Lymphogranuloma venereum

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nate Michalak, B.A.

Lymphogranuloma venereum (LGV), also known as lymphopathia venerea, tropical bubo, climatic bubo, strumous bubo, poradenitis inguinales, Durand-Nicolas-Favre disease, lymphogranuloma inguinale and neekerisankkeri in Finland, is a sexually transmitted disease caused by the invasive serovars L1, L2, or L3 of Chlamydia trachomatis.

LGV was first described by Wallace in 1833 and again by Durand, Nicolas, and Favre in 1913.

Lymphogranuloma venereum (LGV) is caused by serovars L1, L2, or L3 of the bacterium Chlamydia trachomatis. C. trachomatis is an obligate intracellular pathogen transmitted through vaginal, anal, or oral sexual contact. C. trachomatis alternates between two forms: the infectious elementary body (EB) and noninfectious, replicating reticulate body (RB). EBs enter through skin abrasions or microabrasion, or by crossing mucous membranes. EBs produce major out membrane protein (MOMP), which binds to heparan sulfate receptors on epithelial cells and are then phagocytized forming chlamydial inclusions. EBs begin to differentiate into RBs that start replicating. Endocytosis and bacterial replication cause host cell destruction leading to the formation of a papule at the site of inoculation. EBs and RBs then travel through lymphatics to regional lymph nodes, primarily to inguinal lymph nodes. C. trachomatis continues to replicate within monocytes causing lymphadenopathy and eventually the formation of buboes. Associated conditions include coinfection with other sexually transmitted diseases.

Chlamydia trachomatis is a Gram-negative, obligate intracellular pathogen causing Lymphogranuloma venereum.

Lymphogranuloma venereum (LGV) may be classified into three stages: primary LGV characterized by a self-limited papule, secondary LGV characterized by painful lymphadenopathy, and tertiary LGV (genitoanorectal syndrome) characterized by proctocolitis.

Lymphogranuloma venereum (LGV) must be differentiated from other diseases that cause genital ulcers, lymphadenopathy, or proctocolitis including syphilis, Herpes simplex, Behçet’s disease, chancroid, donovanosis, fixed drug eruption, psoriasis, chlamydial diseases caused by C. trachomatis serovars D-K, and diseases characterized with colitis. Sexually transmitted diseases characterized as genital ulcer diseases will present with the most similar symptoms to LGV.

Lymphogranuloma venereum (LGV) is rare in developed countries but the disease has become prevalent in the men who have sex with men (MSM) population. Outbreaks in MSM have occurred in the United Kingdom, Netherlands, Germany and United States. LGV is seen most commonly in white individuals whose ages range from 15 to 40 years. Males typically present and earlier stages than females.

Risk factors for developing lymphogranuloma venereum include HIV-positive serostatus, unprotected sexual intercourse (anal intercourse higher risk than vaginal intercourse) and multiple sex partners.

After an incubation period of 3 – 30 days for Chlamydia trachomatis, a papule develops at the point of inoculation and may ulcerate. The lesion is self-limited and heals in approximately a week. Lymphadenopathy of the inguinal and femoral lymph nodes develops 2 – 6 weeks after onset the primary lesion. Inguinal lymph nodes may develop into fluctuant, suppurative buboes or nonsuppurative abscesses. Iliac and perirectal lymphadenopathy may also develop in patients with rectal exposure, accompanied by hemorrhagic proctocolitis. Chronic inflammation may lead to perirectal fistulas and/or strictures, as well as sclerosing fibrosis that results in elephantiasis of genitalia, esthiomene in women, and frozen pelvis syndrome. Systemic spread may result in arthritis, hepatitis or perihepatitis, pneumonitis, cardiac involvment (rare), aseptic meningitis (rare), ocular inflammatory disease (rare). Prognosis is poor without treatment. However, spontaneous remission is possible. Death can occur from bowel obstruction or perforation.

The most common symptom of primary LGV is a painless papule or ulcer. Secondary LGV is characterized by painful inguinal and/or femoral lymphadenopathy, or Iliac and/or perirectal lymphadenopathy in patients with rectal exposure. Proctolcolits may also develop at this stage. Tertiary LGV symptoms include Lymphatic and rectal fibrosis, genital elephantiasis, esthiomene (chronic ulcerative disease of vulva), edema, tenesmus and rectal discharge. LGV may spread systemically and cause the following symptoms: fever, chills, malaise, myalgia, arthralgia, arthritis, hepatitis or perihepatitis, and pneumonitis.

Primary LGV is characterized by a small, nontender papule or ulcer. The primary lesion is typically unnoticed so few patients present at this stage. Majority of patients that do present are male. Secondary LGV is characterized by tender, swollen lymph nodes, typically unilateral, known as buboes. Enlarged inguinal and/or femoral lymph nodes occur after primary lesion of anterior genital area. Enlarged iliac and/or perirectal lymph nodes occure after primary lesion of posterior genital area. 20% of patients present with “groove sign”. Buboes may be indurated or draining sinuses. Tertiary LGV is characterized by [perirectal]] fistulas and/or strictures, ulcerative proctitis, and/or Elephantiasis of gentials. Males may present with “saxophone penis“. Females may present with with ulceration and thickening of the vulva.

Because of limitations in commercially available tests, clinical presentation, in conjunction to laboratory findings, plays an important role in diagnosis. C. trachomatis can be identified from lesion swabs, bubo aspirate, or rectal mucosa swabs (in patients with proctitis) using culture methods, serologic testing, and nucleic acid amplification tests (NAATs). Culture is impractical since it is time consuming and lacks sensitivity. Compliment fixation and immunofluorescence serologic tests are sensitive but only genus specific. NAATs are the most reliable method for detecting C. trachomatis and real-time PCR can detect the LGV-specific serovar.

There is no vaccine against the bacteria. LGV can be treated with three weeks of antibiotics. CDC STD Treatment Guidelines recommend the use of doxycyline, twice a day for 21 days. An alternative treatment is erythromycin base or azithromycin. The health care provider will determine which is best.

Needle aspiration or incision and drainage of inguinal buboes may be required to prevent ulcer or sinus formation. Patients with rectal strictures as a complication of LGV may need surgery to prevent bowel obstruction and bowel infarction.

Since there is no vaccine for LGV, methods of primary prevention include: abstaining from sexual activity, limiting number of sexual partners and using a male or female condom. The goal of secondary prevention is to stop the spread of disease. Therefore infected individuals should abstain from sexual intercourse until symptoms reside.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nate Michalak, B.A.

Lymphogranuloma venereum was described first by Wallace in 1833 and again by Durand, Nicolas, and Favre in 1913.

• Lymphogranuloma venereum (LGV) was first described by Wallace in 1833.
• Clinical aspects of LGV were described by N. Joseph Durand, Maurice Favre, and Joseph Nicolas in 1913.^[1]
• An outbreak in the Netherlands in 2004 among gay men has led to greater surveillance of LGV in Europe and the United States.^[2][3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nate Michalak, B.A.

Lymphogranuloma venereum (LGV) is caused by serovars L1, L2, or L3 of the bacterium Chlamydia trachomatis. C. trachomatis is an obligate intracellular pathogen transmitted through vaginal, anal, or oral sexual contact. C. trachomatis alternates between two forms: the infectious elementary body (EB) and noninfectious, replicating reticulate body (RB). EBs enter through skin abrasions or microabrasion, or by crossing mucous membranes. EBs produce major out membrane protein (MOMP), which binds to heparan sulfate receptors on epithelial cells and are then phagocytized forming chlamydial inclusions. EBs begin to differentiate into RBs that start replicating. Endocytosis and bacterial replication cause host cell destruction leading to the formation of a papule at the site of inoculation. EBs and RBs then travel through lymphatics to regional lymph nodes, primarily to inguinal lymph nodes. C. trachomatis continues to replicate within monocytes causing lymphadenopathy and eventually the formation of buboes. Associated conditions include coinfection with other sexually transmitted diseases.

• Lymphogranuloma venereum (LGV) may develop after transmission of servars L1, L2, or L3 of the bacterium Chlamydia trachomatis.
• C. trachomatis can be transmitted through vaginal, anal, or oral sexual contact.^[1]
• C. trachomatis is an obligate intracellular pathogen.^[2]

• Inoculation and replication of C. trachomatis serovars L1, L2, or L3 depends on alternation between two forms of the bacterium: the infectious elementary body (EB) and noninfectious, replicating reticulate body (RB).^[3]
• The EB form is responsible for inoculation with C. trachomatis.

• The C. trachomatis EB enters the body through skin abrasions, microabrasions incurred during sexual intercourse or by crossing epithelial cells of mucous membranes.^[4]
• C. trachomatis produces the extracellular ligand major outer membrane protein (MOMP), which is presumed to bind with heparan sulfate host epithelial cells.^[3]
• Once bound, the EB is engulfed by receptor-mediated endocytosis creating vacuoles termed “inclusions”.^[5]

• EB inclusions are able to avoid lysosomal fusion, thus preventing their destruction.
• Once inside the host cell, EBs immediately start differentiating into reticulate bodies (RBs) that undergo replication.
• The process of endocytosis and accumulation of RBs within host epithelial cells causes host cell destruction (necrosis) which leads to the formation of a papule at the site of inoculation which may ulcerate, depending on the extent of infection and number or EBs transmitted.^[5]
• After necrosis, EBs and RBs travel via lymphatics to regional lymph nodes, primarily to inguinal lymph nodes.
• Systemic infection occurs when this process repeats as C. trachomatis is phagocytized by and continues to replicate in monocytes, causing lymphadenopathy and eventually the formation of inguinal buboes.^[1]

• C. trachomatis produces major outer membrane protein (MOMP), which is responsible for attachment of C. trachomatis EBs to mucous membrane epithelial cells
• Functional MOMP is required for C. trachomatis infection.^[6]

• MOMP is 40 kDa ligand composed of 4 symmetrically spaced variable domains (VDs) I to IV.
• VD II and IV have been identified as the domains responsible for attachment:^[6]

• VD II structure promotes electrostatic interactions
• VD IV structure promotes hydrophobic interactions

Coinfection with other sexually transmitted diseases including:

• Gonorrhea
• Syphilis
• Herpes simplex
• Hepatitis C
• Human Immunodeficiency Virus (HIV)

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To learn about other chlamydial infections caused by species other than C. trachomatis, click here.
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]

• Chlamydia trachomatis, an obligate intracellular human pathogen, is one of four bacterial species in the genus Chlamydia.^[1]
• C. trachomatis is a Gram-negative bacterium, therefore its cell wall components retain the counter-stain safranin and appear pink under a light microscope.^[2] It is ovoid in shape.^[3]

• C. trachomatis includes three human biovars, based on variations in the major outer membrane protein (MOMP):

• serovars Ab, B, Ba, or C — cause trachoma: infection of the eyes, which can lead to blindness
• serovars D-K — cause urethritis, pelvic inflammatory disease, ectopic pregnancy, neonatal pneumonia, and neonatal conjunctivitis
• serovars L1, L2 and L3 — lymphogranuloma venereum (LGV)^[4]

• The L2 serovar can be further differentiated into L2, L2′, L2a, and L2b based on significant amino acid differences^[5]

• Many, but not all, C. trachomatis strains have an extrachromosomal plasmid.^[6]

• Chlamydia can exchange DNA between its different strains, thus the evolution of new strains is common.^[7]

Chlamydia species are readily identified and distinguished from other Chlamydia species using DNA-based tests.

Most strains of C. trachomatis are recognized by monoclonal antibodies (mAbs) to epitopes in the VS4 region of MOMP.^[8] However, these mAbs may also cross-react with two other Chlamydia species, C. suis and C. muridarum.

Chlamydiae are obligate intracellular bacterial pathogens, which means they are unable to replicate outside of a host cell. However, to facilitate effective dissemination, these pathogens have evolved a distinct biphasic life cycle wherein they alternate between two functionally and morphologically distinct forms.

• The elementary body (EB) is infectious, but metabolically inert (much like a spore), and can survive for limited amounts of time in the extracellular milieu. Once the EB attaches to a susceptible host cell, it mediates its own internalization through pathogen-specified mechanisms (via type III secretion system) that allows for the recruitment of actin with subsequent engulfment of the bacterium.
• The internalized EB, within a membrane-bound compartment, immediately begins differentiation into the reticulate body (RB). RBs are metabolically active but non-infectious, and in many regards, resemble normal replicating bacteria. The intracellular bacteria rapidly modifies its membrane-bound compartment into the so-called chlamydial inclusion so as to prevent phagosome-lysosome fusion. The inclusion is thought to have no interactions with the endocytic pathway and apparently inserts itself into the exocytic pathway as it retains the ability to intercept sphingomyelin-containing vesicles.
• The mechanism by which the host cell protein is trafficked to the inclusion through the exocytic pathway is not fully understood. As the RBs replicate, the inclusion grows as well to accommodate the increasing numbers of organisms. Through unknown mechanisms, RBs begin a differentiation program back to the infectious EBs, which are released from the host cell to initiate a new round of infection. Because of their obligate intracellular nature, Chlamydiae have no tractable genetic system, unlike E. coli, which makes Chlamydiae and related organisms difficult to investigate.

Chlamydia trachomatis can cause the following conditions:^{[9][10][11][12]}

• Cervicitis
• Conjunctivitis
• Fitz-Hugh-Curtis syndrome
• Lymphogranuloma venereum
• Pelvic inflammatory disease
• Pneumonia in infants
• Reactive arthritis
• Urethritis
• Rectal infection (proctitis)
• Prostatitis
• Ectopic pregnancy

• 
  Photomicrograph of Chlamydia trachomatis taken from a urethral scrape. From Public Health Image Library (PHIL). ^[13]
• 
  McCoy cell monolayers with Chlamydia trachomatis inclusion bodies (200X mag). From Public Health Image Library (PHIL). ^[13]
• 
  McCoy cell monolayers with Chlamydia trachomatis inclusion bodies (50X mag). From Public Health Image Library (PHIL). ^[13]
• 
  Photomicrograph depicts HeLa cells infected with Type-A Chlamydia trachomatis (400X mag). From Public Health Image Library (PHIL). ^[13]
• 
  Patient’s left eye with the upper lid retracted in order to reveal the inflamed conjunctival membrane lining the inside of both the upper and lower lids, due to what was determined to be a case of inclusion conjunctivitis caused by the bacterium, Chlamydia trachomatis. From Public Health Image Library (PHIL). ^[13]
• 
  From Public Health Image Library (PHIL). ^[13]

Bellaminutti, Serena; Seracini, Silva; De Seta, Francesco; Gheit, Tarik; Tommasino, Massimo; Comar, Manola (November 2014). “HPV and Chlamydia trachomatis Co-Detection in Young Asymptomatic Women from High Incidence Area for Cervical Cancer”. Journal of Medical Virology. 86 (11): 1920–1925. doi:10.1002/jmv.24041. Retrieved 13 November 2014.

• Chlamydiae.com
• Template:GPnotebook
• “Chlamydia trachomatis“. NCBI Taxonomy Browser. 813.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nate Michalak, B.A.

Lymphogranuloma venereum (LGV) may be classified into three stages: primary LGV characterized by a self-limited papule, secondary LGV characterized by painful lymphadenopathy, and tertiary LGV (genitoanorectal syndrome) characterized by proctocolitis.

Clincal features of lymphogranuloma venereum (LGV) occur in three stages.

• Characterized by small, painless papule that may ulcerate
• Papule is self-limited^[1]

• Characterized by painful lymphadenopathy
• Lymphodenopathy most commonly involves inguinal lymph nodes
• Lymphadenopathy may present as fluctuant buboes or abscesses^[2]

• Termed genitoanorectal syndrome
• Characterized by proctocolitis^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nate Michalak, B.A.

Lymphogranuloma venereum (LGV) must be differentiated from other diseases that cause genital ulcers, lymphadenopathy, or proctocolitis including syphilis, Herpes simplex, Behçet’s disease, chancroid, donovanosis, fixed drug eruption, psoriasis, chlamydial diseases caused by C. trachomatis serovars D-K, and diseases characterized with colitis. Sexually transmitted diseases characterized as genital ulcer diseases will present with the most similar symptoms to LGV.

Lymphogranuloma venereum (LGV) must be differentiated from other diseases that cause genital ulcers, lymphadenopathy, or proctocolitis including:^[1]

• Syphilis
• Herpes simplex
• Behçet’s disease
• Chancroid
• Donovanosis
• Fixed drug eruption
• Psoriasis
• Chlamydial diseases caused by C. trachomatis serovars D-K
• Diseases characterized with colitis

Sexually transmitted diseases characterized as genital ulcer diseases may present with similar manifestations and lesion characteristics. A diagnosis based only on the patient’s medical history and physical examination frequently is inaccurate. Patients who have genital, anal, or perianal ulcers should be evaluated with laboratory tests to make a definitive diagnosis.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nate Michalak, B.A.

Lymphogranuloma venereum (LGV) is rare in developed countries but the disease has become prevalent in the men who have sex with men (MSM) population. Outbreaks in MSM have occurred in the United Kingdom, Netherlands, Germany and United States. LGV is seen most commonly in white individuals whose ages range from 15 to 40 years. Males typically present and earlier stages than females.

• True incidence is unknown in the United States since national reporting of lymphogranuloma venereum (LGV) ended in 1995.
• Between 2003 and 2012, approximately 2,000 cases of LGV were reported in the United Kingdom.^[1]

• LGV is seen in sexually active individuals, ranging from ages 15 to 40 years.

• LGV affects both sexes equally.
• Males typically present at earlier stages and females at later stages.
• LGV is commonly seen in men who have sex with men (MSM) presenting as proctitis.^[2]

• Although race is not a risk factor, most cases of LGV are among Caucasians.

• LGV is uncommon in developed countries but outbreaks have occurred since 2003 among the MSM population in the United Kingdom, Netherlands, Germany and United States.^[3][4]

• LGV is endemic to tropical regions of the world, including the Caribbean, Africa, and Southeast Asia.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nate Michalak, B.A.

Risk factors for developing lymphogranuloma venereum include HIV-positive serostatus, unprotected sexual intercourse (anal intercourse higher risk than vaginal intercourse) and multiple sex partners.

• Positive HIV serostatus
• Unprotected sexual intercourse^[1]

• Unprotected anal intercourse is a greater risk factor than unprotected vaginal intercourse

• Multiple sex partners^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nate Michalak, B.A.

After an incubation period of 3 – 30 days for Chlamydia trachomatis, a papule develops at the point of inoculation and may ulcerate. The lesion is self-limited and heals in approximately a week. Lymphadenopathy of the inguinal and femoral lymph nodes develops 2 – 6 weeks after onset the primary lesion. Inguinal lymph nodes may develop into fluctuant, suppurative buboes or nonsuppurative abscesses. Iliac and perirectal lymphadenopathy may also develop in patients with rectal exposure, accompanied by hemorrhagic proctocolitis. Chronic inflammation may lead to perirectal fistulas and/or strictures, as well as sclerosing fibrosis that results in elephantiasis of genitalia, esthiomene in women, and frozen pelvis syndrome. Systemic spread may result in arthritis, hepatitis or perihepatitis, pneumonitis, cardiac involvment (rare), aseptic meningitis (rare), ocular inflammatory disease (rare). Prognosis is poor without treatment. However, spontaneous remission is possible. Death can occur from bowel obstruction or perforation.

• Incubation period of Chlamydia trachomatis is approximately 3 to 30 days, after which a papule develops at the point of inoculation.
• The papule may ulcerate.
• The lesion is self-limited and heals in approximately 1 week.
• Individuals with rectal exposure may develop proctitis.^[1][2]

• Lymphadenopathy develops approximately 2 to 6 weeks after onset of the primary lesion.
• If the site of inoculation is on the anterior area of genitalia, patients most commonly develop inguinal and/ or femoral lymphadenitis.^[2]

• Inflammation is more common in men and occurs in approximately 20% of women.
• Lymphadenopathy is unilateral is two-thirds of patients.
• Lymph nodes may develop into fluctuant, suppurative buboes or nonsuppurative abscesses
• Approximately 20% of patients develop “Groove sign” (separation of the inguinal and femoral lymph nodes by the inguinal ligament).^[3]

• If site of inoculation is the posterior area of genitalia or anorectal area, patients commonly develop anorectal syndrome.^[1]

• Patients may develop lymphadenopathy of the iliac or perirectal nodes.
• Patients may develop hemorrhagic proctocolitis.

• Chronic proctocolitis may lead to the formation of perirectal fistulas, strictures, and rectal stenosis.^[4]
• Chronic lymphadenopathy may cause sclerosing fibrosis that results in elephantiasis of genitalia, esthiomene in women, and frozen pelvis syndrome.^[1]

• Strictures and/or fistulas that cause rectal stenosis^[5]

• Fistulas of, but not limited to, the penis, urethra, vagina, uterus, or rectum may develop

• Fibrosis causing genital elephantiasis or esthiomene
• Follicular conjunctivitis due to autoinoculation of infectious discharge
• Systemic spread may result in the following:^[1]

• Arthritis
• Hepatitis or perihepatitis
• Pneumonitis
• Cardiac involvment (rare)
• Aseptic meningitis (rare)
• Ocular inflammatory disease (rare)

• Prognosis is usually poor without treatment. However, spontaneous remission is common.
• Complete cure can be obtained with proper antibiotic treatment (more favorable with early treatment).
• Death can occur from bowel obstruction or perforation.^[6]

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