Background The aim of this study was to characterise the clinical features of adenovirus urethritis in men and to compare the frequency of these between heterosexual men and men who have sex with men (MSM).
Methods This was a review of the clinical and laboratory information from men diagnosed with PCR-confirmed adenovirus urethritis at the Melbourne Sexual Health Centre between January 2006 and April 2014.
Results 102 adenovirus urethritis cases were reported, among which 61 were heterosexual men and 41 MSM. Eighty-nine per cent (n=91) had signs of meatitis or conjunctivitis: 51% had meatitis only; 32% meatitis together with conjunctivitis and 6% with conjunctivitis only. The distribution of symptoms and signs was similar among heterosexual men and MSM (p values >0.1). Adenovirus was the sole pathogen found in 93% of cases, excluding gonorrhoea, chlamydia, Mycoplasma genitalium and herpes simplex virus. Only 37% had ≥5 polymorphs per high-power field from a urethral smear. Where samples were still available for adenoviral sequencing (n=20), all were subgroup D.
Conclusions The clinical features of adenovirus urethritis in men can be distinctive and aid diagnosis, distinguishing it from other treatable causes of male urethritis.
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Adenovirus has been classified into 68 different serotypes and 7 subgroups: A–G.1 Different serotypes have been associated with various clinical syndromes, including keratoconjunctivitis and pharyngoconjunctival fever.1 Previous studies have also shown adenovirus to be a cause of urethritis in men.2–5
The aim of this study was to describe the characteristic clinical features of adenovirus urethritis in a large series of men and to determine if there were any differences in clinical presentation between heterosexual men and men who have sex with men (MSM).
Population, sampling and data collection
This study involved a review of the clinical records of all men diagnosed with laboratory-confirmed adenoviral urethritis at the Melbourne Sexual Health Centre, Victoria, Australia, between January 2006 and April 2014. Adenovirus urethritis-positive cases were identified using positive adenoviral PCR results from the Victorian Infectious Disease Research Laboratory.
During the study period, men attending the clinic with symptomatic urethritis were routinely tested for Chlamydia trachomatis, Mycoplasma genitalium and Neisseria gonorrhoeae. A first pass urine specimen was obtained for C. trachomatis testing by strand displacement amplification and for M. genitalium testing using PCR. A urethral swab was obtained for a urethral smear and Gram stain and N. gonorrhoeae testing using modified Thayer Martin medium. Urethral smears were examined with light microscopy under oil immersion. The number of polymorphonuclear leucocytes (PMNLs) per high-power field (×1000) was recorded. An additional urethral swab or first pass urine was tested for adenovirus and herpes simplex virus using PCR in selected men presenting with urethritis based on clinical suspicion of a viral pathogen.
Testing for adenovirus was undertaken using an in-house PCR targeting the adenoviral hexon gene modified from published methods.6 For samples still available at the time of the study, the first-round hexon gene PCR product was sequenced and compared with sequences in GenBank (NCBI) to determine adenovirus genogroup typing.
Routinely collected clinical and laboratory data were extracted from the clinic's medical records, including reported sexual behaviour, clinical symptoms and signs and laboratory results. Symptoms and signs were compared between heterosexual men and MSM using the χ2 test for categorical variables. The associations between the number of male adenovirus urethritis cases and seasons were measured by the incidence rate ratio using a Poisson regression model. Data were analysed using SPSS V.21.
Characteristics of cases
During the study period, there were 102 men with PCR-confirmed adenoviral urethritis: 61 were heterosexual men and 41 MSM. The median age was 34 years. Two men were HIV positive.
Heterosexual men reported a median of two female sexual partners over the preceding 3 months with 97% (n=59) reporting vaginal sex and 74% (n=45) not using condoms all the time with vaginal sex. MSM reported a median of three male sexual partners over the preceding 3 months with 83% (n=34) reporting insertive or receptive anal sex and 50% (n=20) not using condoms all the time with anal sex.
Cases peaked in autumn (March–May) with the fewest cases in spring (September–November). The Poisson model showed that the expected number of adenoviral urethritis cases was 105% higher in summer (p=0.022), 162% higher in autumn (p=0.003) and 108% higher in winter (p=0.030) in comparison with the expected cases in spring.
Symptoms and signs
The median duration of urethral symptoms—urethral discomfort, dysuria or discharge—was 7 days. This was the same for heterosexual men and MSM. The symptoms reported by men and clinical signs evident on examination are shown in table 1 where these are compared between heterosexual men and MSM. The most common symptom was dysuria, which was reported by 83%. Of men who had dysuria, the dysuria was reported to be severe in 14% (n=12). Urethral discomfort and urethral discharge were reported by 48% and 45% of men, respectively. A sore throat was reported by 12% of men.
The most common examination finding observed was inflammation at the urethral meatus (meatitis), which was evident in 83%. Urethral discharge was visible in 59% and signs of conjunctivitis were observed in 38%. There were no significant differences in the frequency of these signs between heterosexual men and MSM.
The proportion of men with signs of meatitis and conjunctivitis and the extent to which these overlapped in individual men are illustrated in figure 1. Most men (89%) had one or both of these signs: 51% had meatitis only; 32% had meatitis together with conjunctivitis and 6% had conjunctivitis only.
The results of laboratory investigations are shown in table 1. Among the 102 men with positive adenoviral PCR results, 87% were obtained by urethral swab and 13% from urine. Where samples were still available for sequencing (n=20), all were subgroup D.
A urethral smear and Gram stain was performed in 76% of men. Overall, only 37% had ≥5 PMNLs per high-power field. The PMNL counts per high-power field and the proportion of men who had these counts on their urethral smear were 0 (18%); <1 (28%); 1–4 (17%); 5–7 (14%); 8–20 (21%) and >20 (3%).
Few men with adenoviral urethritis had a concurrent urethral pathogen detected. The prevalence of urethral N. gonorrhoeae, C. trachomatis and M. genitalium was 4%, 2% and 1%, respectively. No men tested for urethral herpes simplex virus were found to be positive. Thus in 93% of cases, adenovirus was the sole urethral pathogen identified. Of the 39 men with examination findings of conjunctivitis, 27 had adenovirus PCR testing from one or both eyes. Of these, 23 (85%) had a positive adenoviral PCR result. Of samples available for sequencing, one patient had results from both the conjunctiva and the urethra belonging to adenovirus subgroup D.
In this study, which we believe is the largest case series of adenovirus urethritis cases reported until now, we found the clinical presentation of adenoviral urethritis can be distinctive with signs of meatitis and/or conjunctivitis present in the majority of cases. These clinical findings are not usually present in cases of male urethritis caused by the more common bacterial urethral pathogens gonorrhoea, chlamydia or M. genitalium. All the adenoviral specimens that were genotyped in this study belonged to subgroup D, consistent with some previously published studies where typing on urethral adenovirus has been undertaken.3 ,4
Strengths and limitations
A strength of this study is that testing was undertaken for other known causes of sexually acquired urethritis in men. In 93% of cases, adenovirus was the only pathogen identified. Also, PCR which is a highly sensitive method for detecting adenoviruses was used to confirm adenovirus cases.7 Many of the previous studies of adenoviral urethritis were conducted many years ago using culture for adenovirus. There are a number of study limitations. As adenovirus testing was undertaken in selective cases based on clinical indications, this may have biased towards certain clinical features, and we did not include a control group of men with other causes of urethritis. Furthermore, as this study involved a retrospective review of clinic records, it is possible that some symptoms or signs were under-reported.
In sexually transmitted infections clinics, it has been common practice to base the diagnosis of male non-gonococcal urethritis on the concentration of PMNLs on the urethral smear. By convention, the presence of ≥5 PMNLs per high-power field has commonly been accepted as indicative of infectious urethritis. In this study, 62% of men had fewer than 5 PMNLs per high-power field: this applied to both heterosexual men and MSM. Thus, adenovirus testing should not be dependent on the presence of elevated PMNLs on a urethral smear.
We compared the clinical manifestations of adenoviral urethritis between heterosexual men and MSM and found no differences in presentation between these groups. We undertook this comparison as the mode of transmission of adenovirus resulting in urethritis is not clear and given the differences in sexual behaviour between heterosexual men and MSM it is plausible that presentations may have differed between the two groups. It has previously been suggested that transmission of adenovirus to the urethra might result from direct inoculation from a sexual partner's pharynx via oral sex. Alternatively, transmission could be via vaginal sex: adenovirus has been isolated in the female genital tract.8 Given adenovirus is present in the gastrointestinal tract,9 it is also plausible that transmission between men might occur via anal sex. Alternatively, urethral adenovirus might reflect inoculation elsewhere: as a local manifestation of systemic adenoviral infection or via autoinoculation from a remote site such as the conjunctiva.
Our study suggests that clinicians managing men presenting with urethritis should ascertain whether patients have evidence of meatitis or conjunctivitis and that the presence of these trigger testing for adenovirus. A diagnosis of adenovirus is relevant as antibiotics used to treat bacterial urethral pathogens are not indicated nor is partner management. Given the uncertainty over how adenovirus is transmitted to the urethra, future research on how adenovirus is transmitted between sexual partners would be of interest.
Most cases of adenoviral urethritis in men were associated with meatitis and/or conjunctivitis.
These were similar in heterosexual and homosexual men.
Most did not have increased urethral polymorphs.
Handling editor Jackie A Cassell
Contributors GRS reviewed literature, planned the study, collected and analysed the data and prepared the manuscript draft. MYC conceived of the study, oversaw the analysis and overall study and reviewed the manuscript. KG and JD carried out the laboratory testing, including adenoviral serotyping. EPFC assisted with statistical analyses. All authors contributed to discussion of the study results, writing of the manuscript and approval of the final draft.
Competing interests None declared.
Ethics approval Alfred Hospital Research Ethics Committee (number 260/14).
Provenance and peer review Not commissioned; externally peer reviewed.