Lymphogranuloma Venereum (LGV)

Lymphogranuloma venereum (LGV) is a sexually transmitted infection (STI) caused by specific serovars of Chlamydia trachomatis (L1, L2, L3). LGV is endemic in certain areas of Africa, Southeast Asia, India, the Caribbean, and South America. It was previously thought to be rare in high income countries, but in the last 10 years has been increasingly recognized in North America, Europe, and the United Kingdom as causing outbreaks of proctitis, particularly among men who have sex with men (MSM).[1, 2, 3, 4, 5, 6]

LGV is a subtype of genital ulcer diseases that include other STIs, such as HSV, syphilis, and chancroid. This condition is characterized by self-limited genital papules or ulcers (often unnoticed by patients) followed by painful inguinal and/or femoral lymphadenopathy, which may be the primary clinical manifestation at presentation. Patients with LGV may also present with rectal ulcerations and symptoms of proctocolitis, especially among patients participating in receptive anal intercourse. In these cases, rectal pain, discharge, and bleeding may be confused with other GI conditions such as colitis.[7] If left untreated, disfiguring ulceration and enlargement of the external genitalia, and subsequent lymphatic obstruction may occur. 

C trachomatis is an obligate intracellular bacterium. Of the 15 known clinical serotypes, only the L1, L2, and L3 serotypes cause LGV. These serotypes are more virulent and invasive compared to other chlamydial serotypes. Infection occurs after direct contact with the skin or mucous membranes of an infected partner. The organism does not penetrate intact skin. The organism then travels by lymphatics to regional lymph nodes, where it replicates within macrophages and causes systemic disease. While transmission is predominantly sexual, cases of transmission through laboratory accidents, fomites, and nonsexual contact have been reported.

The L2b serovar has been identified to play a more important role than previously expected. After the diagnosis of 92 cases of LGV in the Netherlands among MSM, Schachter evaluated samples obtained from rectal swabs between 1979 and 1985 from patients infected with HIV in San Francisco and between 2000 and 2005 in Amsterdam.[8] The study revealed the same serotype circulating among patients with HIV and LGV 20-25 years ago. This indicates the L2b serovar has been present and unrecognized for many years.

LGV occurs in 3 stages. The first stage, which is often unrecognized, consists of a rapidly healing, painless genital papule or pustule. The second stage, consisting of painful inguinal lymphadenopathy, occurs 2-6 weeks after the primary lesion. The third stage, which is more common in women and MSM, may have a delayed presentation and is characterized by proctocolitis.

Frequency

United States

LGV is historically a rare disease in developed countries, but today is best thought of as a re-emerging STI[6] . Since 2003, sporadic outbreaks of LGV proctitis have been reported among MSM in North America, Europe, and Australia.[9, 10] However, in the United States, a precise understanding of the prevalence is unknown for a combination of reasons: LGV as such is not a nationally notifiable condition - aside from the requirements to report Chlamydia infections; some states will attempt to track cases of LGV based on syndrome reporting, but most laboratories do not have the capabilitiy to either grow or serotype Chlamydia.[11]  

No universal surveillance data exist for this disease. Twenty four states still mandate reporting of LGV cases to the Center for Disease Control (CDC), which provides limited data for disease prevalance. Since 1972, rates of LGV had declined, with 113 known cases reported to the CDC in 1997. In November 2004, the CDC began offering assistance to test for LGV in the United States. Between November 2004 and January 2006, LGV was identified in 180 specimens, with 27 specimens identified as being obtained from men who have sex with men.  A study published in 2011 reporting LGV surveillance data from multiple sites in the United States found that less than 1% of the samples obtained from rectal swabs of MSM that were positive for C trachomatis tested positive for LGV.[12]   Much like in the United Kingdom, increasing reports of clusters of LGV transmission in the United States, particularly among MSM patients, have occurred in recent years. [13]

International

LGV is an uncommon disease, although it may account for 2-10% of patients with genital ulcer disease in selected areas of India and Africa.[14] The disease is most commonly found in areas of the Caribbean, Central America, Southeast Asia, and Africa. Since 2003, however, the emergence of documented LGV infections, mostly among MSM, but also in women, has prompted increased surveillance and reporting of this disease in developed countries.[15, 16] Proctitis is reemerging as a presentation of LGV in developing countries.[17]

After a cluster of 92 cases was identified in the Netherlands between 2003 and 2004 (where fewer than 5 cases were reported yearly),[18] many countries have begun active surveillance for LGV, and an increasing number of cases has been identified. Evidence exists that among MSM, LGV is endemic in the United Kingdom; between 2004-2008, LGV was documented in 854 isolates by the National Reference Center there.[19, 20, 21, 22, 23, 24, 25]  Evidence supporting the endemicity of LGV in the United Kingdom continues to be published, particularly from the LGV Enhanced Surveillance system which collected data from 2004-2010.[6]  Over this 6-year period of data collection, they reported 1370 cases, of which 28 were females, heterosexual males or unknown, with the rest being men who have sex with men. Of note, nearly 80% of the patients with a single episode of LGV were also living with HIV, further complicating the rise in cases is evidence from the United Kingdom that a higher percentage of these cases may be asymptomatic.[26]

Mortality/Morbidity

With appropriate treatment, the disease is easily eradicated. Death is a rare complication but could possibly result from a small bowel obstruction or perforation secondary to rectal scarring.

Morbidity is common, especially during the third stage of the disease, and includes such conditions as proctocolitis, perirectal fissures, abscesses, strictures, and rectal stenosis. A chronic inflammatory response may lead to hyperplasia of the intestinal and perirectal lymphatics, causing lymphorrhoids, which are similar to hemorrhoids. Strictures and fistulous tracts may lead to chronic lymphatic obstruction, resulting in elephantiasis, thickening or fibrosis of the labia, and edema or gross distortion of the penis and scrotum. Reports show an association between adenocarcinoma (primarily rectal adenocarcinoma) and chronic untreated LGV.

Race

In North America and Europe, most reported cases of LGV have been identified among white males infected with HIV who acquired the condition after having sex with other men after travel or living in endemic areas, and typically after having multiple anonymous sexual contacts.

Sex

LGV is an STD and probably affects both sexes equally, although it is more commonly reported in men. This predilection may be because early manifestations of LGV are more apparent in men and are thus diagnosed more readily. Men typically present with the acute form of the disease, whereas women often present later, after developing complications from late disease.

Most cases in Europe and North America have been identified among White, frequently HIV-positive MSM patients presenting with proctitis.[24, 27, 28, 29]

Age

LGV may affect any age but has a peak incidence in the sexually active population aged 15-40 years.

With prompt and appropriate antibiotic therapy, the prognosis is excellent and patients typically make a full recovery.

Patients must be informed that reinfection and relapses may occur.

Inform patients how to avoid high-risk sexual activities by using condoms and avoiding sexual intercourse with high-risk sexual partners.

For excellent patient education resources, visit eMedicineHealth's Sexual Health Center. Also, see eMedicineHealth's patient education articles Sexually Transmitted Diseases and Chlamydia.

The clinical course of LGV consists of the following stages.

First stage (primary LGV)

This stage occurs 3-30 days after inoculation.

Primary LGV begins as a small, painless papule or pustule that may erode to form a small, asymptomatic herpetiform ulcer that usually heals rapidly without scarring.

The most common sites of infection for men include the coronal sulcus, prepuce, glans, and scrotum. Rarely, symptoms of urethritis occur.

The most common sites of infection in women include the posterior vaginal wall, posterior cervix, fourchette, and vulva.

The initial lesion, especially in women, often goes unnoticed by the patient.

Second stage (secondary LGV)

Secondary LGV begins 2-6 weeks after the primary lesion.

This second stage consists of painful regional lymphadenopathy (usually in the inguinal and/or femoral lymph nodes).

Painful, swollen lymph nodes coalesce to form buboes, which may rupture in as many as one third of patients. Those that do not rupture harden, then slowly resolve.

Inguinal lymphadenopathy occurs in only 20-30% of females with LGV; they more typically have involvement of the deep iliac or perirectal nodes and may only present with nonspecific back and/or abdominal pain.

This stage is when most men present and are diagnosed; most women are not diagnosed in this stage because of their lack of inguinal lymphadenopathy.

Constitutional symptoms associated with the second stage include fever, chills, myalgias, and malaise.

Systemic spread may lead to the following conditions:

• Arthritis

• Ocular inflammatory disease

• Cardiac involvement

• Pulmonary involvement

• Aseptic meningitis

• Hepatitis or perihepatitis

Third stage (tertiary LGV)

Tertiary LGV is termed genitoanorectal syndrome.

This condition is more common in women, secondary to their lack of symptoms during the first two stages.

Rectal involvement is more common in men who have sex with men (MSM) and in women who practice anal-receptive intercourse.

Tertiary LGV is characterized by proctocolitis. Although infectious proctitis is more commonly associated with inflammatory bowel disease, sexually transmitted diseases (STDs) must be considered in the work-up of this diagnosis, especially in MSM. In this patient population, the incidence of infectious proctitis attributed to STDs is on the rise.

Fever of unknown origin (FUO)

Symptoms include the following conditions:

• Bloody purulent discharge

• Rectal pain

• Tenesmus

Large fluctuant buboes or any otherwise unexplained perianal deformity in a young female should suggest a diagnosis of LGV.

First stage (primary LGV)

The initial lesion is usually a small, painless papule, shallow ulcer, or herpetiform lesion in the genital area, which may go unnoticed in the urethra, vagina, or rectum.

Initial lesions may be differentiated from the more common herpetic lesions by the lack of pain associated with the lesion. Differentiation from a syphilitic chancre is more problematic and requires serologic testing.

Second stage (secondary LGV)

Secondary LGV is characterized by painful lymph nodes (usually unilateral) known as buboes.

Enlargement of the inguinal nodes above and the femoral nodes below the inguinal ligament leads to the classic groove sign, which is observed in one third of affected men.

Inguinal lymphadenopathy results from a primary lesion of the anterior vulva, penis, or urethra.

Perirectal or pelvic lymphadenopathy results from a primary lesion involving the posterior vulva, vagina, or anus.

Affected nodes often coalesce and form abscesses, which can rupture and form sinus tracts.

Third stage (tertiary LGV)

Tertiary LGV most often manifests in women.

Patients initially develop proctocolitis.

Patients may present with perirectal fistulas, ulcers, abscesses, strictures, and rectal stenosis.

Hyperplasia of intestinal and perirectal lymphatics may form lymphorrhoids, which are similar to hemorrhoids.

Patients may develop strictures and fistulous tracts secondary to repeated tissue scarring and repair.

Enlargement, thickening, and fibrosis of the labia may occur in women, a condition termed esthiomene.

Chronic lymphatic obstruction may lead to elephantiasis of the genitals.

Penile and scrotal edema and distortion have been termed saxophone penis.

The L1, L2, and L3 serovars of C trachomatis cause LGV. Risk factors include residing in or visiting endemic areas, practicing anal-receptive intercourse, eschewing condoms, and working in the commercial sex trade.

Bubo rupture may lead to fistulas and sinus tracts. This complication typically occurs during the first stage (primary LGV) of infection.

Proctocolitis may lead to fissures, fistulas, abscess, scarring, and strictures.

Testing for LGV is complicated by the lack of widely available serovar specific testing. Diagnosis is often made on the basis of clinical presentation, epidemiologic risk factors, the results of available Chlamydial trachomatis NAAT testing, and exclusion of alternative diagnoses. Serologic testing for specific serovars of LGV is discussed below, but is often not practical due to lack of availability and need to make clinical decisions sooner than data would return. [30]

Laboratory diagnosis ultimately depends on detecting C trachomatis– specific DNA, followed by genotyping to identify serovars L1, L2, or L3 found in LGV.

Diagnosis is based primarily on clinical findings, with increasing evidence supporting the use of nucleic acid amplification tests (NAATs) for confirmation. Serologic testing is problematic because of the difficulty in culturing the organism and cross-reactivity of the many different serotypes.

Needle aspiration of an involved bubo is the best method to obtain tissue for culture.

Culture of C trachomatis, while definitive diagnostically, is technically demanding and expensive and yields an isolate only 30% of the time.

Because of its systemic nature, the disease produces a strong immunologic response that is readily evident on complement fixation testing.

Cross-reactivity between various chlamydial infections occurs on complement fixation testing.

Chlamydial urethritis, cervicitis, or conjunctivitis rarely produce serologic complement fixation titers greater than 1:16. LGV titers are usually more than 1:1024.

A serum complement fixation titer greater than 1:64, when coupled with the appropriate clinical scenario, is considered diagnostic of LGV.[30]

Immunofluorescent testing with monoclonal antibodies and polymerase chain reaction (PCR) testing are also reported to be effective; however, these tests are not widely available for commercial use.[31]

NAATs have shown significant promise in revealing the presence of Chlamydia. Several commercially available NAATS used to identify the presence of Chlamydia in urine demonstrated an increased sensitivity and specificity that ranged from 96-100% and 99.1-100%, respectively.[32] These assays are cleared for use by the US Food and Drug Administration (FDA) with cervical swabs, male urethral swabs, and urine specimens.

Needle aspiration of involved buboes may be performed to ease discomfort or to obtain tissue for culture.

Histologic findings of lymph node biopsies performed in the second and third stages of the disease typically reveal stellate abscesses.

The recommendation for first line treatment of LGV is 21 days of doxycycline (100 mg PO twice daily). This recommendation is based on limited evidence, however, and newer studies suggest that there is an opportunity for further research into the optimal treatment and duration.  A retrospective study of patients in the United Kingdom treated with 7 days of doxycycline for rectal ​Chlamydia, and subsequently confirmed to be cases that were serovars of LGV, supported the argument that shorter courses of doxycycline for nonbubonic LGV might be reasonable.[33]   An open, non-randomized clinical trial compared 21 days of doxycyline with 1 gram of azithromycin weekly for 3three weeks and showed similar efficacy.[34]  Data in support of alternative treatment regimens are ultimately limited. Of note, the update to the 2015 CDC Sexually Transmitted Infection Guidelines (yet to be puslished), will continue to recommend 21 days of doxycycline. [35]  

The complete treatment of patients with LGV includes appropriate antimicrobial coverage and drainage of infected buboes.

The recommended medical treatment for LGV involves one of the following antibiotic regimens:

• Doxycycline 100 mg PO bid for 21 d

• Erythromycin base 500 mg PO qid for 21 d

Doxycycline is the drug of choice in patients who are not pregnant. Pregnant and lactating females should be treated with either azithromycin or erythromycin (erythromycin treatment is often limited by side effects). HIV-positive patients should be treated the same as HIV-negative patients, although they may require prolonged treatment, with longer resolution of symptoms.

Infected patients should abstain from sexual intercourse until antibiotic therapy is completed and symptoms resolve. Some patients with severe disease have failed 21 days of doxycycline and may require more prolonged courses of therapy.[36]  Expert consultation is advised in this clinical scenario.

Sex partners who have had contact with the patient within the past 60 days should be evaluated and treated if symptomatic. If no symptoms are present, they should be treated for exposure as follows:

• Doxycycline 100 mg PO BID for 7 days

• Azythromycin 1 gm PO as a single dose[37]

• Of note, there have been cases of infection after azithromycin prophylaxis - which may prompt clinicians to avoid azithromycin as a post-exposure prophylaxis strategy. [36]

Needle aspiration or incision and drainage of involved inguinal nodes may be required for pain relief and prevention of ulcer formation. Some of the late complications of the third stage of LGV may require surgical repair.

Surgical consultation for lymphadenopathy is generally not required unless extensive buboes require further exploration. For tertiary disease, appropriate surgical consultation is indicated.

No restrictions to physical activities are required; however, patients should abstain from sexual contact until the infection resolves completely.

No vaccine is available to prevent LGV.

Condom use may reduce the risk of LGV transmission but does not prevent transmission from ulcerated areas not covered by the condom.

The emergence of cases of LGV among MSM in developed countries supports the need for careful screening of these patients. High rates of asymptomatic rectal chlamydia infection found in the MSM attending HIV/GUM clinics in the United Kingdom should prompt the clinician to routinely screen for rectal chlamydia in MSM, even in the absence of symptoms. This aids in the diagnosis of a subset of patients with LGV before symptoms are present. Treatment of this group of patients is essential in the attempt to eradicate the disease.[38]

Patients, especially those traveling to endemic areas, should be counseled about safe-sex practices, including condom use. Advise the patient to refrain from intercourse with high-risk individuals.

Inform patients that recovery from infection does not confer immunity against future infection.

For patients who have had incision and drainage of buboes, appropriate outpatient follow-up care may be required to ensure complete healing and to prevent secondary infections.

Multiple guidelines exist that reference the treatment of LGV. The CDC 2015 STI Guidelines are soon to be updated - but will not contain any changes to the recommendation that LGV be treated first line with doxycycline.[35]  The 2019 European guideline on the management of lymphogranuloma venereum is an excellent summary of the clinical data available to date.[39]

WHO recommendations for the treatment of lymphogranuloma venereum (LGV) are as follows[40] :

• In adults and adolescents with LGV, the guidelines suggest doxycycline 100 mg orally twice daily for 21 days over azithromycin 1 g orally weekly for 3 weeks.
• When doxycycline is contraindicated, azithromycin should be provided.
• When neither treatment is available, erythromycin 500 mg orally 4 times a day for 21 days is an alternative.
• Doxycycline should not be used in pregnant women.

The goal of therapy is to eradicate the organism.

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Totally eradicate the causative organism or organisms.

Doxycycline (Bio-Tab, Doxy, Doryx, Vibramycin, Vibra-Tabs)

Inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Erythromycin (E.E.S., E-Mycin, Eryc, Ery-Tab, Erythrocin)

Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest. For treatment of staphylococcal and streptococcal infections. In children, age, weight, and severity of infection determine proper dosage. When bid dosing is desired, half of the total daily dose may be taken q12h. For more severe infections, double the dose.

Azithromycin (Zithromax, Zmax)