Urethral Lymphogranuloma Venereum Infections in Men With Anorectal Lymphogranuloma Venereum and Their Partners

The Missing Link in the Current Epidemic?

Abstract

Urethral lymphogranuloma venereum (LGV) is not screened routinely. We found that in 341 men having sex with men with anorectal LGV, 7 (2.1%) had concurrent urethral LGV. Among 59 partners, 4 (6.8%) had urethral LGV infections. Urethral LGV is common, probably key in transmission, and missed in current routine LGV screening algorithms.

In Brief

A study in a sexually transmitted disease clinic in Amsterdam, the Netherlands, found that urethral lymphogranuloma venereum is common in a selected group, probably key in transmission, and missed in current screening algorithms.

Lymphogranuloma venereum (LGV) has reestablished itself in Western society as an invasive sexually transmitted infection (STI) among men who have sex with men (MSM).¹ Lymphogranuloma venereum is caused by Chlamydia trachomatis (Ct) biovar L. Prompt antibiotic treatment is effective and curative, although it is more extensive than anogenital biovar non-L Ct infections. Broader awareness among clinicians of LGV is needed to enable appropriate investigation and management, prevent irreversible late sequelae, and accelerate the interruption of onward spread. Recently, we see a significant increase in the prevalence of LGV at the STI outpatient clinic in Amsterdam, which indicates that more extensive control measures are warranted.²

Most reported LGV cases among MSM involve anorectal infections.² Very few urogenital infections, also known as inguinal LGV, are described. Even fewer infections of the pharynx have been reported.³ The overrepresentation of anorectal infections in the LGV epidemic is poorly understood but stresses that the mode of transmission of LGV needs additional clarification. It has been suggested that the transmission of rectal LGV may be related to sexual activities such as “fisting,”⁴ but this could not be confirmed later.⁵ We postulated that anorectal LGV is transmitted via receptive anal intercourse and that there is a reservoir of missed genital LGV infections in MSM.

The primary aim of this study was to determine whether there is a reservoir of missed urethral LGV that might contribute to the ongoing LGV epidemic. We performed LGV typing on all Ct-positive urethral samples in index patients with anorectal LGV infections and in visiting partners of indexes with anorectal LGV.

Since 2005, all MSM patients reporting receptive anal intercourse in the past 6 months were tested on anorectal Ct infections by Aptima CT system (GEN-PROBE, San Diego, CA) and tested further for LGV, as described before.^6,7 In case the pmpH test was inconclusive (mainly due to low Ct load), biovar L could not be confirmed and the diagnosis was considered negative for LGV.

Patients who were diagnosed positive (index patients) could notify their partners who were registered at the STI clinic on a voluntary basis. The electronic patient record of the index was linked to the record of the partner. This enabled immediate partner notification in case an infection was diagnosed in an index patient. Moreover, we distributed STI notification slips to infected index patients to distribute to their partners. The notification slip states the date plus the infection found, without personal identification. If the partner returned to the clinic, we could thus identify which infection he was exposed to. Lymphogranuloma venereum partner notification was implemented in case the partner had contact with the index within the past 60 days. For the study, we identified LGV contacts either on the electronic partner link or via the notification slip. Lymphogranuloma venereum contacts were screened routinely for other STIs and treated with a biovar non-L Ct infection regimen (azithromycin 1000 mg orally single dose or doxycycline 100 mg orally twice a day for 7 days) in accordance with the Centers of Disease Control and Prevention 2010 sexually transmitted disease treatment guidelines.⁸ The test and treat policy of the STI outpatient clinic in Amsterdam has been described in more detail in reference 5.

We tested urethral biovar L infections retrospectively in urethral Ct-positive consultations with an anorectal LGV infection and in urethral Ct-positive sexual partners of consultations with an anorectal LGV infection on record between January 2008 and August 2012. All available Ct-positive urine samples stored at −80°C, were retrieved, thawed, and tested with the biovar L–specific polymerase chain reaction.^6,7 Patient data from LGV index patients and partners were retrieved from the electronic patient database. Because we used anonymous routine data, no ethical clearance for this study was needed.

During the study period, 27,504 MSM consultations reporting receptive anal intercourse in the past 6 months were screened at the STI clinic in Amsterdam. The prevalence of anorectal LGV in these men was 1.2% (n = 341). Within this group, 33 (9.7%) urine samples were Ct positive and 7 of these urine samples were biovar L positive (prevalence 2.1%). Nine (2.6%) urine samples were biovar non-L, 15 (4.4%) samples were inconclusive, and 2 (0.6%) samples were missing.

We located 59 sexual partners of MSM diagnosed as having an anorectal LGV on record. All partners were male, and none were diagnosed as having anorectal LGV. Among these partners, 10 (16.9%) urine samples were Ct positive and 4 of these samples were biovar L positive (prevalence 6.8%). One (1.7%) urine sample was biovar non-L, 3 (5.1%) were inconclusive, and 2 (3.4%) were missing.

All 11 patients with anorectal LGV and concurrent urethral LGV (based on a biovar L–positive urine sample) had sexual intercourse with exclusively men, and 9 were HIV positive. Five of the 11 patients with urethral LGV did not report symptoms of urethritis, and only 1 of 11 had lymphadenopathy. Concurrent STIs including gonorrhea (4/11), herpes simplex virus (1/11), and syphilis (1/11) were found among index patients with anorectal LGV. No coinfections besides urethral LGV were found in the partner group. In both groups, condom use was inconsistent, and multiple partners were reported in the preceding 6 months (between 2 and 10).

Various guidelines (British Association for Sexual Health and HIV [BASHH], World Health Organization/International Union against Sexually Transmitted Infections [IUSTI] and Centers of Disease Control and Prevention) recommend routine diagnostic methods for anorectal LGV in MSM, but none recommend routine screening of urethral LGV infections.^8–10 Here we show previously undiagnosed urethral LGV infections both in MSM with anorectal LGV and among partners of anorectal LGV index patients. Probably, urethral LGV is key in the transmission of LGV in MSM, but remains undetected to date. Many clinicians expect to find unilateral lymphadenopathy in an individual with genital LGV. Because only 1 of the 11 patients with urethral LGV had lymphadenopathy, the absence of this finding does not exclude an infection, and molecular testing is warranted.

Moreover, anorectal LGV infections are often missed because of unawareness of the disease,¹¹ lack of appropriate diagnostic tools,¹² or the asymptomatic nature of the infection in a considerable proportion of patients.² These missed anorectal infections might also contribute to the ongoing LGV epidemic among MSM.

Two above-mentioned guidelines recommend partner treatment of LGV index patients with azithromycin 1000 mg once or doxycycline 100 mg twice a day for 7 days, a regimen considered sufficient to eliminate biovar non-L Ct infections. The new BASHH guideline, still under review, suggests extending the duration of partner treatment with doxycycline to 14 days.⁹ We showed earlier that anorectal LGV can persist under doxycycline treatment for 16 days, which stresses the importance of prolonged treatment for at least 21 days.¹³

Here we showed that partners of index patients with anorectal LGV (1) harbor asymptomatic urethral LGV infections, (2) had no other bacterial STI requiring antibiotic treatment, and (3) engaged in high-risk behavior. Because under the current guidelines, they were treated insufficiently, it is feasible that their LGV infection was not eliminated, and further transmission was possible. We detected urethral LGV infections in 6.8% of the partners of patients with anorectal LGV. This is based on a small and incomplete number of partners necessitating further studies on the prevalence of urethral LGV. Until that time, it would be advisable to treat partners of patients with LGV with a 3-week course of doxycycline, considered effective to eliminate biovar L Ct infections.

A limitation in our study is that we only included partners on record with a legitimate notification. Therefore, our results probably show an underestimation of urethral LGV among partners of LGV index cases. Of the Ct-positive urethral samples, 4.4% and 5.1% of patients with anorectal LGV, respectively, and their partners were inconclusive for LGV determination. This is caused by a difference in sensitivity of the biovar-nonspecific commercial Ct test and the LGV-specific in-house developed additional test. As a consequence, an underrepresentation of the true urethral LGV prevalence cannot be excluded.

Lymphogranuloma venereum infection is a serious concern for the MSM community in Western Europe and other industrialized countries. Awareness of, screening for, and prompt treatment of LGV are crucial for the individual patient and to prevent ongoing transmission. We see a significant increase in the prevalence of LGV in Amsterdam in the last year.² Urethral LGV might form a potential undetected reservoir. To further clarify this, we plan to estimate the prevalence of urethral LGV infections among the total MSM population visiting the outpatient clinic. Future findings might indicate the need for adjustment of LGV protocols, especially partner treatment and possibly routine screening for urethral LGV.