection, women who had test results that were positive only for M. genitalium had clinical features that were similar to those of women who had test results that were positive only for C. trachomatis. The clinical characteristics of women who had test results that were positive only for C. trachomatis did not differ from those of women who had test results that were positive for both C. trachomatis and M. genitalium (table 2). The results remained the same after adjustment for BV (data not shown).
Compared with women with gonococcal PID, women with PID due to C. trachomatis were generally less symptomatic and less likely to have elevated systemic inflammatory markers, including elevated oral temperature (0 [0%] of 45 patients vs. 10 [13.9%] of 72 patients; P = .013) or elevated WBC count (9 [22.5%] of 40 patients vs. 42 [64.6%] of 65 patients; P < .001). They were less likely to present with cervicitis (22 [52.4%] of 42 patients vs. 60 [83.3%] of 72 patients; P < .001) or bilateral adnexal tenderness (35 [77.8%] of 45 patients vs. 61 [82.4%] of 74 patients; P = .049) and had statistically significantly lower mean composite pain scores (P = .020).
To our knowledge, this is the first study to compare the clinical characteristics of women with clinically suspected PID who had genital tract infection due to M. genitalium, N. gonorrhoeae, and/or C. trachomatis. Our study suggests that, as in chlamydial PID, upper genital tract infection due to M. genitalium is less symptomatic than gonococcal PID. However, it should be noted that all women in the PEACH study had clinically suspected PID; therefore, they all presented with some signs or symptoms. Because the inclusion criteria minimized the selection of asymptomatic patients, differences in the clinical characteristics between women with and women without M. genitalium infection may be minimized. It would be important to repeat these analyses in a population that includes women with symptomatic PID and women with subclinical or “silent” PID.
Mucopurulent cervicitis and numerous systemic markers of inflammation, including an elevated oral temperature, elevated WBC count, and elevated erythrocyte sedimentation rate, were more prevalent in women with N. gonorrhoeae infection than in women with only M. genitalium infection. In addition, pelvic pain scores were higher among women with N. gonorrhoeae infection. Women with only N. gonorrhoeae infection had clinical features that were similar to those of women with test results that were positive for both N. gonorrhoeae and M. genitalium. This suggests that, in patients with coinfection, the clinical signs and symptoms of N. gonorrhoeae infection dominate.
The clinical features of women who present with upper genital tract M. genitalium infection have not been extensively examined. In a study involving 115 women with histologically confirmed endometritis, 100% of women with M. genitalium infection reported mild abdominal pain, compared with 68% of women without M. genitalium infection (P = .06) . The association of M. genitalium with diseases of the lower genital tract in women has not been consistently reported, which possibly reflects differences in the population studied and criteria used to assess signs and symptoms at this site. Although some studies have shown an association between M. genitalium and cervicitis [9, 25-27], several PCR studies have failed to find a strong association between symptoms and M. genitalium lower genital tract infection [11, 28, 29]. Tosh et al.  conducted a study involving 383 adolescent females who attended a primary care clinic, and they found that women with M. genitalium identified in the lower genital tract were no more symptomatic than were uninfected women. In a group of women with test results that were negative for both C. trachomatis and N. gonorrhoeae, those who had test results that were positive for M. genitalium were not more likely to have signs (i.e., presence of vaginal erythema, vulvar erythema, or vaginal discharge; P = .33) or symptoms (i.e., vaginal itching, vaginal burning, and dyspareunia; P = .35) than were women with test results that were negative for M. genitalium . Manhart et al.  also found that lower genital tract M. genitalium infection was not associated with symptoms. PCR was used to test urine samples obtained from 1714 women who were enrolled in a population-based study, and M. genitalium infections were not associated with symptoms, because none of the participants who had test results that were positive for M. genitalium reported experiencing symptoms of vaginal discharge. Conversely, vaginal discharge was more common among women with lower genital tract M. genitalium infection than it was among women without M. genitalium infection in a study involving 390 minority women with an active sexually transmitted infection who attended a public health clinic . The results were similar after controlling for coinfection with other sexually transmitted diseases. However, vaginal discharge was the only genitourinary sign or symptom that was statistically significantly different between women with positive test results and women who were not infected. Casin et al.  found no association between the identification of M. genitalium in the lower genital tract and urinary symptoms (OR, 1.34; 95% CI, 0.72–2.50) or pelvic pain (OR, 0.93; 95% CI, 0.50–1.73) among women attending a sexually transmitted disease clinic. These PCR studies indicate that M. genitalium does not produce stronger symptoms in women with lower genital tract infections, compared with symptoms in women without M. genitalium infection. The limited symptoms induced by M. genitalium infection are similar to those seen in C. trachomatis infection .
Our study is unique, in that we compared the clinical characteristics of lower and/or upper genital tract M. genitalium infection with infections caused by other known bacterial sexually transmitted diseases. In our study, although women with M. genitalium infection tended to be less symptomatic than women with gonococcal PID, their symptoms were similar to those of women with chlamydial PID. There were no statistically significant differences between women with M. genitalium infection and women with C. trachomatis infection with respect to demographic or clinical characteristics. Although no other study has, to our knowledge, compared the clinical characteristics of women with clinically suspected PID, our results are similar to those of a study  conducted among 465 women either attending a sexually transmitted disease clinic or enrolled in a cervical cancer screening program in Sweden that compared the symptoms of C. trachomatis infection with those of M. genitalium infection of the lower genital tract. In that study , no statistically significant differences between women with test results positive for C. trachomatis and those with test results positive for M. genitalium in the lower genital tract were reported with respect to the presence of symptoms (32% vs. 23%; relative risk, 1.4; 95% CI, 0.6–3.4) or signs (71% vs. 50%; relative risk, 1.4; 95% CI, 0.9–2.3).
Although women with M. genitalium infection present with fewer clinical signs and symptoms than do women with N. gonorrhoeae infection, there is evidence from animal and human studies that supports a pathogenic role of M. genitalium in female upper genital tract infection. M. genitalium has been found to induce salpingitis in experiments involving monkeys , and it adheres to human fallopian tube epithelial cells in organ culture, resulting in damage to the ciliated cells . This bacterium can adhere to human spermatozoa, potentially allowing it to be carried to the female upper genital tract on motile sperm .
M. genitalium PID may lead to subsequent reproductive morbidity, including infertility, recurrent PID, and pelvic pain. In a previous analysis of the PEACH data, Haggerty et al.  found that rates of short-term treatment failure (defined as persistent endometritis and pelvic pain after treatment with cefoxitin and doxycycline; found in 41% of patients), infertility (22%), recurrent PID (31%), and chronic pelvic pain (42%) were high among women with test results positive for endometrial M. genitalium at baseline. These results were similar to those in a subset of women with test results that were negative for N. gonorrhoeae and C. trachomatis. Although the association between M. genitalium and these sequelae did not reach statistical significance, the findings were similar to those previously reported by analyses of the PEACH data, which showed that chlamydial and gonococcal upper genital tract infection was not associated with subsequent morbidity . This could be explained by the fact that women in the comparison groups who did not have test results positive for M. genitalium, C. trachomatis, or N. gonorrhoeae did have signs and symptoms of PID; thus, all women in the PEACH study were at high risk of sequelae, because they had clinically suspected PID.
Infertility after infection with M. genitalium could result from inflammation and scarring of the fallopian tubes because of frequent PID treatment failure, given that 44% of women with test results positive for M. genitalium at baseline had positive test results obtained again 30 days after completion of treatment . A relationship between M. genitalium and tubal factor infertility has also been identified in serological studies . Specifically, M. genitalium antibodies were identified more frequently among women with tubal factor infertility than among women without tubal factor infertility (22% vs. 6%) . In another serological study, 17% of women with tubal factor infertility had antibodies to M. genitalium, compared with only 4% of women with healthy fallopian tubes .
The ability to test for concomitant infections due to C. trachomatis, N. gonorrhoeae, and BV was a strength of our study. However, the unavailability of data on other pathogens may limit the interpretation of our findings. It may be possible that specific BV-associated bacteria, anaerobes, and other mycoplasmal bacteria confounded our analysis. However, adjustment for these bacteria was not possible in our current analysis, because only a subset of women in the PEACH study were tested for these bacteria.
In this study, we compared clinical characteristics and signs and symptoms at presentation by microbial etiology among a population of women with clinically suspected PID. As our study suggests, women with M. genitalium infection may have less symptomatic PID, which, if left untreated, can lead to serious reproductive morbidity, including tubal factor infertility, ectopic pregnancy, chronic pelvic pain, and recurrent PID . Because the etiology of up to 70% of PID cases is unknown, and because M. genitalium has frequently been found in women with PID, detection of the pathogen may help to reduce the burden of untreated PID. However, because clinical symptoms may be mild, and because PID is typically diagnosed through clinical suspicion, women with M. genitalium infection might not seek PID treatment, and cases of M. genitalium PID might go undiagnosed. Additional studies are needed to determine a diagnostic approach for M. genitalium PID and to assess the potential reproductive tract sequelae of M. genitalium upper genital tract infection.
We thank the following investigators, who were involved in the PEACH study: Antonio Amortegui (University of Pittsburgh and Magee-Womens Hospital, Pittsburgh, PA), Susan L. Hendrix (Wayne State University, Detroit, MI), Sharon L. Hillier (University of Pittsburgh and Magee-Womens Hospital, Pittsburgh, PA), Robert L. Holley (University of Alabama School of Medicine, Birmingham, AL), Deborah B. Nelson (University of Pennsylvania, Philadelphia, PA), John Nichols, Jr., Jeffrey Peipert (Washington University, St. Louis, MO), Hugh Randall (Emory University, Atlanta, GA), Diane Schubeck (MetroHealth Medical Center, Cleveland, OH), Steven J. Sondheimer (University of Pennsylvania, Philadelphia, PA), David E. Soper (Medical University of South Carolina, Charleston, SC), Richard L. Sweet (University of Pittsburgh and Magee-Womens Hospital, Pittsburgh, PA), Wayne Trout (Ohio State University, Columbus, OH), Guiliana Trucco (University of Pittsburgh and Magee-Womens Hospital, Pittsburgh, PA), Harold C. Wiesenfeld (Magee-Womens Hospital, Pittsburgh, PA, and Brown University School of Medicine, Providence, RI), and Tamer Yalcinkaya. We thank and acknowledge the efforts of the following interviewers, who recruited and interviewed study participants: Susan Allen, Audrey Baum, Corina Becker, Hope Cohen-Webb, Amy Cooper, Peg Crowner, Leslie Curll, Jackie Faas, Amanda Farmer, Emily Hoffman, Anne Holdredge, Alice Howell, Susan Kay, Faye Leboeuf, Ingrid Macio, Kathy Martin, Margaret McNamee, Ann Meers, Kim Miller, Andrea Montagno, Joy Mowery, Jan Mitton, Cheryl Myers, Brenda Nobels, Tara Pealer, Anne Rideout, Georgia Rothstein, Carol Sams, Tara Schuda, Buffie Schiavoni, Marsha Scott, Kelly Timbers, Sam Whitaker, Lisa Williams, and Mirza Vincetic. We thank consultants Tom Songer, Judy Lave, and Sheryl Kelsey and technical assistant Debra Bass.
Financial support. Agency for Healthcare Research and Quality Development (HS08358-05) and the National Institute of Allergy and Infectious Diseases (1 R01 AI067661-01A2).
Potential conflicts of interest. All authors: no conflicts.