Lymphogranuloma Venereum

6 Interesting Facts of Lymphogranuloma Venereum 

1. Lymphogranuloma venereum is a sexually transmitted infection caused by specific serovars of Chlamydia trachomatis. With penile, urethral, or vulvar inoculation, the main presentation is an inguinal syndrome (also known as classic or bubonic lymphogranuloma venereum). With rectal inoculation, the main presentation is proctitis or proctocolitis (primarily in men who have sex with men), although infection may be asymptomatic
2. Classic lymphogranuloma venereum presents as a painless, primary genital papule or ulcer(s), which quickly resolves and may go unnoticed, followed by systemic symptoms and regional adenopathy. Buboes, abscesses, and draining fistulas may develop. Endemic in heterosexual population in areas of Africa, southeast Asia, South America, and the Caribbean, but historically rare in Europe and the United States
3. Anorectal infection occurs most commonly in men who have sex with men and may be entirely asymptomatic. If symptomatic, presentation is as proctitis or proctocolitis, which may be mistaken for inflammatory bowel disease. Occurring in outbreaks in Europe and the United States 
4. Diagnosis is based on clinical suspicion in an appropriate epidemiologic setting, with laboratory confirmation of Chlamydia trachomatis infection using a nucleic acid amplification test. 2-step testing, using a second test to confirm the presence of lymphogranuloma venereum serovars, is required to discriminate lymphogranuloma venereum from other chlamydia infection; however, such testing is often unavailable and results are not available quickly
5. Recommended treatment is doxycycline 100 mg twice daily continued for 21 days. This treatment duration is much longer than that of other Chlamydia trachomatis infections due to the invasive nature of the infection 
6. Complications are related to tissue destruction and include chronic progressive lymphangitis of inguinal-femoral region (edema, elephantiasis, chronic genital ulceration) and anorectal lymphorrhoids, abscesses, strictures, and stenosis

Pitfalls

• Test people who receive a diagnosis of sexually transmitted chlamydial infection for HIV, gonorrhea, syphilis, hepatitis B, and hepatitis C 
• Lymphogranuloma venereum proctocolitis resembles inflammatory bowel disease and diagnosis may be significantly delayed without a high index of suspicion and nucleic acid amplification testing in men who have sex with men

• Lymphogranuloma venereum is a sexually transmitted infection caused by specific serovars of Chlamydia trachomatis,which is invasive if not treated at the earliest stage and can spread via underlying connective tissue to regional lymph nodes
• Disease severity exists on a spectrum, including asymptomatic infection
• With penile, urethral, or vulvar inoculation, the main presentation is an inguinal syndrome (also known as classic or bubonic lymphogranuloma venereum)
• With rectal inoculation, the main presentation is proctitis or proctocolitis (primarily in men who have sex with men), although infection may be asymptomatic

Diagnosis

Clinical Presentation

History

• Classic (ie, genital, bubonic) lymphogranuloma venereum
  • Early infection
    • Primary lesion (papule or, more commonly, ulcer) appears on genital mucosa or adjacent skin between 3 and 30 days after sexually transmitted infection 
      • Lesion often is completely asymptomatic (painless), resolves quickly, and can therefore go completely unnoticed and untreated, allowing infection to become invasive
      • Typically unilateral
  • Within days to weeks, regional lymphadenopathy (typically unilateral) and systemic symptoms develop
    • Painful adenopathy
      • In men, primary lesion is usually on the penis or in the urethra (inguinal adenopathy)
      • In women, primary lesion is more likely to be in the upper vagina or on the cervix (pelvic adenopathy), manifesting as back pain; however, inguinal adenopathy may be present with initial infection of lower vagina
    • Fever, headache, and myalgias
    • Abscesses and draining fistulas may form in coalesced inflamed lymph nodes
• Variant presentation as anorectal infection
  • Occurs primarily in men via receptive anal intercourse; may occur in epidemics in large cities
    • Genital infections occur in only 1 in 15 lymphogranuloma venereum infections in men who have sex with men; the remainder of infections are anorectal 
    • About 25% of anorectal infections are asymptomatic in men who have sex with men 
  • In women, infection is primarily from lymphatic spread to the rectum after initial inoculation to vagina or cervix
  • Remainder of infections are a symptomatic proctitis or proctocolitis
    • Painful anorectal ulcers, discharge, and bleeding
    • Tenesmus and constipation
    • Back pain and lower abdominal pain due to internal iliac lymphadenopathy
    • In recent outbreaks, genital lesions and inguinal lymphadenopathy (ie, typical symptoms of classic lymphogranuloma venereum) have not preceded anorectal symptoms
    • Systemic symptoms (eg, fever) are uncommon
    • Patients have sometimes been misdiagnosed as having an inflammatory bowel disease

Physical examination

• Small papule or herpetiform ulcer is the primary lesion, typically on the penis and on the vagina (resolves quickly without scarring)
• In classic lymphogranuloma venereum, lymphadenopathy (unilateral in two-thirds of patients) is present in the area that drains the primary lesion 
  • Initially, lymph nodes are discrete, enlarged, and tender with overlying erythema
  • Inflammation and enlargement of the inguinal nodes (above the inguinal ligament) and femoral nodes (below the inguinal ligament) creates “groove sign” in some cases
  • Lymph nodes become matted
  • Later, inflammation of surrounding tissues results in large, tender, soft tissue mass
    • Abscesses may be present within mass
  • Coalescence of abscesses can form a bubo, which may rupture
    • If rupture occurs, smaller loculated abscesses and fistulas or sinus tracts may form
• In patients with proctitis or proctocolitis, examination with a proctoscope is recommended; findings may include:
  • Anorectal ulcerations
  • Mucopurulent and bloody discharge
  • Lymphorrhoids (localized dilation of perianal lymph channel, resembling a hemorrhoid; also described in lymphogranuloma venereum proctitis)

Causes

• Chlamydia trachomatis serovars L1 to L3
  • Sexually transmitted
  • Subvariants (eg, L2b) have been described as spreading among men who have sex with men 
    • Transmission has been attributed largely to asymptomatic anorectal infection in this population

Risk factors and/or associations

Sex

• Anorectal infection has been endemic since 2003 among European men who have sex with men 
  • In the United States, there are reports of sporadic outbreaks among men who have sex with men; however, because national reporting requirement was discontinued in 1994, true prevalence is unknown
  • May also be underreported in this population in the United States because diagnostic tests to differentiate lymphogranuloma venereum from non–lymphogranuloma venereum Chlamydia trachomatis are not widely available 
• Classic (inguinal) lymphogranuloma venereum is endemic in the heterosexual population in many subtropical and tropical areas of Africa, southeast Asia, South America, and the Caribbean but historically has been rare in Europe and the United States

Other risk factors/associations

• HIV-positive men who have sex with men are disproportionately affected by lymphogranuloma venereum 

Diagnostic Procedures

Primary diagnostic tools

• Diagnosis is based on clinical suspicion in an appropriate epidemiologic setting (most commonly, men who have sex with men) and exclusion of other causes of proctocolitis, genital or rectal ulcer(s) (or recent history of such lesions), and inguinal lymphadenopathy 
• Perform a nucleic acid amplification test of an appropriate specimen to identify presence of Chlamydia trachomatis infection 
• If result is positive for Chlamydia trachomatis, additional molecular testing (eg, polymerase chain reaction–based genotyping) can distinguish lymphogranuloma venereum from non–lymphogranuloma venereum serovars 
  • These tests are not widely available in the United States 
  • If molecular testing is unavailable, Chlamydia genus-specific serologic assays can support diagnosis 
    • Criteria for serologic test interpretation have not been standardized, cross-reactive antibody to other Chlamydia species decreases test specificity, and test performance has not been validated for rectal infections
• Test patients who receive a diagnosis of sexually transmitted chlamydial infection for HIV, gonorrhea, syphilis, and hepatitis B. Hepatitis C testing is also recommended based on recent epidemiologic trends among men who have sex with men 

Laboratory

• Nucleic acid amplification test
  • Detects both lymphogranuloma venereum and non–lymphogranuloma venereum serovars, but cannot identify specific serovar (ie, confirms Chlamydia trachomatis infection, in general, but does not confirm presence of lymphogranuloma venereum) 
  • Appropriate test specimens, depending on region of suspected infection, include: 
    • Swab of an ulcer base or exudate from a primary anogenital lesion
    • Rectal swab
      • As of 2019, rectal swabs (previously not approved) are FDA approved for use with several commercially available nucleic acid amplification tests 
    • Urethral swab or first-catch urine
    • Aspirate of a lymph node or bubo using a 21-gauge needle after topical disinfection
• Additional testing for identification of lymphogranuloma venereum–specific serovars
  • Molecular testing (eg, polymerase chain reaction–based genotyping)
    • Can distinguish lymphogranuloma venereum from non–lymphogranuloma venereum serovars 
    • Tests are not widely available in the United States, and results are not available within a clinical timeframe reasonable to influence management decisions
      • Treat empirically for lymphogranuloma venereum when clinical presentation is consistent with the disease and Chlamydia trachomatis nucleic acid amplification test result is positive
    • European guidelines recommend 2-step testing, with a second lymphogranuloma venereum–discriminant nucleic acid amplification test, if available 
  • Serologic testing
    • Infections that result in spread to draining lymph nodes (ie, classic lymphogranuloma venereum) result in a greater likelihood of detectable systemic antibody response than other forms of disease; therefore, serology may aid in diagnosis of inguinal (but not rectal) disease
    • Supportive results, in the appropriate clinical context, include complement fixation titers greater than 1:64 or microimmunofluorescence titers greater than 1:256 
      • Caveats
        • Criteria for serologic test interpretation have not been standardized; cross-reactive antibody to other Chlamydia species decreases test specificity 
        • A low titer does not exclude lymphogranuloma venereum
        • A high titer in an asymptomatic patient does not confirm lymphogranuloma venereum
        • Expected duration of elevated titers has not been clearly defined
        • Test performance has not been validated for rectal infections

Imaging

• Imaging is not routine
• Pelvic CT or MRI can be useful to evaluate back pain due to pelvic and retroperitoneal adenopathy, especially in women with suspected lymphogranuloma venereum 

Other diagnostic tools

• Colonoscopy is sometimes performed in patients with symptoms of proctitis or proctocolitis
  • Lymphogranuloma venereum may be discovered incidentally with this procedure in men who have sex with men who have symptoms similar to those of inflammatory bowel disease or ulcerative colitis
  • Proctitis is defined as inflammatory changes and ulcerations restricted to the distal 15 cm of the rectum; in proctocolitis, these changes extend proximally 
  • Histopathology of lymphogranuloma venereum proctocolitis has shown active colitis, ulcers, cryptitis, and crypt abscesses 

Differential Diagnosis

Most common

• Differential diagnoses to consider depend on patient presentation
  • Regional lymphadenopathy, with or without genital ulcerations
    • In lymphogranuloma venereum, the primary lesion is a painless, usually single, papule or ulcer that resolves spontaneously. Unilateral discreet lymphadenopathy (inguinal and sometimes femoral) appears days to weeks later and becomes matted; may display the groove sign; eventually progresses to an inflamed coalescent mass of abscesses (bubo)
      • Presentation with genital ulcerations and inguinal lymphadenopathy: consider genital herpes simplex, syphilis, or chancroid
        • Genital herpes
          • Painful vesicular lesions on erythematous base; often bilateral on labia, vulva, perineum, perianal areas, or shaft or glans of penis
          • Natural history of herpetic vesicles involves stages of ulceration, crust formation, and resolution over 1 to 2 weeks (sometimes longer in primary infection) 
          • Lesions are superficial and not indurated
          • Bilateral, tender, inguinal adenopathy; more common with primary HSV episodes
          • Confirm HSV lesions with a viral identification test (eg, nucleic acid amplification test, rapid antigen assay, Tzanck test with microscopic examination, viral culture)
        • Primary syphilis
          • Characterized by a painless ulcer at site of inoculation (chancre), most commonly in anogenital region, that presents at a median of 21 days after exposure and persists for 1 to 3 weeks 
          • Usually a single lesion but may be multiple; ulcer is nonexudative with a clean base
          • Regional, painless unilateral adenopathy is usually present
          • First laboratory test for syphilis at any stage is a serologic assay measuring antibodies to nontreponemal antigens (VDRL test or rapid plasma reagin test); positive nontreponemal test result must be confirmed with a test for treponemal antigens (Treponema pallidum particle agglutination test or fluorescent treponemal antibody absorption test)
            • Some laboratories use a reverse sequence screening algorithm that begins with a treponemal enzyme immunoassay; nontreponemal antibody is used for confirmation and for a quantitative titer
          • Definitive diagnosis is by demonstration of Treponema pallidum on darkfield microscopy or by detection with polymerase chain reaction, but these tests are often not readily available
        • Chancroid
          • Extremely rare in the United States
          • Tender erythematous papules, which progress into pustules that rupture and form painful ulcers; papules appear 3 to 7 days after exposure and may last for months 
          • Ulcers are nonindurated and exudative with necrotic base; may appear on opposing area of skin surfaces (known as kissing ulcers)
          • Inguinal lymphadenitis occurs in up to 50% of patients, most often unilateral (ipsilateral to ulcer) with overlying dermal erythema. Painful lymph nodes may progress to fluctuant buboes; may rupture to form a discharging sinus
          • Typically, there are no constitutional symptoms
          • Diagnosis is based on history, clinical findings, and exclusion of other causes of genital ulceration, including HSV, syphilis, and lymphogranuloma venereum
    • Presentation with inguinal adenopathy (without genital ulcerations): consider reactive adenopathy due to other infection (eg, lower-limb infections), lymphoma, and pelvic malignancy
      • Consider (non-chlamydial) infection of the skin and soft tissues of the lower extremities and groin, which may be evident on physical examination. Ultrasonography can distinguish lymphadenopathy from other mass lesions and can suggest an abscess
      • Consider lymphoma, pelvic malignancy, or metastatic pelvic adenopathy
      • 3-dimensional imaging and biopsy may be required to rule-out other conditions
  • Proctitis or proctocolitis in men who have sex with men
    • In lymphogranuloma venereum, symptomatic anorectal infection presents with symptoms of proctitis/proctocolitis (eg, anorectal pain, mucoid and bloody discharge, tenesmus, constipation); fever is uncommon
    • In this population, also consider:
      • Other sexually transmitted infections (eg, gonorrhea, chlamydia serovars A to K, HSV, syphilis), as well as lymphogranuloma venereum infection
        • Coinfection with more than 1 of the above is possible
        • Obtain nucleic acid amplification test testing for gonorrhea and Chlamydia trachomatis, serologic assay measuring antibodies to nontreponemal antigens (VDRL test or rapid plasma reagin test), and HSV viral identification
      • Proctocolitis caused by enteric pathogens acquired through oral-anal contact (eg, Campylobacter species, Shigella species, Entamoeba histolytica)
        • Typically associated with diarrhea or abdominal cramps, in addition to tenesmus and rectal pain
      • Cytomegalovirus or other opportunistic agents in immunosuppressed patients with HIV infection
    • If testing for these pathogens is negative, consider inflammatory bowel disease and obtain a colonoscopy with biopsies

Treatment Goals

• Cure infection and prevent ongoing tissue damage
• Prevent transmission of infection to sexual partners

Disposition

Recommendations for specialist referral

• Consultation with a specialist in infectious diseases or sexually transmitted infections may be helpful
• Any chlamydial infection (not specifically lymphogranuloma venereum) is a nationally reportable disease 
• Worldwide, may be reportable depending on regional and national regulations 
• Surgical consultation may be beneficial for management of fluctuant buboes

Treatment Options

Antibiotic treatment

• Begin presumptive treatment with oral doxycycline if lymphogranuloma venereum is suspected clinically 
  • When doxycycline is contraindicated (eg, pregnancy), erythromycin is an alternative 
  • There is a paucity of consistent evidence to support use of azithromycin 
    • If used, consider test of cure 
• In an appropriate epidemiologic setting, continue antibiotic treatment for 21 days if initial nucleic acid amplification test result is positive for Chlamydia trachomatis 
  • Duration of treatment is longer than that of non–lymphogranuloma venereum Chlamydia infection due to invasive nature of lymphogranuloma venereum
  • If available, perform 2-step testing to confirm lymphogranuloma venereum serovar to determine need for 21-day treatment; however, it is usually unavailable in the United States
  • Assume all cases of severe chlamydial proctitis and proctocolitis are caused by lymphogranuloma venereum strains, and treat them with the 21-day regimen of doxycycline 
• Refer sex partners for evaluation, diagnostic testing (choice of test specimen depending on anatomic exposure site), and presumptive treatment if they had sexual contact with the patient during the 60 days before the patient’s onset of symptoms or lymphogranuloma venereum diagnosis 
  • 2015 United States guidelines recommend shorter course of presumptive treatment for asymptomatic partners (7 days of doxycycline or single 1-g dose of azithromycin) 
    • Some experts use a full 21-day treatment course of doxycycline for these patients regardless of nucleic acid amplification test result 
    • Others treat with a 7-day course of doxycycline and do not prolong therapy duration for a positive nucleic acid amplification test result in an asymptomatic partner
    • Treat for full 21 days if nucleic acid amplification test result is positive for Chlamydia trachomatis 
  • Case reports have suggested failure in asymptomatic contacts treated with single-dose azithromycin 

Drug therapy

• Doxycycline
  • Doxycycline Hyclate Oral tablet; Adolescents: 2.2 mg/kg/dose PO every 12 hours (Max: 100 mg/dose) for 21 days.
  • Doxycycline Hyclate Oral tablet; Adults: 100 mg PO every 12 hours for 21 days.
• Erythromycin base
  • Erythromycin Oral tablet; Adolescents: 500 mg PO 4 times daily for 21 days.
  • Erythromycin Oral tablet; Adults: 500 mg PO 4 times daily for 21 days.
• Guideline-directed presumptive treatment of sexual contacts; extend treatment duration if nucleic acid amplification test result is positive
  • Doxycycline
    • Doxycycline Hyclate Oral tablet; Adults and Adolescents: 100 mg PO twice daily for 7 days. 
  • Azithromycin
    • Azithromycin Oral tablet; Adults and Adolescents: 1 g PO as single dose. 

Nondrug and supportive care

• Management of fluctuant buboes
  • Drain via needle aspiration though healthy overlying skin
  • Surgical excision may result in chronic sinus tract formation, and is not recommended
  • Repeat drainage procedures may be necessary

Comorbidities

• HIV
  • Among men who have sex with men who are diagnosed with lymphogranuloma venereum:
    • Prevalence of comorbid HIV ranges from 67% to 100% (odds ratio of approximately 8 for association compared to men who had non–lymphogranuloma venereum chlamydia infection) 
    • Also may be associated with hepatitis C infection 
  • Patients with both lymphogranuloma venereum and HIV infection receive the same regimens as those who are HIV-negative 
  • A delay in resolution of symptoms might occur and a longer duration of treatment may be required 
• Counsel all patients diagnosed with lymphogranuloma venereum regarding prevention of other sexually transmitted infections, including HIV and hepatitis C 
• Advise HIV-negative patients about the availability of pre-exposure prophylaxis to prevent HIV infection 

Monitoring

• Follow patients closely to ensure clinical response to therapy
• Use clinical response to guide duration of therapy in particularly severe cases; may need to extend therapy, although this is not guided by data
• European guidelines recommend test of cure if an alternative antibiotic is selected for treatment (eg, erythromycin instead of doxycycline) 

Complications

• Chronic progressive lymphangitis of inguinal-femoral region
  • Chronic edema
  • Sclerosing fibrosis
  • Elephantiasis
  • Chronic ulceration of external genitalia (esthiomene)
• Anorectal complications
  • Perirectal abscess
  • Fistulas
  • Rectal stricture and stenosis with constipation, fecal soiling, and possible development of megacolon
  • Lymphorrhoids (swollen, obstructed rectal lymphatic tissue)
• Rare complications include:
  • Inflammatory conditions: reactive arthritis, aseptic cardiac involvement, meningitis, and ocular inflammatory disease
  • Septic conditions: arthritis, pneumonitis, hepatitis, and perihepatitis

Prognosis

• For classic lymphogranuloma venereum, antibiotic therapy rapidly improves constitutional symptoms but has only a limited effect on bubo resolution
  • Scarring may occur but does not result in significant sequelae in most cases 
• If rectal lymphogranuloma venereum is treated before development of strictures, stenosis, or fistulae, there is usually complete resolution of symptoms

Screening

At-risk populations

• Sexually active adolescents and adults are at risk for sexually transmitted Chlamydia infections
  • CDC screening recommendations for women and heterosexual men are designed primarily to identify and treat asymptomatic urogenital chlamydial infection
• Recommendations for women
  • Screen for chlamydia in sexually active women aged 24 years and younger and in older women who are at increased risk for infection (those who have new or multiple sex partners and those reporting that their sex partner may have another concurrent sex partner) 
• Recommendations for pregnant patients
  • US Preventive Services Task Force recommends testing all pregnant patients younger than 25 years and those aged 25 years and older if at increased risk 
  • CDC recommends testing all pregnant patients at the first prenatal visit and retesting patients younger than 25 years or at risk during third trimester 
• Recommendations for men 
  • Evidence is insufficient to recommend routine screening for Chlamydia trachomatis in all sexually active young men. Consider screening young men in high prevalence clinical settings (eg, adolescent clinics, correctional facilities, sexually transmitted disease clinics) or those who are part of populations with high burden of infection (eg, men who have sex with men)
  • Annual screening for chlamydia is recommended in men who have sex with men, based on exposure history, with more frequent screening (3-6 month intervals) in populations at highest risk (defined as persistent risky behaviors or multiple sexual partners)
  • Screen sexually active men who have sex with men at sites of contact (eg, urethra, rectum), regardless of condom use

Screening tests

• Nucleic acid amplification test 

Prevention

• Avoidance of oral, vaginal, or anal sex or engaging in sexual activity only within a mutually monogamous long-term relationship are the most reliable methods for avoidance of sexually transmitted infections 
• Consistent use of a condom lowers risk of developing sexually transmitted infection 

References

1: Rönn MM et al: The association between lymphogranuloma venereum and HIV among men who have sex with men: systematic review and meta-analysis. BMC Infect Dis. 11:70, 2011 Reference