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Nonchlamydial nongonococcal urethritis in men
Urological Science 24 (2013) 73e77
Contents lists available at ScienceDirect
Urological Science journal homepage: www.urol-sci.com
Mini review
Nonchlamydial nongonococcal urethritis in menq
CME Credits
Chia-Chun Tsai*, Ching-Chia Li Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 March 2013 Received in revised form 12 April 2013 Accepted 5 June 2013 Available online 15 August 2013
By definition, nongonococcal urethritis (NGU) is an infectious condition involving urethra inflammation without Neisseria gonorrhoeae infection. According to recent studies, NGU accounts for 10e30% of initial visits to sexually transmitted infection (STI) clinics, and is one of the most common forms of STI in men. Chlamydia trachomatis is the most prevalent and well-established pathogen in NGU. However, nonchlamydial NGU is still a problematic disease in clinics because of its minimally symptomatic or asymptomatic manifestation. Various infection causes, including Mycoplasma, Trichomonas vaginalis, and herpes simplex virus, are possible pathogens in nonchlamydial NGU. In this brief review, we focus on the evaluation and management of nonchlamydial NGU. Copyright Ó 2013, Taiwan Urological Association. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: nonchlamydial urethritis nongonococcal urethritis
1. Introduction
2. Urethritis
According to the National Health Insurance Database in Taiwan, the prevalence of sexually transmitted infection (STI) has been gradually rising in the past decades. Neisseria gonorrhoeae and Chlamydia urethritis are the most common pathogens of STIs in men. Nongonococcal urethritis (NGU), characterized by a urethral inflammation that is not caused by N. gonorrhoeae infection, is probably the most common form of STI in men. It accounts for 10e30% of new male cases in STI clinics.1 Many pathogens can be identified for NGU and Chlamydia trachomatis is the most prevalent and well-established. C. trachomatis infection accounts for 15e40% of cases of initial NGU, and some studies have reported up to 50% of new cases.1,2 However, nonchlamydial NGU is still a problematic disease for clinics. Various infectious pathogens, including Mycoplasma, viruses, and protozoan parasites, are possible causes of NGU3 and exhibit similar symptoms. However, pathogens still cannot be detected in most cases of nonchlamydial NGU.2,4,5 This makes it difficult for physicians to make an accurate diagnosis. In this brief review, we focus on the common pathogens of nonchlamydial NGU: their prevalence, evaluation, and pathogenesis. The recommended regimens and prevention strategies for various causes of nonchlamydial NGU are also discussed in this article.
Urethritis, which is characterized by urethral inflammation, results from infectious, traumatic, and immune sources. In the infectious case, urethritis is usually acquired through an STI and shows similar symptoms and signs. In general, mucopurulent or purulent discharge from the urethral meatus and dysuria are the most common presentations (Fig. 1). An itching or burning sensation in the urethra is also typical. It is diagnosed according to the mentioned findings or one of the following laboratory tests.4 (1) The diagnosis is positive if a Gram stain of urethral discharge shows more >5 white blood cells (WBCs) per oil-immersion field. This recommended microscopic test is rapid, and features high sensitivity and specificity to identify a gonorrheal infection. (2) The diagnosis is positive if a microscopic examination of first-void urine shows >10 WBCs per high-power field. (3) The diagnosis is positive if a leukocyte esterase test of first-void urine shows positive results. Using a urethral swab to collect secretions for cultures, hybridization tests, or nucleic acid amplification tests (NAATs) is a common diagnostic method to confirm a pathogen, whereas first-void urine specimens can only be tested using NAATs. Recently, NAATs have become gradually accepted and preferred for confirmation of the pathogen of infectious urethritis because of their high sensitivity and specificity. If diagnostic tools and microscopic tests are unavailable, the Center for Disease Control and Prevention (CDC) recommends that sexually active patients who present with urethritis upon examination be treated with drug regimens effective against both gonorrhea and chlamydiasis.4 Despite the availability of numerous testing methods, a pathogen still cannot be detected in many cases of urethritis, especially in nonchlamydial NGU. Numerous cases of nonchlamydial NGU go unnoticed because of
* Corresponding author. Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Number 68, Zhonghua 3rd Road, Cianjin District, Kaohsiung City 80145, Taiwan. E-mail address: [email protected] (C.-C. Tsai). q There are 3 CME questions based on this article.
1879-5226/$ e see front matter Copyright Ó 2013, Taiwan Urological Association. Published by Elsevier Taiwan LLC. All rights reserved. http://dx.doi.org/10.1016/j.urols.2013.06.001
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C.-C. Tsai, C.-C. Li / Urological Science 24 (2013) 73e77
Fig. 1. Nonchlamydial nongonococcal urethritis presents with mucopurulent discharges from the urethral meatus.
their minimally symptomatic or asymptomatic manifestations. Although the prevalence of nonchlamydial NGU is not uniform among communities and populations, it is usually highest in adolescents and adults <25 years old. It is estimated that 10e20% of chlamydial NGU and 20e30% of nonchlamydial NGU may be recurrent within 6 weeks after symptomatic resolution.1 Incorrect diagnosis, combined STIs, incomplete therapeutic regimens, and reinfection by an infected sexual partner are the major causes of recurrent or persistent NGU. To minimize transmission, a complete course of treatment should be initiated immediately after diagnostic confirmation. Men with documented NGU have a high rate of reinfection within 6 months after treatment, therefore, repeat testing of all men diagnosed with NGU is recommended 3e6 months after treatment.6,7 Additionally, because asymptomatic infection is common and the risk of coinfection is high, partners of men with initial NGU should be evaluated and considered for treatment. The CDC suggests that all sexual partners within the preceding 60 days be referred for evaluation, testing, and empirical treatment with a drug regimen effective against Chlamydia. To eliminate the risk of reinfection, men treated for NGU should also be asked to refrain from sexual behavior for at least 7 days after symptomatic resolution and complete a therapeutic regimen.4 STIs are important cofactors in HIV transmission, thus, it is also recommended that patients who have been diagnosed with initial NGU receive testing for other STIs, especially human immunodeficiency virus (HIV) infection and syphilis.
most NGU patients. Recent data supporting U. urealyticum as a commensal or pathogenic bacterium are inconsistent.2,3,5 Further studies are required to improve our understanding of the role of U. urealyticum in NGU. In a clinical manifestation of NGU, the urethral discharge is usually clear or mucoid, and has >5 WBCs per oil-immersion field. Although M. genitalium infection of NGU usually induces symptoms of urethral inflammation, asymptomatic infection is still common. The typical diagnostic methods used to detect M. genitalium urethritis are culture or direct microscopic smear. However, these two methods have relatively low sensitivity. A culture test requires swab specimens from the urethra. M. genitalium is more difficult to culture than other species of Mycoplasma, therefore, cultures have little benefit in clinical diagnosis. In recent clinical practice, M. genitalium-related NGU has been detected with NAATs by testing first-void urine or collecting urethral discharges.10 Mycoplasma spp. have no cell wall, thus, M. genitalium is resistant to all b-lactams or cephalosporins. The recommended antibiotics for M. genitalium-related NGU are macrolides (such as azithromycin) or tetracyclines (such as doxycycline). The dose regimens are the same as for chlamydial infection, and treatment should start after diagnosis. Some studies have reported that a single 1-g dose of azithromycin is more effective than doxycycline.4,11 However, treatment using these two antibiotics fails in some cases of chronic NGU caused by inadequate treatment and recurrent infection.9,12 4. Trichomoniasis Trichomoniasis is caused by Trichomonas vaginalis and is the most prevalent nonviral STI in sexually active populations, and affects an estimated 170 million people worldwide.13,14 Trichomoniasis, which is primarily observed in women, presents as an asymptomatic manifestation in up to one-third of infected women. Symptomatic manifestations involve inflammation, an itching sensation around the genital area, vulvar irritation and erythema,
3. Mycoplasma Mycoplasma, a type of Gram-negative bacteria without a cell wall, represents several original species. Among several recognized species of genital mycoplasmas, Mycoplasma genitalium, Ureaplasma spp., and Mycoplasma hominis, are believed to be possible pathogens in the genitourinary tract of humans. However, only M. genitalium and Ureaplasma urealyticum have been recognized as possible etiological agents of NGU. Mycoplasma genitalium infection is the most frequently reported pathogen in nonchlamydial NGU. Approximately 15e25% of cases of NGU are thought to be caused by M. genitalium.2 Previous studies8,9 have demonstrated a strong association between M. genitalium infection and NGU in men, especially among those with recurrent or persistent NGU. In contrast to the positive correlation of M. genitalium to NGU, U. urealyticum is relatively uncommon and weakly associated with
Fig. 2. Light microscopic picture of Trichomonas vaginalis in smear.
C.-C. Tsai, C.-C. Li / Urological Science 24 (2013) 73e77
purulent vaginal discharge, decreased vaginal pH level, and a typical erythematous cervix with punctate areas of exudation, also known as a strawberry cervix. However, the prevalence of the T. vaginalis infection in men is not well known because most infected men have minimal or no symptoms and transmit the pathogen unknowingly.15 In a recent study, 75% of infected men were asymptomatic.16 Other screenings of the community showed that the prevalence of trichomoniasis in men is approximately 10%17 in nonclinical cases and 12e17% in STI clinical cases.18e20 Other infected male patients may have symptoms similar to those of other NGUs. T. vaginalis has been recognized as a cause of nonchlamydial NGU in men, in whom it has the potential to induce balanoposthitis, epididymitis, urethral stricture, prostatitis, infertility, and even prostate cancer.21e25
75
Various diagnostic methods are used to detect T. vaginalisrelated NGU. Typically, diagnosis of trichomoniasis in men is confirmed by direct microscopic examination of secretions from all genitourinary sites, such as the urethra, epididymis, prostate, and semen (Fig. 2). However, this method has relatively low sensitivity, and is impractical in clinical and nonclinical settings.4 Culture testing of a urethral swab, first-void urine, or semen is another highly specific option. However, it is still not a sensitive diagnostic method. Urethral cultures are able to grow T. vaginalis in only 60% of cases.25 However, recent polymerase chain reactions and rapid antigen tests for the detection of T. vaginalis from first-void urine or urethral swabs have superior sensitivity for T. vaginalis diagnosis in men, and have become increasingly popular.18,26e28 A single 2-g dose of metronidazole or tinidazole, taken orally, is the regimen
Fig. 3. The algorithm for the management of nonchlamydial nongonococcal urethritis in men. HSV ¼ herpes simplex virus; IgG ¼ immunoglobulin G; NAAT ¼ nucleic acid amplification tests; PCR ¼ polymerase chain reaction.
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recommended by the CDC for T. vaginalis infection, or recurrent NGU, in men. The alternative regimen is 500 mg metronidazole taken orally twice a day for 7 days.4 Patients should avoid drinking alcohol during treatment, and for at least 24 hours after completion of metronidazole or 72 hours after completion of tinidazole, to prevent a disulfiram-like reaction. This infection is typically acquired during sexual intercourse, and other circumstances of contamination are rare. Even without symptoms, an asymptomatic carrier continues to infect or reinfect a sexual partner until he or she has been treated. In a previous study, T. vaginalis was isolated from 67e100% of female partners of infected men and 14e60% of male partners of infected women.29 A more recent study also indicated that 73% of male sexual partners of women who had trichomoniasis were positive for T. vaginalis infection.16 Another community-based study showed that the prevalence of trichomoniasis was 10.7% in women and 6.3% in their male partners.30 Therefore, we suggest a concomitant survey and, if necessary, treatment of sexual partners of the infected person when the diagnosis of T. vaginalis infection is confirmed. 5. Herpes simplex virus Herpes simplex virus (HSV) is an important pathogen in genital and oral isolates and is separated into two types. Both HSV-1 and HSV-2 have been recognized as causes of chronic, life-long genital infections. HSV-2 infection has been identified as the dominant cause of most recurrent genital ulcers. However, most people infected with HSV-2 are asymptomatic and have not been diagnosed with genital herpes. It is a major problem that many of these people tend to be unaware of their infection, and transmit the infection to their sexual partners. However, in populations with a high frequency of orogenital exposure and anal intercourse, an increasing proportion of anogenital HSV-1 infection has been noted. Up to 50% of primary genital herpes is caused by HSV-1, but its recurrence and subclinical shedding are much less frequent than for genital HSV-2 infections.4,5,31 The typical clinical manifestation of a genital HSV infection is painful genital, anal, or perianal vesicles and ulcers, but many genital HSV infections are still subclinical. HSV is also a reported pathogen of NGU. Genital itching, dysuria, vaginal or urethral discharge, and tender inguinal lymphadenopathy are other predominant local symptoms of HSV infection. Urethral discharge and dysuria, which are similar to the classical symptoms of NGU, are noted in approximately one-third of men with a primary HSV infection.5 Bradshaw et al2 have indicated that HSV, usually HSV-1, accounts for 2e5% of cases of NGU. Consequently, sexually active patients and sexual partners with genital herpes or mucocutaneous lesions should be tested for HSV infection when NGU is diagnosed. Virological tests, identification of HSV from first-void urine or urethral swab using a cell culture or NAAT, are more reliable than a physical examination, but are not widely available. Type-specific serological assays for immunoglobulin G antibodies of HSV, which determine the virus type, are more useful in clinical settings to survey latent-virus infection. Conversely, immunoglobulin M serological tests are not suggested as a diagnostic method because of long-term persistence in chronic herpes, the frequency of false results, and non-type-specific assays. Unlike recurrent genital HSV, which is usually self-limited, all primary genital herpes-related NGUs should be treated with recommended regimens of acyclovir, famciclovir, or valacyclovir, in addition to azithromycin or doxycyclin.1,4 The regimens recommended by the CDC are: 400 mg acyclovir taken orally three times daily for 7e10 days, or 200 mg acyclovir taken orally five times daily for 7e10 days; 250 mg famciclovir taken orally three times daily for 7e10 days, or 1 g valacyclovir taken orally twice daily for 7e10 days. Systemic antiviral
drugs, which are capable of controlling the symptoms and reducing the duration of herpes episodes, offer clinical benefits to most symptomatic patients. However, these drugs cannot destroy latent viruses. To reduce recurrence of HSV, suppressive therapy for recurrent genital herpes has been established. Suppressive antiviral therapy has been reported to reduce the frequency of genital herpes recurrences by 70e80%.4,32 Topical therapies with antiviral drugs have minimal and limited benefits. 6. Conclusion Asymptomatic infections are common and many patients are treated without diagnostic confirmation. Therefore, the prevalence of nonchlamydial NGU is likely to be much higher than reported. In clinical practice, it is a major problem that accurate diagnoses or adequate solutions are usually absent in most cases of nonchlamydial NGU. M. genitalium is the most common pathogen and causes 15e25% of nonchlamydial NGU. Recurrent and persistent nonchlamydial NGU should be evaluated for drug compliance and uncommon infection, such as T. vaginalis, U. urealyticum, or HSV infection. All persons with nonchlamydial NGU should remain abstinent from sexual activity for at least 7 days after complete treatment and symptomatic resolution. Comprehensive surveys of other STIs, especially HIV infection, syphilis, and gonorrhea, are recommended in the general treatment of nonchlamydial NGU because the infections are commonly combined. Finally, this paper describes clinical strategies in the management of nonchlamydial NGU in men (Fig. 3). Conflicts of interest statement The authors declare that they have no financial or non-financial conflicts of interest related to the subject matter or materials discussed in the manuscript. Sources of funding None. References 1. Handsfield HH. Nongonococcal urethritis. In: Color atlas & synopsis of sexually transmitted disease. 3rd ed. New York, NY: McGraw-Hill; 2011. p. 207e15. 2. Bradshaw CS, Tabrizi SN, Read TR, Garland SM, Hopkins CS, Moss LM, et al. Etiologies of nongonococcal urethritis: bacteria, viruses, and the association with orogenital exposure. J Infect Dis 2006;193:336e45. 3. Martin DH. Nongonococcal urethritis: new views through the prism of modern molecular microbiology. Curr Infect Dis Rep 2008;10:128e32. 4. Workowski KA, Berman S. Sexually transmitted diseases treatment guidelines, 2010. MMWR Morb Mortal Wkly Rep 2010;59:1e110. 5. Martin DH. Urethritis in males. In: Holmes KK, Sparling PF, Stamm WE, Piot P, Wasserheit JN, Corey L, et al., editors. Sexually transmitted diseases. 4th ed. New York, NY: McGraw-Hill; 2008. p. 1007e26. 6. Fung M, Scott KC, Kent CK, Klausner JD. Chlamydial and gonococcal reinfection among men: a systematic review of data to evaluate the need for retesting. Sex Transm Infect 2007;83:304e9. 7. Kissinger PJ, Reilly K, Taylor SN, Leichliter JS, Rosenthal S, Martin DH. Early repeat Chlamydia trachomatis and Neisseria gonorrhoeae infections among heterosexual men. Sex Transm Dis 2009;36:498e500. 8. Taylor-Robinson D, Gilroy CB, Thomas BJ, Hay PE. Mycoplasma genitalium in chronic non-gonococcal urethritis. Int J STD AIDS 2004;15:21e5. 9. Wikström A, Jensen JS. Mycoplasma genitalium: a common cause of persistent urethritis among men treated with doxycycline. Sex Transm Infect 2006;82:276e9. 10. Dupin N, Bijaoui G, Schwarzinger M, Ernault P, Gerhardt P, Jdid R, et al. Detection and quantification of Mycoplasma genitalium in male patients with urethritis. Clin Infect Dis 2003;37:602e5. 11. Mena LA, Mroczkowski TF, Nsuami M, Martin DH. A randomized comparison of azithromycin and doxycycline for the treatment of Mycoplasma genitaliumpositive urethritis in men. Clin Infect Dis 2009;48:1649e54. 12. Hamasuna R, Osada Y, Jensen JS. Antibiotic susceptibility testing of Mycoplasma genitalium by TaqMan 50 nuclease real-time PCR. Antimicrob Agents Chemother 2005;49:4993e8.
C.-C. Tsai, C.-C. Li / Urological Science 24 (2013) 73e77 13. Johnston AJ, Mabey DC. Global epidemiology and control of Trichomonas vaginalis. Curr Opin Infect Dis 2008;21:56e64. 14. Van Der Pol B. Trichomonas vaginalis infection: the most prevalent nonviral sexually transmitted infection receives the least public health attention. Clin Infect Dis 2007;44:23e5. 15. Watson-Jones D, Mugeye K, Mayaud P, Ndeki L, Todd J, Mosha F, et al. High prevalence of trichomoniasis in rural men in Mwanza, Tanzania: results from a population based study. Sex Transm Infect 2000;76:355e62. 16. Hobbs MM, Lapple DM, Lawing LF, Schwebke JR, Cohen MS, Swygard H, et al. Methods for detection of Trichomonas vaginalis in the male partners of infected women: implications for control of trichomoniasis. J Clin Microbiol 2006;44: 3994e9. 17. Chai SJ, Aumakhan B, Barnes M, Jett-Goheen M, Quinn N, Agreda P, et al. Internet-based screening for sexually transmitted infections to reach nonclinic populations in the community: risk factors for infection in men. Sex Transm Dis 2010;37:756e63. 18. Wendel KA, Erbelding EJ, Gaydos CA, Rompalo AM. Use of urine polymerase chain reaction to define the prevalence and clinical presentation of Trichomonas vaginalis in men attending an STD clinic. Sex Transm Infect 2003;79:151e3. 19. Schwebke JR, Hook III EW. High rates of Trichomonas vaginalis among men attending a sexually transmitted diseases clinic: implications for screening and urethritis management. J Infect Dis 2003;188:465e8. 20. Borchardt KA, al-Haraci S, Maida N. Prevalence of Trichomonas vaginalis in a male sexually transmitted disease clinic population by interview, wet mount microscopy, and the InPouch TV test. Genitourin Med 1995;71:405e6. 21. STARK JR. Prospective study of Trichomonas vaginalis infection and prostate cancer incidence and mortality: Physicians’ Health Study. J Natl Cancer Inst 2009;101:1368e9. 22. Krieger JN. Review Trichomoniasis in men: old issues and new data. Sex Transm Dis 1995;22:83e96.
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23. Krieger JN, Riley DE, Roberts MC, Berger RE. Prokaryotic DNA sequences in patients with chronic idiopathic prostatitis. J Clin Microbiol 1996;34: 3120e8. 24. Kuberski T. Trichomonas vaginalis associated with nongonococcal urethritis and prostatitis. Sex Transm Dis 1980;7:135e6. 25. Krieger JN, Jenny C, Verdon M, Siegel N, Springwater R, Critchlow CW, et al. Clinical manifestations of trichomoniasis in men. Ann Intern Med 1993;118: 844e9. 26. Kurth A, Whittington WL, Golden MR, Thomas KK, Holmes KK, Schwebke JR. Performance of a new, rapid assay for detection of Trichomonas vaginalis. J Clin Microbiol 2004;42:2940e3. 27. Nye MB, Schwebke JR, Body BA. Comparison of APTIMA Trichomonas vaginalis transcription-mediated amplification to wet mount microscopy, culture, and polymerase chain reaction for diagnosis of trichomoniasis in men and women. Am J Obstet Gynecol 2009;200:188e97. 28. Hossein YD, Firuzeh A, Nozhat Z, Hossein AY, Hedayat S. Development of a latex agglutination test as a simple and rapid method for diagnosis of Trichomonas vaginalis infection. Avicenna J Med Biotechnol 2010;2:63e6. 29. Krieger JN. Urologic aspects of trichomoniasis. Invest Urol. 1981;18:411e7. 30. Klinger EV, Kapiga SH, Sam NE, Aboud S, Chen CY, Ballard RC, et al. A community-based study of risk factors for Trichomonas vaginalis infection among women and their male partners in Moshi urban district, northern Tanzania. Sex Transm Dis 2006;33:712e8. 31. Engelberg R, Carrell D, Krantz E, Corey L, Wald A. Natural history of genital herpes simplex virus type 1 infection. Sex Transm Dis 2003;30:174e7. 32. Romanowski B, Marina RB, Roberts JN. Patients’ preference of valacyclovir once-daily suppressive therapy versus twice-daily episodic therapy for recurrent genital herpes: a randomized study. Sex Transm Dis 2003;30: 226e31.
Contents lists available at ScienceDirect
Urological Science journal homepage: www.urol-sci.com
Mini review
Nonchlamydial nongonococcal urethritis in menq
CME Credits
Chia-Chun Tsai*, Ching-Chia Li Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 March 2013 Received in revised form 12 April 2013 Accepted 5 June 2013 Available online 15 August 2013
By definition, nongonococcal urethritis (NGU) is an infectious condition involving urethra inflammation without Neisseria gonorrhoeae infection. According to recent studies, NGU accounts for 10e30% of initial visits to sexually transmitted infection (STI) clinics, and is one of the most common forms of STI in men. Chlamydia trachomatis is the most prevalent and well-established pathogen in NGU. However, nonchlamydial NGU is still a problematic disease in clinics because of its minimally symptomatic or asymptomatic manifestation. Various infection causes, including Mycoplasma, Trichomonas vaginalis, and herpes simplex virus, are possible pathogens in nonchlamydial NGU. In this brief review, we focus on the evaluation and management of nonchlamydial NGU. Copyright Ó 2013, Taiwan Urological Association. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: nonchlamydial urethritis nongonococcal urethritis
1. Introduction
2. Urethritis
According to the National Health Insurance Database in Taiwan, the prevalence of sexually transmitted infection (STI) has been gradually rising in the past decades. Neisseria gonorrhoeae and Chlamydia urethritis are the most common pathogens of STIs in men. Nongonococcal urethritis (NGU), characterized by a urethral inflammation that is not caused by N. gonorrhoeae infection, is probably the most common form of STI in men. It accounts for 10e30% of new male cases in STI clinics.1 Many pathogens can be identified for NGU and Chlamydia trachomatis is the most prevalent and well-established. C. trachomatis infection accounts for 15e40% of cases of initial NGU, and some studies have reported up to 50% of new cases.1,2 However, nonchlamydial NGU is still a problematic disease for clinics. Various infectious pathogens, including Mycoplasma, viruses, and protozoan parasites, are possible causes of NGU3 and exhibit similar symptoms. However, pathogens still cannot be detected in most cases of nonchlamydial NGU.2,4,5 This makes it difficult for physicians to make an accurate diagnosis. In this brief review, we focus on the common pathogens of nonchlamydial NGU: their prevalence, evaluation, and pathogenesis. The recommended regimens and prevention strategies for various causes of nonchlamydial NGU are also discussed in this article.
Urethritis, which is characterized by urethral inflammation, results from infectious, traumatic, and immune sources. In the infectious case, urethritis is usually acquired through an STI and shows similar symptoms and signs. In general, mucopurulent or purulent discharge from the urethral meatus and dysuria are the most common presentations (Fig. 1). An itching or burning sensation in the urethra is also typical. It is diagnosed according to the mentioned findings or one of the following laboratory tests.4 (1) The diagnosis is positive if a Gram stain of urethral discharge shows more >5 white blood cells (WBCs) per oil-immersion field. This recommended microscopic test is rapid, and features high sensitivity and specificity to identify a gonorrheal infection. (2) The diagnosis is positive if a microscopic examination of first-void urine shows >10 WBCs per high-power field. (3) The diagnosis is positive if a leukocyte esterase test of first-void urine shows positive results. Using a urethral swab to collect secretions for cultures, hybridization tests, or nucleic acid amplification tests (NAATs) is a common diagnostic method to confirm a pathogen, whereas first-void urine specimens can only be tested using NAATs. Recently, NAATs have become gradually accepted and preferred for confirmation of the pathogen of infectious urethritis because of their high sensitivity and specificity. If diagnostic tools and microscopic tests are unavailable, the Center for Disease Control and Prevention (CDC) recommends that sexually active patients who present with urethritis upon examination be treated with drug regimens effective against both gonorrhea and chlamydiasis.4 Despite the availability of numerous testing methods, a pathogen still cannot be detected in many cases of urethritis, especially in nonchlamydial NGU. Numerous cases of nonchlamydial NGU go unnoticed because of
* Corresponding author. Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Number 68, Zhonghua 3rd Road, Cianjin District, Kaohsiung City 80145, Taiwan. E-mail address: [email protected] (C.-C. Tsai). q There are 3 CME questions based on this article.
1879-5226/$ e see front matter Copyright Ó 2013, Taiwan Urological Association. Published by Elsevier Taiwan LLC. All rights reserved. http://dx.doi.org/10.1016/j.urols.2013.06.001
74
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Fig. 1. Nonchlamydial nongonococcal urethritis presents with mucopurulent discharges from the urethral meatus.
their minimally symptomatic or asymptomatic manifestations. Although the prevalence of nonchlamydial NGU is not uniform among communities and populations, it is usually highest in adolescents and adults <25 years old. It is estimated that 10e20% of chlamydial NGU and 20e30% of nonchlamydial NGU may be recurrent within 6 weeks after symptomatic resolution.1 Incorrect diagnosis, combined STIs, incomplete therapeutic regimens, and reinfection by an infected sexual partner are the major causes of recurrent or persistent NGU. To minimize transmission, a complete course of treatment should be initiated immediately after diagnostic confirmation. Men with documented NGU have a high rate of reinfection within 6 months after treatment, therefore, repeat testing of all men diagnosed with NGU is recommended 3e6 months after treatment.6,7 Additionally, because asymptomatic infection is common and the risk of coinfection is high, partners of men with initial NGU should be evaluated and considered for treatment. The CDC suggests that all sexual partners within the preceding 60 days be referred for evaluation, testing, and empirical treatment with a drug regimen effective against Chlamydia. To eliminate the risk of reinfection, men treated for NGU should also be asked to refrain from sexual behavior for at least 7 days after symptomatic resolution and complete a therapeutic regimen.4 STIs are important cofactors in HIV transmission, thus, it is also recommended that patients who have been diagnosed with initial NGU receive testing for other STIs, especially human immunodeficiency virus (HIV) infection and syphilis.
most NGU patients. Recent data supporting U. urealyticum as a commensal or pathogenic bacterium are inconsistent.2,3,5 Further studies are required to improve our understanding of the role of U. urealyticum in NGU. In a clinical manifestation of NGU, the urethral discharge is usually clear or mucoid, and has >5 WBCs per oil-immersion field. Although M. genitalium infection of NGU usually induces symptoms of urethral inflammation, asymptomatic infection is still common. The typical diagnostic methods used to detect M. genitalium urethritis are culture or direct microscopic smear. However, these two methods have relatively low sensitivity. A culture test requires swab specimens from the urethra. M. genitalium is more difficult to culture than other species of Mycoplasma, therefore, cultures have little benefit in clinical diagnosis. In recent clinical practice, M. genitalium-related NGU has been detected with NAATs by testing first-void urine or collecting urethral discharges.10 Mycoplasma spp. have no cell wall, thus, M. genitalium is resistant to all b-lactams or cephalosporins. The recommended antibiotics for M. genitalium-related NGU are macrolides (such as azithromycin) or tetracyclines (such as doxycycline). The dose regimens are the same as for chlamydial infection, and treatment should start after diagnosis. Some studies have reported that a single 1-g dose of azithromycin is more effective than doxycycline.4,11 However, treatment using these two antibiotics fails in some cases of chronic NGU caused by inadequate treatment and recurrent infection.9,12 4. Trichomoniasis Trichomoniasis is caused by Trichomonas vaginalis and is the most prevalent nonviral STI in sexually active populations, and affects an estimated 170 million people worldwide.13,14 Trichomoniasis, which is primarily observed in women, presents as an asymptomatic manifestation in up to one-third of infected women. Symptomatic manifestations involve inflammation, an itching sensation around the genital area, vulvar irritation and erythema,
3. Mycoplasma Mycoplasma, a type of Gram-negative bacteria without a cell wall, represents several original species. Among several recognized species of genital mycoplasmas, Mycoplasma genitalium, Ureaplasma spp., and Mycoplasma hominis, are believed to be possible pathogens in the genitourinary tract of humans. However, only M. genitalium and Ureaplasma urealyticum have been recognized as possible etiological agents of NGU. Mycoplasma genitalium infection is the most frequently reported pathogen in nonchlamydial NGU. Approximately 15e25% of cases of NGU are thought to be caused by M. genitalium.2 Previous studies8,9 have demonstrated a strong association between M. genitalium infection and NGU in men, especially among those with recurrent or persistent NGU. In contrast to the positive correlation of M. genitalium to NGU, U. urealyticum is relatively uncommon and weakly associated with
Fig. 2. Light microscopic picture of Trichomonas vaginalis in smear.
C.-C. Tsai, C.-C. Li / Urological Science 24 (2013) 73e77
purulent vaginal discharge, decreased vaginal pH level, and a typical erythematous cervix with punctate areas of exudation, also known as a strawberry cervix. However, the prevalence of the T. vaginalis infection in men is not well known because most infected men have minimal or no symptoms and transmit the pathogen unknowingly.15 In a recent study, 75% of infected men were asymptomatic.16 Other screenings of the community showed that the prevalence of trichomoniasis in men is approximately 10%17 in nonclinical cases and 12e17% in STI clinical cases.18e20 Other infected male patients may have symptoms similar to those of other NGUs. T. vaginalis has been recognized as a cause of nonchlamydial NGU in men, in whom it has the potential to induce balanoposthitis, epididymitis, urethral stricture, prostatitis, infertility, and even prostate cancer.21e25
75
Various diagnostic methods are used to detect T. vaginalisrelated NGU. Typically, diagnosis of trichomoniasis in men is confirmed by direct microscopic examination of secretions from all genitourinary sites, such as the urethra, epididymis, prostate, and semen (Fig. 2). However, this method has relatively low sensitivity, and is impractical in clinical and nonclinical settings.4 Culture testing of a urethral swab, first-void urine, or semen is another highly specific option. However, it is still not a sensitive diagnostic method. Urethral cultures are able to grow T. vaginalis in only 60% of cases.25 However, recent polymerase chain reactions and rapid antigen tests for the detection of T. vaginalis from first-void urine or urethral swabs have superior sensitivity for T. vaginalis diagnosis in men, and have become increasingly popular.18,26e28 A single 2-g dose of metronidazole or tinidazole, taken orally, is the regimen
Fig. 3. The algorithm for the management of nonchlamydial nongonococcal urethritis in men. HSV ¼ herpes simplex virus; IgG ¼ immunoglobulin G; NAAT ¼ nucleic acid amplification tests; PCR ¼ polymerase chain reaction.
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recommended by the CDC for T. vaginalis infection, or recurrent NGU, in men. The alternative regimen is 500 mg metronidazole taken orally twice a day for 7 days.4 Patients should avoid drinking alcohol during treatment, and for at least 24 hours after completion of metronidazole or 72 hours after completion of tinidazole, to prevent a disulfiram-like reaction. This infection is typically acquired during sexual intercourse, and other circumstances of contamination are rare. Even without symptoms, an asymptomatic carrier continues to infect or reinfect a sexual partner until he or she has been treated. In a previous study, T. vaginalis was isolated from 67e100% of female partners of infected men and 14e60% of male partners of infected women.29 A more recent study also indicated that 73% of male sexual partners of women who had trichomoniasis were positive for T. vaginalis infection.16 Another community-based study showed that the prevalence of trichomoniasis was 10.7% in women and 6.3% in their male partners.30 Therefore, we suggest a concomitant survey and, if necessary, treatment of sexual partners of the infected person when the diagnosis of T. vaginalis infection is confirmed. 5. Herpes simplex virus Herpes simplex virus (HSV) is an important pathogen in genital and oral isolates and is separated into two types. Both HSV-1 and HSV-2 have been recognized as causes of chronic, life-long genital infections. HSV-2 infection has been identified as the dominant cause of most recurrent genital ulcers. However, most people infected with HSV-2 are asymptomatic and have not been diagnosed with genital herpes. It is a major problem that many of these people tend to be unaware of their infection, and transmit the infection to their sexual partners. However, in populations with a high frequency of orogenital exposure and anal intercourse, an increasing proportion of anogenital HSV-1 infection has been noted. Up to 50% of primary genital herpes is caused by HSV-1, but its recurrence and subclinical shedding are much less frequent than for genital HSV-2 infections.4,5,31 The typical clinical manifestation of a genital HSV infection is painful genital, anal, or perianal vesicles and ulcers, but many genital HSV infections are still subclinical. HSV is also a reported pathogen of NGU. Genital itching, dysuria, vaginal or urethral discharge, and tender inguinal lymphadenopathy are other predominant local symptoms of HSV infection. Urethral discharge and dysuria, which are similar to the classical symptoms of NGU, are noted in approximately one-third of men with a primary HSV infection.5 Bradshaw et al2 have indicated that HSV, usually HSV-1, accounts for 2e5% of cases of NGU. Consequently, sexually active patients and sexual partners with genital herpes or mucocutaneous lesions should be tested for HSV infection when NGU is diagnosed. Virological tests, identification of HSV from first-void urine or urethral swab using a cell culture or NAAT, are more reliable than a physical examination, but are not widely available. Type-specific serological assays for immunoglobulin G antibodies of HSV, which determine the virus type, are more useful in clinical settings to survey latent-virus infection. Conversely, immunoglobulin M serological tests are not suggested as a diagnostic method because of long-term persistence in chronic herpes, the frequency of false results, and non-type-specific assays. Unlike recurrent genital HSV, which is usually self-limited, all primary genital herpes-related NGUs should be treated with recommended regimens of acyclovir, famciclovir, or valacyclovir, in addition to azithromycin or doxycyclin.1,4 The regimens recommended by the CDC are: 400 mg acyclovir taken orally three times daily for 7e10 days, or 200 mg acyclovir taken orally five times daily for 7e10 days; 250 mg famciclovir taken orally three times daily for 7e10 days, or 1 g valacyclovir taken orally twice daily for 7e10 days. Systemic antiviral
drugs, which are capable of controlling the symptoms and reducing the duration of herpes episodes, offer clinical benefits to most symptomatic patients. However, these drugs cannot destroy latent viruses. To reduce recurrence of HSV, suppressive therapy for recurrent genital herpes has been established. Suppressive antiviral therapy has been reported to reduce the frequency of genital herpes recurrences by 70e80%.4,32 Topical therapies with antiviral drugs have minimal and limited benefits. 6. Conclusion Asymptomatic infections are common and many patients are treated without diagnostic confirmation. Therefore, the prevalence of nonchlamydial NGU is likely to be much higher than reported. In clinical practice, it is a major problem that accurate diagnoses or adequate solutions are usually absent in most cases of nonchlamydial NGU. M. genitalium is the most common pathogen and causes 15e25% of nonchlamydial NGU. Recurrent and persistent nonchlamydial NGU should be evaluated for drug compliance and uncommon infection, such as T. vaginalis, U. urealyticum, or HSV infection. All persons with nonchlamydial NGU should remain abstinent from sexual activity for at least 7 days after complete treatment and symptomatic resolution. Comprehensive surveys of other STIs, especially HIV infection, syphilis, and gonorrhea, are recommended in the general treatment of nonchlamydial NGU because the infections are commonly combined. Finally, this paper describes clinical strategies in the management of nonchlamydial NGU in men (Fig. 3). Conflicts of interest statement The authors declare that they have no financial or non-financial conflicts of interest related to the subject matter or materials discussed in the manuscript. Sources of funding None. References 1. Handsfield HH. Nongonococcal urethritis. In: Color atlas & synopsis of sexually transmitted disease. 3rd ed. New York, NY: McGraw-Hill; 2011. p. 207e15. 2. Bradshaw CS, Tabrizi SN, Read TR, Garland SM, Hopkins CS, Moss LM, et al. Etiologies of nongonococcal urethritis: bacteria, viruses, and the association with orogenital exposure. J Infect Dis 2006;193:336e45. 3. Martin DH. Nongonococcal urethritis: new views through the prism of modern molecular microbiology. Curr Infect Dis Rep 2008;10:128e32. 4. Workowski KA, Berman S. Sexually transmitted diseases treatment guidelines, 2010. MMWR Morb Mortal Wkly Rep 2010;59:1e110. 5. Martin DH. Urethritis in males. In: Holmes KK, Sparling PF, Stamm WE, Piot P, Wasserheit JN, Corey L, et al., editors. Sexually transmitted diseases. 4th ed. New York, NY: McGraw-Hill; 2008. p. 1007e26. 6. Fung M, Scott KC, Kent CK, Klausner JD. Chlamydial and gonococcal reinfection among men: a systematic review of data to evaluate the need for retesting. Sex Transm Infect 2007;83:304e9. 7. Kissinger PJ, Reilly K, Taylor SN, Leichliter JS, Rosenthal S, Martin DH. Early repeat Chlamydia trachomatis and Neisseria gonorrhoeae infections among heterosexual men. Sex Transm Dis 2009;36:498e500. 8. Taylor-Robinson D, Gilroy CB, Thomas BJ, Hay PE. Mycoplasma genitalium in chronic non-gonococcal urethritis. Int J STD AIDS 2004;15:21e5. 9. Wikström A, Jensen JS. Mycoplasma genitalium: a common cause of persistent urethritis among men treated with doxycycline. Sex Transm Infect 2006;82:276e9. 10. Dupin N, Bijaoui G, Schwarzinger M, Ernault P, Gerhardt P, Jdid R, et al. Detection and quantification of Mycoplasma genitalium in male patients with urethritis. Clin Infect Dis 2003;37:602e5. 11. Mena LA, Mroczkowski TF, Nsuami M, Martin DH. A randomized comparison of azithromycin and doxycycline for the treatment of Mycoplasma genitaliumpositive urethritis in men. Clin Infect Dis 2009;48:1649e54. 12. Hamasuna R, Osada Y, Jensen JS. Antibiotic susceptibility testing of Mycoplasma genitalium by TaqMan 50 nuclease real-time PCR. Antimicrob Agents Chemother 2005;49:4993e8.
C.-C. Tsai, C.-C. Li / Urological Science 24 (2013) 73e77 13. Johnston AJ, Mabey DC. Global epidemiology and control of Trichomonas vaginalis. Curr Opin Infect Dis 2008;21:56e64. 14. Van Der Pol B. Trichomonas vaginalis infection: the most prevalent nonviral sexually transmitted infection receives the least public health attention. Clin Infect Dis 2007;44:23e5. 15. Watson-Jones D, Mugeye K, Mayaud P, Ndeki L, Todd J, Mosha F, et al. High prevalence of trichomoniasis in rural men in Mwanza, Tanzania: results from a population based study. Sex Transm Infect 2000;76:355e62. 16. Hobbs MM, Lapple DM, Lawing LF, Schwebke JR, Cohen MS, Swygard H, et al. Methods for detection of Trichomonas vaginalis in the male partners of infected women: implications for control of trichomoniasis. J Clin Microbiol 2006;44: 3994e9. 17. Chai SJ, Aumakhan B, Barnes M, Jett-Goheen M, Quinn N, Agreda P, et al. Internet-based screening for sexually transmitted infections to reach nonclinic populations in the community: risk factors for infection in men. Sex Transm Dis 2010;37:756e63. 18. Wendel KA, Erbelding EJ, Gaydos CA, Rompalo AM. Use of urine polymerase chain reaction to define the prevalence and clinical presentation of Trichomonas vaginalis in men attending an STD clinic. Sex Transm Infect 2003;79:151e3. 19. Schwebke JR, Hook III EW. High rates of Trichomonas vaginalis among men attending a sexually transmitted diseases clinic: implications for screening and urethritis management. J Infect Dis 2003;188:465e8. 20. Borchardt KA, al-Haraci S, Maida N. Prevalence of Trichomonas vaginalis in a male sexually transmitted disease clinic population by interview, wet mount microscopy, and the InPouch TV test. Genitourin Med 1995;71:405e6. 21. STARK JR. Prospective study of Trichomonas vaginalis infection and prostate cancer incidence and mortality: Physicians’ Health Study. J Natl Cancer Inst 2009;101:1368e9. 22. Krieger JN. Review Trichomoniasis in men: old issues and new data. Sex Transm Dis 1995;22:83e96.
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23. Krieger JN, Riley DE, Roberts MC, Berger RE. Prokaryotic DNA sequences in patients with chronic idiopathic prostatitis. J Clin Microbiol 1996;34: 3120e8. 24. Kuberski T. Trichomonas vaginalis associated with nongonococcal urethritis and prostatitis. Sex Transm Dis 1980;7:135e6. 25. Krieger JN, Jenny C, Verdon M, Siegel N, Springwater R, Critchlow CW, et al. Clinical manifestations of trichomoniasis in men. Ann Intern Med 1993;118: 844e9. 26. Kurth A, Whittington WL, Golden MR, Thomas KK, Holmes KK, Schwebke JR. Performance of a new, rapid assay for detection of Trichomonas vaginalis. J Clin Microbiol 2004;42:2940e3. 27. Nye MB, Schwebke JR, Body BA. Comparison of APTIMA Trichomonas vaginalis transcription-mediated amplification to wet mount microscopy, culture, and polymerase chain reaction for diagnosis of trichomoniasis in men and women. Am J Obstet Gynecol 2009;200:188e97. 28. Hossein YD, Firuzeh A, Nozhat Z, Hossein AY, Hedayat S. Development of a latex agglutination test as a simple and rapid method for diagnosis of Trichomonas vaginalis infection. Avicenna J Med Biotechnol 2010;2:63e6. 29. Krieger JN. Urologic aspects of trichomoniasis. Invest Urol. 1981;18:411e7. 30. Klinger EV, Kapiga SH, Sam NE, Aboud S, Chen CY, Ballard RC, et al. A community-based study of risk factors for Trichomonas vaginalis infection among women and their male partners in Moshi urban district, northern Tanzania. Sex Transm Dis 2006;33:712e8. 31. Engelberg R, Carrell D, Krantz E, Corey L, Wald A. Natural history of genital herpes simplex virus type 1 infection. Sex Transm Dis 2003;30:174e7. 32. Romanowski B, Marina RB, Roberts JN. Patients’ preference of valacyclovir once-daily suppressive therapy versus twice-daily episodic therapy for recurrent genital herpes: a randomized study. Sex Transm Dis 2003;30: 226e31.