Interim Statement on the Diagnosis, Treatment and Reporting of Lymphogranuloma venereum (LGV) In Canada

Lymphogranuloma venereum (LGV) in Canada: Recommendations for Diagnosis and Treatment and Protocol for National Enhanced Surveillance

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Lymphogranuloma venereum (LGV) is a sexually transmitted infection caused by C. trachomatis serotypes L1, L2, and L3. Unlike serovars A-K, LGV serovars are invasive, preferentially affecting the lymph tissue. LGV can be transmitted through vaginal, anal or oral sexual contact, and can be prevented through the use of condoms or other barrier methods. If left untreated, LGV can cause serious complications such as swelling, deformity/destruction of the genitals/rectum (including rectal stricture), and can uncommonly lead to meningoencephalitis, hepatitis and death. Having LGV can increase the chances of acquiring or transmitting HIV, other STIs and other blood-borne pathogens, such as hepatitis C.

Epidemiology

Until recently, LGV has been a rare infection in industrialized countries, and was usually acquired in endemic areas. LGV is endemic to parts of Africa, Asia, South America and the Caribbean, and is thought to account for approximately 2-10% of genital ulcer disease in areas of Africa and India. However recent cases have been reported in men having sex with men (MSM) in Europe, starting in 2003 in the Netherlands, and more recently in North America.

Cases have been reported in:

• the Netherlands
• Belgium
• France
• Germany
• Sweden
• UK
• USA

Recent cases in MSM have been associated with concurrent STI including HIV as well as hepatitis C, casual sex gatherings (leather scene parties) and higher risk sexual activities such as “fisting”.

Clinical Picture and Diagnostic Features

LGV is commonly divided into 3 stages:

1. Primary LGV

• incubation period of 3-30 days
• small, painless papule at site of inoculation (vagina, penis, rectum, occasionally cervix), that may ulcerate
• self-limited and may go unnoticed

2. Secondary LGV

• begins within 2-6 weeks of primary lesion
• often accompanied by significant systemic symptoms such as low-grade fever, chills, malaise, myalgias, arthralgias; occasionally by arthritis, pneumonitis or hepatitis/perihepatitis; rarely with cardiac involvement, aseptic meningitis and ocular inflammatory disease
• abscesses and draining sinuses possible (< 1/3 of patients)
• involves the inguinal/femoral lymph nodes OR anus and rectum
  • Inguinal Secondary LGV characterized by painful inguinal and/or femoral lymphadenopathy (usually unilateral) - painful lymph nodes are referred to as buboes
    • “groove sign” - inguinal nodes above and femoral nodes below the inguinal ligament(once considered pathognomonic for LGV)
  • cervical lymphadenopathy has been described in cases with oral contact
• Anorectal Secondary LGV characterized by acute haemorrhagic proctitis
  • bloody, purulent or mucous discharge from the anus

3. Tertiary LGV (chronic, untreated LGV)

• more common in females than males
• chronic inflammatory lesions lead to scarring:
  • lymphatic obstruction causing genital elephantiasis
  • rectal strictures and fistulae
• possible extensive destruction of genitalia (esthiomene)

Diagnosis

The diagnosis of LGV is not always straightforward. The symptoms and signs of LGV significantly overlap those of other STI, other infections, drug reactions and malignancies. The diagnosis is often based on the history and clinical picture and is supported by laboratory testing, although in Canada confirmatory testing for LGV is now readily available in some laboratories (see Laboratory Testing below).

Diagnostic Procedures

• anoscopy/sigmoidoscopy/proctoscopy
  • pattern similar to ulcerative colitis
  • granular or ulcerative proctitis
• bubo aspiration
  • buboes in LGV usually contain small amount of milky fluid
  • may require injection of 2-5ml of sterile saline for aspiration
  • buboes should be aspirated through healthy skin

Specimen Collection

For a definitive diagnosis of LGV, emphasis should be placed on clinical specimens such as swabs and aspirates. Serology, though less definitive, may provide support for the diagnosis. The following section describes the types of specimens that may be collected for the diagnosis of LGV by stage. For more information and detailed descriptions of the testing modalities see the Laboratory Testing section below.

• Primary
  • swab of lesion for:
    • culture or
    • NAAT

Because the invasive nature of LGV has not yet manifested in the primary stage of the infection, serology at this stage is unlikely to be helpful

• Secondary
  • bubo aspirate for:
    • culture or
    • NAAT

Identification of C. trachomatis in bubo fluid is highly suggestive of LGV, even prior to or without identification of LGV serovars

• rectal, vaginal or urethral swab for:
  • culture or
  • NAAT*

* NAAT not officially approved in Canada for use with rectal or oropharyngeal swabs. Repeat testing is advised to confirm a positive test

• urine for:
  • NAAT
• serology (method varies by laboratory)
  • microimmunofluorescence (MIF) test
  • complement fixation (CF) test
    
    • See note in Laboratory Testing below
• Tertiary
  • as for secondary (see above)

Laboratory testing

The availability and type of testing for LGV varies by laboratory. Some local laboratories are able to test specifically for LGV while others will need to involve the National Microbiology Laboratory (NML) via their Provincial Laboratory. Please check with your local laboratory for more information on how to collect and transport specimens. Where possible, suspected cases of LGV should have both swab and sera samples submitted for laboratory testing.

For samples being sent to NML, the following storage and shipping recommendations apply:

• dry swabs should be stored and shipped frozen
• swabs stored in viral or chlamydial transport media should be kept frozen at -80°C if culture will be done, or at -20°C if culture will not be done
• urine samples should be stored frozen

Many laboratory testing modalities do not distinguish between LGV and non-LGV serovars of C. trachomatis. Some methods are suggestive of LGV. Two methods, restriction fragment length polymorphism (RFLP) and DNA sequencing, are available in Canada to definitively diagnose LGV (availability varies by laboratory).

Non-specific tests

• Culture for C. trachomatis
  • does not definitively distinguish between LGV and non-LGV serovars; however, LGV serovars will yield a positive culture without centrifugation (non-LGV serovars require centrifugation)
    • dilution (1:10) of anal/rectal swabs may be required because of fecal toxicity
    • positive cultures may be sent for further definitive testing to identify LGV serovars (see below)
      
• Nucleic acid amplification testing (NAAT) for C. trachomatis
  • include polymerase chain reaction (PCR), ligase chain reaction (LCR), transcription mediated amplification (TMA) and strand displacement amplification (SDA)
  • differences in sensitivity and specificity in detecting LGV and non-LGV serovars is unknown
  • does not differentiate between LGV and non-LGV serovars
    • positive specimens may be sent for further definitive testing to identify LGV serovars (see below)
• Serology
  • because of the invasive nature of LGV, serology titres are in general significantly higher in LGV vs. non-LGV C. trachomatis infections
  • serology can be suggestive of LGV infection but is not definitive
  • testing modalities vary by laboratory:
    • microimmunofluorescence (MIF) test for C. trachomatis: high titre (titre >= 1:256)
    • complement fixation (CF) test for chlamydiae: positive (titre >= 1:64)
      
      • MIF is a more specific test for LGV than CF
      • cross-reactivity may be an issue with CF
• Frei skin test is no longer used

LGV specific tests (Confirmatory)

• DNA sequencing
  • samples that test positive for C. trachomatis
    with NAAT or culture can be sent for DNA
    sequencing
  • definitively identifies LGV serovars
  
  
• Restriction fragment length polymorphism (RFLP)
• • samples that test positive for C. trachomatis
    with NAAT or culture can be sent for RFLP
    testing
  • definitively identifies LGV serovars

Laboratories sending samples to NML for confirmatory testing, please note that it is the orig inal sample that must be tested by PCR for omp1, and this PCR product is what must be sent for sequencing to NML.

Treatment

• First line:
  • Doxycycline 100 mg PO BID x 21 days (B2)
• Alternative:
  • Erythromycin 500 mg PO QID x 21 days (C3)
• Possible:
  • Azithromycin 1g PO once weekly for three weeks* (C3)
    

*While some experts believe azithromycin to be effective in the treatment of LGV, clinical data are lacking.

Erythromycin dosage refers to the use of erythromycin base. Equivalent dosages of other formulations may be substituted (with the EXCEPTION that the estolate formulation is contraindicated in pregnancy).
Erythromycin (NOT the estolate formulation) should be used in pregnancy.

• Aspiration of buboes may help symptomatically. However, incision/drainage or excision of nodes is not helpful and may delay healing.

Treatment of partners

Sexual partners from the last 60 days should be contacted and treated (regard less of whether signs/symptoms are present) as follows:

• Azithromycin 1g PO in a single dose (C3) OR
• Doxycycline 100mg PO BID x 7 days (C3)

 

Level and Quality of Evidence
Level
A	Good evidence (benefit substantially outweighs harm)
B	Fair evidence (benefit outweighs harm)
C	Too close to justify a general recommendation
D	Ineffective (harm outweighs benefit)
I	Insufficient evidence (lacking, poor quality, conflicting)
Quality
I	Evidence from >= 1 RCT
II	Evidence from >= 1 clinical trial without randomization (cohort, case-control, time-series, dramatic results in uncontrolled experiment)
III	Expert opinion

Reporting and Partner Notification

• LGV is not a nationally reportable disease; however, in light of recent cases an enhanced surveillance system was initiated by the Public Health Agency of Canada in partnership with the provinces and territories in February 2005.
  • LGV should be reported by local public health authorities to the appropriate regional and provincial/territorial authorities. The provinces and territories have agreed to report LGV to the Sexual Health and STI Section of the Public Health Agency of Canada at (613) 946-8637 (please see Enhanced Surveillance Protocol and case guide below).

Follow-up

Patients should be followed until chlamydial tests such as culture or NAAT are negative (test of cure). Serology should not be used to monitor treatment response as the duration of antibody response has not been defined.

• Test of cure should be performed at 3 to 4 weeks after the completion of effective treatment to avoid false positive results due to the presence of non-viable organisms (especially if using NAAT).

Sexual partners from the last 60 days should be contacted and treated (see treatment section).

Surgery may be required to repair genital/rectal damage of tertiary LGV.

Consideration for other STI

• Because of rates of co-infection, testing for HIV, syphilis, HSV, gonorrhea, hepatitis B, and hepatitis C is recommended in patients with LGV.
• Testing for chancroid and donovanosis (granuloma inguinale) should also be considered in patients with LGV, especially if there has been travel to regions where these infections are endemic.
• In general, HIV appears to have little effect on the clinical presentation though atypical presentations in HIV+ patients have been rarely reported
  • disease duration may be prolonged in HIV+ patients
• In pregnancy, erythromycin should be used for the treatment of LGV.
• The estolate formulation of erythromycin is contraindicated in pregnancy.
• Immunization for hepatitis B should be offered to non-immune patients.
• The opportunity to provide safer-sex counselling should not be missed.

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