Gillespie, Catherine W. PhD*†; Manhart, Lisa E. PhD†‡; Lowens, M. Sylvan PA-C§¶; Golden, Matthew R. MD†§¶
From the *Children’s Research Institute, Children’s National Medical Center, Washington, DC; †Center for AIDS and STD, Departments of ‡Epidemiology §Medicine, University of Washington, Seattle, WA; and ¶Public Health–Seattle and King County STD Clinic, Seattle, WA
Supported by the University of Washington Sexually Transmitted Infections and Topical Microbicides Cooperative Research Center (Grant No. NIH/NIAID U19 AI31448) and by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (Grant No. NIH/NIAID R01 AI072728). Dr Gillespie was funded by a University of Washington STD/AIDS Research Training Fellowship grant (Grant No. NIH/NIAID T32 AI07140).
Previous presentations: This work was presented, in part, at the 2010 CDC National STD Prevention Conference; Atlanta, GA, USA; March 8–11, 2010 (Abstract No. B3c).
Conflicts of interest: There are no conflicts of interest to disclose.
Correspondence: Catherine W. Gillespie, PhD, Children’s National Medical Center, Children’s Research Institute, Center for Translational Science, 111 Michigan Ave NW, Washington, DC 20010. E-mail: firstname.lastname@example.org.
Received for publication July 23, 2012, and accepted November 2, 2012.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (http://www.stdjournal.com).
Urethritis, or inflammation of the urethra, is typically characterized by urethral discharge, dysuria, or irritation.1 Most urethritis cases are diagnosed among symptomatic men, and clinicians do not routinely evaluate patients for urethral inflammation in the absence of specific complaints. Thus, the prevalence and clinical significance of urethral inflammation among asymptomatic men is poorly defined. We sought to estimate the prevalence of microscopically defined urethritis among asymptomatic men and to identify correlates of this condition, including infection with recognized sexually transmitted pathogens and behaviors typically associated with an elevated risk of sexually transmitted infection.
From July 2007 to September 2009, we recruited 236 men 16 years or older from an emergency department waiting area at a large urban medical center to participate in a “health study for men.” The study population consisted of friends or family members of patients being treated in the emergency department and men with nonemergent problems awaiting care. All men denied urethral symptoms (e.g., discharge from the penis and/or burning with urination) when asked during screening. Those who reported antibiotic use in the prior month or known allergies to azithromycin or tetracycline were not eligible.
Consenting men were escorted to the sexually transmitted disease (STD) clinic located within the same medical center where an experienced STD clinician conducted a focused physical and genital examination, including urethral massage performed by the clinician. The clinician then obtained a urethral specimen for Gram stain by inserting a Dacron swab 1.5 cm into the urethra and rotating one full turn. Urethritis was defined by the presence of at least 5 polymorphonuclear neutrophils (PMNs) per high-powered field (1000×)2 averaged over 3 or more fields on the Gram-stained urethral smear. After examination of the genitalia and urethral swabbing, all men provided a first-void urine specimen, which we tested for Neisseria gonorrhoeae and Chlamydia trachomatis (CT) using APTIMA Combo 2, Trichomonas vaginalis (TV) using research-use only APTIMA TV analyte-specific reagents (Gen-Probe Incorporated, San Diego, CA), and Mycoplasma genitalium (MG) using in-house polymerase chain reaction (PCR).3 We also tested for the newly differentiated ureaplasma species Ureaplasma urealyticum (UU) and Ureaplasma parvum (UP) using culture, followed by in-house species-specific PCR assays.4 In preliminary experiments, this method of UU/UP detection demonstrated improved sensitivity over PCR alone. Finally, we collected detailed sociodemographic and behavioral data via face-to-face interview. A computer-assisted self-interview captured supplemental information about risk factors not covered during the routine clinical evaluation. All study procedures were approved by the University of Washington Human Subjects Division, and written informed consent was obtained from all participants.
We estimated the prevalence of asymptomatic urethritis by calculating the proportion of men with microscopic evidence of urethral inflammation. We identified clinical and sociobehavioral factors associated with urethritis among these asymptomatic men using Pearson χ2 tests and Fisher exact tests for categorical variables and t tests and Wilcoxon rank sum tests for continuous variables. Because asymptomatic urethritis was common in our study population, we used multivariable Poisson regression with a log link and robust standard errors to identify factors independently associated with this finding. In addition to age and race, which were considered a priori to be potentially important confounding factors, characteristics that were marginally significant in univariate analyses (P ≤ 0.1) were entered into the multivariable model. Terms with the largest nonsignificant P values were removed one by one, and the model was refit; age and race were unconditionally retained. Covariates that remained significantly (P ≤ 0.05) associated with asymptomatic urethritis and those whose removal resulted in meaningful (≥10%) changes to remaining point estimates were retained in the final multivariable model. Characteristics initially considered for inclusion included country of birth; highest level of education; annual income; history of incarceration; illicit drug use; exchanging money or drugs for sex; sex of sex partners; sexual repertoire (i.e., oral, anal, and/or vaginal sexual practices); number of sex partners; condom use; previous diagnoses of nongonococcal urethritis, gonococcal infection, chlamydial infection, or depression; circumcision status; time since last void before the examination; presence, amount, and character of urethral discharge seen on examination; and detection of urethral organisms. Given the inconsistent data on the relationship between UU and urethral inflammation5–8 and the absence of an association with UP, we did not assess these organisms as pathogens in our multivariable analyses. All analyses were performed in Stata Version 11.2 (StataCorp, College Station, TX).
Among these 236 asymptomatic men recruited from a medical center waiting area who denied urethral symptoms, mean age was 37.2 years (range, 16.2–63.0 years). Most reported black (52.1%) or white (33.5%) race and having sex with only women in the previous 12 months (94.1%). Most were circumcised (84.0%), less than half reported any prior STD diagnosis (42.2%), and approximately one-quarter (25.9%) reported no sexual activity in the 2 months before the study.
Thirty-eight (16.1%; 95% confidence interval [CI], 11.4%–20.8%) men had evidence of urethral inflammation on Gram-stain microscopy. The study clinician observed a urethral discharge in a total of 20 men, including 16 (42.1%) of 38 (95% CI, 25.7%–58.6%) with positive Gram stains, and 4 of the 198 men with negative Gram stains (2.0%; 95% CI, 0.04%–4.0%). Overall, 80% (95% CI, 60.7%–99.2%) of men with an unrecognized urethral discharge on physical examination had microscopic evidence of inflammation. These findings correspond to a positive predictive value of 80.0% for diagnosing asymptomatic urethritis on the basis of a brief genital examination alone and a negative predictive value of 89.8% in these men with no urethral complaints.
Gonorrhea was not detected among any study participants. C. trachomatis, MG, and/or TV were detected in 6.4% of men (95% CI, 3.2%–9.5%). These pathogens were found almost 5 times more often among asymptomatic men with objective evidence of urethral inflammation (18.4%; 95% CI, 5.5%–31.3%), compared with other asymptomatic men (4.0%; 95% CI, 1.3%–6.8%). Only 33.3% (95% CI, 6.3%–60.4%) of the men with an identified urethral pathogen had a visible urethral discharge (Supplemental Table 1, http://links.lww.com/OLQ/A53).
Asymptomatic urethral inflammation was associated with the following characteristics in univariate analyses (Table 1): black race, having more than a high school education, ever exchanging money or drugs for sex, reporting sexual activity in the 2 months before the study, as well as reporting male sex partners, any insertive anal sex (with men or women), having had at least 1 new sex partner, and having a greater number of sex partners in the 2 months before the study. Men with asymptomatic urethritis were also more likely to report having voided more than 2 hours before the examination and to test positive for CT. We observed a similar trend for MG, TV, UU, and UP, although these differences were not significant. Similarly, although men with asymptomatic urethral inflammation were more likely to be uncircumcised and to have a history of STD than men without urethral inflammation and less likely to report consistent condom use, these differences were also not statistically significant.
Results from multivariable analyses are shown in Table 2. After adjusting for age, asymptomatic urethritis was associated with black or mixed race (adjusted relative risk [aRR], 3.2; 95% CI, 1.3–8.0 and aRR, 3.3; 95% CI, 1.1–9.8), detection of an established urethral pathogen (i.e., CT, MG, or TV) (aRR, 2.6; 95% CI,1.4–4.7), 2 hours or more since last voiding (aRR, 2.3; 95% CI,1.1–4.5), reporting any insertive anal sex in the prior 2 months (aRR, 2.1; 95% CI,1.2–3.9), and greater number of sex partners in the prior 2 months (aRR, 1.1 per partner; 95% CI, 1.1–1.1). Results did not change when pathogen-positive men were excluded.
In summary, we found that the prevalence of urethral inflammation among asymptomatic men recruited from an emergency department waiting area was 16%. Although a urethral infection was detected in less than 20% of these cases, the characteristics independently associated with asymptomatic urethritis were the same as those typically associated with sexually transmitted pathogens. These findings demonstrate that, at least in some populations, asymptomatic urethritis is common and may be a consequence of unidentified sexually transmitted organisms. Although the clinical significance of asymptomatic urethritis is uncertain, our findings highlight the need to better understand the etiology of this syndrome and define its clinical implications, both in men and in their female sex partners.
We conducted this analysis, in part, to determine the extent to which risk factors traditionally associated with sexually transmitted infections might also be associated with asymptomatic idiopathic urethritis. As hypothesized, our detailed sexual behavior data suggest strong associations between this condition and traditionally recognized risk factors for sexually transmitted infections. After accounting for 3 recognized pathogens—CT, MG, and TV (gonorrhea was not detected in any study participants)—the behavioral and physiological correlates of asymptomatic urethral inflammation identified in this study suggest that there may be undetected organisms or irritants to which these men were exposed during insertive anal intercourse or other sexual encounters. It is also possible that some of these individuals may have been infected with known pathogens that had been cleared before testing, whereas an inflammatory response persisted; this phenomenon has been previously described in the context of CT infection.9
We did not have resources to test for viral pathogens including herpes simplex virus and adenovirus, which have both been associated with urethral inflammation, albeit infrequently1,7; nonetheless, our findings contribute additional information to ongoing debates concerning the identification and management of asymptomatic urethritis. Several investigators have assessed the extent to which the identification of asymptomatic urethritis should be an important clinical priority,10–12 reaching mixed conclusions. Also, although there is currently very little evidence to suggest that asymptomatic urethritis, specifically nongonococcal and nonchlamydial cases, results in serious sequelae among affected men and their sex partners, the existing data are scant.13 A recent systematic review14 identified no studies investigating clinical outcomes in men diagnosed as having asymptomatic nonchlamydial, nongonococcal urethritis, and only 2 published reports assessing sequelae in the female sex partners of men with this condition.12,15 Other investigators have observed associations between urethral inflammation and increased HIV-1 shedding16 and semen abnormalities17 among patients with urethritis with and without symptoms.
Our results revive a number of questions for which we still have no answers. Does PMN migration into the urethra always indicate pathology, even in the absence of all other clinical findings? Moreover, would there be psychological sequelae associated with giving this condition a diagnosis of possible or presumed sexually transmitted etiology? An early study by Swartz and Kraus18 suggests that a substantial fraction of cases detected among men without signs or symptoms may spontaneously resolve within a week, and cases that resolve spontaneously are much less likely than those that persist to have a recognized pathogen such as CT detected. In addition, previous investigators have detected a positive correlation between the presence or severity of symptoms and the magnitude of the inflammatory response among men with urethritis.19,20 Furthermore, the degree of urethral inflammation has also been shown to be positively associated with detection of a known pathogen,19 and the pertinent threshold for pathogen-positive cases may be lower than the standard diagnostic criterion of 5 or more PMNs.21 In an age when gonococcal and chlamydial infections can be detected in a urine specimen without an examination, some argue that clinical examinations among asymptomatic men have become obsolete,22 especially in resource-limited settings. However, the proportion of urethritis cases attributed to gonorrhea or chlamydia is in decline.1 If future research will show that idiopathic urethritis is a clinically meaningful outcome, our results suggest that more than 80% of cases could be missed in the absence of routine examinations and microscopy. In addition, although conventional wisdom suggests that men are generally aware of signs of genital tract infections, we noted a somewhat surprising prevalence of unrecognized urethral discharge (nearly 10%) among our asymptomatic study participants. Although data on the prevalence of unrecognized urethral discharge are scarce, this is consistent with at least one prior set of findings from a cross section of STD clinic attendees in the United Kingdom. In that study, 9.1% of 680 patients with and without objectively defined urethritis denied symptoms of urethral discharge, yet had a discharge noted during the examination.23 In our study, this previously unrecognized urethral discharge was strongly predictive of microscopically defined urethral inflammation, highlighting the use of the brief genital examination when used in conjunction with more confirmatory diagnostic approaches such as subsequent microscopy and screening for recognized sexually transmitted pathogens.
During the last 3 decades, efforts to control sexually transmitted bacterial infections have evolved from an exclusive focus on the highest virulence pathogens, syphilis and gonorrhea, to a broader effort that includes frequently asymptomatic microorganisms associated with a somewhat lower risk of adverse sequelae, such as CT and MG. Our findings suggest that the spectrum of less virulent sexually transmitted pathogens remains incompletely defined. Although the clinical implications of our findings are uncertain, we believe that additional efforts to define the broader spectrum of sexually transmitted pathogens and the implications of such infections merit additional study. Studies incorporating repeated assessments of urethral inflammation over time would also provide valuable information about the nature of this finding.
1. Martin DH. Urethritis in males. In: Holmes KK, Sparling PF, Stamm WE, et al.., eds. Sexually Transmitted Diseases, 4th ed. New York: McGraw Hill, 2008: 1107–1126.
2. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2010. MMWR Morb Mortal Wkly Rep 2010; 59: 1–110.
3. Dutro SM, Hebb JK, Garin CA, et al.. Development and performance of a microwell-plate-based polymerase chain reaction assay for Mycoplasma genitalium. Sex Transm Dis 2003; 30: 756–763.
4. Haggerty CL, Totten PA, Ferris M, et al.. Clinical characteristics of bacterial vaginosis among women testing positive for fastidious bacteria. Sex Transm Infect 2009; 85: 242–248.
5. Povlsen K, Bjornelius E, Lidbrink P, Lind I. Relationship of Ureaplasma urealyticum biovar 2 to nongonococcal urethritis. Eur J Clin Microbiol Infect Dis 2002; 21: 97–101.
6. Deguchi T, Yoshida T, Miyazawa T, et al.. Association of Ureaplasma urealyticum (biovar 2) with nongonococcal urethritis. Sex Transm Dis 2004; 31: 192–195.
7. Bradshaw CS, Tabrizi SN, Read TR, et al.. Etiologies of nongonococcal urethritis: Bacteria, viruses, and the association with orogenital exposure. J Infect Dis 2006; 193: 336–345.
8. Wetmore CM, Manhart LE, Lowens MS, et al.. Ureaplasma urealyticum is associated with nongonococcal urethritis among men with fewer lifetime sexual partners: A case-control study. J Infect Dis 2011; 204: 1274–1282.
9. Horner P. The etiology of acute nongonococcal urethritis—The enigma of idiopathic urethritis? Sex Transm Dis 2011; 38: 187–189.
10. Horner P. Asymptomatic men: Should they be tested for urethritis? Sex Transm Infect 2007; 83: 81–84.
11. Shahmanesh M, Radcliffe KW. Is the urethral smear necessary in asymptomatic men attending a genitourinary medicine clinic? Sex Transm Infect 2007; 83: 79–81.
12. Blume A, Main C, Patel R, Foley E. Should men with asymptomatic non-specific urethritis be identified and treated? Int J STD AIDS 2008; 19: 744–746.
13. Ross JCD. Screening asymptomatic men for non-specific urethritis. Sex Transm Infect 2007; 83: 79.
14. Saunders JM, Hart G, Estcourt CS. Is asymptomatic non-chlamydial non-gonococcal urethritis associated with significant clinical consequences in men and their sexual partners: A systematic review. Int J STD AIDS. 2011; 22: 338–341.
15. Manayi K, McMillan A, Young H. Non-chlamydial non-gonococcal urethritis or undiagnosed chlamydial urethritis? Int J STD AIDS 2006; 17: 296–298.
16. Johnson LF, Lewis DA. The effect of genital tract infections on HIV-1 shedding in the genital tract: A systematic review and meta-analysis. Sex Transm Dis 2008; 35: 946–959.
17. Carne CA, Chilcott S, Palmer C, et al.. Low sperm counts in genitourinary medicine clinic attendees: Results from a case-control study. Sex Transm Infect 2012; 88: 422–426.
18. Swartz S, Kraus S. Persistent urethral leukocytosis and asymptomatic chlamydial urethritis. J Infect Dis 1979; 140: 614–617.
19. Wiggins RC, Holmes CH, Andersson M, et al.. Quantifying leukocytes in first catch urine provides new insights into our understanding of symptomatic and asymptomatic urethritis. Int J STD AIDS 2006; 17: 289–295.
20. Moi H, Reinton N, Moghaddam A. Mycoplasma genitalium is associated with symptomatic and asymptomatic non-gonococcal urethritis in men. Sex Transm Infect 2009; 85: 15–18.
21. Reitmeijer CA, Mettenbrink CJ. Recalibrating the Gram stain diagnosis of male urethritis in the era of nucleic acid amplification testing. Sex Transm Dis 2012; 39: 18–20.
22. O, Mahony C. View from the frontline: New tests, new ways, old resistance! Int J STD AIDS 2004; 15: 498.
23. Leung A, Eastick K, Haddon LE, et al.. Mycoplasma genitalium is associated with symptomatic urethritis. Int J STD AIDS 2006; 17: 285–288.