Nongonococcal urethritis (NGU) is one of the commonest treatable conditions in men attending sexually transmitted diseases (STD) departments yet despite considerable research efforts the etiology of up to 50% of cases remains unknown.1,2 It is assumed that the etiological agents of NGU could potentially cause complications in the female partner.2 Neisseria gonorrhoeae, Chlamydia trachomatis (CT), and probably Mycoplasma genitalium (MG) have been implicated in upper genital tract inflammation in women, in particular pelvic inflammatory disease.3–5 However, this remains to be substantiated for pathogen-negative NGU.2 Wetmore et al,6 in this issue, report on a case comparison study of men with acute NGU. They conclude that idiopathic urethritis (IU) may not have an infectious etiology or possibly an as yet unidentified infectious agent(s). They comment that if a sizeable proportion is not due to infectious agents it will be important to learn how to distinguish noninfectious cases as they would not require antimicrobial therapy and partner notification.
This is one of the largest, in depth studies of acute NGU reported to date.6,7 A total of 370 men with acute NGU were studied. The majority were clinically symptomatic, that is, complaining of a discharge and/or dysuria or had a discharge on examination and/or had urethritis on Gram stained urethral smear. Information was collected on patient demographics, sexual behavior, clinical symptoms or signs, and detailed microbiology was undertaken using sensitive and specific molecular techniques to detect N. gonorrhoeae, CT, MG, Trichomonas vaginalis (TV), and Ureaplasma urealyticum, the major sexually transmitted infection (STI) pathogens which have been identified as causing urethritis in men. Pathogens were detected in only 50.7% of the 367 eligible cases, and were associated with a variety of traditional risk factors and clinical features, whereas IU tended to be diagnosed among lower-risk men. Notably, sexual behavior influenced the likelihood of a pathogen being detected with CT being associated with men who sex with men, MG with paying for sex and having partner of black ethnicity, and TV with black ethnicity and having an older female partner.
Are the conclusions of Wetmore et al6 reasonable or are there alternative hypotheses which should be considered? More importantly, how should we as clinicians apply the findings of Wetmore et al to our clinical practice and what further research is needed in order to improve our current, imperfect, clinical management algorithms.6 Although this is a large and detailed study, it has some methodological weaknesses. Most importantly, there was no control group of men without NGU. Although the men with IU were at lower risk of acquiring an STI, this is relative to the men presenting with acute NGU. Certainly, this study population of men with acute NGU appear at increased risk of an STI pathogen compared to the general population, in terms of previous incarceration, illicit drug use, and probably previous history of NGU and sexual behaviour. Not having a control group of men who are representative of the population at risk of the condition (sexually active men) introduces bias and does not allow us to comment accurately on whether men with IU are indeed at lower risk of an STI pathogen than men in general. Certainly, the men with IU were at risk of acquiring an STI given the mean duration of sexual relationship is of 32 days (range: 1–503). Men with IU were older and as sexual activity decreases with age this could potentially explain this observation.8 In addition, there was no testing for herpes simplex virus, adenovirus which Bradshaw et al7 undertook, and urinary tract infection9 all of which have been associated with NGU. However, these are infrequent causes1,2 and probably only account for 5% in total and at most 10% which still leaves 40% to 45% of men with IU. Finally, partners were not examined and no information on the prevalence of STI pathogens in partners was available.
What are the other potential explanations for these observations? Is it possible that some men with IU may have recently been exposed to CT and resolved the infection because of a sterilizing immune response? Men with IU were significantly associated with a history of urethritis compared to men with chlamydia urethritis.6 Individuals who are CT-positive can resolve the infection spontaneously, and about 1/3 of partners of CT-positive individuals are themselves CT-negative.10–13 This suggests that the immune response may be important in infection resolution.14,15 Although, there are limited studies which have looked at partners of men with IU, these studies suggest that up to 20% will have a CT-positive partner, indicating recent exposure.16,17 Certainly in trachoma, which is caused by CT serovars A-C, it is recognized that the inflammatory response can continue weeks after the person is CT-negative.18 In this context, it would be of interest to investigate, using the technique developed by Wiggins et al, whether the local mucosal immune response is different in men with IU compared to pathogen-positive NGU.19–22 Whether such mechanisms may be involved following exposure to other pathogens is unknown.
Is it possible that there are as yet unidentified microorganisms which can cause NGU in men, are sexually transmissible, and can cause upper genital tract disease in women? Of those treated with a tetracycline or azithromycin approximately 80% to 90% are cured, suggesting that if other pathogens do exist they are bacterial.1 A diverse microbial flora has been identified in the male urethra, rectum, and vagina.23–28 Using molecular techniques, it is now clear that the majority of the microbial genital tract flora are not detected using standard culture techniques.2,27–29 Bacterial vaginosis and Gram-negative anaerobes have been associated with IU in men, although their exact causal role remains uncertain.1,2,23 More recently, the work of Bradshaw et al suggest that unidentified oral flora may have a role in IU associated with insertive fellatio.7 Interestingly, a small study has suggested using molecular technology which can identify both culturable and nonculturable bacteria that Pseudomonas sp. or pseudomonas-like organisms may have a role in IU.25 Such microorganisms might be expected to be more pathogenic if the urethral mucosa has been previously disrupted. Such a mechanism has been proposed in trachoma, as CT is only infrequently detected in individuals with chronic disease.18,30 However, there is currently no evidence that such microorganisms can cause upper genital tract disease, even in high-risk women.31 Establishing whether there are indeed unidentified microorganisms which can cause NGU, using traditional case control studies, is likely to be challenging given the large number of potential microorganisms which have recently been identified.
Thus, partner notification is likely to be of importance in some men with IU but not all and it is also likely that antimicrobial therapy will be efficacious in some men with IU. Historical, placebo controlled, studies indicate that about 20% to 40% of men with NGU will resolve without treatment, with higher rates in CT-negative men.22,26,32,33 This suggests that at least some men with IU may not require antimicrobial therapy in order to be clinically cured. However, chronic urethritis is a significant clinical problem in genitourinary medicine2 and it would seem premature to advocate such an approach without the evidence from clinical trials. Nevertheless, all men diagnosed with NGU following treatment are currently advised that they are likely to have an STD and that their partner(s) need to be treated.2,34 As STDs are associated with considerable stigma and have major implications for men and their partners who believe they are in a closed relationship, this has the potential to do harm as well as good, particularly if another partner was not involved and treatment is not necessary.
Thus, a better understanding of IU would have 2 important benefits (1) it would inform the development of more effective management strategies and (2) allow clinicians and patients to make an informed decision about partner(s) management. This is likely also to be valued by patients. The literature currently focuses on expert medical opinion and not the views of patients as to what would benefit them and this imbalance needs to be addressed.2,34–36 The studies by Wetmore et al, Bradshaw et al, and Horner et al have shown the way forward for research in NGU.6,7,37 Their findings do not support the concept that all cases of NGU are due to an STI acquired from a recent sexual partner which is also potentially transmissible, particularly if they do not have a discharge with ≥5PMNs/HPF. This is consistent with other studies.36 Horner has proposed that the risk of detecting an STI pathogen increases with the degree of urethral inflammation and that age, sexual behavior, and clinical presentation also can be used to estimate the risk of a man with urethritis having or being recently exposed to an STI which is consistent with the observations of Wetmore et al.6,36
Large case control studies which collect detailed epidemiologic, sexual behavior, and clinical information, including degree of urethral inflammation, which use NAATs to detect CT, MG, U. urealyticum, TV, herpes simplex virus, and adenovirus, and screen midstream urine specimens for bacterial urinary tract infections and also includes partners will be needed so that we can develop reliable clinical algorithms. Consideration should also be given to detailed molecular microbiologic investigation using broad-range 16S rRNA gene PCR, a cultivation-independent method28 before the existence of unidentified sexually transmissible pathogen(s), which could cause disease in women, can be discounted as causing IU. The potential role of prior exposure to CT, whether recently or in the more distant past also merits further investigation. For this, we need knowledge of their partner(s) infection status and/or a reliable biomarker of exposure to CT in men who are NAAT detection negative. Such a biomarker is not currently available,19 but recent advances in serology with the development of specific assays merits exploration as such a tool, especially if the assay sensitivity in men can be improved.38
Undertaking such studies will be a major challenge for the international research community. Not only are such studies likely to be beyond the resources of a single institution but also, as there is a geographical variation in STI prevalence, probably within sub groups as well, the findings from one institution may not be applicable elsewhere. One potential solution would be to agree to a generic protocol which could be applied internationally so that smaller studies can be combined using the technique of meta-analysis, a methodological approach which is now widely applied to other conditions. Noninvasive home sampling strategies should help facilitate with partner recruitment.39,40 These findings can then inform intervention studies and be incorporated into clinical management algorithms which can then be rigorously evaluated in order to refine their application in clinical practice at a National and/or local level. Last but not least, patient involvement, not just as a participant, will be required in order to maximize patient benefit.
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