OBJECTIVE: To examine the effect of human immunodeficiency virus (HIV)–1 infection on treatment outcome of laparoscopically verified acute salpingitis.
METHODS: Women aged 18–40 years with laparoscopically verified acute salpingitis received antibiotic therapy that included cefotetan 2 g intravenously and doxycycline 100 mg orally every 12 hours and laparoscopically guided drainage of tuboovarian abscesses of 4 cm or more. Clinical investigators blinded to HIV-1 serostatus used predetermined clinical criteria, including calculation of a clinical severity score and a standard treatment protocol to assess response to therapy.
RESULTS: Of the 140 women with laparoscopically confirmed acute salpingitis, 61 (44%) women had mild, 38 (27%) had moderate, and 41 (29%) had severe disease (ie, pyosalpinx, tuboovarian abscesses, or both). Fifty-three (38%) were HIV-1–infected. Severe disease was more common in HIV-1–infected in comparison with HIV-1–uninfected women (20 [38%] compared with 21 [24%], P = .02). Defined as time of hospital discharge or 75% or more reduction in baseline clinical severity score, HIV-1–infected women with severe (6 days [4–16] compared with 5 days [3–9], P = .09) but not those with either mild (4 days [2–6] compared with 4 days [2–6] P = .4) or moderate salpingitis (4 days [3–7] compared with 4 days [3–6] P = .32) tended to take longer to meet criteria for clinical improvement. The need for intravenous clindamycin or additional surgery was not different in HIV-1–infected and uninfected cases (15 [28%] compared with 18 [21%], P = .3).
CONCLUSION: Although HIV-1 infection may prolong hospitalization in women with severe salpingitis, all women hospitalized with acute salpingitis responded promptly to antibiotic therapy and surgical drainage regardless of HIV-1 infection status.
LEVEL OF EVIDENCE: II-2
Human immunodeficiency virus-1 serostatus was not associated with treatment response for women hospitalized with laparoscopically verified acute salpingitis.
From the 1Department of Obstetrics and Gynecology, Kenyatta National Hospital, Nairobi, Kenya; 2Centre for Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya; the Departments of 3Obstetrics and Gynecology and 4Medicine, University of Washington, Seattle, Washington; and the Departments of 5Statistics and 6Obstetrics and Gynecology, University of Nairobi, Nairobi, Kenya.
Supported by the STD Clinical Trials Unit (AI75329). N. R. Mugo was supported by the University of Washington International AIDS Research Training Program (T22 TW00001).
Current affiliation of Dr. Kiehlbauch is the Maryland Department of Health and Mental Hygiene Laboratories Administration, Baltimore, Maryland. Current affiliation of Dr. Cohen is the Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, California.
Presented at the International Society of Sexually Transmitted Disease and Research, Ottawa, Canada, July 27–31, 2003.
The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Corresponding author: Craig R. Cohen, MD, MPH, 50 Beale Street, Suite 1200 UCSF, Box 0886, San Francisco, CA 94105; e-mail firstname.lastname@example.org.
Pelvic inflammatory disease (PID), one of the most common serious gynecologic disorders, can result in debilitating sequelae, including infertility, chronic pelvic pain, and ectopic pregnancy.1 In Africa, HIV-1 seroprevalence rates among patients with acute PID have ranged from 15% to 39% and are 2 to 7 times greater than found among antenatal clinical attendees from the same population.2–7 As the global epidemics of sexually transmitted infections and HIV-1 continue in parallel, it is important to better understand the effect of concomitant HIV-1 infection on the clinical course of acute PID.
Until the release of the 2002 Centers for Disease Control (CDC) sexually transmitted infection treatment guidelines, the CDC recommended hospitalization and intravenous (IV) antibiotics for all known HIV-1–infected women with PID.8,9 In part this recommendation was based on several studies finding that HIV-1 infection was associated with pyosalpinx and tuboovarian abscess in women diagnosed with PID.2,6,10 Similarly, it had been suggested that HIV-1 infection might lead to a delayed clinical response to therapy.2 Nevertheless, worldwide, greater than 90% of women with PID receive outpatient therapy,11 and a recent study conducted in the United States among HIV-1–seronegative women clinically diagnosed with PID found that broad-spectrum IV and oral antibiotic therapy led to a nonsignificantly different therapeutic response, fertility rate, and risk of PID sequelae.12
Our earlier investigation of the effect of HIV-1 infection on the treatment outcome of laparoscopically verified salpingitis found that HIV-1–seropositive and seronegative women had comparable median lengths of hospitalization (6 compared with 5 days, P = .37) and duration of antibiotic therapy (13 compared with 13 days, P = .20).6 Among HIV-1–infected women, those with CD4% less than 14% required a longer median duration of hospitalization (8 compared with 5 days, P < .02) and longer antibiotic therapy (16 compared with 13 days, P = .07) than did those with CD4% of 14% or more.6 A major limitation of this prospective study was that like other similar investigations the investigator evaluating the clinical response to therapy was not blinded to HIV-1 serostatus, thus potentially resulting in observer bias.
Thus, for this investigation we set out to determine prospectively the effect of HIV-1 infection and degree of immunosuppression on the treatment outcome of women with laparoscopically verified salpingitis while maintaining blinding of HIV-1 serostatus for both the investigators and participants until the time of hospital discharge. These findings should prove useful for updating clinical care guidelines for PID.
MATERIALS AND METHODS
The study protocol was approved by the Institutional Review Board for Human Subjects at the University of Washington and by the Ethical Review Committee at Kenyatta National Hospital and the Kenya Medical Research Institute, Nairobi, Kenya. Procedures followed were in accordance with the ethical standards for human experimentation established by the Declaration of Helsinki of 1975, revised in 1983. As part of an investigation of the cause of acute salpingitis women aged 18–40 years presenting with clinically suspected PID at Kenyatta National Hospital were screened for study participation between April 2000 and January 2003. Inclusion criteria included a complaint of low abdominal-pelvic pain for 2 weeks or less plus 1 or more of the following signs or symptoms: temperature 38°C or more, dysuria, and complaint of abnormal vaginal discharge. Women who reported pregnancy, abortion, or surgery within the past 6 weeks were excluded.
After giving written informed consent, study participants underwent HIV-1 pretest counseling, a detailed questionnaire, and general and gynecologic examination. To assess and record severity of PID, a clinical severity scoring system adopted by McCormack et al13 was used. A score was given for direct (0–12) and rebound (0–12) abdominal tenderness, cervical motion (0–3), uterine (0–3) and right (0–3) and left (0–3) adnexal tenderness, and right (0–3) and left (0–3) adnexal masses on palpation; the maximum possible clinical severity scoring system was 42. During pelvic examination, vaginal specimens were obtained for detection of Trichomonas vaginalis, and cervical specimens were obtained for Neisseria gonorrhoeae and Chlamydia trachomatis polymerase chain reaction (PCR). Blood was obtained for HIV-1 and syphilis serologies, and CD4 and CD8 lymphocyte counts. Only HIV-1 seropositive women had CD4 and CD8 counts performed.
To confirm the clinical diagnosis of acute PID and visually stage the severity of acute salpingitis, laparoscopy was performed on all subjects within 6 hours of recruitment by 1 of 2 gynecologists (NRM and JWG). At surgery, the gynecologist was blinded to laboratory findings, including HIV-1 serostatus. After induction of anesthesia, an endometrial biopsy was obtained with a pipette suction curette (Unimar, Inc., Wilton, CT) for N gonorrhoeae and C trachomatis testing. The severity of acute salpingitis was graded as1 mild (tubal erythema or edema, mobile tubes, and with or without spontaneous exudate),2 moderate (marked tubal erythema and edema, limited tubal mobility, questionable or no tubal patency, and gross exudate), and3 severe (pyosalpinx or tuboovarian abscess).14 At laparoscopy, samples from peritoneal fluid, tubal ostia biopsies, and when available, pyosalpinx-tuboovarian abscess aspirates were obtained for N gonorrhoeae and C trachomatis PCR. Furthermore, to improve treatment outcome abscesses 4 cm or larger were drained by laparoscopically guided transabdominal drainage during the laparoscopic procedure, with a drain left in situ. When laparoscopic drainage was not possible, a laparotomy drainage procedure was performed.
Subjects with laparoscopic evidence of acute salpingitis received treatment with IV cefotetan 2 g every 12 hours and doxycycline 100 mg orally every 12 hours for at least 3 days, and the clinical severity scoring system was reduced by 75% or more over the baseline score,15 with the woman afebrile 48 hours or more. Intravenous clindamycin 500 mg use 4 times daily was added to increase coverage of anaerobic bacteria for the following indications1: temperature 38°C or more on day 3,2 less than 50% reduction in clinical severity scoring system score in comparison with initial score by day 3, and3 pelvic mass 4 cm or larger on examination or ultrasonography (if clinically indicated) at 1 week. At discharge, all subjects were treated with an additional week of metronidazole 500 mg every 8 hours and doxycycline 100 mg every 12 hours. Women received HIV-1 posttest counseling at time of hospital discharge. Participants were scheduled for reevaluation at 1, 2, and 4 weeks after discharge. The investigators, clinical team, and participants were blinded to the HIV-1-serostatus until the time of hospital discharge.
Samples from the cervix, endometrium, Fallopian tube, and abscess (if present) were collected in a dry tube; 800–1,000 μL of 0.2 M sucrose in phosphate buffer at pH 7.5 was added to each tube. All samples were frozen at –20°C until examined by PCR following manufacturer's instructions for N gonorrhoeae and C trachomatis (AMPLICOR, Roche Diagnostic Systems, Branchburg, NJ) in Kenya. Trichomonas vaginalis infection was assessed by culture (InPouch TV, BioMed Diagnostics, Inc., San Jose, CA). Serum was tested for HIV-1 antibodies by enzyme-linked immunosorbent assay (Detect HIV, BioChem ImmunoSystems, Montreal, Canada), with positive results confirmed by a second enzyme-linked immunosorbent assay (Recombigen, Cambridge Biotech, Ireland). Serologic testing for syphilis was performed using Rapid Plasma Reagin (Becton-Dickinson, Baltimore, MD) for screening and Treponema pallidum hemagglutination assay (TPHA, Biotech Laboratories, United Kingdom) for confirmation. A FACSCAN (Becton-Dickinson, Baltimore, MD) was used to enumerate CD4 and CD8 lymphocyte subsets.
Data were analyzed using SPSS for Windows 11.5 (SPSS Inc., Chicago, IL). Analyses included Pearson's χ2, Fisher exact test for categorical data, Mann-Whitney U test, and Student t test for continuous variables.
Of the 160 women recruited with clinical PID, 140 (88%) had laparoscopically verified acute salpingitis: 61 (44%) with mild, 38 (27%) with moderate, and 41 (29%) with severe salpingitis as defined above. Fifty-one (36%) of the women with salpingitis were HIV-1 seropositive at enrollment; an additional 2 participants seroconverted within 30 days of enrollment and were considered HIV-1 infected for the sake of this analysis. Among HIV-1–seropositive participants, the median CD4 T cell count was 237 cells per microliter (range 2–1,144) and 23 (14%) had a CD4 T cell count less then 200 cells per microliter.
The relationships between HIV-1 infection and demographic, clinical, and laboratory findings are presented in Table 1. Although chronologic age, age at first intercourse, and contraceptive history were not associated with HIV-1 serostatus, HIV-1–infected participants had fewer years of education and were more likely divorced or separated and to have had sex with an uncircumcised partner than HIV-1–uninfected subjects. History of PID was not associated with laparoscopic disease severity.
HIV-1–infected women had more severe disease as measured clinically through calculation of the clinical severity scoring system (HIV-1 seropositive = 17.8 ± 6.6 compared with HIV-1 seronegative = 14.7 ± 7.9, P < .02) and application of the laparoscopic scoring system (Table 2). Among HIV-1–infected women, the CD4 T cell count was not associated with the severity of salpingitis (data not shown). In addition, other clinical findings, such as elevated temperature at enrollment and presence of chronic pelvic and perihepatic adhesions, were positively correlated with HIV-1 infection (Table 2). Although not significant, N. gonorrhoeae and C. trachomatis were detected less frequently in HIV-1–infected than HIV-1–uninfected women with acute salpingitis (22% compared with 28%, P = .14).
We performed an analysis to determine factors associated with the time to hospital discharge or a reduction of baseline clinical severity scoring system by 75% or more. Because some subjects, principally those with mild disease, were discharged before observing a 75% or more reduction of baseline clinical severity scoring system, and others were retained in the hospital for social and other medical conditions, such as anemia, tuberculosis, and renal failure, we combined both outcomes to create a single dependent variable labeled “clinical improvement.” For both HIV-1–infected and uninfected women with salpingitis, severe disease in comparison with mild disease was associated with delayed clinical improvement (Table 2). Although not statistically significant, HIV-1 infection was associated with a trend toward prolonged time to reach clinical improvement for those with severe salpingitis (6 days [range 4–16] compared with 5 days [range 3–9], P = .09); for those with mild and moderate disease, the time to clinical improvement was not associated with HIV-1 infection (Table 2).
A strict protocol was used to guide the use of additional therapies for women not responding to standard treatment. Nevertheless, HIV-1 serostatus was not associated with the need to add IV clindamycin, additional surgical drainage procedure, or either event when considered in aggregate as a complicated course (Table 3). Seventy-two hours after commencing antibiotic treatment, 19% of HIV-1–infected compared with 4% of HIV-1–uninfected subjects had a temperature 38°C or more (odds ratio 10, 95% confidence interval 2.1–47.7; Table 3) (Table 4).
In the current investigation women with laparoscopically proven salpingitis responded universally well to standardized treatment regardless of HIV-1 serostatus; notwithstanding this, HIV-1 infection was associated with a nonstatistically significant increased time to clinical improvement (6 compared with 5 days, P = .09), limited to those with severe salpingitis (ie, pyosalpinx and tuboovarian abscesses). Human immunodeficiency virus-1 serostatus also failed to correlate with a complicated clinical course, including the need for additional surgical drainage or change of antibiotic regimen due to treatment failure. Controversy has remained regarding the effect of HIV-1 infection on the clinical response ever since the first retrospective studies completed in the United States found that HIV-1 seropositive women with acute PID more often failed medical therapy and required change in therapy and surgical intervention.5,10,16 A single U.S. study found that HIV-1–infected women required longer hospitalization.10 These early studies on the effect of HIV-1 infection on the response to treatment led the CDC to recommend hospitalization and IV treatment for all HIV-1–infected women diagnosed with PID.8 However, more recent prospective investigations6,17,18 led the CDC to revise these guidelines in 2002 and eliminated the recommendation to hospitalize and administer IV antibiotics to all HIV-1–infected women diagnosed with PID.9 Our current data are consistent with these later studies and should lead to further endorsement and clarification of the CDC recommendations regarding the management of HIV-1–infected women with PID.
Women diagnosed laparoscopically with mild and moderate salpingitis had a similar time to clinical improvement, a finding that was unaffected by HIV-1 serostatus. A randomized treatment trial of IV compared with oral therapy among HIV-1–uninfected women with mild and moderate PID did not detect any differences in clinical outcome or long-term sequelae between treatment arms.11 Furthermore, Bukusi et al18 found that among women presenting with outpatient PID confirmed by endometrial histopathology, clinical improvement was not statistically different between HIV-1–infected and uninfected women. Data from the current investigation and those cited provide strong evidence to support the use of outpatient treatment of less severe cases of PID regardless of concomitant HIV-1 infection.
This study used several methods to reduce observer bias and misclassification of results.17 Unlike earlier investigations, research participants and the entire research team were blinded to the HIV-1 test results until the time of hospital discharge in the current study. Although none of the subjects knew their HIV-1 serostatus before study participation, other clinical conditions may have led to suspicion of HIV-1 infection and immunosuppression. Thus, although observer bias was reduced, it could not be fully eliminated. In addition, we used a standard algorithm to measure clinical improvement that included a 75% or more decline in baseline clinical severity scoring system scores or time of hospital discharge; in 65% of cases the decision to discharge subjects was predicated on the 75% or more reduction in baseline clinical severity scoring system score. If we would have instead relied on time of hospital discharge as our measure of clinical response, those remaining in the hospital for other diagnoses besides PID, eg, treatment of tuberculosis, may have affected our results. Last, we used objective laparoscopic criteria to confirm the clinical diagnosis of salpingitis.1 The clinical diagnosis of acute PID has been imprecise, with only a 46–90% positive predictive values when compared with laparoscopy.6,19 Thus, reliance on clinical criteria alone would have led to significant case misclassification.
In summary, women hospitalized in Nairobi with confirmed acute salpingitis responded well to appropriate therapy and had few complications regardless of HIV-1 serostatus. These findings support the recommendation of hospitalization, standard IV antimicrobial therapy, and drainage of tuboovarian abscesses for women with severe salpingitis and as an extension to outpatient management and oral antibiotics for women with uncomplicated PID for both HIV-1–infected and uninfected patients.
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© 2006 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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