Dermatology

Lymphogranuloma venerum

Are You Confident of the Diagnosis?

What you should be alert for in the history

Lymphogranuloma venerum (LGV) should be suspected in any person with genital ulcerations or painful unilateral inguinal lymphadenopathy, especially in tropical and subtropical areas of the world. In developed countries, it rarely causes disease, but in endemic areas and in the cases of outbreaks, clinicians should be aware of the disease, and especially of atypical presentations, such as proctitis. Classic findings on physical examination should prompt consideration even in less common geographic regions.

Characteristic findings on physical examination

--Primary LGV

Incubation is 3 to 12 days. Primary LGV begins as a small, painless papule or pustule. It may erode to form a small, painless papule, ulcer, or herpetiform lesion that usually heals rapidly without scarring. The most common sites of infection for men include the coronal sulcus, prepuce, glans, and scrotum. Urethritis is an uncommon manifestation.

Lesions are often missed in women but common sites of infection include the posterior vaginal wall, posterior cervix, fourchette, and vulva.

--Secondary LGV

Secondary LGV begins 2 to 6 weeks after presentation of the primary lesion. Localized spread of infection causes painful regional lymphadenopathy (usually in the inguinal and/or femoral lymph nodes). This manifestation is more common in men. These lymph nodes can then coalesce to form buboes, which will spontaneously resolve in two-thirds of patients but may rupture in one third of patients.

Systemic spread has been reported to cause the following conditions:

Arthritis

Ocular inflammatory disease

Cardiac involvement

Pulmonary involvement

Aseptic meningitis

Hepatitis or perihepatitis

--Tertiary LGV

Expected results of diagnostic studies

Diagnosis confirmation

Chancroid similarly can present with inguinal lymphadenopathy and buboes (albeit usually with painful ulcerations) and should be included in the differential. Geographic and demographic predilections overlap among the two diagnoses. Syphilis can also mimic LGV lesions and can be difficult to differentiate, requiring serologic testing. Herpes simplex can usually be excluded by the lack of pain at the site of ulceration. Granuloma inguinale is also a consideration. Colitis needs to be ruled out in patients with predominantly proctitis.

LGV is a difficult diagnosis to establish on purely clinical grounds but, from a practical standpoint, the diagnosis usually rests predominantly on clinical findings. Definitive confirmation requires laboratory testing in the form of nucleic acid amplification, serologic testing or culture. However, few centers have the capability of adequately testing samples. In the United States, the CDC developed a nucleic acid amplification test that identifies the L-serovar strains.

Serologic testing has historically been of low yield, cannot differentiate present and past infections, and is not serovar-specific. More recently in 2006, the Centers for Disease Control and Prevention (CDC) developed a very accurate polymerase chain reaction (PCR) assay.

Several commercially available nucleic acid amplification tests used to identify the presence of Chlamydia in urine demonstrated an increased sensitivity and specificity that ranged from 96% to 100% and 99.1% to 100%, respectively. Although culture of lymph node aspirate is the gold standard, it yields a diagnosis only 30% of the time and is technically demanding.

Tertiary LGV is also known as genitoanorectal syndrome and is characterized by proctocolitis, perirectal fissures, strictures, abscesses, and rectal stenosis. Symptoms include bloody purulent discharge, rectal pain, and tenesmus. This panoply of symptoms can be misdiagnosed as an infectious or inflammatory colitis.

Hyperplasia of the intestinal and perirectal lymphatics as a result of chronic inflammation can result in lymphatic obstruction, causing genital edema or distortion as well as lymphorroids, which resemble hemorrhoids.

Enlargement, thickening, and fibrosis of the labia may occur in women, a condition termed esthiomene. Chronic lymphatic obstruction may lead to genital elephantiasis. This condition is more common in women because of late diagnosis and in patients practicing receptive anal intercourse. Penile and scrotal edema is known as saxophone penis.

There is a possible association between chronic untreated LGV and development of rectal adenocarcinoma.

Inguinal lymphadenopathy occurs in only 20% to 30% of females with LGV; they more typically have involvement of the deep iliac or perirectal nodes and may only present with nonspecific back and/or abdominal pain.

Some patients may experience constitutional symptoms (fever, chills, myalgias, and malaise). An anorectal syndrome with rectal ulcerations and proctitis can occur in patients having receptive anal intercourse. In these cases, disease can mimic an infectious or inflammatory colitis.

Who is at Risk for Developing this Disease?

The disease is more common in developing countries and in tropical and subtropical locales. Even in these areas, LGV is a less common cause of genital ulcerations. In a study of patients with genital ulcerations from Madagascar, chlamydial antibodies were noted in 79% but LGV was confirmed by PCR in only 8%.

HIV positivity is the strongest risk factor associated with infection. It should also be considered in men who have sex with men (MSM). There have been several large outbreaks of LGV in New York City, Australia, the Netherlands, and in the United Kingdom. In developed countries, the disease is thought to be rare. However, definitive quantification has been difficult since there is no standardized definition or testing protocol. Other risk factors include traveling to endemic areas, anal intercourse, recurrent ulcerations, and prior sexually transmitted infections (STIs).

LGV probably occurs in both sexes with equal incidence but is more commonly reported in males. This discrepency is likely explained by the earlier manifestations of disease in men and earlier treatment. Women tend to present later in the disease course and have more complications.

What is the Cause of the Disease?

LGV is caused by Chlamydia trachomatis erotypes L1, L2, and L3 and is transmitted by direct mucosal contact with an infected individual. Transmission is usually sexual, but some cases of nonsexual transmission via fomites have occurred. All chlamydial strains attach to the epithelium via heparan sulfate receptors.

In contrast to the other serovars, which cause only mucosal inflammation, the L serovars become invasive and affect the lymphatics. They proliferate and extend directly from the primary site of infection to the lymphatic circulation. It multiplies in macrophages in regional lymph nodes, causing enlarged lymph nodes, buboes, and resultant obstruction. Regional necrosis and abscesses may form as the disease progresses.

Systemic Implications and Complications

Proctitis is a common manifestation noted in the outbreaks in NYC and the UK mentioned above. Tertiary disease leading to disfigurement and consequences of systemic spread were discussed above. Adenocarcinoma of the rectum is a rare complication.

Treatment Options

- Doxycycline 100mg orally twice a day for 21 days

- Erythromycin base 500mg orally 4 times daily (if pregnant) for 21 days

- Azithromycin 1g orally once weekly for 3 weeks (if pregnant). Clinical data is lacking but this is believed to be effective based on efficacy against Chlamydia.

- Treatment for proctocolitis: Doxycycline 100mg orally twice a day for 21 days plus ceftriaxone 125mg intramuscularly once

- Treatment for sexual partners who have had contact within 60 days: Doxycycline 100mg orally twice a day for 7 days or azithromycin 1g orally once

- Surgical: Buboes may require aspiration or incision and drainage to prevent rupture and development of sinus tracts or for tissue for diagnosis.

Optimal Therapeutic Approach for this Disease

Complete treatment must encompass antibiotics and drainage of buboes if necessary. Doxycycline is the preferred antibiotic. However, if the patient is pregnant or cannot tolerate doxycycline, azithromycin is the second-line agent. It is known to be highly effective against Chlamydia. This antibiotic has not been clinically confirmed to be curative given the paucity of cases, but it is believed to be effective. Incision and drainage can usually be performed. Tertiary disease may require surgical intervention.

Patient Management

All patients should be counseled on safe sexual practices and should be screened for other STIs and hepatitis. Patients should abstain from all sexual contact until infection resolves. Sexual contacts should be informed that they will need to seek evaluation for the disease. This is currently not a reportable condition to the CDC.

Unusual Clinical Scenarios to Consider in Patient Management

All individuals with sexual contact with known symptomatic LGV patients within 60 days should be evaluated, tested for chlaymdial antibodies, and treated with standard Chlamydia treatment (azithromycin 1g orally once or doxycycline 100mg orally twice daily for 7 days). Patients with LGV should be concurrently tested for other STIs (HIV, syphilis, gonorrhea, herpes simplex virus). One should also consider testing for hepatitis B and C given high rates of coinfection in MSM.

Figure 1.

Saxophone penis (Coutesy of Sanjeev Vaishampayan, Indian J Dermatol Venereol Leprol 2008;74:270)

What is the Evidence?

(Older article but excellent descriptions of dermatologic manifestations of all STDs and includes photos of inguinal adenopathy in LGV along with pictures of other STDs.)

Blank, S, Schillinger, JA, Harbatkin, D. "Lymphogranuloma venereum in industrialised countries". Lancet.. vol. 365. 2005. pp. 1607-8.

(Brief overview of LGV in a developed setting but also includes a good discussion of microbiologic diagnosis and serovars.)

Schachter, J, Moncada, J, Liska, S, Shayevich, C, Klausner, JD. "Nucleic acid amplification tests in the diagnosis of chlamydial and gonococcal infections of the oropharynx and rectum in men who have sex with men". Sex Trans Dis. vol. 35. 2008. pp. 637.

(Discussion of laboratory methods of diagnosis and the newer methods of detection.)

Hampton, T. "Lymphogranuloma venereum targeted: those at risk identified, diagnostic test developed". JAMA. vol. 295. 2006. pp. 2592.

(Discussion of microbiologic diagnosis.)

Behets, FM, Andriamiadana, J, Randrianasolo, D, Randriamanga, R, Rasamilalao, D, Chen, CY. "Chancroid, primary syphilis, genital herpes, and lymphogranuloma venereum in Antananarivo, Madagascar". J Infect Dis. vol. 180. 1999. pp. 1382-5.

(An example of one of the LGV outbreaks in a less developed region.)

Nieuwenhuis, RF, Ossewaarde, JM, Götz, HM, Dees, J, Thio, HB, Thomeer, MG. "Resurgence of lymphogranuloma venereum in Western Europe: An outbreak of Chlamydia trachomatis serovar L2 proctitis in the Netherlands among men who have sex with men". Clin Infect Dis. vol. 39. 2004. pp. 996-1003.

(An example of LGV outbreaks in industrialized countries. Brief overview of LGV in a developed setting but also includes a good discussion of microbiologic diagnosis and serovars)

Mabey, D, Peeling, RW. "Lymphogranuloma venereum". Sex Trans Infect. vol. 78. 2002. pp. 90.

(Covers pathophysiology.)

McLean, CA, Stoner, BP, Workowski, KA. "Treatment of lymphogranuloma venereum". Clin Infect Dis. vol. 44. 2007. pp. S147-52.

(A review of the literature on LGV from 1998-2004, conducted as part of the development of the 2006 STD guidelines from the CDC. Now, STD treatment guidelines from 2010 are available on the CDC website.)

"National guideline for the management of lymphogranuloma venereum". Sex Trans Dis. vol. 75. 1999. pp. S40.

(Guideline for treatment of LGV.)

Swink, RL. "Lymphogranuloma venereum associated with squamous cell carcinoma". Southern Med J. vol. 42. 1949. pp. 217-220.

(Excellent descriptions of clinical manifestations of LGV.)
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