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Abstract
Objective To determine whether Mycoplasma genitalium is associated with balanitis and/or posthitis in a previous study of the role of M genitalium in men with acute non-gonococcal urethritis (NGU).
Methods In a previous study of men with acute NGU, the existence of balanitis and/or posthitis was recorded. Chlamydia trachomatis, M genitalium and ureaplasmas were sought in urethral swabs and urine using a direct fluorescent antibody test and in-house PCR, an in-house PCR and a culture method, respectively. Men were treated with doxycycline or erythromycin.
Results M genitalium was associated significantly (p=0.01) with balanitis and/or posthitis in 114 men with acute NGU. This association persisted when there was control for C trachomatis and urethral discharge (p=0.021, OR 4.1, 95% CI 1.2 to 13.5). C trachomatis and ureaplasmas were not associated with balanitis and/or posthitis.
Conclusion Detection of M genitalium in men with acute NGU was associated significantly with balanitis and/or posthitis. The association is biologically plausible and may have a role in HIV-1 transmission and susceptibility.
- Mycoplasma genitalium
- Balanoposthitis
- balanitis
- non-gonococcal urethritis
- NGU
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Inflammation of the glans penis (balanitis) and inflammation of the prepuce (posthitis) frequently occur together (balanoposthitis). Balanitis alone is seen occasionally in circumcised men. However, primary infections of the glans and prepuce with discharge and urethral involvement may occur due to, for example, herpes simplex virus or Candida albicans, and sometimes it may be difficult to ascertain whether a primary infection of the urethra (gonococcal or non-gonococcal) has led to balanoposthitis.
Following the detection by culture of Mycoplasma genitalium organisms in specimens from men with non-gonococcal urethritis (NGU)1 and the development a decade later of a PCR to detect the organisms sensitively, we undertook a study of the aetiology of NGU.2–4 Chlamydia trachomatis and M genitalium were independently and significantly associated with the disease. We also observed that some of the men had balanitis and/or posthitis. M genitalium can infect vaginal epithelial cells in vitro.5 These are stratified non-keratinised squamous epithelial cells,6 which suggests that M genitalium might therefore be capable of infecting skin epithelia, particularly the foreskin which is poorly keratinised.7 This prompted us to look at the association of M genitalium with balanoposthitis in men we had previously studied with urethritis. We also felt it was worthy of analysis in view of the importance of foreskin as a cofactor in HIV transmission, the ability of sexually transmitted infections to increase the transmission of HIV and the recent association of M genitalium with HIV infection.8–10
Methods
As described in detail elsewhere,2–4 114 men with acute clinically symptomatic NGU were studied between 1991 and 1993 as part of a larger study investigating the aetiology of acute and chronic NGU. Men attending the Jefferiss Wing at St Mary's Hospital for a sexual health assessment were eligible for inclusion. Men with clinical symptoms (ie, either complaining of a discharge, dysuria, penile irritation, genital discomfort or having an urethral discharge on examination after an urethral massage) and clinically asymptomatic men were recruited as part of the study. For this study, NGU was diagnosed at initial presentation if there were ≥5 polymorphonuclear leucocytes (PMNLs) per high power field (HPF; ×1000) in five or more fields of a Gram-stained urethral smear. As part of the larger study, we also included men with clinical symptoms who had a negative urethral smear but evidence of urethritis on Gram staining a first-pass urinary thread which had ≥10 PMNLs per HPF, and clinically asymptomatic men if there were ≥5 PMNLs per HPF (×1000) in five or more fields of a Gram-stained urethral smear or, if negative, ≥10 PMNLs per HPF on Gram staining a first-pass urinary thread.4 Subjects were asked to complete a questionnaire requesting details about discharge, dysuria and penile irritation. Other information such as age, ethnicity, number of sexual partners and time since last voiding urine was recorded by the physician. The patient was examined and the occurrence of balanitis and/or posthitis and whether a discharge was present before or after urethral massage was recorded. Balanitis and/or posthitis was/were diagnosed if there was erythema of the glans and/or prepuce; no distinction was made between balanitis and balanoposthitis on the study proforma. Men with Neisseria gonorrhoeae, a herpes simplex virus infection or a urinary tract infection were excluded. Men were treated with doxycycline 200 mg given initially and then 100 mg/day for 13 days, or enteric-coated erythromycin 500 mg given four times per day for 14 days if they were intolerant of doxycycline. Details of specific treatment for balanitis and/or posthitis were not available. A total of 86 men re-attended at least once 10–92 days after receiving treatment.
As detailed previously,2–4 C trachomatis was diagnosed using a direct fluorescent antibody test (Syva, Milton Keynes, UK) in which detection of one or more elementary bodies was regarded as a positive result on a urethral smear and/or the centrifuged deposit from a first-pass urine (FPU) specimen. An in-house C trachomatis PCR was also undertaken at presentation on an FPU deposit from those patients who returned for follow-up. Men were considered C trachomatis-positive if any test was positive and C trachomatis-negative if at least one specimen was available for examination by any test and this was negative. Results were not available for six men. Forty-five (42%) of 108 evaluable men were C trachomatis-positive. A PCR was used on the centrifuged deposit from an FPU specimen to detect M genitalium, as described elsewhere.2–4 Results were not available for four men. Thirty-one (28%) of 110 evaluable men were M genitalium-positive. At follow-up only men who tested M genitalium-positive at presentation or who had chronic urethritis were tested using the M genitalium PCR.3 Ureaplasmas were sought by culture using a FPU specimen.3 Results were not available for five men. Thirty-three (30%) of 109 evaluable men were ureaplasma-positive. Speciation of the ureaplasmas was not undertaken as, at the time of the study, the greater significance of one or other of the two separate ureaplasma species was not appreciated.
Statistical analysis
Univariate associations were explored using the Fisher exact test with SPSS for Windows Version 15 and ORs with 95% CIs using EpiInfo Version 6. Binary logistic regression was used for multivariate analyses. As detailed previously, the data were not complete for every individual recruited.3
Results
Details of urethral discharge were available for 113 men; of these, 96 (85%) had a discharge, of whom 29 (30%) were unaware since it was present only on examination after urethral massage, 51% (57 of 112) had dysuria, 56% (63 of 113) had penile irritation and/or genital discomfort and 18% (19 of 103) had balanitis and/or posthitis. Of the 113 evaluable men with details of urethral discharge available, 17 (15%) did not complain of discharge, dysuria or penile irritation and only had an urethral discharge on examination.
The presence of balanitis and/or posthitis was not associated with discharge, dysuria or penile irritation and/or discomfort (data not shown). The presence of C trachomatis was not associated with balanitis and/or posthitis. In complete contrast, the presence of M genitalium was associated significantly with balanitis and/or posthitis. Ureaplasmas were not associated with balanitis and/or posthitis (table 1).
Relation of balanitis and/or posthitis with Chlamydia trachomatis, Mycoplasma genitalium and ureaplasmas
We have previously shown2–4 that M genitalium and C trachomatis were associated with discharge. Because of this we undertook a logistic regression analysis to control for discharge and for the presence of the other micro-organism. The detection of M genitalium continued to be associated with balanitis and/or posthitis (p=0.021, OR 4.1, CI 1.2 to 13.5) and discharge (p=0.07, OR 7.7, CI 0.86 to 69.9). At follow-up examination, four men had balanitis and/or posthitis. Of these, two had had M genitalium originally, including one man in whom balanitis and/or posthitis was/were not diagnosed at presentation; both were M genitalium-negative at follow-up.
Discussion
The primary aim of the original study2–4 had been to determine the relationship between M genitalium and NGU. In this analysis we show that M genitalium is associated with balanitis and/or posthitis in men with acute NGU and that this is independent of the presence of an urethral discharge.
The strength of the study is that it is a well-characterised group with detailed microbiological investigations undertaken blinded to clinical presentation. Weaknesses of the study are that, despite including 114 men, the study is still small and no distinction was made on the study proforma between balanitis and/or posthitis. Also, whether any of the men with acute urethritis were circumcised was not recorded, and the result cannot be extrapolated to balanitis and/or posthitis in men who are clinically asymptomatic and in whom urethritis is not present. In future studies it will be important to have balanitis and/or posthitis as the primary focus and to ascertain whether the association is with one or the other, or both, and consider the relation of micro-organisms to the disease in men who also have urethritis and in those who do not.
We are not aware of other studies which have investigated the association of M genitalium with balanoposthitis. We suspect that this is because nobody has looked for it, as information on the presence of balanoposthitis is not routinely collected in studies of men with acute NGU. Because patients with balanitis and/or posthitis also had urethritis, the association of M genitalium might be with NGU and only spuriously with balanitis and/or posthitis. It was therefore interesting to find that an apparent real association exists between M genitalium and balanitis and/or posthitis which is independent of the presence of urethral discharge. This is emphasised by the apparent lack of association found for C trachomatis. Furthermore, biologically this makes sense since C trachomatis organisms infect mucosal columnar epithelial cells and not squamous epithelial cells, and there is evidence that M genitalium can infect non-keratinous squamous epithelial cells.5 6 We originally failed to confirm a univariate association of M genitalium with balanitis and/or posthitis following logistic regression analysis in the extended study of all men with urethritis while controlling for co-infection, sexual lifestyle and clinical disease.4 The additional men with urethritis consisted of clinically asymptomatic men whose recruitment as potential controls began later in the study, but were found to have urethritis on Gram staining. We also included both clinically symptomatic and asymptomatic men who had a negative urethral smear but evidence of urethritis on Gram staining a first-pass urinary thread which had ≥10 PMNLs per HPF.4 Seven of these additional 55 men had balanitis and/or posthitis, none of whom was infected with M genitalium. For the multivariate analysis, 70 (41%) of the 169 men could not be included because of missing data, including 11 (42%) of 26 men with balanitis and/or posthitis. We believe that the exclusion of such a large number of individuals from the multivariate analysis probably introduced unknown bias(es) related to data collection and provided an unreliable result. In addition, four clinically asymptomatic men without urethritis (controls) from the original study were M genitalium-positive and none had balanitis and/or posthitis. Although this may have been due to a lower load, it could also be because of the small number of M genitalium-positive men studied in the control group leading to a type 2 statistical error.3 4 11
These results imply that men with balanoposthitis should be asked about symptoms of discharge, dysuria and penile irritation and examined for the presence of a discharge by undertaking urethral massage.2–4 12 In this study, 15% of men with acute NGU did not have symptoms of urethritis but did have a discharge present on examination before or after urethral massage. If these symptoms and/or signs are present, an urethral smear examination should be undertaken to exclude urethritis. If urethritis is present, our results suggest that M genitalium may be the cause and patients should be offered treatment accordingly. Currently, testing for urethritis is only recommended in men with a circinate balanitis.12 It is possible that men in this study did indeed only have circinate balanitis but, from clinical experience, this condition is uncommon and is usually associated with reactive arthiritis,12 and we believe this is unlikely. This requires further study. The results also suggest that the presence of balanoposthitis could be an important cofactor in increasing both the risk of HIV transmission and acquisition following exposure in men with M genitalium infection.
We believe that the association of M genitalium with balanitis and/or posthitis merits further investigation, particularly the potential to facilitate HIV transmission and acquisition. M genitalium is common (6.6%) in men who have sex with men who remain at high risk of acquiring HIV,10 13 and is also a common cause of urethritis in men from sub-Saharan Africa.9
Key messages
Balanoposthitis is associated with M genitalium in men with acute NGU.
In men with balanoposthitis, symptoms of urethritis and the presence of an urethral discharge should be sought and an urethral smear undertaken if present.
The association of M genitalium with balanoposthitis merits further investigation, particularly the potential to facilitate HIV transmission and acquisition.
References
Footnotes
Funding This research was funded by Medical Research Council Programme Grant G9225810.
Competing interests None.
Ethics approval This study was conducted with the approval of the St Mary's Hospital research ethics committee and signed consent was obtained from all patients.
Provenance and peer review Not commissioned; externally peer reviewed.