Epidemiology
Lymphogranuloma venereum is caused by Chlamydia trachomatis (CT) serovars L1-3 and continues to affect MSM worldwide (15). L2b is the serovar identified in the majority of LGV cases that have been diagnosed in Australia (16-21) and globally (22-24).
Nationally, this infection is usually diagnosed in MSM, the vast majority of whom present with symptoms of proctitis (18, 20, 21, 25) with an incubation period of one to four weeks (26). In addition, LGV has, historically, disproportionately affected those co-infected with HIV (16, 20, 25, 27).
LGV was removed from the list of Australian nationally notifiable diseases in 2001 after 5 consecutive years with no LGV notifications (28). Currently, it only remains notifiable to public health authorities in New South Wales, Queensland, Western Australia, the Northern Territory and Tasmania. Since that time, as with other jurisdictions globally (29-31), LGV diagnoses have markedly increased in Australia (32, 33).
Chlamydia trachomatis transmission among MSM can occur via anogenital contact. However, given that the ratio of genital compared with anorectal LGV infections has been reported to be as high as 1 in 15 (34), other modes of transmission are likely. Although initially suggested (35), sharing sex toys and fisting have subsequently been dismissed (36). Additionally, there is no evidence of differing tissue tropism between anorectal and genital sites (37, 38). Chlamydiae spp. in almost all natural animal hosts are transmitted faecal-orally and reside naturally in the gastrointestinal tract for long periods without causing disease or inflammation (39). Mice infected orally with Chlamydia muridarum become infected in the lower gastrointestinal tract and are unable to clear the infection (40). In addition, a report from four decades ago described neonates who were infected with perinatal nasopharyngeal and conjunctival CT subsequently testing positive on anorectal samples (41). Thus, a recently proposed hypothesis for the large disparity between genital and anorectal infections is that oral infection acquired via “rimming” may lead to asymptomatic pharyngeal infection in MSM which passes through the gastrointestinal tract to the anorectum. Subsequently, L2 serovars may induce LGV proctitis or asymptomatic infection which could contribute to ongoing LGV transmission in the gay community (42).
Clinical presentation
LGV is important to distinguish from non-LGV CT infection because of its frequently severe clinical presentation and sequelae, the need for a longer course of antibiotic therapy, and the possible consequence of enhanced HIV and Hepatitis C virus transmission (26). The traditional presentation of LGV is a primary ulcerative genital lesion, leading to a secondary inguinal syndrome of buboes (painful unilateral inguino-femoral lymphadenopathy which may suppurate) (26). There are a few reports in Australia of penile ulcers progressing to inguinal bubo in men with HIV infection (43, 44).
An important differential diagnosis of the painless anogenital ulcer of LGV is the primary chancre of syphilis (17) and consideration should be given to nucleic acid amplification testing (NAAT) of painless ulcers for LGV. In addition, there are multiple case reports in the literature of LGV being misdiagnosed as inflammatory bowel disease (45-51) and malignancies (52-55), leading to protracted symptoms due to inappropriate management and delayed LGV therapy.
Recently, genital LGV has also been described in HIV-negative Australian MSM on HIV pre-exposure prophylaxis (PrEP) (17). This observation highlights the possibility of increasing LGV diagnoses among HIV-negative MSM as a result of increasing unprotected anal intercourse between HIV-positive men and HIV-negative men on PrEP, as has been observed in Europe (56).
If LGV proctocolitis is left untreated, perirectal abscesses, fistulas, strictures and stenosis of the rectum may occur with haemorrhoid-like swellings of obstructed rectal lymphatic tissue (“lymphorrhoids”). Oedema and sclerosing fibrosis resulting in strictures and fistulas can ultimately lead to elephantiasis (22, 26). There is no evidence that the clinical severity or course of LGV infection is influenced by HIV status (26).
A curious disparity exists between the clinical presentation of anorectal LGV among MSM in Europe compared with Australia. Between 5% and 53% of LGV infections identified during systematic anorectal testing of clinic attendees in several European jurisdictions have been asymptomatic (29, 34, 57-60). In contrast, systematic genotyping of confirmed rectal CT infections among community-based cohorts (19) and clinic attendees (18, 21) has failed to identify a reservoir of asymptomatic rectal LGV in Australian MSM. Given frequent sexual activity during international travel of many MSM (61-63), the reason for this notable difference in asymptomatic LGV between MSM resident in Australia and those from overseas remains unclear. No commercial LGV assays are validated for use on rectal specimens (22), thus variability in performance of the multiple in-house or laboratory-developed assays used to diagnose LGV globally may be a possible explanation for this finding.
Management
In published studies of LGV treatment, the majority of participants have been HIV-positive. Treatment recommendations for LGV do not differ between HIV-positive and -negative individuals (22, 26). One syndromic management study of genital ulcer disease compared treatment outcomes by HIV status and showed no difference in response to treatment of genital ulcers by HIV status, including for ulcers caused by LGV (64).
A systematic review and meta-analysis of doxycycline efficacy for rectal LGV in MSM, which included nine prospective and retrospective observational studies between 1940 and 2016, reported that among 282 MSM, most of whom were HIV-positive and symptomatic, the cure rate of doxycycline 100mg BD for 3 weeks was 98.5% (95% CI 96.3%–100%) (65). Nonetheless, treatment failures with this regimen have been reported among both HIV-positive and -negative MSM with inguinal LGV, more clinically severe and/or extensive rectal LGV infections (24, 44, 66-68). In such cases, longer courses of doxycycline or alternative treatment with moxifloxacin have usually achieved clinical and microbial cure.
Recent data have suggested that shorter courses of 7-14 days of doxycycline may be curative for rectal LGV (69), although half of cases in this retrospective study were asymptomatic. An alternative is weekly azithromycin 1g orally for 3 weeks (25, 70). However, insufficient evidence currently exists for these regimens to be recommended as first-line options for treatment of LGV and 3 weeks of doxycycline remains the recommended therapy (4).