Sexually Transmitted Diseases:
Lymphogranuloma Venereum in Men Who Have Sex With Men: Are We Missing a Reservoir of Infection?
Ward, Helen PhD; Rönn, Minttu MPH
From the Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, London, UK
HW has received funding for research on lymphogranuloma venereum from the UK Medical Research Council and support from the Imperial National Institute for Health Research (NIHR) Biomedical Research Centre.
Conflict of interest: None declared.
Correspondence: Helen Ward, PhD, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, Norfolk Place, London W2, UK. E-mail: email@example.com.
Received for publication June 18, 2013, and accepted June 18, 2013.
Over the past decade, lymphogranuloma venereum (LGV) has become endemic among men who have sex with men (MSM) in many European countries, primarily affecting men with HIV, and there have been reports of increasing numbers of cases over recent years in the UK,1 Amsterdam,2 Barcelona,3 and Madrid.4 The reemergence and persistence of this invasive form of Chlamydia trachomatis have occurred despite the implementation of control measures such as diagnostic testing, case finding, surveillance, and prevention campaigns.
Diagnosed and reported infections have been mainly rectal, with few reports of urogenital (from urethral swabs, urine, ulcers, or buboes) or pharyngeal sites. This could indicate an undiagnosed reservoir of infection in the urethra or pharynx, or in the rectum of asymptomatic men. In this issue, de Vrieze and colleagues5 report results of a study to test whether there is a reservoir of urethral infection. They measured the prevalence of urethral LGV among patients with rectal LGV and their contacts; 2.1% of patients with rectal LGV and 6.8% of their 59 contacts had urethral LGV, and only 1 of the 11 cases had inguinal lymphadenopathy. They conclude that we are missing such cases that may be the hidden link in transmission.
The existence of such a reservoir of urethral infection has been suggested before, but there is sparse evidence. Urogenital infections have formed small minority of cases in surveillance data and research reports.2,3,6 This may reflect the lack of diagnostic testing for urethral LGV and, therefore, more systematic case finding has been undertaken, but this, too, has identified few cases of urogenital LGV. In a separate report from the Amsterdam group, positivity of LGV in anorectal samples tested for chlamydia was 1.2% compared with 0.6% for inguinal LGV (from genital ulcer swabs).2 In an earlier study of unselected MSM attending clinics in the UK, urethral LGV prevalence was estimated at 0.04% compared with 0.9% for rectal LGV.7 A more recent study from Germany included screening of 1883 MSM; chlamydia-positive specimens from the rectum, pharynx, and urethra or urine were genotyped. Lymphogranuloma venereum was identified in 17 of 103 chlamydia-positive rectal specimens, 2 of 13 pharyngeal specimens, and none of 8 urethral/urine specimens.8 In Madrid, 2.6% (10/338) of urethral chlamydia-positive samples were found to be LGV, all symptomatic, although 4 of these were in heterosexual men. The overall positivity of urethral LGV was 0.4% (10/2420).4 There was no urogenital LGV in Finland among the MSM who had rectal LGV.9
It is possible that there is transient urethral infection in MSM and that screening studies are missing this. There is indication for tissue tropism in other C. trachomatis serovars,10,11 and although LGV distribution is highly concentrated in rectal infection, it might be partially explained by LGV serovars’ higher affinity to rectal mucosa compared with urethral epithelia.
Without further evidence building on that presented by de Vrieze and colleagues, it is therefore difficult to conclude that there is a substantial urethral, or pharyngeal, reservoir, although it may of course be important in the dense networks within which LGV and HIV are circulating.
The other potential reservoir is the rectum, with the possibility that some form of rectal-to-rectal transmission occurs and that infection might be sustained by asymptomatic rectal cases.12 There is certainly evidence of a higher prevalence in the rectum. In Madrid, 19.6% (82/419) of rectal chlamydia cases were typed as LGV, an overall LGV rectal positivity of 2.6% (82/3185).4 In the German study, the authors estimated the overall LGV prevalence to be 1.7% (11/632) among HIV-positive men and 0.6% (8/1251) among HIV-negative men, the majority being rectal cases, half of which (8/15) reported no recent rectal symptoms.8
This latter finding of a significant proportion of asymptomatic rectal LGV is interesting and fits with reports from the Netherlands. In Amsterdam, 27.2% of anorectal cases were asymptomatic,2 whereas in Madrid, approximately 1 in 10 (9/82) rectal cases were reported as asymptomatic.4 In the UK, there continues to be a predominance of symptomatic infection, but this may again reflect testing protocols that recommend LGV typing for chlamydia cases with symptoms indicative of LGV and their contacts.
Asymptomatic and nonrectal LGV therefore seem to account for relatively small “reservoirs” that may make control more difficult, although further research is needed. In particular, we need to see if there are undiagnosed and persistent infections within the high-risk networks where LGV is mostly circulating. These networks include men with a high prevalence of HIV and other infections such as gonorrhea and hepatitis C, who report drug use, multiple partners, often anonymous, and unprotected sex.13,14 These dense networks are linked to seroadaptive behaviors such as preferential mixing by HIV status (serosorting), a strategy adopted by some MSM with the intention of reducing HIV transmission while permitting unprotected sex with appropriate partners, which can increase the risk of STI acquisition.15 Such behaviors, often alongside other risks such as recreational drug use, are likely to be underlying outbreaks of infections such as LGV, hepatitis C, syphilis, gonorrhea (including resistant strains), and enteric infections such as Shigella flexneri in MSM.16 Control programs in these settings are going to be challenging and require outreach work to venues, targeted prevention messages, and awareness campaigns using the Internet and other media.
It has been suggested that both testing and treatment guidelines need to change in response to the evidence of nonrectal and asymptomatic LGV infections. Haar et al.8 discuss 2 possible options in the absence of clear clinical predictors for LGV in the presence of asymptomatic cases: treat all chlamydia-positive patients with a regimen that is adequate to cure LGV, or test all chlamydia-positive samples in MSM for LGV. De Vrieze and colleagues point out that without urethral LGV testing, a number of the contacts in their study would not have received appropriate treatment, considered as 3 weeks of therapy. There is some limited evidence that LGV may require more than 2 weeks of therapy for clearance, but treatment trials are clearly needed to confirm this.17 Increasing the duration of treatment to 3 weeks would have to be weighed against the potential for increased adverse effects and reduced adherence. UK guidelines focus testing toward symptomatic MSM who test positive for chlamydia and their contacts, whereas in the Amsterdam STI clinic, they are now recommending testing all inguinal and rectal chlamydia-positive samples from MSM for LGV.2 Germany has no guidelines for asymptomatic MSM.8 Those drafting revised guidelines should consider recommending 3 weeks of therapy for LGV contacts; further case-finding exercises, including in high-risk populations and contacts, are required to inform future testing guidelines.
1. Hughes G, Alexander S, Simms I, et al. Lymphogranuloma venereum diagnoses among men who have sex with men in the UK: Interpreting a cross sectional study using an epidemic phase-specific framework. SexTransm Inf 2013; doi:10.1136/sextrans-2013-051051.
2. De Vrieze NHN, Van Rooijen M, Van der Loeff MFS, et al. Anorectal and inguinal lymphogranuloma venereum among men who have sex with men in Amsterdam, the Netherlands: Trends over time, symptomatology and concurrent infections. Sex Transm Infect 2013 Feb 20. [Epub ahead of Print].
3. Vargas-Leguas H, Garcia de Olalla P, Arando M, et al. Lymphogranuloma venereum: A hidden emerging problem, Barcelona, 2011. Euro Surveill 2012; 17: pii: 20057.
4. Rodríguez-Domínguez M, Puerta T, Menéndez B, et al. Clinical and epidemiological characterization of a lymphogranuloma venereum outbreak in Madrid, Spain: Co-circulation of two variants. Clin Microbiol Infect 2013.
5. De Vrieze NHN, Van Rooijen M, Speksnijder AGCL, et al. Urethral lymphogranuloma venereum infections in men with anorectal lymphogranuloma venereum and their partners: The missing link in the current epidemic? Sex Transm Dis 2013.
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7. Ward H, Alexander S, Carder C, et al. The prevalence of lymphogranuloma venereum infection in men who have sex with men: Results of a multicentre case finding study. Sex Transm Infect 2009; 85: 173–175.
8. Haar K, Dudareva-Vizule S, Wisplinghoff H, et al. Lymphogranuloma venereum in men screened for pharyngeal and rectal infection, Germany. Emerg Infect Diss 2013; 19: 488–492.
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13. Heiligenberg M, Wermeling PR, Van Rooijen MS, et al. Recreational drug use during sex and sexually transmitted infections among clients of a city sexually transmitted infections clinic in Amsterdam, the Netherlands. Sex Transm Dis 2012; 39: 518–527.
14. Kirby T, Thornber-Dunwell M. High-risk drug practices tighten grip on London gay scene. Lancet 2013; 381: 101–102.
15. Marcus U, Schmidt AJ, Hamouda O. HIV serosorting among HIV-positive men who have sex with men is associated with increased self-reported incidence of bacterial sexually transmissible infections. Sex Health 2011; 8: 184–193.
16. Gilbart VL, Simms I, Gobin M, et al. High-risk drug practices in men who have sex with men. Lancet 2013; 381: 1358–1359.
17. De Vries HJ, Smelov V, Middelburg JG, et al. Delayed microbial cure of lymphogranuloma venereum proctitis with doxycycline treatment. Clin Infect Dis 2009; 48: e53–e56.
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