Lymphogranuloma venereum

 

Salient features

·        Lymphogranuloma venereum is a rare sexually transmitted infection caused by Chlamydia trachomatis serovars L 1-3.

·        Endemic in Africa, Southeast Asia, and South and Central America, and rare in developed countries.

·        Outbreaks have occurred among men who have sex with men.

·        Clinically manifests as inguinal and anorectal syndromes, in 3 stages.

·        Hematogenous spread with manifestations of systemic infection.

·        Diagnosis is by identification of organism and by serology or genotyping.

·        Doxycycline or azithromycin (second-line) treatment is curative if given early in the infection course.

 

 

Introduction

 

Lymphogranuloma venereum (LGV) is mainly a disease of lymphatic tissue due to their tropism for the lymphatic system that spreads to tissue surrounding lymphatics. LGV is an acute and chronic sexually transmitted infection caused by one of three serovars (L1, L2 and L3) of the obligate intracellular bacterium Chlamydia trachomatis. These subtypes infect macrophages. L2 is the most common strain involved.

 

Asymptomatic female carriers are probably the primary source of infection. Men present with ulcers or tender inguinal and/or femoral lymphadenopathy that is usually unilateral. Women and male homosexuals might have proctocolitis or inflammatory involvement of perirectal lymphatic tissues that can result in fistulas and strictures.

 

Epidemiology

 

Incidence and prevalence

LGV is contracted by direct contact with infectious secretions, usually through any type of unprotected intercourse, whether oral, vaginal, or anal.

Age/Sex

 

Lymphogranuloma venereum may occur in sexually active adults of all ages. It is more common in men (15 to 40 years). Men are six times more likely than women to manifest clinical infection.

 

Etiology and transmission

·        Causative pathogen: Chlamydia trachomatis serovars L1, L2 and L3. Subvariants have been described such as L2b, currently frequently spreading among MSM.

·        Heterosexual transmission of the strains found in MSM is extremely rare.

·        In contrast to serovars A–K, which remain confined to the mucosa, serovar L strains are invasive and can disseminate via underlying connective tissue and spread to regional lymph nodes.

·        Worldwide, LGV is thought to account for 2–10% of genital ulcerative disease. In many high income countries, LGV is endemic among MSM, mainly those co‐infected with HIV.

·        Transmission has been attributed largely to asymptomatic carriers.

·        Transmission in the MSM population can partially be explained via anogenital contact.

 

Pathogenesis

Caused by specific Chlamydia trachomatis serovars (L1–3), LGV affects mainly the lymphatic tissue in the genitorectal area. The organisms enter the body via microscopic defects in the mucosa or the skin, replicate within macrophages, and find their way to enter the lymphatics, leading to thrombo-lymphangitis, perilymphangitis and infection of lymph nodes. Multiple necrotic foci appear within the lymph nodes. There is an infiltrate of neutrophils and plasma cells. The necrotic areas enlarge and coalesce to form stellate abscesses. Over a period of many weeks to months, the inflammatory process expands and results in periadenitis, involvement of a few neighboring lymph nodes, the development of abscesses (which can rupture), and the formation of fistulas and sinus tract. As the infection subsides, fibrosis replaces acute inflammation with resulting obliteration of lymphatic drainage, chronic edema, and stricture.

The pathological process in the rectum consists of ulceration of the mucosa, formation of granulomatous tissue, cryptitis and crypt abscesses without distortion of crypt architecture. The granulomatous process may affect the bowel wall and the ensuing fibrosis may lead to stricture formation.

 

Local progression and systemic dissemination are both influenced by host immunity. Latent persistence of the microorganism within involved tissues may last for many years.

 

 

Clinical features

 

In MSM, about 25% of the anorectal LGV infections are asymptomatic. Clinical manifestations are protean, depending on the sex of the patient, acquisition mode, and the disease stage. Three clinical stages characterize LGV. Nonspecific cutaneous lesions such as erythema nodosum, erythema multiforme, urticaria, and scarlatiniform exanthema may occur with any of these stages.

 

History

 

Patients present with complaints of genital ulceration, inguinal swelling or rectal discharge and bleeding. Late‐stage disease presents with chronic genital swelling.

 

 

Stages of lymphogranuloma venereum

Stage	Incubation period	Clinical features
Primary	3–30 days	Small papule/pustule/ulcer at the site of inoculation which heals spontaneously with no scarring Hemorrhagic proctitis may occur in those engaging in anal intercourse
Secondary	Days to weeks	Lymphatic involvement of nodes that drain the primary lesion Classic form: tender unilateral or bilateral inguinal and/or femoral adenopathy (‘groove’ sign) If primary infection is in the rectum the deep iliac lymph nodes are affected, but remain unnoticed. This can also occur in women due to drainage of the cervical or upper vaginal area to the perirectal lymph nodes The lymph nodes may coalesce to form a ‘bubo’ or abscesses that may rupture spontaneously with the development of fistulae or sinus tracts There may be systemic features such as malaise and fever
Tertiary	Years after chronic untreated infection	Chronic granulomatous inflammatory process with lymphatic obstruction leading to fistula formation, strictures and disfiguring conditions such as genital elephantiasis and esthiomene, which refers to hypertrophic enlargement with ulceration of the external genitalia

 

Primary stage

 

Three to 30 days after infection, painless erythematous papule (s) or small herpetiform ulcers appear at the site of inoculation. In males, the lesion is usually found on the coronal sulcus, prepuce, or glans penis; and in females on the posterior wall of the vagina, vulva, or, occasionally, the cervix. Inoculation may also be rectal or pharyngeal. The primary lesion is transient, often heals without scarring within a week, and may go unnoticed.

 

Secondary stage

 

The secondary stage occurs on average 2–6 weeks after the primary stage. A few weeks after the primary lesion appears, the infected macrophages drain to the regional lymph nodes and hematogenous dissemination occurs, manifested by variable signs and symptoms, including fever, myalgia, decreased appetite, and vomiting. Photosensitivity may develop in up to 35% of the cases, often 1–2 months after bubo formation. Less commonly, patients may develop meningoencephalitis, hepatosplenomegaly, arthralgia, and iritis. The lymphadenitis episodes often resolve spontaneously in 8–12 weeks. Depending on the mode of transmission, two major syndromes are distinguished.

 

The acute genital syndrome (GS) or inguinal syndrome is characterized by inguinal and/or femoral LN involvement and is the major presentation in men. Initially, the skin overlying the affected LN is erythematous and indurated. Over the subsequent 1–2 weeks, the LN enlarges and coalesces to form a firm and tender, immovable mass (bubo) in the groin. The lymphadenopathy is usually unilateral. Bilateral involvement occurs in one-third of the cases. About one‐third of patients may have the characteristic ‘groove sign’ – a groove‐like depression caused by femoral and inguinal lymph node enlargement above and below the inguinal ligament. The groove sign is considered pathognomonic of LGV. Inguinal buboes may suppurate and rupture spontaneously through the skin; pus may drain through numerous sinus tracts, followed by healing. In women, inguinal /femoral lymphadenitis is unusual because the lymphatic drainage of the vagina and cervix is to the deep pelvic/retroperitoneal LN. When these nodes are enlarged, low abdominal/back pain that exacerbates upon lying supine and pelvic adhesions may ensue.

The acute anorectal syndrome (ArS) is characterized by perirectal nodal involvement, acute hemorrhagic proctitis, and pronounced systemic symptoms. It is the most common presentation in women and in homosexual men who practice anal sex. The major source of rectal spread in women is the internal lymphatic drainage of the lower two-thirds of the vagina. Patients may complain of anal pruritus, bloody rectal discharge, tenesmus, diarrhea, constipation, and lower abdominal pain. Proctoscopic examination reveals multiple discrete and irregular superficial ulcerations and friable granulation tissue, usually confined to the distal 10 cm of the anorectal canal.

 

Tertiary stage

 

This stage is more seen in women with untreated ArS.  C. trachomatis incites a chronic inflammatory response and destruction of tissue in the involved areas including proctitis and proctocolitis. This may occur any number of years after infection. Proctocolitis or inflammatory involvement of perirectal lymphatic tissues may lead to perirectal abscesses and rectal strictures (most common) and abscesses, perineal sinuses, rectovaginal fistulae (leading to “watering can perineum”), and “lymphorrhoids” (perianal haemorrhoid‐like swellings of obstructed rectal lymphatic tissue). The resultant fibrosis leads to lymphatic obstruction and genital lymphedema. Chronic edema (elephantiasis) of the female external genitals is a late manifestation of lymphatic obstruction. The enlargement, thickening, ulceration and fibrosis of the labia are termed esthiomene. Infertility and “frozen pelvis” are potential sequelae of ruptured deep pelvic nodes in women. Late sequelae of the GS are less common and include urethral strictures and elephantiasis of the male genitalia, leading to penile and/or scrotal edema and gross distortion of the penis are called “saxophone penis. ”If left untreated, LGV proctitis can lead to rectal strictures, with subsequent sequelae of soiling, pain, constipation and the possible development of mega colon.

 

Laboratory Tests

LGV should be suspected in any patient with infected sexual contacts, genital ulcer, perianal fistula, or bubo. The organism is difficult to culture. The diagnosis depends mainly on nucleic acid amplification tests and serology. Routine syphilis and HIV serologies are recommended and should be repeated after 3–6 months.    

The diagnosis is confirmed by the detection of Chlamydia-specific DNA in lesional tissue by PCR or other nucleic acid amplification assays. This method is diagnostically more sensitive than is isolation of the organism via tissue culture. PCR testing has performed well on the following specimens:

 

Specimens can be used to diagnose LGV

Samples include: (i) swab of ulcer base, or exudate from primary anogenital lesions; (ii) rectal mucosal specimens (swabs or biopsies, ideally collected from the mucosal lining under proctoscopic vision, but also self‐collected rectal swabs in asymptomatic MSM); (iii) lymph node or bubo aspirates using a 21‐gauge needle after topical disinfection (in suspected cases of inguinal LGV); iv) urethral swab or first‐catch urine specimen when LGV is suspected; and (v) pharyngeal swabs from MSM and women exposed at those sites.

 

The following tests are usually done:

·        The diagnosis of LGV should be confirmed by the detection of serovar‐specific C. trachomatis DNA.

·        For sensitive and specific detection of LGV serovar (L1, L2 and L3, including subvariant)‐specific C. trachomatis DNA, laboratories are currently recommended to use a two‐step procedure:

 

·       A commercially available NAAT is used to detect C. trachomatis DNA/RNA in suspected clinical samples. These tests cannot discriminate between LGV and non‐LGV serovars.

·       If C. trachomatis DNA/RNA is detected, LGV serovar‐specific C. trachomatis DNA should be detected from the same specimen. There are multiplex NAATs for genital ulcerative disease that detect LGV but these have not yet been appropriately evaluated in the context of rectal LGV.  The sensitivities of these NAATs are generally lower than the commercially available C. trachomatis screening NAAT.

 

For clinical management, identification of the LGV serovar should be performed in a timely manner (preferably within 1 week).

 

Chlamydia serology (complement fixation titers >1:64) can support the diagnosis of LGV.

  

Complications

In addition to the complications seen in the tertiary stage, the ulcerative nature of LGV may facilitate the acquisition and transmission of blood-borne pathogens such as HIV and hepatitis C.

 

Prognosis and Clinical Course

Antibiotic treatment, if given early, is curative, with the acute ArS responding more dramatically than the acute GS.

 

 

2019 European guideline on the management of lymphogranuloma venereum

 

Management

·        The prevalence of HIV among MSM with LGV ranges from 67% to 100%. There is a significant association between HIV and LGV. Moreover, hepatitis C is associated with LGV in the current epidemic among MSM.

·        Therefore, tests for other STIs (at a minimum syphilis and gonorrhoea), including HIV (if not already known HIV‐positive), hepatitis B and hepatitis C should be offered before starting therapy.

·        If no LGV diagnostic test is readily available, consider LGV treatment in case of severe proctitis in MSM with a C. trachomatis positive anorectal test result.

 

Information, explanation and advice for the patient

·        Patients should be informed that LGV is a sexually transmitted infection that can invade connective tissue and regional lymph nodes but is curable with antibiotics. Left untreated it can have serious and permanent adverse sequelae. Most of these complications are preventable if treatment is initiated at an early stage.

·        In anorectal disease, symptoms should resolve within 1–2 weeks of commencing antibiotic therapy.

·        In inguinal disease, symptoms might persist for many weeks and follow‐up visits should be implemented.

·        Patients should abstain from any sexual contact until they have completed therapy.

·        Screening for STIs (at a minimum syphilis and gonorrhoea), including HIV (if not already known HIV‐positive), hepatitis B and hepatitis C should be advised during a follow‐up visit 3 months after an LGV diagnosis to cover window periods and exclude reinfections.

 

Therapy

Doxycycline is the first‐line recommended therapy, followed by macrolides. Prolonged courses of antibiotics (at least 3 weeks) are required. There is neither indication nor evidence that HIV co‐infection requires a different therapeutic approach.

Adjunctive therapy

·        Apart from oral antibiotic therapy, fluctuant buboes should be drained via needle aspiration through healthy overlying skin. Repeat visits might be necessary to ensure re‐emerging buboes are drained.

·        Surgical incision of buboes is not recommended due to potential complications such as chronic sinus formation.

·        Patients with residual fibrotic lesions or fistulae do not benefit from further courses of antibiotics.

·        Surgery is often required in late stages and includes rectal stricture dilatation, rectovaginal fistula repair, genital reconstruction, and colostomy.

 

Partner notification and treatment

Partner notification should be initiated when the diagnosis is made. Sexual contacts within the last 3 months should be offered testing from all exposed sites for C. trachomatis /LGV and empiric treatment with doxycycline commenced until C. trachomatis /LGV has been excluded in the partner.

 

Follow‐up

All patients diagnosed with LGV should be followed up at the end of treatment:

·        to ensure treatment compliance, assess side effects, and ensure resolution of symptoms and signs of infection;

·        to check that adequate partner notification has been completed;

·        to address any patient concerns;

·        to arrange suitable follow‐up testing for syphilis, gonorrhoea and blood‐borne viruses including hepatitis B, C and HIV;

 

Prevention/health promotion

Patients diagnosed with LGV should be counselled regarding prevention of other STIs including HIV and hepatitis C:

·        Offer regular sexual health screening including HIV testing.

·        Condom use should be demonstrated and promoted.

·        Offer hepatitis A and B vaccination for MSM.

·        HIV‐negative patients should be advised of the availability of Pre-exposure prophylaxis to prevent HIV infection.

·        In particular, HIV‐positive MSM should be made aware of recent trends in hepatitis C epidemiology and warned of the risks of unprotected anal sex, serosorting, recreational drug use [chemsex] and mucosally traumatic sexual practices such as the use of toys and fisting. Enema use does not seem associated with STI infection. It is prudent to advise against sharing any enema/douching equipment and to wash equipment thoroughly after use. If patients engage in chemsex, associated problems should be addressed and referral to substance use care offered.

 

Notification of LGV cases

According to local, regional and national regulations, it might be required that LGV cases need to be reported to authorities.

 

Auditable outcome measures (target 95% for all)

·        All cases of suspected LGV should be subjected to appropriate laboratory investigations.

·        All patients should be interviewed for the purpose of partner notification and this should be documented in the case notes. Sexual contacts within at least the last 3 months should be traced, tested and treated.

·        In all patients, screening for concomitant STIs should be offered before starting therapy and after 3 months.

·        Suspected or confirmed cases of LGV should be reported and relevant surveillance data collected according to local and national guidelines.

 

Therapeutic ladder

First line

·        Doxycycline 100 mg twice daily orally for 21 days

Second line

·        Erythromycin 500 mg four times daily orally for 21 days

Third line

·        Azithromycin 1 g orally weekly for 3 weeks (although clinical data are lacking it is probably effective based on its chlamydial antimicrobial activity).