Lymphogranuloma Venereum (LGV) in Emergency Medicine

Lymphogranuloma venereum (LGV) is a sexually transmitted infection (STI) that primarily infects the lymphatics.[1]

In 1833 the disease was first explained by Wallace, but at the time thought to be a "tropical bulbo"; however, in 1912 Rost discovered the disease was venereal in origin.[2]

LGV synonyms include lymphopathia venerea, tropical bubo, climatic bubo, strumous bubo, poradenitis inguinales, Durand-Nicolas-Favre disease, and lymphogranuloma inguinale.

LGV is caused by serovars L1, L2, L2b, and L3 of Chlamydia trachomatis.[3] It gains entrance into the body through skin breaks and abrasions, or it crosses the epithelial cells of mucous membranes. The organism travels via the connective tissue into the lymphatic system to multiply within mononuclear phagocytes in regional lymph nodes.

Transmission is predominantly sexual. However, transmission by fomites, nonsexual personal contact, and laboratory accidents have been documented. The creation of aerosols of this organism has been associated with infection and pulmonary symptoms.

LGV can be asymptomatic or present as progressive symptoms in 3 stages.[3]

Primary stage

The primary stage presents as a small, painless papule that can ulcerate to form a herpetiform lesion or chancre. Mucopurulent discharge of the rectum, urethra, or cervix may occur during this stage depending on the initial site of pathogen inoculation. 

Secondary stage

The secondary stage is classically described as the inguinal stage, which starts approximately 2-6 weeks after the primary lesion presents. The inguinal stage is defined by painful inguino-femoral lymphadenopathy, referred to as "buboes". This is the hallmark sign of the disease. 

Receptive anal sex can result in rectal incoculation that causes proctitis and infection of the perirectal and pelvic lymph nodes. Due to the location of these lymph nodes pelvic, lower abdominal, or low back pain may occur. In women, these nodes may also become involved as a result of lymphatic spread from the cervix and posterior vaginal wall.

Early in the course of the disease, the nodes appear fleshy and show diffuse reticulosis.

Later, suppurative granulomatous lymphadenitis and perilymphadenitis occur with matting of the nodes. Frequently, these nodes coalesce to form stellate abscesses.

Histologically, these abscesses are nearly diagnostic, but the clinical appearance may be similar to those seen in other infections, including cat scratch fever and mycobacterial granulomatous infections.

Tertiary stage

If left untreated, LGV can progress to the tertiary stage several years after the initial infection. In this stage, an anogenitorectal syndrome may occur with resultant rectal stricture or elephantiasis of the genitalia.

This syndrome is found predominantly in women and homosexual men, because of the location of the involved lymphatics.

During the tertiary stage, proctitis can advance to proctocolitis, which is caused by hyperplasia of intestinal and perirectal lymphatic tissue.

This inflammation forms perirectal abscesses, ischiorectal abscesses, rectovaginal fistulas, anal fistulas, and rectal stricture. In very late stages, fibrosis and granulomas is likely to occur.

Chlamydial organisms are scarce at this stage.

Extragenital inoculation sites

Extragenital inoculation sites can produce regional lymphadenopathy. Examples are of mediastinal lymphadenopathy from inhalation of C trachomatis, or submandibular and cervical chain lymphadenopathy following inoculation after oral sex.[4]

Frequency

United States

Sporadic cases occur in North America, Australia, and most of Asia. Most cases in the United States involve recent travel to an endemic area where the patient was sexually active; therefore, obtaining a travel history is important. Historically, the average number of LGV cases in the United States has been fewer than 600 per year. However, in 2015-2016 there was an outbreak of 38 confirmed, probable and suspected cases among men who have sex with men and were co-infected with HIV in Michigan.[5] However, within the United States there is likely under-detection of LGV due to the lack of widespread testing for chlaymdia trachomatis serovars. 

International

LGV is endemic in East and West Africa, India, Southeast Asia, South America, the Caribbean, and Australia.[6]  In 2003, an outbreak of LGV among men who have sex with men occurred in the Netherlands.[7]  Since 2003, the L2 and L2b serovars of LGV have been endemic among men who have sex with men in western Europe and Australia,[8, 9, 10, 11]  with the United Kingdom having the largest documented outbreak.[7]  

Mortality/Morbidity

If treated appropriately and during stage I or II, patients usually have complete resolution of symptoms.

Death can occur from tertiary LGV if complete bowel obstruction from rectal stricture leads to perforation, however this is rare.

Sex

LGV is diagnosed in men up to 6 times more frequently than in women.

Age

LGV infection is most common in the second and third decades when sexual activity is highest.

Primary lymphogranuloma venereum (LGV)

LGV has an incubation period of about 1-4 weeks; after which the primary stage may occur. 

During the initial stage, a painless papule or pustule that erodes into a herpetiform ulcer may form. 

If the primary lesion is in the urethra, mucopurulent discharge may occur.

The most common sites of primary infection in men include the coronal sulcus, frenulum, prepuce, penis, urethra, glans, and scrotum.

In women, the most common sites of the primary lesion include the posterior vaginal wall, fourchette, posterior lip of the cervix, and vulva.

The primary lesion is seen in one third of affected men but rarely is found in affected women.

Primary lesions of the mouth can result from orogenital intercourse. 

Secondary LGV

If the primary stage is left undetected, undiagnosed, or untreated the secondary stage of LGV can occur. The incubation period for the secondary stage is typically 2-6 weeks, but it may be up to 6 months. The secondary stage of LGV is characterized by tender, enlarged, unilateral lymph nodes, known as buboes. 

Patients may also present with constitutional symptoms, such as fever, headache, malaise, chills, nausea, vomiting, and arthralgias.

Tertiary LGV

In the tertiary stage symptoms are caused from chronic inflammation of the genital, anal, and rectal lymph nodes, depending on where initial inoculation occurred. Inflammation of the rectum progresses to include the colon, leading to the classical proctocolitis of this late stage. Symptoms of protocolitis can include anal pruritus, bloody mucopurulent rectal discharge, fever, rectal pain, tenesmus, constipation, pencil-thin stools, and weight loss. Symptoms mimic chronic inflammatory bowel disease, such as Crohn's disease, which can cause misdiagnosis. 

During the tertiary stage, anogenital strictures, anal fistulas, necrosis of the lymph nodes, and elephantiasis of the genital organs can also develop due to the chronic inflammation.[12]

Usually, LGV is considered based on physical findings of large fluctuant buboes or draining sinuses. The presence of rectal stricture and/or perineal deformity in a young woman is highly suggestive of LGV.

Primary LGV

The initial lesion may be a painless papule, pustule, shallow ulcer, or herpetiform grouping of lesions.

A cordlike lymphangitis of the dorsal penis may develop in primary LGV. This may progress to the formation of a solitary, large, tender lymphoid nodule, or bubonulus. These bubonuli may rupture to form sinuses and/or fistulas.

Secondary LGV

Buboes, which are enlarged, tender, regional lymph nodes, may be present. Buboes are usually unilateral, but occasionally may be bilateral. The location of lymph node involvement is related directly to the site of the primary lesion. Inguinal lymphadenopathy occurs if the primary lesion involves the anterior vulva, penis, or urethra. Perirectal and pelvic lymphadenopathy results if the primary lesion involves the posterior vulva, vagina, or anus. Lymphadenitis of the submandibular and cervical glands occurs if the site of primary inoculation is the mouth.

Seventy-five percent of all patients have deep iliac nodal involvement, which seldom suppurates.

When LGV includes inguinal lymph node involvement, a groove sign may be seen. The groove sign develops when lymphadenopathy of the inguinal nodes above, and femoral nodes below the inguinal ligament coalesce. This sign, however, is only seen in about 20% of patients affected, with the majority being men. 

Two thirds of patients with inguinal involvement have unilateral inguinal bubo formation with edema and erythema of the overlying skin. Often these nodes coalesce to form stellate abscesses. One third of these abscesses rupture; two thirds involute. Prior to rupture, the skin overlying the buboes may become a dark, bluish-gray color. After a buboe ruptures, pain decreases; however, a discharge may continue for weeks to months with the formation of a fistula or sinus tract.

Cutaneous manifestations may accompany infection, including erythema multiforme, scarlatiniform eruption, urticaria, and, in 10% of cases, erythema nodosum.

Complications of LGV that may be noted on physical examination include arthritis, conjunctivitis, and hepatomegaly. Pericarditis, pneumonia, and meningoencephalitis rarely occur.

Tertiary LGV

This stage is characterized by proctocolitis from chronic inflammation of the rectum that spreads to the colon.

On examination of the rectum, lymphorrhoids or perianal condylomata may be seen. These structures appear similar to hemorrhoids and are the result of an obstruction of lymphatics. They are composed of dilated lymph vessels with perilymphatic inflammation.

Rectal examination at this stage also may reveal a granular mucosa and palpable, enlarged lymph nodes under the bowel wall. Stricture usually occurs 2-5 cm above the anocutaneous margin, and digital examination above the stricture may reveal smooth healthy mucosa.

Lymph node fibrosis and granulomas are typical in very late stages. In women, esthiomene (eating away) occurs, which results in hypertrophic, chronic granulomatous enlargement of the vulva and subsequent ulceration. This may not appear for 1-20 years after the primary infection. In men, elephantiasis of the genitalia may occur.

The causal organism is Chlamydia trachomatis, serovars L1, L2, L2b, and L3.

Serovar L2 (including L2b) is most common, however serovar-specific serologic tests of C. trachomatis are not widely available.

Risk factors are similar to risks for transmission of other sexually transmitted infections. Risk factors include the following:

• Unprotected sex

• Anal sex

• Residing in or visiting certain developing countries, where LGV is endemic 

• Prostitution

• HIV 

When treated early, complications from LGV are rare. However, if LGV is left untreated the tertiary stage can result. The tertiary stage is characterized by proctocolitis. Complications associated with proctocolitis from LGV may include anal or vaginal fistulas, colonic perforation, anal strictures, and elephantiasis of the genitalia. 

Due to higher risks, testing for LGV is recommended for all men who have sex with men (MSM) with a C. trachomatis positive anorectal sample.[3]

Initial laboratory analysis may reveal mild leukocytosis.

These nonspecific results do not aid the clinician in the diagnosis of lymphogranuloma venereum (LGV).

Previously, the Frei test was the only method available to identify a chlamydial infection. The Frei intradermal test is only of historical interest. The test was based on a positive hypersensitivity to an intradermal standardized antigen, lymphogranuloma venereum, which indicated past or present chlamydial infection. The Frei test would become positive 2-8 weeks after infection. Unfortunately, the Frei antigen is common to all chlamydial species and is not specific to LGV. Commercial manufacturing of Frei antigen was discontinued in 1974.

Complement fixation (CF) is more sensitive than the Frei skin test, but it has some cross-reactivity with other chlamydial species. CF sensitivity is 80% for LGV. A test titer of 1:16 is strongly suggestive of LGV and a titer of >1:64 indicates active LGV. A 4-fold rise or fall in titer further supports the diagnosis.

The microimmunofluorescence test for the L-type serovar of C trachomatis is a more sensitive and specific test. A titer greater or equal to 1:512 is diagnostic. However, availability of this test is limited. 

Application of nucleic acid amplification techniques have been used to confirm the diagnosis with much greater certainty. Polymerase chain reaction (PCR) assays have been used for diagnosis recently in several outbreaks. PCR is a far superior test but has limited availability to reference laboratories. Multiplexed real-time PCR assays have been developed for the rapid detection of Chlamydia trachomatis and specific serovars.[13] As these tests are refined and approved for widespread use, they will speed detection and diagnosis.

Dermatopathology is not pathognomonic for LGV, and cytology using Giemsa stain or iodine stain fails to provide a high percentage of diagnoses.

Definitive diagnosis may be made by aspiration of the bubo and growth of the aspirated material in cell culture. C trachomatis can be cultured in as many as 30% of cases.

Arnold et al emphasize the need to screen for LGV in routine anocolonic biopsies to ensure timely treatment, avoid misdiagnosis, and prevent STI transmission.[14]

CT scan may be useful if retroperitoneal adenitis or intraabdominal abscess is suspected, but it is rarely necessary in the ED.

Lymphography does not outline buboes, but it may demonstrate the extent of lymph node involvement. This test is seldom ordered in the ED. 

A barium enema may reveal the characteristic elongated stricture in rectal LGV.

Venereal Disease Research Laboratory (VDRL) test or rapid plasma reagin (RPR), PCR assays for Haemophilus ducreyi and HSV-2, and HIV antibodies should be considered because patients with LGV may be co-infected with other sexually transmitted diseases.

A bubo may be aspirated to speed healing, but this is not necessary for culture since other diagnostic methods are more sensitive and specific.

Aspiration of fluctuant buboes may prevent spontaneous rupture and reduce morbidity.

At least 3 weeks of antibiotic therapy is needed to treat ongoing infection.[15]

Patients with lymphogranuloma venereum (LGV) have been known to harbor other sexually transmitted diseases. Thus testing for other STDs, such as HIV, gonorrhea, syphilis, hepatitis B should be considered. 

Symptomatic treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) may be beneficial.

Local heat may provide minor pain relief.

In the acute bubonic stage, consultation with a surgeon may be considered for the aspiration of fluctuant nodes.

The methods for prevention of LGV are the same as prevention of other sexually transmitted infections (STI). Limiting the number of sex partners and use of barrier protection, including male or female condoms and dental dams are the best methods for prevention. 

WHO recommendations for the treatment of lymphogranuloma venereum (LGV) are as follows[16] :

• 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.
• Good practice dictates treatment of LGV, particularly for men who have sex with men and for people with HIV infection.
• 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 Infectious Disease Society of America (IDSA) recommends doxycycline 100 mg orally twice daily for 21 days as first-line treatment.[17]  No clinical studies currently support azithromycin for treatment.

The CDC recommends patients with symptoms concerning for LGV be treated as follows[18] :

• Doxycycline 100mg orally twice a day for 21 days 
• Alternative Regimen: Erythromycin 500mg orally four times a day for 21 days. Erythromycin is the preferred treatment for patients who are lactating or in their second or third trimesters of pregnancy.  
• If Doxycycline and Erythromycin are contraindicated, Azithromycin 1g once a week for 3 weeks may be considered. Clinical data on the efficacy of azithromycin is lacking. This regimen is presumed based on the known chlamydial antimicrobial activity of Azithromycin. 

Depending on state laws, cases of LGV should be reported to the health department. Until clinical symptoms resolve, patients should be monitored with frequent follow-up appointments. Testing for HIV, syphilis, gonorrhea, and hepatitis B should be performed for all patients with a presumed LGV diagnosis. 

The goal of therapy is to eradicate the pathogen. Medication therapy should last a full 3 weeks. 

Class Summary

Therapy must cover all likely pathogens in the context of the clinical setting.

Doxycycline (Doryx, Bio-Tab, Vibramycin)

Broad-spectrum, synthetically derived bacteriostatic antibiotic in the tetracycline class. Almost completely absorbed, concentrates in bile, and is excreted in urine and feces as a biologically active metabolite in high concentrations.

Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. May block dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Treatment should be 21 days duration.

Sexual contacts of confirmed cases seen within 30 d of confirmed case diagnosis need to receive a prophylactic regimen of either azithromycin or doxycycline.

Erythromycin (EES, Ery-Tab, Erythrocin)

Inhibits RNA-dependent protein synthesis, possibly by stimulating dissociation of peptidyl tRNA from ribosomes. This inhibits bacterial growth. In children, age, weight, and severity of infection determine proper dosage. This is considered an alternative treatment by the Centers for Disease Control and Prevention and likewise should be administered for 21 days. When bid dosing desired, half-total daily dose may be taken every 12 h. For more severe infections, dose may be doubled.

Azithromycin (Zithromax)

Acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected.

Concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.

Recent evidence suggests that use of azithromycin for 3 wk is a sufficient course. However, more studies using this regimen need to be completed.

Sexual contacts of confirmed cases seen within 30 d of confirmed case diagnosis need to receive a prophylactic regimen of either azithromycin or doxycycline.

Infection confers little or no protective immunity against future infection.

Sexual contacts should be referred for evaluation, testing, and empiric treatment with an anti-chlamydia regimen (doxycycline 100mg orally twice a day for 7 days) possible treatment. If tests return positive the duration of doxycycline should be extended to the full 21 day regimen. 

Encourage the practice of safe sex.

Secondary lymphogranuloma venereum (LGV): Bubonuli may rupture to form sinuses or fistulas. This may result in long-term complications, including fibrosis and deforming scars at the penile base. In women, cervicitis, perimetritis, or salpingitis may occur.

Tertiary LGV: Complete bowel obstruction from an anal stricture may occur. Bowel perforation from chronic rectal inflammation and scarring may develop. 

Other complications of LGV: arthritis, conjunctivitis, hepatomegaly and, rarely, pericarditis, pneumonia, and meningoencephalitis.

Generally, full recovery is expected with appropriate treatment, especially when treated during the primary or secondary stages. 

Reinfection and relapse may occur.

For excellent patient education resources, visit eMedicineHealth's patient education articles on Sexually Transmitted Diseases, How to Use a Condom, Birth Control, and Chlamydia.