Initial reports and current status

The first 13 cases among MSM were diagnosed between April and November 2003 and reported to the local health authorities in Rotterdam in December 2003 [2,6]. Most of the men were HIV positive, and the majority had reported unprotected anal intercourse in the past year. Only one patient, with onset of illness in April 2003, had symptoms usually associated with the classical picture of LGV (i.e., buboes and a painful genital ulcer). All other patients had gastrointestinal symptoms, (e.g., bloody proctitis with a purulent or mucous anal discharge and constipation) [6]. The majority of LGV patients had participated in casual sex gatherings during the 6–12 months period before onset of symptoms. LGV patients also reported having numerous sex contacts in cities in Europe and the United States. An alerting report was sent to the EWRS (Early Warning and Response System), the ESSTI (European Surveillance of Sexually Transmitted Infections) Network [7,8], and to the CDC [9]. Subsequently, case reports were received from Antwerp [10], Paris [11,12] Stockholm [13,14] Hamburg [15,16], Barcelona [17], the USA [9] and – later – Canada [18] suggesting that the LGV outbreak was not restricted to the Netherlands.

Since LGV is not a reportable disease in most European countries, it complicated the public health response. Enhanced surveillance was started in the Netherlands (January 2004), France (April 2004), Germany (May 2004), Sweden (June 2004) and the UK (October 2004) [19,14]. Except for Sweden [20], these surveillance systems yielded hundreds of cases: 244 rectal cases in France by December 2005 [4], 61 confirmed cases in Germany by November 2005 [3], 179 cases in the Netherlands by December 2005, and 344 cases in the United Kingdom by March 2006 [21]. In addition, several countries reported a few cases each. Considering no active case-finding was implemented in many countries, the actual number of cases may be higher. In Sweden, however, no additional cases were detected during the intensified epidemiological surveillance or in the course of the retrospective analysis [20]. Comparison between countries is hindered due to their different surveillance methods and lack of harmonisation concerning case definitions and questionnaires, e.g. in France only rectal cases were included. Nonetheless, common features in these reports were: MSM, Caucasian race / ethnicity, mean age above 35 years, predominantly (>70%) co-infected with HIV and a relatively large proportion of MSM with unknown HIV status, and frequent concurrent STIs and HCV [21,22]. Most of them presented with rectal symptoms and only a few with inguinal lesions. The majority reported large number of partners and unprotected anal intercourse. The practice of ‘fisting’ and use of sex toys were also reported. However, the precise identification of risk factors for LGV has not been assessed so far and further analytical studies are needed.

An unusual clinical picture for LGV?

The classical picture of LGV usually involves adenopathy and is characterized by buboes [23]. This current epidemic, however, is mainly characterized by cases presenting with severe proctitis. LGV proctitis in MSM is well recognised [24]. In the early 80’s, serovar L2 was found to be associated with more severe forms of proctitis than non-LGV strains [24-27]. Serovar L1/L2 was also identified in 68 cases of LGV among 101 rectal samples of symptomatic men in San Francisco [28] and L1 in proctitis cases in Seattle [29]. An epidemic of LGV among heterosexuals, recently described by Bauwens et al, was linked to crack cocaine use and HIV infection, suggesting that LGV is not just a tropical disease but that it also has the potential to interact with HIV as was observed before with herpes [30]. Recognition of the current epidemic of proctitis LGV was hampered by poor clinical awareness, poor public health intervention and atypical clinical presentation [31]. Clinicians in industrialised countries would not be expected to consider LGV as a likely cause for gastrointestinal illness [32-34]. The clinical presentation of LGV was therefore easily missed as evidenced by the retrospective case reports from the Netherlands [5,35,36], France [4] , England [37], and Switzerland [38]. LGV proctitis may be far more common among MSM than previously thought. Before 2003, however, it was unusual to perform additional testing if chlamydial proctitis was diagnosed [39,40]. LGV proctitis causes more rectal symptoms (pain, tenesmus) and clinical manifestations (rectal discharge, bleeding) than rectal infections with serovars D-K [40]. The clinical presentation remains to be studied in more detail as asymptomatic and sub-clinical cases were also identified [35,36]. For instance, it is still unclear why inguinal cases were found less frequently in these LGV cases. Only one case of urethritis due to genovar L2b has been reported so far [41]. Studies including asymptomatic individuals are needed to unravel the epidemiology of these infections, as suggested by Schachter in June 2005 [31]. In a retrospective case-control study among MSM, a positive HIV status, proctitis findings and elevated white blood cell counts in anal smears were the only clinical features that revealed to be predictive for LGV [42].

Will LGV become endemic?
Finally, we have to address the question whether we are dealing with an epidemic of LGV in Europe that was overlooked previously? An unexpected or adverse event in STI is defined as a greater number of observed cases than expected over a defined time period or any event related to STIs that required a public health intervention (available at: www.essti.org). Unfortunately, no baseline data before the recent case reports were available as LGV is not a notifiable disease in most countries (and when it is, only the classic form is usually considered). However, the increasing number of cases, the number of linked cases - through international travel and import of infection as well [10,14,17] - and the geographical clustering strongly favour the hypothesis of an epidemic. But these findings could be biased by the enhanced surveillance systems and the availability of diagnostic capacity. However, there is increasing evidence for rising STIs among MSM and their association with HIV and high risk behaviours [43-50].
Moreover, there has been very little systematic testing in the past 20 years, despite the rise in anorectal infections causing cases to remain unnoticed. Diagnostic support for disease confirmation was not widely available and hampered the development of guidelines for testing anorectal specimens. The development of a real-time PCR, both in the Netherlands and the US, allowing to distinguish LGV from non-LGV serovars can facilitate a more timely diagnosis of LGV on a wider scale in routine microbiological laboratory conditions [51]. In this outbreak, the new strain identified, L2b, was found in all genotyped cases in Amsterdam and France (mainly Paris) [4,35]. This strain is also highly prevalent in the UK and Germany, but not exclusively as demonstrated by Meyer [16]. More retrospective testing of stored specimens is needed to help unravel some of these issues. Investigation of anal swabs confirmed that the L2b strain was already circulating in San Francisco in the early 80’s and could be traced back in Amsterdam as early as 2000 [35-36]. However, retrospective testing in Sweden yielded no additional cases [20].
Over the past two years, LGV has become an increasingly important public health issue. LGV may be contributing to the HIV epidemic - and the transmission of hepatitis C virus [22] - in facilitating transmission through prejudicing the integrity of the anal skin and mucous membrane. That is certainly plausible and has been observed in heterosexual transmission. It is striking that LGV seems to be limited to a high-risk network of MSM and involves many who are living with HIV. The extent of serosorting, the selection of partners and risk behaviours in these networks remain to be determined [50,52]. Even so, Marcus and colleagues hypothesize in this issue that increasing HIV incidence rates could be due to transmission during highly infective early HIV infection in similar networks, acquired mostly from casual partners [53].

In this epidemic, information on new cases and new findings traveled fast via international electronic STI and public health practitioners networks and via peer-reviewed literature. European-wide collaboration was initiated to discuss the state of the art, the surveillance and epidemiology of LGV, and to identify knowledge gaps in clinical studies [54]. However, prospective clinical studies, ongoing surveillance and epidemiological studies need further European partnerships. The lack of harmonisation would rather represent a missed opportunity to gather more information on this once rare STI.

The LGV epidemic seems to be evolving at a relatively slow pace with an undeterrmined dynamics so far. By now, it may have peaked in the Netherlands; the number of cases seems to have doubled quite rapidly in the UK, although LGV may not have been introduced at all in some other countries. However, LGV cases may still be missed easily if its diagnosis is not considered or if appropriate diagnostic tools are not available. Individual patients may remain undiagnosed and develop severe complications. Active case-finding and contact tracing ensuring effective treatment and prevention of further transmission of STIs and HIV should be a priority in the control of LGV among this specific high-risk network of MSM in Europe before it becomes endemic. In addition, primary prevention of STIs should be addressed more thoroughly within sexual health programmes for those living with HIV.