Lymphogranuloma Venereum: What Does the Clinician Need to Know?

Home , Chlamydia, Lymphangitis, Lymphogranuloma venereum, Pinta (disease), Syphilis, Yaws

CME Genitourinary medicine

Lymphogranuloma venereum: and constipation. Systemic symptoms such as fever and malaise can accompany what does the clinician need to know? this stage.

Tertiary stage

John White MBBS FACh SHM, Locum clinical course of LGV is classically divided Untreated infection may then progress to Consultant in Genitourinary Medicine, Guy’s into three stages. chronic inflammation and destruction of and St Thomas’ NHS Foundation Trust, tissue in the involved areas, including: London Primary stage • chronic proctocolitis mimicking Catherine Ison PhD FRCPath, Director, inflammatory bowel disease (IBD) Sexually Transmitted Bacteria Reference The primary lesion is usually transient fistulae Laboratory, Health Protection Agency Centre and often unnoticed. It may appear at the • strictures for Infections, London site of inoculation as a painless papule, • pustule or ulcer, most likely in the • chronic granulomatous conditions Clin Med 2008;8:327–30 anogenital region. Incubation periods of the external genitalia, including from 3–30 days after sexual contact have lymphoedema and elephantiasis. It has been surprising to see that lym- been observed. Proctitis in homosexual These tertiary sequelae tend not to phogranuloma venereum (LGV), caused men can occur as a primary manifestation reverse with antibiotic therapy alone. by the L-serovars of Chlamydia tracho- of infection following direct inoculation matis, a sexually transmitted infection of the rectal mucosa. Symptoms of proc- Presentation of lymphogranuloma (STI) previously rare in industrialised titis may arise within days of anoreceptive venereum in homosexual men countries, has emerged as a significant sexual exposure. disease among homosexual men over the LGV detected among homosexual men in 1,2 past three years. Following the recogni- Secondary stage the UK has so far largely presented as tion of a large number of cases of LGV overt proctitis (Fig 1), possibly as either a proctitis among homosexual men in the The secondary stage of LGV involves the primary or a secondary manifestation of Netherlands in 2004,3 an epidemic is now subsequent spread of C. trachomatis to disease, in many cases with severe local well established in the UK,2,4 Western regional lymph nodes, which leads to and systemic symptoms. Some cases were Europe and the USA. Thus far, the infec- inflammation and swelling, and the misdiagnosed with ulcerative colitis or tion has been confined almost exclusively entire chain can become matted with Crohn’s disease and long delays occurred to the homosexual male population, considerable periadenitis. Suppuration before LGV was recognised and treated especially those coinfected with HIV,2 and bubo formation can ensue, which appropriately. Endoscopic appearances hepatitis C5 and other STIs, most cases may then ulcerate and discharge pus and histopathological findings from rectal presenting with severe proctitis. from multiple points creating chronic biopsies in LGV show severe inflam- Diagnostic delays have occurred, com- fistulae. Rectal involvement at this stage matory changes in common with IBD monly due to the non-specific nature of may develop in both men and women, (Fig 2), and no pathognomonic features the clinical presentation. Even inguino- presenting as an acute haemorrhagic have yet been described that can be attrib- genital manifestations of LGV such as proctitis with symptoms of mucopuru- utable to LGV. A small number of men buboes and genital ulcers, usually seen in lent discharge, pain, bleeding, tenesmus have presented with inguinogenital regions of the world where LGV is endemic, are beginning to be recognised.2 Prompt antibiotic treatment is effective Fig 1. Endoscopic view of the rectum in a and curative, yet broader awareness 42-year-old HIV-positive homosexual man among a wide range of clinicians is needed with a nine-month history of intermittent to enable appropriate investigation and diarrhoea and constipation associated management and the interruption of with blood, mucus and pain on defecation. onward spread. Rectal biopsy showed severe non-specific inflammation and the patient was treated empirically with steroid suppositories for Clinical presentation possible irritable bowel disease. Following genitourinary medicine review, a rectal swab In contrast to the D-K serovars of C. tra- specimen tested positive for Chlamydia trachomatis, subsequently typed as the L2 chomatis responsible for genital mucosal strain. Symptoms abated completely after disease, the LGV-associated serovars are three weeks’ treatment with doxycycline. lymphotropic and thus capable of regional dissemination and systemic disease. The

Fig 2. Rectal biopsy specimen from an addition, no diagnostic service has been HIV-positive homosexual man with a six- available for genotyping C. trachomatis month history of purulent anal discharge, to identify the L-serovars. bleeding and constipation. Histological features included rectal mucosal ulceration and non-specific inflammatory changes Detection of lymphogranuloma within the lamina propria, including both cryptitis and crypt abscesses. venereum in rectal specimens In October 2004, the Sexually Trans- mitted Bacteria Reference Laboratory (STBRL) at the Health Protection Agency (HPA) Centre for Infections Fig 3. Ruptured inguinal bubo in a established a testing algorithm for the homosexual man who had presented with detection of LGV in rectal specimens. a three-week history of painful bilateral This includes confirmation of the pres- inguinal swellings. Lymphogranuloma ence of C. trachomatis using a real-time venereum-associated Chlamydia trachomatis DNA was isolated from aspirated pus. polymerase chain reaction (RT-PCR) that uses primers different from any commercial assay.11 Residual samples from both NAATs and EIAs or dry swabs can be tested. Any specimens giving a negative result are confirmed using the Qiagen RT-PCR (which is not used extensively in the UK) and a report syndrome including anogenital ulceration responses have been observed in LGV issued. All samples confirmed to contain and buboes (Fig 3). Less common presen- infection with the recommended treat- C. trachomatis-specific DNA are then tations have been described such as ure- ment of oral doxycycline 100 mg bid for tested to determine whether this belongs thritis6 and bubonulus7 (primary stage of three weeks.9,10 to an LGV serovar (L1, L2 or L3), using disease with large tender lymphangial an RT-PCR which detects a deletion in nodule and lymphangitis of dorsal penis). Laboratory diagnosis the pmp gene present only in L-serovars Asymptomatic rectal infections have been of C. trachomatis.12 detected only rarely within a large case- The laboratory diagnosis of LGV requires This test gives a positive result for finding exercise in the UK, suggesting that the detection of C. trachomatis belonging LGV-associated serovars and a negative a large reservoir of ‘silent’ infection is to serovars L1, L2 and L3 from clinical result for other serovars and provides a unlikely.8 samples. Historically, growth in tissue timely result allowing a positive report to culture cells has been the only ‘approved’ be issued. All positive specimens are then Differential diagnosis method. However, this facility is available confirmed using a nested PCR that in very few laboratories in the UK, is tech- amplifies the omp1 gene which is present The differential diagnosis of proctitis nically difficult and has a low sensitivity in single copy, followed by digestion with among homosexual men includes rectal even in the most experienced laborato- restriction endonucleases.13,14 The pat- gonorrhoea, which is usually less severe ries. Alternative methods include direct tern obtained is compared with control clinically and often asymptomatic. immunofluorescence, a test licensed for strains and can be confirmed by DNA Anorectal herpes simplex virus-1 or -2 detection of C. trachomatis from rectal sequencing. infection, especially if a primary infec- swabs from symptomatic patients, but STBRL has now tested over 4,000 speci- tion, can cause severe anorectal pain often again technically demanding and with mens and identified over 600 LGV positive out of proportion to other proctitis symp- low sensitivity. Enzyme immunoassays results in the UK. All LGV positive speci- toms and may also cause regional neuro- (EIAs) and nucleic acid amplification mens were found to belong to the serovar logical symptoms including urinary tests (NAATs) have been widely used but L2 where full genotyping was possible retention and constipation. Non-LGV neither is licensed for use with rectal (S. Alexander; personal communication). rectal C. trachomatis infection caused by specimens. Only 36% of the specimens originally serovars D-K is usually asymptomatic but The lack of an available licensed com- tested positive for C. trachomatis by EIA can occasionally show clinical features of mercial test to detect C. trachomatis in were confirmed compared with 92% of overt proctitis. Syphilis infection is on the rectal specimens may have prevented the those originally tested by NAATs.15 This rise again among homosexual men, and true extent of the outbreak being recog- highlights the lack of specificity of EIA for in its role as ‘the great imitator’ can cause nised. Many microbiologists have been detection of C. trachomatis from rectal clinical proctitis. reluctant to use an unlicensed test as it specimens. It also provides robust valida- Excellent clinical and microbiological may compromise their accreditation. In tion that NAATs can – and should – be

Key Points References 1 Collins L, White JA, Bradbeer C. Lymphogranuloma venereum (LGV) is a common cause of severe proctitis among Lymphogranuloma venereum. BMJ 2006; homosexual men 332:66. 2 Jebbari H, Alexander S, Ward H et al. LGV may also present as anogenital ulceration or inguinal lymphadenitis/abscesses Update on lymphogranuloma venereum in the United Kingdom. Sex Transm Infect Nucleic acid amplification tests for Chlamydia trachomatis from swab specimens are 2007;83:324–6. the most appropriate diagnostic tools, but specific molecular typing of the 3 Nieuwenhuis RF, Ossewaarde JM, Gotz sample is needed to confirm LGV HM et al. Resurgence of lymphogranuloma venereum in Western Europe: an outbreak Cases respond well clinically to three weeks’ doxycycline therapy of Chlamydia trachomatis serovar L2 proctitis in The Netherlands among men Clinicians outside genitourinary settings need to be vigilant for clinical who have sex with men. Clin Infect Dis presentations consistent with LGV occurring among male homosexual patients 2004;39:996–1003. 4 Ward H, Martin I, Macdonald N et al. KEY WORDS: chlamydia, lymphogranuloma venereum, proctitis Lymphogranuloma venereum in the United Kingdom. Clin Infect Dis 2007;44:26–32. 5 Gotz HM, van Doornum G, Niesters HG used as the test of choice for detecting only two known cases occurred in het- et al. A cluster of acute hepatitis C virus infection among men who have sex with C. trachomatis in rectal specimens. erosexuals. The largest number of cases men — results from contact tracing and Diagnostic material for LGV confir- was seen in 2005, but cases continue to public health implications. AIDS 2005;19 mation has also been obtained from be identified. Homosexual men with :969–74. needle aspirates from inflamed lymph LGV report a large number of contacts, 6 Herida M, Kreplack G, Cardon B, nodes and buboes, ulcer swabs from most of whom are untraceable, with Desenclos JC, de Barbeyrac B. First case of urethritis due to Chlamydia trachomatis anogenital ulcers and first void urine most men reporting high-risk sexual genovar L2b. Clin Infect Dis 2006;43:268–9. from men with urethritis. Some compli- behaviour, including meeting new sexual 7 Spenatto N, Boulinguez S, de Barbeyrac B, cated cases presented to gastroenterolo- partners at sex on premises venues, sex Viraben R. First case of ‘bubonulus’ in L2 gists and detected by retrospective testing parties or on the internet. lymphogranuloma venereum. Sex Transm of biopsy samples16 have resolved fol- Infect 2007;83:337–8. 8 Alexander S, Thornton A, Dean G et al. lowing treatment for LGV. Local geni- Conclusions What is the prevalence of tourinary medicine clinics in the UK lymphogranuloma venereum in the United have managed most clinical cases of LGV An established epidemic of LGV exists Kingdom among men who have sex with to date and welcome referred patients for among homosexual men in the UK men, and is there an asymptomatic a full diagnostic work-up. causing many cases of severe proctocol- reservoir of infection? 17th ISSTDR meeting, Seattle, Washington DC, 29 July itis and rarer inguinogenital syndromes. to 1 August 2007. Poster 107. LGV may also be contributing to the epi- Epidemiology 9 McLean CA, Stoner BP, Workowski KA. demics of HIV and hepatitis C among Treatment of lymphogranuloma venereum. Enhanced surveillance data are requested homosexual men by facilitating trans- Clin Infect Dis 2007;44(Suppl 3):S147–52. on all laboratory confirmed cases as part mission. Further control efforts are 10 White J, Tong CY, Ward H, Ison C. Doxycycline treatment for lympho- of the alert issued in October 2004 by the required, including awareness cam- granuloma venereum proctitis: clinical and HPA. Epidemiological and behavioural paigns, continued detailed surveillance microbiological responses. 22nd IUSTI- data on 423 cases detected between and expanded chlamydia testing among Europe Conference on Sexually Transmitted October 2004 and the end of April 2007 homosexual men. All clinicians should Infections, Versailles, France, 21 October showed LGV in the UK follows a similar be aware of the current epidemiological 2006. Oral presentation 45. 11 Chen CY, Chi KH, Alexander S et al. The and clinical features of LGV infection in pattern to Europe: cases are found pre- molecular diagnosis of lymphogranuloma dominantly among homosexual men of the UK. Appropriate testing and referral venereum: evaluation of a real-time white ethnicity who are often coinfected should be initiated promptly when multiplex polymerase chain reaction test with HIV (78%) and other STIs confronted with the relevant clinical using rectal and urethral specimens. Sex including hepatitis C, gonorrhoea, and scenarios among homosexual male Transm Dis 2007;34:451–5. 12 Morré SA, Spaargaren J, Fennema JS et al. 2 patients. syphilis. Cases have been distributed Real-time polymerase chain reaction to widely across the UK, but the highest diagnose lymphogranuloma venereum. number has been seen in London and Further information Emerg Infect Dis 2005;11:1311–2. Brighton. Most cases of LGV have been 13 Lan J, Ossewaarde JM, Walboomers JM, symptomatic, usually presenting with Please see the Health Protection Agency Meijer CJ, Brule AJ. Improved PCR sensitivity for direct genotyping of proctitis, with a few cases as contacts. website, www.hpa.org.uk/cfi/stbrl/lgv_ surveillance.htm Chlamydia trachomatis serovars by using a LGV in the UK has seldom presented nested PCR. J Clin Microbiol 1994;32: with urethral or inguinal symptoms and 528–30.

14 Lan J, Walboomers JM, Roosendaal R et al. Clinical presentation Direct detection and genotyping of Syphilis: an update Chlamydia trachomatis in cervical scrapes Entry of T. pallidum probably occurs by using polymerase chain reaction and through areas of ‘microtrauma’, usually restriction fragment length polymorphism Vincent Lee MRCP DipGUM DipHIVMed, in mucous membranes, and most sexual analysis. J Clin Microbiol 1993;31:1060–5. Consultant Genitourinary Physician, 15 Alexander S, Martin IM, Ison CA. Manchester Centre for Sexual Health, transmission of syphilis probably occurs Confirming the Chlamydia trachomatis Manchester Royal Infirmary from the genital and mucous membrane status of referred rectal specimens. Sex lesions of primary and secondary George Kinghorn FRCP, Consultant Transm Infect 2007;83:327–9. syphilis. 16 Martin IM, Alexander SA, Ison CA et al. Genitourinary Physician, Department of Syphilis is classified as: Diagnosis of lymphogranuloma venereum Genitourinary Medicine, Royal Hallamshire from biopsy samples. Gut 2006;55:1522–3. Hospital, Sheffield • acquired: early (primary, secondary and early latent <2 years of Clin Med 2008;8:330–3 infection) and late (late latent >2 years of infection) • congenital: early (diagnosed in the first 2 years of life) and late Syphilis is caused by infection with the (presenting after the age of spirochaete bacterium Treponema pal- 2 years). lidum. Transmission from one person to another is by direct contact with an infectious lesion (usually occurring Acquired syphilis during sexual contact), during preg- Primary syphilis nancy from mother to child or via infected blood products. T. pertunue and Primary syphilis is characterised by an T. carateum, organisms almost identical ulcer (the chancre) and regional lym- to T. pallidum, cause yaws and pinta, phadenopathy. The incubation period is respectively. They are indistinguishable 9–90 days, but the primary lesion most microscopically and all three give posi- often appears about three weeks after tive results on standard serological tests transmission. The chancre is classically for syphilis. However, yaws and pinta in the anogenital region, is single, pain- affect skin and bone almost exclusively less and indurated with a clean base dis- and are generally found only in patients charging clear serum. However, chancres from endemic areas. may be multiple, painful, purulent, destructive, extragenital (most fre- quently oral) and may cause the Epidemiology syphilitic balanitis of Follman. There Syphilis remains common worldwide. may also be mixed aetiology. Social disruption, mobility, lack of med- ical services and changing sexual behav- Secondary syphilis iours have contributed to epidemics. Early syphilis has re-emerged in Western Secondary syphilis is characterised by Europe since the late 1990s.1 multisystem involvement within the first Most sexually acquired infectious two years of infection, the manifestations syphilis in the UK is among men who first appearing about eight weeks after have sex with men (MSM). New diag- transmission. The rash of secondary noses of all sexually transmitted infec- syphilis is initially roseolar or macular, tions (STIs) in MSM have risen with more long-standing lesions consistently for the last 10 years. This becoming papular or nodular. This skin indicates a resurgence in sexual risk rash is typically non-irritant but may be taking by MSM which has probably led associated with itch in dark-skinned per- to continuing HIV transmission within sons. There are often condylomata lata, this population in the UK. In parallel mucocutaneous lesions, generalised lym- with the outbreak of syphilis in MSM, phadenopathy and, less commonly, patchy clusters of early syphilis among hetero- alopecia, anterior uveitis, meningitis, cra- sexual men and women have been nial nerve palsies, hepatitis, splenomegaly, reported.2,3 periosteitis and glomerulonephritis.