Extragenital gonorrhea (GC) and chlamydial (CT) infections among men who have sex with men (MSM) are common, with prevalences of rectal GC, pharyngeal GC, and rectal CT among MSM sexually transmitted disease (STD) clinic patients documented to be as high as 9.8%, 9.2%, and 8.2%,1–4 respectively. Most extragenital infections are asymptomatic,1,5 and inadequate screening of extragenital sites in MSM is thought to be an important factor fostering the persistence of high levels of GC and CT infection in that population.1,2 A growing body of literature supports the use of nucleic acid amplification tests (NAATs) for extragenital GC and CT screening,6–12 both for its increased sensitivity and ease of processing.13 In 2010, the Centers for Disease and Control Prevention recommended the use of NAAT for testing of extragenital sites in MSM14; however, uptake of NAATs for extragenital testing outside specialty care settings has been limited.13
In 2011, the Public Health–Seattle & King County (PHSKC) STD Clinic switched from culture to NAAT for routine extragenital GC and CT testing in MSM. This analysis compares clinical and laboratory data collected in the PHSKC STD Clinic in 2010, the final year in which extragenital testing was performed primarily by culture, and 2011, the first year in which our clinic used NAAT for routine extragenital testing. The primary objective was to assess how much the change in testing technology affected case finding in a real-world STD clinic setting.
MATERIALS AND METHODS
The PHSKC STD Clinic phased in the routine use of NAAT (Aptima Combo 2; GenProbe, San Diego, CA) for pharyngeal and rectal GC and CT testing in the last 2 months of 2010. By January 1, 2011, NAATs became the main method for testing for GC and CT at extragenital sites. Before that time, extragenital GC and CT testing was performed exclusively by culture. For the study period, we chose to compare 2 calendar years of data: 2010, the last year in which extragenital GC and CT testing occurred primarily by culture, and 2011, the first year in which extragenital testing was routinely performed using NAAT. (The testing technologies overlapped briefly at the end of 2010, which would potentially lead to an underestimate of the effect of the change to NAAT testing.)
For purposes of this analysis, we defined any man who reported having sex with a man in the prior 12 months to be an MSM, including men who also reported having sex with women. For clinic visits where data on the sex of sex partner were missing, if the participant had a prior clinic visit during which the sex partner sex was recorded, we used that information to define the partner sex for the current analysis. Our study population includes all MSM new problem visits, and participants could have been included in the analysis more than once. New problem visits were defined to include all visits occurring at least 30 days after a prior visit, or visits occurring less than 30 days after a prior visit if the patients indicated on their registration form or to front desk staff that they were seeking care for a new concern. Our outcomes of interest were the number of GC and CT infections and cases identified. We defined an infection as any positive test result and defined a case as any individual with a positive test result for either pathogen in a specimen obtained from at least 1 anatomical site. Thus, cases could have multiple sites of infections. Clinical data were entered into an electronic database. All data used for this study were de-identified, and the University of Washington Institutional Review Board determined that the study did not require human participants review.
Clinic and Laboratory Protocol
All patients attending the clinic for a new problem visit complete a structured interview (either by a clinician or via a computer self-interview) that includes questions that identify anatomical sites potentially exposed to infection. The clinic’s protocol during the study period was to test MSM for rectal GC and CT infection if they reported having receptive anal intercourse in the prior 12 months and to test men who reported performing fellatio in the previous 2 months for pharyngeal GC. Throughout the study period, men without symptoms who reported insertive anal sex or receiving oral sex in the prior 2 months were tested for urethral GC and CT infection using Aptima Combo 2 testing on urine specimens. Men with signs or symptoms of urethritis underwent Gram stain and culture for Neisseria gonorrhoeae on urethral specimens in addition to urine NAAT testing. Although clinic policy for routine screening was as outlined above, in some instances, clinicians deviated from testing protocol based on their clinical judgment.
Beginning in 2011, after an internal validation study, clinicians were able to offer patients the option to self-collect extragenital specimens. Patients who chose this option were provided with verbal instructions by their provider during the procedure; 43% of rectal swabs and 15% of pharyngeal swabs in 2011 were collected in this manner.
We considered patient-reported symptoms, as well as provider-documented physical findings, as signs or symptoms for this analysis. Urethral symptoms included patient-reported urethral discharge, dysuria, or other nonspecified urethral symptoms; signs included urethral discharge on physical examination. Rectal symptoms consisted of patient-reported anorectal pain or discharge; men with anorectal discharge on examination were defined as having signs of rectal infection. Patient-reported odynophagia or provider-documented pharyngeal erythema or exudates were considered pharyngeal signs or symptoms, respectively.
For the purposes of this study, either a positive NAAT or a positive culture was considered a positive test result. Before initiating extragenital NAAT testing, the King County Public Health laboratory undertook an internal validation study to become Clinical Laboratory Improvement Amendment certified for use of the Aptima Combo 2 on specimens from the pharynx and the rectum.
Descriptive statistics included proportions (number and percent) for binary variables and means with SDs for continuous variables. χ2 Tests were used to assess for differences in proportions. Because we observed a decline in the number of cases of urethral GC and CT in our study population and there was a decline in the number of gonococcal cases reported in King County15 over the course of the study period, we included in our analysis an effort to control for a possible secular trend in the occurrence of these infections. To do this, we compared the number of extragenital cases to the number of urogenital cases of GC and CT diagnosed in the clinic. We then calculated the percent change in the ratio of rectal to urethral and pharyngeal to urethral specimens between the 2 periods. Because our clinic used NAAT on urethral and urine specimens throughout the study period, and we are not aware of large new sources of STD care for MSM in Seattle during the study period, we believe that changes in the number of urethral infections diagnosed in the clinic over time primarily reflect changes in community morbidity. This would be particularly true of urethral GC, which was almost always associated with symptoms throughout the study period. Data analysis was performed with Stata 9.2 or higher (StataCorp; College Station, TX). An α of 0.05 was considered significant.
A total of 3039 MSM attended the STD clinic during 4877 total visits and 4028 new problem visits in 2010. In 2011, 3034 MSM attended the clinic during 4991 total visits and 4011 new problem visits. Over the 2-year period, men were similar in mean age (36.0 years vs. 36.8 years), racial/ethnicity distribution (data not shown), and their average number of sexual partners (3.3 vs. 3.9). Among men reporting pharyngeal, rectal, or urethral sexual exposure, anatomical site-specific testing coverage remained largely unchanged over the 2 study years (Table 1).
Test Positivity and Number of Infections and Cases Detected
Between 2010 and 2011, the number of cases diagnosed with GC, CT, or both among MSM attending the PHSKC STD Clinic increased from 630 to 690. After the adoption of NAAT in 2011, there was a small, nonsignificant increase in the percentage of rectal and pharyngeal specimens testing positive for N. gonorrhoeae (9.0% vs. 9.7% [P = 0.435] and 5.8% vs. 6.5% [P = 0.305], respectively), representing an 8% and 12% increase. The number of extragenital infections detected also increased in 2011 with 33 more pharyngeal and 29 more rectal GC infections detected, representing a 21% and 15% increase, respectively (Table 1). Most of these infections were asymptomatic (82% of rectal and 92% of pharyngeal GC, 2011). Both the proportion of rectal specimens that tested positive for Chlamydia trachomatis (7.4% vs. 11.9%, P < 0.001) and the absolute number of rectal CT infections detected increased (152 in 2010 and 268 in 2011; a 76% increase). These infections were primarily asymptomatic (87%). Before 2011, our clinic did not screen for pharyngeal CT; however, 2.3% (n = 52) of pharyngeal specimens obtained from MSM in our clinic in 2011 tested positive for C. trachomatis by NAAT.
At the same time, we diagnosed 66 fewer gonococcal urethral infections, and there was a statistically significant decline in the percentage of urethral or urine specimens testing positive for urethral GC between 2010 and 2011 (7.7% vs. 5.5%, P = 0.001; Table 1). Although both the number of CT urethritis infections (156 in 2010 vs. 122 in 2011) and urethral CT test positivity (5.7% vs. 4.5%, P = 0.055) declined, this did not reach statistical significance. Among men with urethral infections, 351 (96%) of 366 MSM with GC and 194 (70%) of 278 MSM with CT infection had signs or symptoms of urethritis; the proportion of men with urethral GC or CT who had signs or symptoms of urethritis did not significantly vary between the 2 study years (data not shown).
Increased Extragenital Infections Standardized Against the Number of Urethral Infections
Because the proportion of MSM with urethral gonococcal infections declined between 2010 and 2011, suggesting a possible secular trend in GC in the population, we sought to better define the potential impact of our adoption of NAAT on case yields by looking at the ratio of extragenital and genital tract infections in MSM (Fig. 1). In 2010, there were 88 rectal GC infections for every 100 urethral GC infections. In 2011, that ratio rose to 146 rectal GC infections per 100 urethral GC infections, a 66% increase. Similarly we observed a 74% increase in the ratio of pharyngeal to urethral gonococcal infections. The impact of NAAT testing was greater still for rectal CT infection; after implementation of NAAT-based extragenital testing, the ratio of rectal to urethral CT infection increased 127%.
Proportion of Isolated Extragenital Infections
In 2010, among those tested for both urethral and extragenital infections, 43% of 591 GC and CT cases were isolated to the pharynx and/or rectum; after the adoption of NAAT in 2011, that proportion increased to 57% of 579 cases (P = 0.056). Although the absolute number of cases of GC declined from 432 to 414 between 2010 and 2011 (data not shown), among men tested at both the urethra and at least 1 extragenital sites, the proportion of all GC infections diagnosed that were isolated to the extragenital sites increased from 46% to 58% (Fig. 2). In contrast, both the absolute number of cases of CT and the proportion of CT infections in men tested at both the urethra and either the rectum or pharynx or both that were isolated to extragenital sites increased during the study period: in 2010, there were 290 cases of CT, 43% of which were isolated extragenital infections; in 2011, the clinic diagnosed 396 cases of CT infection, 63% of which were isolated to the pharynx and/or rectum.
This analysis demonstrates that routine extragenital NAAT for GC and CT substantially increased the detection of GC and CT infections among MSM in our STD clinic. Our findings support the Centers for Disease and Control Prevention’s 2010 STD Treatment Guidelines recommendation that NAAT should be used routinely to test rectal and pharyngeal GC and CT infection. The improved infection detection rate was primarily led by the large gain in detection of rectal CT infections, which is reminiscent of the change to from culture to NAAT testing for genital tract infections over a decade ago.16,17 To our knowledge, the 12% prevalence of rectal CT infection among tested MSM in our clinic exceeds prior reports of rectal test positivity (7.8%–8.2%)4,18 and highlights the importance of rectal STD screening in MSM.
In our study, if MSM were tested for urethral but not rectal or pharyngeal infections, 57% of all GC or CT cases among MSM in our clinic would have been missed. This quantity is comparable with previously published estimates of the proportion of extragenital infections among MSM that occur in the absence of urethral infections.2,18 Some investigators have postulated that the pharynx and the rectum serve as largely undetected reservoirs of ongoing GC and CT transmission within the MSM community.5,19 Infections at these sites are overwhelmingly asymptomatic, and testing coverage, even at most STD clinics, remains suboptimal.20 Given that a large proportion of GC and CT infections are isolated to the extragenital spaces and not identified with urine testing alone, under current testing practices, we suspect that most GC and CT infections among MSM receiving medical care related to STDs in the United States remain undiagnosed and untreated.
There were several limitations to this study. Most importantly, we did not directly compare culture and NAAT-based testing. However, the operational nature of our study is also a strength. Prior studies have compared NAAT and culture testing directly and have consistently demonstrated the superiority of NAATs to culture.6–8,10,11 Our aim was to evaluate increases in bacterial STD detection due to a change in clinic policy to use a more sensitive test. Also, although we did not observe large changes in the composition of our MSM clinic population over the course of our study and used urethral to extragenital ratios as a means to control for a possible secular trend in STD incidence that occurred during our study period, our findings could have been affected by other, unmeasured changes in the population studied and their risk of STDs. Second, our data are subject to the limitations inherent in research derived from clinical documentation. Our clinic has worked hard to use consistent documentation through use of a standardized charting form. It is also important to note that in 2011, we introduced the option of self-obtained testing with NAAT for extragenital testing. Although, in our unpublished analyses, we have not seen any differences in positivity between clinician- and self-collected specimens, other published reports have found either an increased21–23 or decreased23 yield with self-collected specimens, possibly introducing bias into our findings. Lastly, our study represents the findings of a single metropolitan STD clinic and thus may not be generalizable to some other populations of MSM. However, the high prevalence of asymptomatic extragenital STI we observed is consistent with findings from other STD clinics,1–4 suggesting that the substantial increase in case finding we observed would likely occur in other clinical settings that provide care to MSM at high risk for STD.
In conclusion, our findings demonstrate that the institution of NAAT for routine rectal and pharyngeal testing of MSM STD clinic patients dramatically increases GC and CT detection. Case finding and treatment is a longstanding cornerstone of STD prevention, and the emergence of N. gonorrhoeae with decreased susceptibility to oral cephalosporins demands a more aggressive clinical and public health approach to GC control. One advantage of NAATs is that they provide the option for testing outside the clinical setting, such as in the home or at community venues, increasing testing opportunities. However, NAATs have the disadvantage of not providing antimicrobial susceptibility data on circulating gonococci. In our clinic, we attempt to obtain cultures from all men who have positive GC screening test results, a practice that permits us to capitalize on the increased sensitivity of NAATs while still obtaining some antimicrobial susceptibility data for surveillance. Extragenital NAAT testing represents a potentially important advance in the control of bacterial STD in MSM. Our findings should add momentum to efforts to identify and treat extragenital GC and CT infection.
1. Morris SR, Klausner JD, Buchbinder SP, et al. Prevalence and incidence of pharyngeal gonorrhea in a longitudinal sample of men who have sex with men: The EXPLORE study. Clin Infect Dis 2006; 43: 1284–1289.
2. Kent CK, Chaw JK, Wong W, et al. Prevalence of rectal, urethral, and pharyngeal chlamydia and gonorrhea detected in 2 clinical settings among men who have sex with men: San Francisco, California, 2003. Clin Infect Dis 2005; 41: 67–74.
3. Gunn RA, O’Brien CJ, Lee MA, et al. Gonorrhea screening among men who have sex with men: Value of multiple anatomic site testing, San Diego, California, 1997–2003. Sex Transm Dis 2008; 35: 845–848.
4. Annan NT, Sullivan AK, Nori A, et al. Rectal Chlamydia—A reservoir of undiagnosed infection in men who have sex with men. Sex Transm Infect 2009; 85: 176–179.
5. Kinghorn G. Pharyngeal gonorrhoea: A silent cause for concern. Sex Transm Infect 2010; 86: 413–414.
6. Stary A, Ching SF, Teodorowicz L, et al. Comparison of ligase chain reaction and culture for detection of Neisseria gonorrhoeae
in genital and extragenital specimens. J Clin Microbiol 1997; 35: 239–242.
7. Ota KV, Tamari IE, Smieja M, et al. Detection of Neisseria gonorrhoeae
and Chlamydia trachomatis
in pharyngeal and rectal specimens using the BD Probetec ET system, the Gen-Probe Aptima Combo 2 assay and culture. Sex Transm Infect 2009; 85: 182–186.
8. Schachter J, Moncada J, Liska S, et al. Nucleic acid amplification tests in the diagnosis of chlamydial and gonococcal infections of the oropharynx and rectum in men who have sex with men. Sex Transm Dis 2008; 35: 637–642.
9. Young H, Manavi K, McMillan A. Evaluation of ligase chain reaction for the non-cultural detection of rectal and pharyngeal gonorrhoea in men who have sex with men. Sex Transm Infect 2003; 79: 484–486.
10. Bachmann LH, Johnson RE, Cheng H, et al. Nucleic acid amplification tests for diagnosis of Neisseria gonorrhoeae
and Chlamydia trachomatis
rectal infections. J Clin Microbiol 2010; 48: 1827–1832.
11. Bachmann LH, Johnson RE, Cheng H, et al. Nucleic acid amplification tests for diagnosis of Neisseria gonorrhoeae
oropharyngeal infections. J Clin Microbiol 2009; 47: 902–907.
12. McNally LP, Templeton DJ, Jin F, et al. Low positive predictive value of a nucleic acid amplification test for nongenital Neisseria gonorrhoeae
infection in homosexual men. Clin Infect Dis 2008; 47: e25–e27.
13. Fairley CK, Chen MY, Bradshaw CS, et al. Is it time to move to nucleic acid amplification tests screening for pharyngeal and rectal gonorrhoea in men who have sex with men to improve gonorrhoea control? Sex Health 2011; 8: 9–11.
14. Workowski KA, Berman S. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep 2010; 59: 1–110.
15. Kerani RP. 2011 King County Sexually Transmitted Diseases Epidemiology Report. Seattle, WA: Public Health–Seattle & King County, 2011.
16. Johnson RE, Green TA, Schachter J, et al. Evaluation of nucleic acid amplification tests as reference tests for Chlamydia trachomatis
infections in asymptomatic men. J Clin Microbiol 2000; 38: 4382–4386.
17. Scoular A, McCartney R, Kinn S, et al. The ‘real-world’ impact of improved diagnostic techniques for Chlamydia trachomatis
infection in Glasgow. Commun Dis Public Health 2001; 4: 200–204.
18. Marcus JL, Bernstein KT, Kohn RP, et al. Infections missed by urethral-only screening for chlamydia or gonorrhea detection among men who have sex with men. Sex Transm Dis 2011; 38: 922–924.
19. Weinstock H, Workowski KA. Pharyngeal gonorrhea: An important reservoir of infection? Clin Infect Dis 2009; 49: 1798–1800.
20. CDC. Sexually Transmitted Disease Surveillance, 2008. Atlanta, GA: U.S. Department of Health and Human Services; 2009 November, 2009.
21. Sexton ME, Baker JJ, Nakagawa K, et al. How reliable is self-testing for gonorrhea and chlamydia among men who have sex with men? J Fam Pract 2013; 62: 70–78.
22. Freeman AH, Bernstein KT, Kohn RP, et al. Evaluation of self-collected versus clinician-collected swabs for the detection of Chlamydia trachomatis
and Neisseria gonorrhoeae
pharyngeal infection among men who have sex with men. Sex Transm Dis 2011; 38: 1036–1039.
23. van der Helm JJ, Hoebe CJ, van Rooijen MS, et al. High performance and acceptability of self-collected rectal swabs for diagnosis of Chlamydia trachomatis
and Neisseria gonorrhoeae
in men who have sex with men and women. Sex Transm Dis 2009; 36: 493–497.