Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) are the 2 most common bacterial sexually transmitted infections (STIs) in the United States. In women, screening efforts have focused primarily on genitourinary screening.1 Despite the high frequency of receptive anal intercourse (RAI) among young heterosexual adults,2–7 there are no recommendations for routine extragenital screening.1 In men who have sex with men (MSM), the Centers for Disease Control and Prevention (CDC) recommends annual gonorrhea and chlamydia screening based on risk. Despite numerous publications outlining the rising prevalence of rectal gonorrhea and chlamydia, extragenital screening for these STIs is not always performed when indicated.8
Extragenital CT and GC may be important reservoirs for ongoing disease transmission. High rates of extragenital gonorrhea and chlamydia among MSM have been well documented.9–14 Previous studies have reported that among MSM, 65% to 70% of extragenital gonorrheal and 75% to 85% of extragenital chlamydial infections were documented in men having no urethral infections.12,15 Thus, there is recent rediscovery that urogenital testing alone misses a large proportion of men who are positive for STIs.16 Urogenital screening in women is reported to miss a smaller percentage of total infections compared with MSM, but the numbers of missed infections in women have been reported to range from 25% to 30% for GC 16,17 and 14% to 44% for CT.16–19
The objective of this prospective study was to determine the prevalence of CT and GC in men and women using the same inclusion criteria, namely, reporting a lifetime history of RAI.
MATERIALS AND METHODS
Study Population and Design
This cross-sectional study was conducted from March 2014 to March 2015 at 2 centers in Pittsburgh, PA: Allegheny County Health Department (an STI clinic) and Magee-Womens Hospital of UPMC (an outpatient women's health clinic). Inclusion criteria included a reported lifetime history of RAI. Participants were excluded if they reported use of oral antibiotics over the previous 7 days, use of rectal douche or other rectal products in the past 24 hours, and, if female, use of vaginal douche or vaginal product in the previous 24 hours, to prevent dilution of sample. The study was approved by the University of Pittsburgh Institutional Review Board, Pittsburgh, PA. After written informed consent was obtained, a questionnaire was administered to determine age, ethnicity, sexual activity history, pharyngeal and rectal symptoms, and vaginal symptoms in women or urinary symptoms in men.
The 2 swabs collected use nucleic acid amplification test (NAAT) technology: GenProbe's Aptima Unisex Collection Swab (Aptima, Aptima Combo 2; Hologic Inc, Bedford, MA) and the Cepheid Xpert CT/NG Assay (Xpert; Cepheid Innovation, Sunnyvale, CA). Study clinicians inserted 2 sequential NAAT swabs approximately 2.5 cm above the anal verge and placed each swab into the appropriate transport media. Pharyngeal swabs were collected from each lateral posterior wall, including tonsillar crypts. For men, urine samples were obtained as first-pass collection at least 1 hour or later after last void. For women, vaginal swabs were obtained by clinicians by placing the swab approximately 10 cm past the introitus and rotating the swab, without placement of a speculum. The order of collection of the 2 NAAT swabs was predetermined by computer randomization. An additional swab was obtained from the pharynx for GC culture, which was obtained first per CDC guidelines.1 Culture for GC was not initially included in the study because previous studies found a very low level of sensitivity for culture from rectal swab samples.20,21 However, after an interim analysis of the first 150 participants enrolled and the high number of pharyngeal samples positive for GC, culture testing of the remaining 249 pharyngeal samples was added.
Laboratory Testing for CT and GC
Testing was conducted per package insert (Aptima Combo 2 package insert IN0037-04 Rev A; GeneXpert package insert CXCT/NG-CE-10). Xpert is Food and Drug Administration (FDA) cleared for the detection of CT and GC from genitourinary samples. Neither of the NAAT methods has been FDA cleared for detection of these pathogens from rectal or pharyngeal samples, but Aptima had been previously validated in the reference laboratory (Magee-Womens Research Institute, Pittsburgh, PA) for testing of CT and GC from rectal samples.
The Dacron swab from the pharynx was used to inoculate 2 selective agar plates (Modified Thayer-Martin agar and GC-Lect agar) and chocolate agar. The plates were transported in a candle jar and, in the laboratory, were transferred to a 37°C, 6% CO2 incubator. After 24 to 48 hours, agar plates were examined and gram-negative diplococci having indophenol oxidase enzyme were confirmed using API NH (bioMerieux, Inc, Marcy-I'Etoile, France).
Definition of a Positive Test Result
Because both Aptima and Xpert are FDA cleared for genitourinary samples, any positive result from the urine or vagina was defined as positive for infection. For rectal and pharyngeal GC and CT swab samples, any Aptima- or Xpert-positive result (including a discrepant test result) was verified using the appropriate Aptima CT or Aptima GC assay, which targets different nucleic acid sequences. A pharyngeal culture identifying GC was also defined as a true positive, although there were no instances in which culture was positive and NAAT was negative for GC.
Descriptive statistics including median, range, and frequency distributions were performed for all demographic and risk behavior characteristics. P values were calculated using Fisher exact or Mann-Whitney U tests. Data analyses were conducted using SPSS statistical software, release 22.0. (IBM Corp, Armonk, NY). Venn diagrams were created using eulerAPE, version 1.0 (University of Kent, Canterbury, UK).
Characteristics of Study Population
A total of 399 participants were recruited: 224 men and 175 women. The median age of the men and women was similar (26 vs. 27 years), but men had a higher median number of male partners in the previous month (Table 1). Condom use with RAI was reported significantly more for men than for women (86.6% vs. 37.7%, P < 0.001). RAI after vaginal sex using the same condom in 6 of the last 10 sexual encounters was reported in half of women. Evaluation of swab collection order showed that there was no significant difference in test positivity by order of collection (data not shown).
Symptoms Associated With Infection
Men with GC were more likely to be symptomatic at any anatomical site (P = 0.02) or have urogenital symptoms (P = 0.001) when compared with men without STIs (Table 2). Men with CT were not more likely to have symptoms at any site than those who tested negative for STIs. Men with GC or CT identified in either rectal or pharyngeal samples were not more likely to be symptomatic than those with no infection. In contrast, women who had pharyngeal GC and CT were more likely to have pharyngeal symptoms than uninfected women (P = 0.003 and 0.02, respectively). Genital infection was not related to urogenital symptoms in women (Table 2).
Infections by Site
N. gonorrhoeae was more common in men versus women (22.8% vs. 3.4%), and more men tested positive for GC from rectal swabs than women, 11.6% to 2.3%, respectively (Table 3). Similarly, a greater proportion of men tested positive for GC from pharyngeal swabs than women, at 16.5% versus 2.3%, respectively. Overall, 21.9% of men versus 12.6% of women had CT at any site (Table 3). More women tested positive for genitourinary chlamydia than men at 10.3% compared with 4.5%. Of the 249 pharyngeal swab samples evaluated by culture for GC, only 13 (5.2%) were positive, all of which were also positive by both NAATs.
Venn diagrams were created to visually display the patterns of STIs by site to demonstrate how many cases of extragenital gonorrhea or chlamydia would be missed if only genitourinary screening occurred (Figs. 1 through 4). In MSM, 39 (80%) of 49 who tested positive for CT and 39 (77%) of 51 who tested positive for GC were only positive in extragenital sites. Among the 22 women who tested positive for CT at any site, 82% were positive using the vaginal swab sample. Of the 6 women who tested positive for GC at any site, 5 (83%) were positive from the vaginal swab sample. The remaining 1 woman was positive for GC on pharyngeal swab by both NAATs.
This study adds to the growing body of evidence reporting a high prevalence of extragenital STIs among men and women who have a lifetime history of RAI. In MSM, the overall prevalence of infection at any site was 22.8% for GC and 21.9% for CT. In women, the prevalence of infection at any site was 3.4% for GC and 12.6% for CT. Notably, if genitourinary screening alone was relied upon for men, 80% of chlamydia and 77% of gonorrhea would be missed, a finding that is consistent with other reports.9–16 The results of this study support the current CDC guidelines, which recommend site-specific risk-based screening in MSM. A limitation of the present study is that the frequency of receptive anal and oral intercourse was not obtained, and we are thus unable to determine if intercourse frequency predicts GC and CT prevalence.
The population studied resembled the population demographics of other similar studies with respect to age, race, STI history, and sexual practices.4,5 In MSM, the prevalence of 11.6% for GC and 17.4% for CT in rectal swab samples was higher than those published from an earlier study with similar inclusion criteria, where rates were 6.2% and 8.9%, respectively.20 The current study also found a higher prevalence of infection compared with various studies of MSM, where the prevalence ranged from 8% to 14% for rectal CT and from 6% to 10% for rectal GC.9–15 Our study showed that pharyngeal infection in MSM was 16.5% for GC and 2.2% for CT, higher than previously reported by a CDC-coordinated study in 2007.21 It is unclear whether the high rates of infections observed in the present and other recent studies are attributable to increased rates of infections, a higher level of ascertainment due to the use of multiple tests, or both.
Our results along with published studies suggest that if vaginal screening alone is used, missed infection ranges from 18% to 40% for GC 5,16,17,22 and 6% to 25% for CT.4,5,16,17,19 Although there was past debate about whether the rectum was truly infected in women having STIs,23 recent reports document that the rectum can serve as a reservoir.24,25 Gratrix et al.18 reported that when CT testing was expanded to include evaluation of rectal swabs, case detection for CT increased by 44%, leading them to support universal screening of women attending STI clinics.
Oral sex is common in men and women, and urogenital organisms are increasingly transmitted to the pharynx. Peters et al.17 demonstrated that of women who tested positive for CT or GC at any site, one-third were positive in the pharynx only. In our study, women with pharyngeal GC or CT were more likely to report pharyngeal symptoms in comparison to those without STIs. Although there have been reports of pharyngeal infection resolving spontaneously,26 those with infection can be symptomatic and infections can be transmitted to men by fellatio,27 albeit probably with low efficiency,28 suggesting that the presence CT or GC reflects an important reservoir of infection. Further research addressing gaps in understanding of the role of pharyngeal CT infection and transmission of STIs deserves further study.
Neither of the NAAT tests used to identify CT or GC by pharyngeal swab has been FDA cleared for use in pharyngeal samples. There is concern that NAAT techniques can be falsely positive for GC due to cross-reaction with the nucleic acid sequences of related organisms, such as Neisseria meningitidis.29 In the present study, all gonococcal infections of the pharynx were confirmed by culture and/or 2 or more NAATs targeting different sets of primers, suggesting that the high rate of pharyngeal infection was not due to false-positive cross-reactivity.
Although there has been a long-standing recognition of the importance of extragenital infections among people having STIs,13,14 this study provides additional data from both men and women who report a lifetime history of RAI. In our study population, screening MSM using only urogenital specimens missed most extragenital infections, whereas urogenital screening in women missed greater than 17% of bacterial STIs. Careful history taking will help to identify both men and women at risk for extragenital infection, and site-appropriate testing using NAAT techniques should be considered.
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