Update on Sexually Transmitted Infections

September 17-20, 2007; Chicago, Illinois

David N. Fisman, MD, MPH, FRCP(C)

Disclosures

February 28, 2008

In This Article

Lymphogranuloma Venereum: Exotic No More

Dr. Angelika Stary, of the Outpatients' Centre for the Diagnosis of Infectious Venero-Dermatological Diseases in Vienna, Austria, presented an update on lymphogranuloma venereum (LGV), an STI that has increased in incidence in Western Europe and North America in the past several years. As Dr. Stary noted, STIs are often distributed unevenly in populations, such as men who have sex with men (MSM), commercial sex workers, and teens, and sexual contacts of individuals in these groups are frequently at increased risk for STIs. This "heterogeneity" is important for the definition of risk in populations, and for the effective targeting of disease control efforts, but also has biological importance. Sexually transmitted diseases that are relatively inefficiently transmitted rely on "core groups" of individuals with high rates of sex partner change to avoid extinction; transmission from core groups to the wider population occurs via "bridging" individuals who have sex partners from both groups.

In the context of LGV reemergence in Western Europe, the relevant "core group" appears to be MSM. This reemergence occurs in the context of recent increases in HIV incidence and prevalence in MSM in Western Europe, as well as increases in syphilis and genital chlamydial infection in the same group. In 2003 and 2004, reports emerged from The Netherlands of the occurrence of LGV in individuals with underlying HIV infection; since that time, reports of local LGV in MSM have emerged from much of Western Europe as well as the United States and Canada.

Epidemiology of LGV

Prior to 2003, LGV was regarded as an STI most likely to be acquired in the developing world, particularly in India, Southeast Asia, and Africa. LGV cases identified in Europe and North America were sporadic in nature, and often represented disease acquired during vacations in endemic regions. However, in 2003 a sudden increase in LGV case occurrence was noted in Amsterdam, The Netherlands. Prior to 2003, The Netherlands had reported fewer than 5 cases of LGV annually; in 2003 this total rose sharply to 30 cases, and to 62 cases in 2004; elevated rates persisted in 2005. Most LGV cases were caused by serovar L2b, which has been seen in association with proctocolitis in MSM since at least 1981.[1] The demographic features of cases occurring in The Netherlands in 2003-2004 included the occurrence of cases exclusively in MSM, a high percentage of infected individuals having known HIV coinfection, and a large proportion of cases aged 45 and over.[2] Most cases presented with proctitis or proctocolitis, with purulent or mucopurulent discharge.

Sexual risk behaviors that may have contributed to LGV risk in infected individuals include high annual numbers of reported sex partners (mean, 12; range, 0-100 in the original Dutch outbreak[3]), a high frequency of group sex and attendance at "leather parties," use of sex toys, and unprotected receptive and insertive anal intercourse. In the original Dutch outbreak, 18 of 24 men for whom complete data were available were HIV-infected, and of these, only 8 reported that they disclosed their HIV status to sex partners.[3]

Between 2003 and 2005, marked increases in LGV incidence were noted in a number of European countries, including Belgium, France, Germany, and the United Kingdom.[4] Since 2004, a surge in LGV incidence has been noted in MSM in major urban areas in the United States and Canada[5] as well as in Australia.[6] As in the original Netherlands outbreak, LGV in these other areas has occurred overwhelmingly in older (age 35+) MSM, with an extremely high prevalence (> 50%) of HIV coinfection, as well as coinfection with other sexually transmitted pathogens. The high rate of coexistent HIV infection is a major concern because LGV facilitates both transmission and acquisition of HIV infection by sex partners.[7]

Microbiology and Natural History

LGV is an infection caused by Chlamydia trachomatis, the same organism that causes chlamydial urethritis and cervicitis familiar to many clinicians. However, it is often not appreciated that this Chlamydia species can be subdivided into a number of distinct serovars; serovars D through K cause "typical" genital tract infections in North America, and serovars A through C cause trachoma, a common cause of blindness in the developing world. LGV is associated with serovars L1, L2, and L3.

The clinical course of LGV reflects the predilection of these microorganisms for invasion of lymphoid tissue, and in contrast to genital tract infection with usual chlamydial serovars, LGV manifests signs and symptoms of systemic infection. As Dr. Stary pointed out, the natural history of LGV is also more reminiscent of an STI-like syphilis in its multiple stages, propensity to cause genital tract ulceration, and chronicity than it is to more common genital tract infections with non-L1,L2,L3 serovars. In MSM, the first stage of infection is a primary papule or vesicle that may ulcerate. Primary infection follows an incubation period of about 7-10 days. Secondary manifestations of infection occur 2-6 weeks later, and include lymphadenopathy and constitutional symptoms; the location of enlarged lymph nodes depends on the site of primary infection. (Dr. Stary also had very good pictures of penile LGV, and of the manifestations of "anogenitalrectalsyndrome.") Inguinal lymphadenopathy is most common, and approximately one third of individuals will develop actual "buboes," ie, large, pus-filled necrotic lymph nodes with spontaneous drainage.

The incidence of lymphadenopathy and bubo formation appears to be lower in women with LGV, although the reasons for this are unclear. In MSM, the second stage of LGV infection may also manifest as an "anorectal syndrome," with development of a proctitis with itching, anorectal ulceration, discharge, fever, pain, tenesmus, and hyperplasia of the intestinal and perirectal tissues. Individuals who practice receptive anal intercourse may also experience bleeding with sex; the major differential diagnosis for this condition is inflammatory bowel disease. The differential diagnosis also includes carcinoma, lymphoma, anogenital tract ulceration associated with HIV infection, histoplasmosis, cytomegalovirus or herpes simplex virus infection, and syphilis.

Untreated LGV will initially become quiescent, but chronic infection results in scarring, with obliteration of lymphatic channels, strictures, and ulceration and fistula formation (again, possibly mimicking Crohn's disease). Genital lymphedema and even elephantiasis can occur as a result of destruction of lymphatics. Chronic complications of LGV typically manifest 5-10 years after initial infection. Of note, urethritis can occur with L1-L3 serovars of C trachomatis but is apparently uncommon.[8]

Diagnosis

Given the broad differential diagnosis and the historical rarity of locally acquired LGV in North America and Western Europe, diagnosis hinges upon a high index of suspicion and careful history taking. Physical examination may include anoscopy or referral for sigmoidoscopy. Gram stain of material from lesions is likely to show many polymorphonuclear cells, and no bacteria. The histology of lesions depends on stage: Early-stage lesions show inflammatory cell infiltrates and granulomata; intracellular chlamydial inclusions can be seen; stage II is characterized by granulomatous inflammation of lymphatics; late-stage disease is characterized by chronic inflammatory changes and fibrotic change.[9] Culture of superficial genital or rectal material may lead to the isolation of C trachomatis, although this would not distinguish LGV from other Chlamydia-related syndromes; however, the isolation of C trachomatis by culture from material aspirated from a bubo is strongly suggestive of LGV, even in the absence of further strain characterization. The most sensitive diagnostic approach for LGV involves use of nucleic acid amplification testing for C trachomatis followed by polymerase chain reaction (PCR) and sequence analysis (generally of the chlamydial ompA gene), which permits identification of the infecting serovar. Unfortunately, such identification must generally be performed by a public health reference laboratory. One major concern related to diagnosis of LGV relates to the fact that commercially available nucleic acid amplification testing is not approved for rectal and pharyngeal specimens in many jurisdictions. Serology is generally not recommended as a first-line diagnostic modality, due to lack of availability, cross-reactivity of different serovars, and lack of differentiation between current and past infection.

Antimicrobial Therapy and Control

First-line therapy for LGV is doxycycline, 100 mg twice daily for 21 days. Second-line therapy is with macrolides (erythromycin 500 mg 4 times a day) or sulfas (sulfamethoxazole/trimethoprim, 80/400 mg twice daily), again for 21 days. Case reports suggest that azithromycin may also be effective. Antimicrobial resistance is not a concern with LGV at this time. Although Dr. Stary did not discuss partner treatment during her talk, many public health agencies (such as the Public Health Agency of Canada) recommend that sex partners of individuals with LGV receive a single 1-g oral dose of azithromycin or doxycycline 100 mg twice daily for 7 days. Public health control measures may be complicated by the fact that LGV may not be classified as a notifiable infectious disease, separate from other "routine" chlamydial infections; this both impedes understanding of the epidemiology of the disease and makes aggressive case-finding and partner treatment difficult.

Summary

In summary, LGV resurgence in North America and Western Europe provides important lessons about the potential rapid reemergence of "controlled" STIs, particularly in populations and groups with high rates of sex partner acquisition and change. The serious, long-term morbidity associated with this infection, combined with its impact on enhanced HIV transmission and acquisition, highlight the public health importance of LGV control. LGV should be an important diagnostic consideration in individuals with signs and symptoms of proctitis, particularly if the individual in question is a man with a history of sex with other men, and consequently sensitive and accurate history taking is of the utmost importance for diagnosis. In such a scenario, performance of diagnostic proctoscopy or sigmoidoscopy, with material collected for chlamydial diagnostic studies, should be strongly considered.

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