Herpes simplex virus (HSV) is a highly prevalent viral sexually transmitted infection (STI) among men and women. Seroprevalence surveys in men estimate a global prevalence of HSV-2 of 8%1 in men aged less than 50 years, and this accords with Australian data.2 Genital HSV is the most common cause of genital ulceration, is often shed asymptomatically, and HSV-2 can increase the risk for HIV transmission.3–5 Genital HSV infections occur with both HSV-1 and HSV-2, each accounting for roughly half of initial genital herpes cases; however, HSV-1 is a more common cause of first episodes of genital herpes in young adults.6
Non-gonococcal urethritis (NGU) in males is one of the most common STI-associated clinical presentations to health care providers. The most common pathogens seen in men with NGU are Chlamydia trachomatis which accounts for 20–50% of cases followed by Mycoplasma genitalium which has been identified in 10% to 25% of cases.7–12 Herpes simplex virus has been reported as a less common causative agent in men presenting with NGU with rates of between 2% and 10%.8,9,13–16 Previous studies of the contribution of HSV to NGU have been limited by small numbers of HSV cases.8,9,13–16
We aimed to compare the clinical characteristics seen in men with HSV urethritis with those in men with chlamydial urethritis to identify any key differences in presentation. This information would help determine when testing for HSV may be indicated in men presenting with NGU and might influence clinical management.
We identified all cases of male HSV PCR-positive urethritis diagnosed at the Melbourne Sexual Health Centre, Victoria, Australia, between January 2000 and September 2015. We chose chlamydial urethritis as a comparator as chlamydia is the most common pathogen found in men with NGU and has clinical features indistinguishable from other causes of NGU caused by M. genitalium or pathogen-negative NGU.8 The men with chlamydia consisted of 80 consecutive cases of men attending the clinic with NGU between August 2014 and December 2014 who tested positive for C. trachomatis on urine testing. These men were not matched with HSV urethritis cases, and chlamydia was the sole urethral pathogen: men with concurrent urethral Neisseria gonorrhoea and M. genitalium were excluded.
We included men who described symptoms suggestive of urethritis—urethral discharge, urethral discomfort and/or dysuria—and where the clinician made a diagnosis of NGU. As a previous study from the same clinic showed a significant proportion of men with urethral pathogens have less than 5 polymorphonuclear leukocytes per high-power field (PMNLs/HPF),8 we did not use PMNL/HPF as a diagnostic criterion for NGU. Men with urethral symptoms were assessed by a sexual health clinician and underwent genital examination and investigation for urethral pathogens. A first-pass urine specimen was collected and tested for C. trachomatis by strand displacement amplification (ProbeTec-ETCT amplified DNA assay; Becton, Dickinson) and M. genitalium. 17 A urethral swab was performed when a urethral discharge was present for microscopy and N. gonorrhoeae culture using modified Thayer Martin medium. The gram stained urethral smear was examined with light microscopy under oil immersion and the number of PMNL/HPF (×1000) recorded. Testing for HSV and/or adenovirus by first-pass urine or urethral swab was performed when the clinician suspected a viral cause of urethritis. This was based on a prior case-control study of NGU8 conducted at the same clinic which showed that meatitis and severe dysuria with or without conjunctivitis were significantly associated with viral NGU. The clinic's guidelines recommended testing for adenovirus and HSV in the presence of these clinical features. The HSV detection was by polymerase chain reaction (PCR) targeting the glycoprotein B gene using conventional PCR and a real-time version of this.18 All HSV cases included in this study were positive in either the first-pass urine or urethral sample. Adenoviral detection was by PCR targeting the hexon gene using conventional PCR and real-time PCR modified from Allard et al.19
Routinely collected data were extracted from the clinic's medical records including recent sexual practices, reported symptoms, physical findings, and laboratory results. We classified dysuria as severe when the clinician recorded dysuria as being severe. As these data were extracted from clinical records, a scale was not available. Differences between men with HSV and chlamydial urethritis were tested using the chi-square test or the Wilcoxon-Mann-Whitney test for categorical and continuous variables respectively. Data were analyzed using STATA Release 13. Ethical approval for the study was granted by the Alfred Hospital Human Research Ethics Committee (number 339/15). We followed the RECORD statement, an extension of the STROBE statement, to report this observational study using routinely collected health data (www.record-statement.org).
During the study period, 15,788 men were diagnosed with NGU, 514 men were tested for urethral HSV and 80 men had PCR confirmed HSV urethritis. Of the 80 HSV cases, 55 (68%, 95% confidence interval [CI], 58–78) were caused by HSV-1 and 25 (32%, 95% CI, 22–42) by HSV-2. During the period, there were 2201 men diagnosed with chlamydia confirmed NGU: 80 sequential chlamydial urethritis cases diagnosed between August and December 2014 were selected into the study. There were no differences between men with HSV and chlamydia associated NGU with regard to age, HIV status, or proportion who were men who have sex with men.
There was no change in the proportion of men with HSV urethritis that were HSV 1–positive over time: 68% (95% CI, 49–82) between 2000 and 2007, and 67% (95% CI, 53–79) between 2008 and 2015 (p diff = 0.96). The majority of men (86%) had HSV detected by urethral swab, and the remainder were by first-pass urine.
The median age of men in both groups was similar: 29 years (interquartile range [IQR], 24–38) for men with HSV urethritis and 26 years (IQR, 23–31) for men with chlamydial urethritis (p diff = 0.64). Forty-one men reported sex with men (MSM): 21 in the HSV urethritis group and 20 in the chlamydial urethritis group (p diff = 0.86). There were 3 men with HIV: 1 with HSV urethritis and 2 with chlamydial urethritis.
Heterosexual men with HSV urethritis reported fewer female sexual partners in the preceding 3 months compared with men with chlamydial urethritis (median of 1 vs 2, P < 0.01). The MSM with HSV urethritis reported a median of 2 male sexual partners in the preceding 3 months, whereas those with chlamydial urethritis reported a median of three male partners (P = 0.39).
Symptoms and Signs
The median duration of urethral symptoms before presentation—urethral discomfort, dysuria, or discharge—was similar for HSV urethritis (8 days; IQR, 6–10) and chlamydial urethritis (7 days; IQR, 4–14) (Table 1).
Key differences were noted in reported symptoms and physical findings between men with HSV and chlamydial urethritis (Table 1). Significantly fewer men with HSV urethritis reported urethral discharge compared with men with chlamydial urethritis (19% vs 54%, P < 0.01). Severe dysuria was reported significantly more often by men with HSV urethritis compared with men who had chlamydial urethritis (20% vs 0%, P < 0.01). Constitutional symptoms (fever, myalgia, and/or fatigue) were also significantly more common in men with HSV urethritis compared with men with chlamydial urethritis (15% vs 0%, P < 0.01). Within the HSV urethritis group, men with HSV-1 were more likely to present with severe dysuria (25% vs 4%, P = 0.02) and constitutional symptoms (22% vs 0%, P = 0.02) than those with HSV-2 (Table 2). However, there were significantly more probable initial herpes infections among men with HSV-1 compared with HSV-2 (16% vs 0%, P = 0.03), defined as men without a history of herpes who had at least 2 of the following: constitutional symptoms; widespread, multiple or bilateral lesions; and/or bilateral lymphadenopathy.20 Table 3 summarizes the clinical features of HSV urethritis with and without genital ulceration.
On physical examination, men with HSV urethritis were significantly less likely to have a visible urethral discharge compared to men who had chlamydial urethritis (32% vs 69%, P < 0.01). However, men with HSV urethritis were significantly more likely to have meatitis (62% vs 23%, P < 0.01). Although 37% of men with HSV urethritis had genital ulceration and 30% had inguinal lymphadenopathy, neither of these were found in any men with chlamydial urethritis. Among the 29 men who had HSV urethritis with genital ulceration, the location of ulcers was: penile shaft (n = 9), meatus (n = 9), glans penis or foreskin (n = 6), or unspecified (n = 5). Of the 29 men who had genital ulceration, 22 had the ulcer swabbed, and 19 had HSV detected by PCR from the ulcer, in addition to having HSV detected in the urethral or urine sample. Of the 19 men with ulcers, 13 had multiple lesions, 4 were noted to be tender, and 2 had vesicles. No men reported a history of genital herpes, whereas 1 reported previous oral herpes. Of the 29 men who had genital ulceration, 28 had syphilis serology performed, and 16 had ulcer syphilis PCR testing for Treponema pallidum, all of which were negative.
Figure 1 contains information about the physical examination findings for men presenting with HSV or chlamydial urethritis. This Venn diagram demonstrates that HSV urethritis may present with a variety of overlapping signs, in comparison with chlamydial urethritis where men predominantly presented with urethral discharge with some overlap with meatitis.
A urethral smear was performed for microscopy in 71% (n = 113) of men—60% for chlamydial urethritis and 81% for HSV urethritis (Table 1). There was no significant difference in the proportion of men who had raised (≥5) PMNLs/HPF between the 2 groups (52% for HSV urethritis vs 60% for chlamydial urethritis, P = 0.46). Few men with HSV urethritis had a concurrent urethral pathogen detected: among those tested, the proportion of men with concurrent urethral C. trachomatis or M. genitalium was 6% and 2%, respectively. No men tested for urethral N. gonorrhoea or adenovirus were found to be positive for these.
In this study, which we believe is the largest case series of HSV urethritis cases reported to date, we found that men with HSV urethritis may present with distinctive clinical features that differ from those usually seen in chlamydial urethritis. Urethral discharge was significantly less common, and meatitis significantly more common on physical examination in men with HSV urethritis. Furthermore, inguinal lymphadenopathy was present in approximately one third of men with HSV urethritis but not seen in any men with chlamydial urethritis. Where present, these features in men presenting with NGU should alert clinicians to a possible diagnosis of HSV and guide testing and management. Notably, only a third of men with HSV urethritis had visible genital ulceration.
A strength of this study is that PCR was used for the detection of HSV in urine providing a highly sensitive detection method compared with viral isolation.18 Our results should be read with a number of study limitations including potential biases in mind. As this study involved a retrospective review of medical records, it is possible that there was ascertainment bias with underreporting or overreporting of symptoms or signs. For example, there was no standardized grading of the severity of symptoms, such as dysuria used in the clinic. Selection bias of herpes cases may also have occurred. Clinicians may have been more likely to test men with severe dysuria or meatitis for HSV because these have previously been associated with HSV urethritis. Further, 8 men with HSV urethritis did not receive a chlamydia test, indicating that some clinicians may have felt confident enough to attribute a viral cause for NGU and not investigate for bacterial aetiologies. On the other hand, clinicians may not have performed urethral HSV testing in men with typical genital herpes lesions, even where urethral symptoms were reported. A more accurate evaluation of the clinical spectrum of HSV urethritis would require testing all men presenting with urethritis for HSV rather than clinician-selected testing. The comparator group selected for this study were men who presented with NGU and who subsequently tested positive for chlamydia. This was intentional as cases with HSV also presented with NGU and were therefore assessed and investigated in a similar way.
Recent studies have provided fresh insights into the highly dynamic interactions between HSV and host immune responses in the genital tract and the role of mucosal T cells in the prevention and development of clinical herpetic lesions.21 The presence of severe dysuria and more frequent meatitis seen in men with HSV suggests the mucosal immune response in the urethra differs between HSV and chlamydia. Studies have shown that genital HSV frequently reactivates and sheds over multiple separate genital sites.21,22 In our study, most men with HSV urethritis and concurrent genital ulceration had HSV detected from both the ulcer and urethra. Most men with HSV urethritis in this series, however, did not have concurrent genital ulceration, suggesting isolated HSV infection within the urethra in these men. We could not definitively establish whether HSV infections were initial infections or recurrent episodes as HSV serology was not performed; however, using a clinical definition, it appears most of the likely initial herpes urethritis infections occurred in men with HSV-1 rather than HSV-2 and may have accounted for many of the cases where constitutional symptoms or severe dysuria were reported.
Genital HSV infection is common among men1,23; however, genital HSV presenting as urethritis is uncommon.8,9,13–16 It is therefore appropriate that testing for urethral HSV is performed selectively based on clinical features rather than in all men presenting with NGU. The findings from this study suggest that clinicians managing men presenting with urethritis should ascertain whether patients have evidence of severe dysuria, constitutional symptoms, lymphadenopathy, meatitis or genital ulceration and that the presence of these features may be an indication for HSV testing. Clinicians may consider offering empirical treatment with antivirals to those with signs and symptoms consistent HSV urethritis while awaiting the test results; however, further research on the effectiveness of antivirals for HSV urethritis specifically is required.
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