Lymphogranuloma venereum – an overview: update on UK cases of LGV

Leighton Davies MD, for HIV i-Base

Lymphogranuloma venereum (LGV) is a sexually transmitted infection caused by the L1-L3 serovars of the obligate intracellular bacterium Chlamydia trachomatis. These particular strains of chlamydia are more virulent and tend to produce more invasive disease in humans. Chlamydial serovars A-K, which are largely confined to infecting columnar epithelial surfaces of the genital tract and the eye are far more prevalent than the LGV serovars which predominantly infect monocytes and macrophages, passing through epithelial surfaces to regional lymph nodes usually resulting in disseminated infection.

LGV, which was relatively common in industrialised countries until the advent of broad-spectrum antibiotics in the first half of the twentieth century, has become a rare disease, while remaining endemic in parts of Africa, Asia, South America and the Caribbean. Clinically it is difficult to distinguish from other causes of genital ulcer disease – especially those associated with “bubo” formation (large, swollen lymph nodes), such as chancroid. However, there has recently been a resurgence of its appearance in the western world, with subtle changes in its mode of presentation. It is estimated that LGV accounts for between 10 and 20% of genital ulcer disease in parts of the world where it is endemic, with chancroid, syphilis and herpes simplex infection being far more common. Indeed, 10% of patients presenting with buboes to a clinic in Bangkok were found to have LGV, with a large epidemic recently reported among crack cocaine users in the Bahamas. [1-3]

Clinical features

Classically the clinical course has been divided into three stages: The primary stage involves the site of inoculation, the secondary stage the regional lymph nodes and occasionally the anorectum, with the tertiary stage comprising late sequelae affecting the genitals or rectum.

The primary stage occurs after an incubation period of 3-30 days with the formation of a small painless papule, which may ulcerate occurring at the site of inoculation. This primary lesion is virtually always self-limiting and may not always occur and in most cases passes unnoticed by the patient.

The secondary stage occurs some weeks after the primary lesion and can take one of two forms:

(1) The inguinal form – commoner in men since the lymphatic drainage of the vagina and cervix is to the retroperitoneal rather the inguinal lymph nodes. Its cardinal feature is the presence of painful inguinal and/or femoral lymphadenopathy, which is usually uniltateral. Adenopathy above and below the inguinal ligament is termed the ‘groove sign’ and was once thought to be pathognomonic of LGV. The lymph nodes are usually firm and necrotic. The necrotic areas may enlarge and coalesce to form stellate abscesses, which eventually break down to form discharging sinuses, although this is relatively uncommon and more a feature of chancroid.

(2) The ano-rectal form – classically more common in women; and in men who have sex with men (MSM) who practise receptive anal intercourse. It usually presents as a haemorrhagic proctitis. Patients present with bleeding per rectum and pronounced proctalgia, often associated with systemic features – pyrexia, chills and weight loss. Proctoscopy reveals a granular or ulcerative proctitis (similar to ulcerative colitis), which is nearly always confined to the distal 10cm of the ano-rectal canal (4). Extragenital lymphadenopathy has also been described.

The tertiary stage occurs usually as the result of chronic untreated LGV: fibrosis leads to lymphatic obstruction causing elephantiasis of the genitals in either sex with rectal involvement leading to the formation of strictures and fistulae. This often leads to surgical correction of the problem, which can often be severe and debilitating. The tertiary stage occurs far more commonly in women giving rise to a syndrome known as esthiomene (Greek = “eating away”), with widespread destruction of the external genitalia.

Diagnosis

The differential diagnosis of sexually acquired genital ulceration includes chancroid, herpes simplex, syphilis and donovanosis (granuloma inguinale). Less commonly this may arise as a result of trauma, non-sexually transmissible infections e.g. cutaneous leishmaniasis and a fixed drug eruption. The differential diagnosis of inguinal adenopathy includes chancroid, herpes and syphilis although a genital ulcer usually precedes lymphadenopathy in these cases. More generalised lymphadenopthy has a wider differential including lymphoma and HIV.

Laboratory diagnosis of LGV largely depends on serological tests which are genus specific and do not distinguish between infection with other chlamydial species. However, since LGV is far more invasive than other members of the genus it usually leads to higher titres of serum immunoglobulins than uncomplicated infections of C trachomatis serovars D-K. A titre of > 1:256 strongly supports the diagnosis while a titre of <1:32 virtually rules it out except in the very early stages of infection. The microimmunofluorescence (MIF) test can distinguish between infection by different chlamydial species but is not widely used in clinical practice. However, a MIF IgG titre of > 1:128 strongly suggests LGV although invasive genital infection by serovars D-K (eg pelvic inflammatory disease) can also give rise to high titres of anti-chlamydial antibody.

Further identification of the organism can be achieved by aspirating bubo fluid or in ulcer material and isolating C Trachomatis in tissue culture. This technique is also not widely available. In contrast to diagnosing infection with serovars D-K by commercially available enzyme immuno-assays (EIAs), which are used extensively to diagnose urethral and cervical infection, this form of diagnosis has not been widely evaluated for LGV. Similarly, DNA amplification assays (PCR or LCR) which detect Chlamydia specific genomic or plasmid DNA have also not been widely evaluated for the detection of LGV – although PCR was used extensively to diagnose LGV in samples taken from ulcer samples in the Bahamas.

The detection of C Trachomatis in bubo material by any of these methods strongly supports the diagnosis of LGV while detection of the organism in ulcer material only supports the diagnosis if it can be shown to be an LGV strain by DNA sequencing or typing with a monoclonal antibody – methods which by and large are not routinely available in day to day practice.

Management

Recommended treatment for both bubonic and anogenital LGV is doxycycline 100mg twice daily for at least 21 days. In pregnant women or persons otherwise intolerant of tetracyclines a macrolide antibiotic such as erythromycin 500mg four times daily, also for 21 days should be employed. Azithromycin is also likely to be effective against LGV although the exact duration of treatment has not been correctly determined; one suggested course would be 1g daily for 10-14 days.

LGV in the 21st Century

Since December 2003 a worrying number of outbreaks of LGV have been reported in European and North American cities. These appear to be largely confined to HIV positive MSM and most appear to be caused by the L2 genotype. Most cases present with a haemorrhagic proctitis and are confined largely to men of white ethnicity. High levels of concurrent sexually transmitted infections (Gonorrhoea, syphilis, HSV and hepatitis B virus) were also seen. Transmission of Hepatitis C virus (HCV) has been associated with the LGV outbreak in Rotterdam in the Netherlands. Contact tracing has largely proven to be a futile exercise as most of the infected men reported numerous anonymous sexual encounters with high levels of unprotected anal intercourse and other high risk practices such as fisting (which itself is strongly associated with the sexual transmission of HCV) and sharing of sex toys.

In response to these outbreaks the Health Protection Agency for England initiated enhanced surveillance measures for LGV. These were established in October 2004 after several sexual health clinics (predominantly in London) reported increased numbers of cases of bloody proctitis. Clusters of LGV have so far been identified in Rotterdam (>92 cases), Antwerp (27 cases), Paris (38 cases) and confirmed cases in Stockholm and Hamburg in addition to sporadic cases in New York, San Francisco and Atlanta in the USA. These outbreaks appear to be concentrated in sexual networks of gay men and appear to be associated with sex parties that have attracted men from across Europe.

The HPA sent out an alert to GUM clinics in England and established a case definition, reference service and reporting system for LGV. [5] The case definition used by the HPA is confirmation of C Trachomatis and presence of LGV serovars – L1, L2 or L3 by genotyping. The HPA reference service tests rectal specimens from patients with ano-rectal symptoms (bloody proctitis, rectal discharge) or urethral specimens from patients with inguinal lymphadenopathy known to be positive for C Trachomatis.

In January 2005, the first 24 cases of LGV were reported in the UK – most from London clinics. Enhanced surveillance data were available for 19 cases and confirmed characteristics similar to other European cities: all were MSM, 17 HIV positive, 4 were also HCV positive and most had symptoms suggestive of LGV.

Up to the middle of February 2005, a total of 34 cases of LGV have been reported in the UK. [6] In addition other anecdotal cases have been reported from other centres in the UK which were not subject to the HPA’s enhanced surveillance (eg in Swansea an HIV positive MSM presented with a haemorrhagic proctitis and high levels of anti-chlamydial antibodies, (>1:256), genotyping was not available but the diagnosis of LGV was made presumptively and he responded to 21 days treatment with doxycycline 100mg bd). [7]

Noteworthy features of the recent outbreaks are that they tend to occur in white MSM, although some patients have reported sexual encounters with men from Africa or Latin America. Furthermore, very few cases of urethral infection have been reported alongside rectal infections, which further confounds the epidemiology of the outbreaks.

Conclusions

The implications are quite clear: All clinicians who deal with HIV positive gay men’s sexual health should be vigilant to the possible presenting symptoms of LGV and wherever possible enrol the assistance of the HPA in establishing a diagnosis. Adequate treatment should be initiated as soon as possible thereby avoiding the potentially serious sequelae of untreated LGV. Ultimately it should not be forgotten that infection with LGV is usually associated with concomitant infection with another STI – this is especially true for HIV, which is propagated far more easily in the presence of genital ulcer disease.

Comment

LGV was the focus of presentations at the BHIVA Spring conference in Dublin that stressed the importance of treatment for similar symptoms, even if a diagnosis is not confirmed or available.

Awareness of the additional information and the surveillance system that was established at the end of 2004 by the Health Protection Agency is clearly important for all GU treating physicians.

The HPA website includes useful pages on LGV, including:

References:

Hitun Y et al. Comparison of clinically directed, disease specific and syndromic protocols for the management of genital ulcer disease in Lesotho. Sex Transm Inf 1998 74 (suppl 1) S23-28.
Viravan C et al. A prospective clinical and bacteriologic study of inguinal buboes in Thai men. Clin Infect Dis 1996 22, 233-239.
Bouwens JE et al. Epidemic LGV during epidemics of crack cocaine use and HIV infection in the Bahamas (in press)
Quinn TC et al. Chlamydia trachomatis proctitis N Engl J Med 1984 311 1543-1546.
Health Protection Agency. Enhanced surveillance of LGV in England. Commun Dis Rep CDR Wkly [serial online] 2004. 14 (41). News – available at:
http://www.hpa.org.uk/cdr/PDFfiles/2004/cdr4104.pdf
Macdonald N et al. Initial results of enhanced surveillance for LGV in England. Eurosurveillance 2005 10 20. January 2005 (available at:
http://www.eurosurveillance.org/ew/2005/050127.asp
Personal communication with Dr K. Yoganathan, Consultant GU Physician, Singleton Hospital, Swansea, UK.