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ORIGINAL RESEARCH |
From the Departments of Obstetrics and Gynecology, Biostatistics, and Pathology, University of Washington, Seattle, Washington.
Address reprint requests to: L. O. Eckert, MD, University of Washington, Harborview Medical Center, Department of Obstetrics and Gynecology, 325 9th Avenue, Box 359865, Seattle, WA 98104; E-mail: eckert{at}u.washington.edu.
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ABSTRACT |
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METHODS: This was a cross-sectional study of 42 HIV-infected women enrolled from a single clinic. Subjects underwent standardized history, examination, and laboratory determinations, including endometrial biopsy. Women with suspected pelvic inflammatory disease were excluded. All women were given antibiotics and repeat evaluation in 5–7 weeks. Histologic endometritis was defined by at least one stromal plasma cell per 120x field and five or more surface polymorphonuclear leukocytes per 400x field. Chi-square and Fisher exact tests were used as appropriate.
RESULTS: Histologic endometritis was present among 16 (38%) of 42 evaluable HIV-infected women, none of whom had Chlamydia trachomatis or Neisseria gonorrhoeae. Douching three or more times per month, history of ectopic pregnancy, and two or more prior urinary tract infections were associated with endometritis, as was elevated erythrocyte sedimentation rate (P 
.05). Physical examination findings and mean CD4+ lymphocyte count were similar among those with and without endometritis. In the nine HIV-infected women with a repeat biopsy, endometritis decreased from four (44%) to two (22%) after treatment (P = .30).
CONCLUSION: The prevalence of histologic endometritis in HIV-infected women was high despite few examination findings and no demonstrated pathogens. Endometritis in HIV-infected women might be related to pathogens not evaluated, to prior infection, or to reduced immunity from HIV.
Endometritis and salpingitis are common clinical syndromes. Several studies compared the presentation and outcome between human immunodeficiency virus (HIV)-infected and HIV-uninfected women with salpingitis. These studies demonstrated that HIV-infected patients with salpingitis have an increased prevalence of tuboovarian abscesses,1–3 requirement for surgical drainage,3,4 increased length of hospital stay and days of therapy before fever defervescence, and more frequent change in antibiotic regimen.5 Female HIV-infected patients presenting with abdominal pain had an increased risk of endometritis on endometrial biopsy compared with HIV-uninfected patients (odds ratio 3.0; 95% confidence interval 1.5, 5.9).6 Both HIV-infected and HIV-uninfected patients were treated successfully in these studies with standard antimicrobial regimens, and no outcome differences were noted 30 days after therapy.1–3,5,6 These reports support currently recommended antimicrobial regimens in women with suspected upper genital tract infection, independent of HIV serostatus. However, only subjects with symptoms and signs of salpingitis were included in these studies, and asymptomatic HIV-positive women have not been studied.
Recently, endometritis was characterized as a distinct syndrome, with less severe symptoms and signs and some different risk factors than salpingitis.7 However, in HIV-uninfected women, endometritis is consistently linked to Chlamydia trachomatis, Neisseria gonorrhoeae, a history of prior pelvic inflammatory disease (PID) and, to a lesser extent, bacterial vaginosis.8–10 Endometritis is present in 7% of asymptomatic infertility patients,11 and in women without vaginitis, cervicitis, or known infection.12 Subacute endometritis has important implications for HIV-infected women, who might have infection that is more difficult to clear than in women with normal immunocompetence. Additionally, increased endometrial inflammation could increase the transmission of HIV from the mother to the fetus during pregnancy. Because endometritis is not characterized in asymptomatic HIV-infected women, the purpose of this study was to determine the prevalence, risk factors, clinical symptoms and signs, and response to antimicrobial therapy of histologic endometritis in HIV-infected women without clinical salpingitis.
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MATERIALS AND METHODS |
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All study patients underwent the same standardized history and physical examination. Demographic characteristics; medical, contraceptive, and sexual histories; symptoms and physical signs; and laboratory results were recorded on standardized forms. First-void urine was collected for ligase chain reaction (Abbott Laboratories, North Chicago, IL) detection of C trachomatis and a pregnancy test. A standardized physical examination and oral temperature was performed. A Dacron swab from the oral pharynx was collected for N gonorrhoeae culture. The abdomen was assessed for direct and rebound tenderness and guarding. The vulva was inspected for lesions, erythema, urethral discharge, or tenderness. Urethral and periurethral swabs were collected for C trachomatis testing (culture and ligase chain reaction), and a Dacron swab was inserted into the urethra for N gonorrhoeae culture.
A speculum was placed and specific attention directed to record abnormalities of the vagina (noting amount, color, and viscosity of discharge), and cervix (erythema, friability, and color of cervical mucus). The pH of the vagina was measured directly with Color-pHast indicator sticks (MCB Manufacturing Chemists Inc., Cincinnati, OH). The lateral and posterior vaginal walls were swabbed with a cotton-tipped applicator, which was mixed with 0.2 mL of physiologic saline in a test tube and examined microscopically for motile trichomonads, clue cells, and white blood cells. One drop of 10% potassium hydroxide was added to one drop of the mixture, assessed for amine odor, covered with a coverslip, and evaluated for hyphal elements at 400x power. Vaginal swab specimens also were collected for bacterial and Trichomonas vaginalis culture. A ligase chain reaction swab and Dacron swabs were collected from the endocervix to detect C trachomatis by ligase chain reaction and C trachomatis and N gonorrhoeae by culture. Endocervical mucous was assessed by Gram stain for the presence of neutrophils. A Dacron swab for C trachomatis detection via direct fluorescent antibody staining (Syva Corp., Palo Alto, CA) was collected from the endocervix. A patient with any positive C trachomatis test or N gonorrhoeae test was considered positive for that organism. Cervicitis was diagnosed clinically by yellow mucous on the face of the cervix after wiping off vaginal discharge or yellow endocervical mucous on a swab placed into the endocervical canal and/or microscopically by the presence of 30 or more polymorphonuclear leukocytes per 1000x field on Gram stain. The speculum was removed, and a bimanual examination was performed to detect cervical motion, uterine and adnexal tenderness, and adnexal masses.
To perform the biopsies, a speculum was reinserted, and a cervical biopsy was taken at the cervical squamocolumnar junction with biopsy forceps (Tischler-Morgan, Euro-Med, Trumball, CT), placed in formalin, and histologically examined for cervicitis.13 A tenaculum was placed on the anterior lip of the cervix, a Pipelle (CooperSurgical, Trumball, CT) was passed through the unprepared cervix, and endometrial tissue was obtained with suction. The distal 5 mm of the Pipelle was trimmed with sterile scissors and the tissue placed in a sterile Petri dish. Swab specimens were taken from the tissue for C trachomatis detection by ligase chain reaction and direct fluorescent antibody staining. A portion of this endometrial tissue was also assessed by culture for C trachomatis, N gonorrhoeae and aerobic and anaerobic bacteria.14 The remaining tissue was placed in formalin and examined for histologic endometritis according to previously defined criteria of five or more neutrophils per 400x field in the endometrial surface epithelium, together with one or more plasma cells per 120x field in the endometrial stroma.11
A venipuncture was performed for C trachomatis serology,15 C-reactive protein, erythrocyte sedimentation rate, and white blood cell count,7 and CD4+ cell count level (if no CD4+ cell count within 4 months). T-cell subsets were assessed by flow cytometry.
Methods used to isolate Mycoplasma hominis and Ureaplasma urealyticum from the vagina, aerobic and anaerobic bacteria from the vagina and endometrium, and N gonorrhoeae and C trachomatis by culture have been previously published.14 Microorganisms other than Lactobacillus species and diphtheroids were considered pathogenic when isolated from the endometrium. Specifically, we considered Escherichia coli, Enterococcus, non-pigmented Prevotella species, black anaerobic gram-negative rods, Streptococcus pneumoniae, B-hemolytic Streptococcus, all aerobic and anaerobic gram-negative rods, and all aerobic and anaerobic gram-negative cocci pathogenic endometrial isolates. We diagnosed bacterial vaginosis clinically16 and by Gram stain criteria.17
To test for herpes simplex virus (HSV) and cytomegalovirus in tissue, polymerase chain reaction was performed on cervical and endometrial biopsy specimens as previously described.18,19
After the clinical evaluation, all subjects underwent an endometrial biopsy and were treated with single oral doses of cefixime 400 mg, azithromycin 1 g, and metronidazole 500 mg twice daily for 7 days. The patient evaluation was repeated at a return visit 5–7 weeks after therapy completion. If histologic endometritis or a positive endometrial culture for pathogenic bacteria was found in the original endometrial biopsy, a repeat endometrial biopsy was done at the follow-up visit. Of the 42 HIV-infected women who had an initial biopsy, 22 had a second visit, and nine had a repeat biopsy.
Factors associated with histologic endometritis among HIV-infected women were evaluated by comparing those with endometritis to those without endometritis at enrollment, with Student t test used for continuous variables and Pearson 
2 and Fisher exact tests for categoric variables. Antibiotic treatment effect on clinical findings were evaluated by comparing symptoms, signs, microscopic and laboratory results with McNemar 2 test.
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RESULTS |
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Of the 42 HIV-infected women with evaluable tissue, 16 (38%) had histologic endometritis. The prevalence of historical factors in the 16 women with histologic endometritis is compared with the 26 women without histologic endometritis in Table 1
. Douching more than three times per month, a history of prior PID and/or ectopic pregnancy, and two or more prior urinary tract infections were factors associated with histologic endometritis. However, douching, a history of prior PID and/or ectopic pregnancy, and prior urinary tract infections were not related to CD4+ cell count among HIV-infected patients in this study (data not shown). Abnormal bleeding, lifetime number of sexual partners, frequency of intercourse, prior C trachomatis or N gonorrhoeae infection, and birth control methods were among the many factors not associated with endometritis. In HIV-infected women, 38% of 16 with endometritis and 24% of 25 without endometritis were currently using antiretroviral therapy (P = .20). Antiretroviral therapy consisted of a single agent in all subjects.
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. Cervicitis and mild cervical motion or uterine tenderness on physical examination were not associated with histologic endometritis, nor was bacterial vaginosis, even among those who douched. Only 19 of the 42 women had cervical biopsies adequate for histologic interpretation, and inflammation on cervical biopsy was associated with endometritis (P < .001). Neither the mean CD4+ cell count nor a CD4+ cell count less than 500 per µL was associated with endometritis. Other serum indicators of systemic inflammation and C trachomatis antibody were not related to endometritis. No significant differences were found in bacterial culture results from endometrial biopsies in HIV-infected women with and without endometritis (data not shown). Hydrogen peroxide (H2O2) producing lactobacilli were present in four (20%) of 16 in those with endometritis and five (19%) of 26 in those without endometritis (P = .70). Similarly, lactobacilli negative for H2O2 were present in three (19%) of 16 in those with endometritis and in two (8%) of 26 without endometritis (P = .30). Ureaplasma urealyticum and E coli were each detected in one HIV-infected woman with endometritis and in no HIV-infected woman without endometritis. Gardnerella vaginalis was cultured from the endometrium of one HIV-infected woman with and five of 26 HIV-infected women without endometritis (P = .20).
Cervical biopsies taken at the initial visit in 19 HIV-infected women also were tested by polymerase chain reaction (PCR) for HSV and cytomegalovirus. Two (11%) of 19 women had HSV in the cervical biopsy tissue: one with and one without histologic endometritis. Cytomegalovirus deoxyribonucleic acid (DNA) was detected in the cervical biopsies of three (37%) of eight women with and three (27%) of 11 women without endometritis (P = .60). Because only three of these eight women with cervical HSV or cytomegalovirus DNA detected had adequate cervical biopsy tissue to assess histologic cervicitis, we cannot determine whether the presence of this viral DNA is associated with cervicitis.
Twenty endometrial biopsy specimens were available for HSV PCR testing. Herpes simplex virus was not detected by PCR in the endometrium. Cytomegalovirus was detected by PCR in the endometrium of one (11%) of nine with endometritis and three (27%) of 11 without endometritis (P = .40). Endometrial cytomegalovirus was not related to the blood CD4+ cell count.
The effect of antibiotic therapy on the 22 HIV-infected women who returned for repeat evaluation is presented in Table 2. Abnormal bleeding (P < .001) was significantly reduced after antibiotic therapy. Uterine tenderness was reduced from 18% to 0 after treatment but did not reach significance (P = .10). The prevalence of pathogenic bacteria in the endometrial biopsy culture and the prevalence of histologic endometritis decreased modestly after therapy.
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DISCUSSION |
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Data in this study demonstrate that HIV-infected women who douched three or more times per month had a significant increase in endometritis, consistent with prior studies in HIV-uninfected women, in which douching was associated with salpingitis7,9 and with ectopic pregnancy.20,21 This study provides further data that women, particularly HIV-positive women, should not douche.
Abnormal bleeding is associated with endometritis in HIV-uninfected women.8–10,12,22 In this study, abnormal bleeding was present in approximately 50% of women with endometritis. A significant decrease in abnormal bleeding occurred after antibiotic therapy in these HIV-infected women (Table 2). However, we also found a significant reduction in bleeding in women without endometritis in a prior study (Eckert LO, unpublished data). Because we did not have a control group of women with abnormal bleeding who received no antibiotic therapy, it is not possible to determine from this study, or the prior study (Eckert LO, unpublished data) whether antibiotics improved the bleeding or whether the reduction in bleeding simply reflects the natural history of abnormal bleeding.
A history of prior PID and/or a history of prior ectopic pregnancy were more common in HIV-infected women with than without endometritis. Antibiotics given to HIV-infected women reduced histologic endometritis. These data, combined with the lack of detection of traditional pathogens, such as chlamydia and gonorrhea, suggest that in HIV-infected women, endometritis might represent a relatively asymptomatic, low-grade chronic infection that responds to antibiotics. This hypothesis is supported by a study of HIV-uninfected women who more frequently had acute C trachomatis and N gonorrhoeae infection (Eckert LO, unpublished data). In this study, the highest risk for endometritis was in women with a combination of both prior PID and acute cervical chlamydial or gonorrheal infection. The combination of these risk factors seemed additive compared with women with either prior PID or acute cervical infection alone. As with HIV-infected women, endometritis resolved with antibiotic therapy (Eckert LO, unpublished data).
A potential cause of the endometritis might be previous C trachomatis infection that remained in the endometrium from prior PID but was not detected by our analyses. In experiments with macaque monkeys, C trachomatis inoculated in the endocervix results in salpingitis. After the induced salpingitis, antimicrobial therapy led to negative cervical and tubal cultures in these macaques, but C trachomatis DNA persisted in the fallopian tubes.23 In HIV-infected women, altered immune function might further contribute to difficulty clearing endometrial pathogens. Further work is needed in both HIV-infected and HIV-uninfected women to understand both defenses against and clearance mechanisms of endometrial infection. These data do suggest that chronic low-grade endometrial infection can be eliminated by antibiotics in the short term, but longer-term follow-up in a larger study population is required to assess duration of the therapeutic effect.
Histologic inflammation on cervical biopsy was associated with endometritis in HIV-infected women despite the absence of mucopurulent cervicitis, or demonstrated endocervical pathogens, such as chlamydia and gonorrhea. Herpes simplex virus and cytomegalovirus also were rarely found in cervical biopsies. A correlation of cervical histologic inflammation and endometritis has not been previously demonstrated to our knowledge, and the clinical significance deserves further evaluation. Altered immune function that might contribute to endometritis prevalence in HIV-infected women might also be associated with histologic cervicitis. Cervical tissue inflammation might represent a chronic, nonspecific process in this study population, but if the association between cervical inflammation and endometritis is confirmed in other studies, cervical tissue biopsy might offer a less invasive test for endometritis.
Increased prevalence of endometritis in HIV-infected women with a history of prior urinary tract infections (Table 1) has not been reported. A history of urinary tract infection was not related to CD4+ cell count. This finding could be spurious, but in HIV-uninfected women, repeated urinary tract infections were related to specific blood group antigens.24 Presence of these blood group antigens is associated with a lack of secretion of proteins that help block uroepithelial attachment of uropathogens, such as E coli.24 The risk of endometritis in HIV-uninfected women with nonsecretor status has not been studied. It is possible that some HIV-infected women with a history of recurrent urinary tract infections might have genetic differences in the attachment of bacteria to genital as well as uroepithelium.
These data suggest that HIV-infected women with abnormal bleeding might be candidates for endometrial biopsy. In addition, endometrial biopsy should be considered in HIV-infected women who douche, have frequent urinary tract infections, prior PID or ectopic pregnancy, or have inflammation found on cervical biopsy. Treatment should be based on biopsy result. In this study, we used single-dose azithromycin and cefixime, with 7 days of metronidazole, and demonstrated resolution of endometritis. However, this regimen has not been compared with recommended standard therapy. Similar studies in other HIV-infected populations are needed to verify our results and to further refine suggestions regarding the clinical utility of endometrial biopsy in this population.
This study has several strengths. All HIV-infected patients had a standardized, comprehensive evaluation by the same examiner (LOE). We used intensive microbiologic techniques.14 Because clinical diagnosis of upper genital tract infection lacks sensitivity and specificity,25 repeat biopsy after therapy offers a histologic confirmation that endometritis has resolved.
This study also has limitations. The small numbers of patients provided a low power to detect significant findings, such as an association of CD4+ cell count with endometritis. It is possible that other pathogens exist that were not identified by techniques used in this study. We might have missed pathogens because of the relative insensitivity of culture. Mycoplasma genitalium has recently been associated with endometritis, especially in women with mild symptoms26 and with cervicitis.27 We did not test for M genitalium or for Mycobacterium tuberculosis. We used nucleic acid amplification for C trachomatis, HSV, and cytomegalovirus, but not for other microorganisms. Additionally, recruitment was not randomized. We enrolled all HIV-infected eligible women reporting to the clinic for care who agreed to participate in the study. This study was performed before viral load was followed routinely, and patients had single antiretroviral agent therapy. Newer highly active antiretroviral therapy, which provides subsequent decreased viral load of HIV and resultant improved immune function, might alter the prevalence of endometritis in asymptomatic HIV-infected women.
Additional studies are needed to quantitate the viral concentration of genital tract HIV in women with and without endometritis. Increased viral shedding is associated with cervical infection with C trachomatis and N gonorrohoeae, and treatment of these infections decreases HIV viral shedding.28,29 It is possible that endometrial and/or cervical inflammation increase genital HIV shedding and might increase the acquisition of HIV by male sexual partners. Given the 38% prevalence of endometritis in this study population, if endometritis treatment is associated with decreased HIV shedding, then treatment and resolution of endometritis could have a vast impact. Such a natural history study might offer additional insight into the pathogenesis and resolution of endometrial inflammation and might suggest strategies to reduce transmission of HIV.
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Footnotes |
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Dr. Watts is currently working in the Pediatric, Adolescent, and Maternal AIDS Branch, Center for Research for Mothers and Children, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
S. S. Thwin is currently a doctoral candidate in Biostatistics at Boston University, Boston, Massachusetts.
doi:10.1016/S0029-7844(03)00857-3
Received March 19, 2003. Received in revised form June 6, 2003. Accepted July 17, 2003.
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REFERENCES |
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2. Cohen CR, Sinei S, Reilly M, Bukusi E, Eschenbach D, Holmes KK, et al. Effect of human immunodeficiency virus type 1 infection upon acute salpingitis: A laparoscopic study. J Infect Dis 1998;178:1352–8.[Medline]
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