The Enigma of Lymphogranuloma Venereum Spread in Men Who Have Sex With Men: Does Ano-Oral Transmission Plays a Role?

In this issue you will find an interesting case series of 26 men who have sex with men (MSM) diagnosed in Madrid Spain with lymphogranuloma venereum (LGV) proctitis caused by the Chlamydia trachomatis strain L2b.1 It is an illustration of an ongoing and established epidemic among gay men living in Western cities across the globe of which the first cases were found in Rotterdam dating back to 2003.2,3 Let alone a few reported cases in women, LGV caused by the L2b strain is a focused epidemic exclusively found in MSM.4 Most reports arise from European nations. In the United Kingdom, national data show a sharp increase in diagnoses of LGV since 2012.5 The majority of cases live in London, with high rates of co-infection with human immunodeficiency virus (HIV) and other sexually transmitted infections. The Madrid case series describes a similar picture; 24 of the 26 were HIV positive, including 5 newly diagnosed HIV infections. The majority of the patients reported tenesmus (85%), rectal pain (88%), constipation (62%), or anal discharge (96%). These symptoms seem important to identify LGV proctitis and reaffirm earlier findings in a UK study concluding that tenesmus alone or in combination with constipation made a diagnosis of LGV in MSM presenting with rectal symptoms likely.6 Although LGV proctitis can cause symptoms, these are also quite nonspecific. As a result, infections may easily be misdiagnosed as Crohn disease and not treated adequately.7,8 This occurs especially when patients with LGV are referred to gastroenterologists for whom the sexual preference is often not taken into account in their patient history. A definite LGV diagnosis requires confirmation with a genovar specific C. trachomatis nucleic acid amplification test. Because these tests are not available commercially, they need “in house” laboratory development, and are generally restricted to research laboratories or public health settings. When appropriate diagnostics are lacking, many infections are missed, as was illustrated in a recent epidemiological report from the Czech Republic where 48 cases were diagnosed between 2010 and 2014, but in 2015 alone, already 40 LGV infections.9 So what are the epidemiological explanations for the current LGV epidemic in MSM? Seroadaptation has been suggested as one of the facilitating factors of LGV transmission.10 Moreover, in a UK study analyzing LGV patients from 2004 to 2010, 5.2% reported repeat LGV infections.11 Risk factors alone did not explain these repeat infections. It was speculated that the central position of “LGV repeaters” in the sexual network may be an important factor in the perpetuating epidemic. Nonetheless, the “biological” mode of transmission of LGV proctitis among MSM remains enigmatic. Before 2003, LGV was primarily seen in tropical regions and was characterized by a typical clinical presentation of a destructive infection of the external genitalia with an extensive inflammatory response leading to the formation of suppurating inguinal bubo's and systemic symptoms like fever, arthritis, and malaise. This “classical” presentation is also known as inguinal LGV. In the long run, inguinal LGV disseminates further into the lower pelvic region and leads to late irreversible sequellae like frozen pelvis syndrome, rectal strictures, fistulas, plus elephantiasis and esthiomene of the external genitalia due to destruction of the regional lymphatic system.3 In contrast to the “classical” presentation, the largest majority of MSM with LGV in the current Western epidemic presents with a severe proctitis and/or proctocolitis.12 To explain the asymmetric distribution of anorectal and inguinal LGV infections, tissue tropism (with a higher affinity of LGV serovars to rectal mucosa compared with urethral epithelia) has been suggested, but so far not yet confirmed.13–15 Thus, the majority of reported infections in MSM are found in the anorectal canal and not urogenital. How a man with LGV proctitis transmits the infection to his partner who subsequently also develops an anorectal infection remains a conundrum, and leaves the mode of transmission within the MSM network unclear. In the early days of the epidemic, sharing toys or fisting practices have been suggested as transmission modes,16 but subsequently dismissed.17 A drawback of the Madrid case series is its focuses on symptomatic LGV patients only. For long, there was the false assumption that LGV infections were symptomatic in the majority of cases.18 This in contrast to an earlier prospective study from Amsterdam showing that about a quarter of the anorectal LGV cases did not present with symptoms when screened systematically19; this ratio has not changed significantly since.12 A recent prospective study performed in the United Kingdom now affirms the Amsterdam finding of a considerable proportion of asymptomatic LGV cases (27%) in a large nationwide cohort.20 From a patient perspective, the detection of asymptomatic LGV cases seems obvious; many asymptomatic patients are possibly presymptomatic and early detection can prevent considerable morbidity and irreversible damage on the longer run. Yet, from a public health perspective, it is of utmost importance to prevent the ongoing “silent” transmission in the population. Currently, most guidelines (including the 2015 Centers for Disease Control STD guideline and the 2013 British Association for STI and Sexual Health LGV guideline) do not recommend screening for LGV in asymptomatic MSM but only on clinical or epidemiological suspicion and after exclusion of other causes of proctitis.21,22 An exemption is the European IUSTI LGV guideline which recommends to screen all MSM who report receptive anal sexual practices in the previous 6 months for anorectal C. trachomatis infection. Subsequently, MSM who are anorectal C. trachomatis positive are advised to screen for LGV proctitis according to local guidelines.23 Screening for asymptomatic infections seems justified now the prevalence found in Amsterdam has been confirmed in the UK study. Given the increasing trend, the LGV endemic is clearly not under control. Therefore, directed screening must be intensified. Apart from the focus on the 25% asymptomatic anorectal infections, LGV infections at other locations, (eg, urethral and pharyngeal) are possibly of importance within the transmission network. A few years ago, we reported in this journal that in 341 MSM with anorectal LGV, 2.1% had concurrent urethral LGV, and among their partners, 6.8% had urethral LGV infections.24 In the accompanying editorial in the same issue, Ward and Ronn25 questioned whether nonrectal LGV can account for substantial “reservoirs” that need targeted screening to get this epidemic under control. Prospective studies are required to see if routine screening of nonrectal LGV in MSM is needed and cost-effective. A daring explanation for persistent C. trachomatis infections in women was suggested recently by Rank and Yeruva26 in an article called “An Alternative Scenario to Explain Rectal Positivity in Chlamydia-Infected Individuals.” They bring forward that chlamydiae in virtually every natural animal host reside naturally in the gastro-intestinal tract and are transmitted via the fecal-oral route. They can persist in the gastro-intestinal tract for long periods in the absence of apparent inflammation and pathology.27 Igietseme et al.28 proved back in 2001 that mice infected orally with the mouse chlamydia, Chlamydia muridarum, become infected in the lower intestinal tract and are unable to clear the infection. This paradigm could possibly account as an explanation for the unanswered findings in the current LGV epidemic in MSM. Anogenital transmission of L2b C. trachomatis could occur between men, but oral infection may also occur via ano-oral sex or mechanical transmission (Fig. 1). Oral infection may result in clinical or subclinical pharyngitis, and the organisms may pass through the gastrointestinal tract to the large intestine and rectum. Here, L2b strains could either induce symptomatic LGV proctitis or induce an asymptomatic infection; in both cases contributing to the ongoing transmission. Whether this theory proves right in the human situation is to be seen, and its contributing factor to the LGV epidemic in MSM remains to be addressed in future research.Figure 1: Depiction of proposed transmission patterns of lymphogranuloma venereum in men who have sex with men. Genitoanal transmission occurs between men (grey arrows), but ano-oral infection may also occur via oral sex or mechanical transmission (black solid arrows). Oral infection may result in clinical or subclinical pharyngitis, and the organisms may pass through the gastrointestinal tract to the large intestine and rectum, where they can be shed (dashed black arrows). Adapted from Figure 2 from Rank and Yeruva.27 Icon made by Freepik in people from www.flaticon.com.