Lymphogranuloma Venereum (LGV)

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Background

Lymphogranuloma venereum (LGV) is an uncommon sexually transmitted disease (STD) caused by Chlamydia trachomatis. LGV is endemic in certain areas of Africa, Southeast Asia, India, the Caribbean, and South America. It is rare in industrialized countries, but in the last 10 years has been increasingly recognized in North America, Europe, and the United Kingdom as causing outbreaks of proctitis among men who have sex with men (MSM).[1, 2, 3, 4]

LGV is a subtype of genital ulcer diseases that include other STDs, such as HSV-2, syphilis, and chancroid. This condition is characterized by self-limited genital papules or ulcers followed by painful inguinal and/or femoral lymphadenopathy, which may be the only clinical manifestation at presentation. Patients with LGV may also present with rectal ulcerations and symptoms of proctocolitis, especially among patients participating in receptive anal intercourse. In these cases, rectal pain, discharge, and bleeding may be confused with other GI conditions such as colitis.[5] If left untreated, disfiguring ulceration and enlargement of the external genitalia, and subsequent lymphatic obstruction, may occur. 

Pathophysiology

C trachomatis is an obligate intracellular bacterium. Of the 15 known clinical serotypes, only the L1, L2, and L3 serotypes cause LGV. These serotypes are more virulent and invasive compared to other chlamydial serotypes. Infection occurs after direct contact with the skin or mucous membranes of an infected partner. The organism does not penetrate intact skin. The organism then travels by lymphatics to regional lymph nodes, where it replicates within macrophages and causes systemic disease. While transmission is predominantly sexual, cases of transmission through laboratory accidents, fomites, and nonsexual contact have been reported.

The L2b serovar has been identified to play a more important role than previously expected. After the diagnosis of 92 cases of LGV in the Netherlands among MSM, Schachter evaluated samples obtained from rectal swabs between 1979 and 1985 from patients infected with HIV in San Francisco and between 2000 and 2005 in Amsterdam.[6] The study revealed the same serotype circulating among patients with HIV and LGV 20-25 years ago. This indicates the L2b serovar has been present and unrecognized for many years.

LGV occurs in 3 stages. The first stage, which is often unrecognized, consists of a rapidly healing, painless genital papule or pustule. The second stage, consisting of painful inguinal lymphadenopathy, occurs 2-6 weeks after the primary lesion. The third stage, which is more common in women and MSM, may occur many years after the original infection and is characterized by proctocolitis.

Epidemiology

Frequency

United States

LGV is historically a rare disease in developed countries. Since 2003, however, sporadic outbreaks of LGV proctitis have been reported among MSM in North America, Europe, and Australia.[7, 8] However, in the United States, the true incidence is unknown because national reporting of LGV ended in 1995.

Currently, no universal surveillance data exist for this disease. Twenty four states still mandate reporting of LGV cases to the Center for Disease Control (CDC), which provides limited data for disease prevalance. Since 1972, rates of LGV have steadily declined, with 113 known cases reported to the CDC in 1997. In November 2004, the CDC began offering assistance to test for LGV in the United States. Between November 2004 and January 2006, LGV was identified in 180 specimens, with 27 specimens identified as being obtained from homosexual males.

A study published in 2011 reporting LGV surveillance data from multiple sites in the United States found that less than 1% of the samples obtained from rectal swabs of MSM that were positive for C trachomatis tested positive for LGV.[9]

International

LGV is an uncommon disease, although it may account for 2-10% of patients with genital ulcer disease in selected areas of India and Africa.[10] The disease is most commonly found in areas of the Caribbean, Central America, Southeast Asia, and Africa. Since 2003, however, the emergence of documented LGV infections, mostly among MSM, but also in women, has prompted increased surveillance and reporting of this disease in developed countries.[11, 12] Proctitis is reemerging as a presentation of LGV in developing countries.[13]

After a cluster of 92 cases was identified in the Netherlands between 2003 and 2004 (where fewer than 5 cases were reported yearly),[14] many countries have begun active surveillance for LGV, and an increasing number of cases has been identified. Evidence exists that among MSM, LGV may be endemic in the UK; between 2004-2008, LGV was documented in 854 isolates by the National Reference Center there.[15, 16, 17, 18, 19, 20, 21]

Mortality/Morbidity

With appropriate treatment, the disease is easily eradicated. Death is a rare complication but could possibly result from a small bowel obstruction or perforation secondary to rectal scarring.

Morbidity is common, especially during the third stage of the disease, and includes such conditions as proctocolitis, perirectal fissures, abscesses, strictures, and rectal stenosis. A chronic inflammatory response may lead to hyperplasia of the intestinal and perirectal lymphatics, causing lymphorrhoids, which are similar to hemorrhoids. Strictures and fistulous tracts may lead to chronic lymphatic obstruction, resulting in elephantiasis, thickening or fibrosis of the labia, and edema or gross distortion of the penis and scrotum. Reports show an association between adenocarcinoma (primarily rectal adenocarcinoma) and chronic untreated LGV.

Race

In North America and Europe, most reported cases of LGV have been identified among white males infected with HIV who acquired the condition after having sex with other men after travel or living in endemic areas, and typically after having multiple anonymous sexual contacts.

Sex

LGV is an STD and probably affects both sexes equally, although it is more commonly reported in men. This predilection may be because early manifestations of LGV are more apparent in men and are thus diagnosed more readily. Men typically present with the acute form of the disease, whereas women often present later, after developing complications from late disease.

Most cases in Europe and North America have been identified among white, frequently HIV-positive MSM patients presenting with proctitis.[20, 22, 23, 24]

Age

LGV may affect any age but has a peak incidence in the sexually active population aged 15-40 years.

Prognosis

With prompt and appropriate antibiotic therapy, the prognosis is excellent and patients typically make a full recovery.

Patients must be informed that reinfection and relapses may occur.

Patient Education

Inform patients how to avoid high-risk sexual activities by using condoms and avoiding sexual intercourse with high-risk sexual partners.

For excellent patient education resources, visit eMedicineHealth's Sexual Health Center. Also, see eMedicineHealth's patient education articles Sexually Transmitted Diseases and Chlamydia.

History

The clinical course of LGV consists of the following stages.

First stage (primary LGV)

This stage occurs 3-30 days after inoculation.

Primary LGV begins as a small, painless papule or pustule that may erode to form a small, asymptomatic herpetiform ulcer that usually heals rapidly without scarring.

The most common sites of infection for men include the coronal sulcus, prepuce, glans, and scrotum. Rarely, symptoms of urethritis occur.

The most common sites of infection in women include the posterior vaginal wall, posterior cervix, fourchette, and vulva.

The initial lesion, especially in women, often goes unnoticed by the patient.

Second stage (secondary LGV)

Secondary LGV begins 2-6 weeks after the primary lesion.

This second stage consists of painful regional lymphadenopathy (usually in the inguinal and/or femoral lymph nodes).

Painful, swollen lymph nodes coalesce to form buboes, which may rupture in as many as one third of patients. Those that do not rupture harden, then slowly resolve.

Inguinal lymphadenopathy occurs in only 20-30% 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.

This stage is when most men present and are diagnosed; most women are not diagnosed in this stage because of their lack of inguinal lymphadenopathy.

Constitutional symptoms associated with the second stage include fever, chills, myalgias, and malaise.

Systemic spread may lead to the following conditions:

Third stage (tertiary LGV)

Tertiary LGV is termed genitoanorectal syndrome.

This condition is more common in women, secondary to their lack of symptoms during the first two stages.

Rectal involvement is more common in men who have sex with men (MSM) and in women who practice anal-receptive intercourse.

Tertiary LGV is characterized by proctocolitis. Although infectious proctitis is more commonly associated with inflammatory bowel disease, sexually transmitted diseases (STDs) must be considered in the work-up of this diagnosis, especially in MSM. In this patient population, the incidence of infectious proctitis attributed to STDs is on the rise.

FUO

Symptoms include the following conditions:

Physical

Large fluctuant buboes or any otherwise unexplained perianal deformity in a young female should suggest a diagnosis of LGV.

First stage (primary LGV)

The initial lesion is usually a small, painless papule, shallow ulcer, or herpetiform lesion in the genital area, which may go unnoticed in the urethra, vagina, or rectum.

Initial lesions may be differentiated from the more common herpetic lesions by the lack of pain associated with the lesion. Differentiation from a syphilitic chancre is more problematic and requires serologic testing.

Second stage (secondary LGV)

Secondary LGV is characterized by painful lymph nodes (usually unilateral) known as buboes.

Enlargement of the inguinal nodes above and the femoral nodes below the inguinal ligament leads to the classic groove sign, which is observed in one third of affected men.

Inguinal lymphadenopathy results from a primary lesion of the anterior vulva, penis, or urethra.

Perirectal or pelvic lymphadenopathy results from a primary lesion involving the posterior vulva, vagina, or anus.

Affected nodes often coalesce and form abscesses, which can rupture and form sinus tracts.

Third stage (tertiary LGV)

Tertiary LGV most often manifests in women.

Patients initially develop proctocolitis.

Patients may present with perirectal fistulas, ulcers, abscesses, strictures, and rectal stenosis.

Hyperplasia of intestinal and perirectal lymphatics may form lymphorrhoids, which are similar to hemorrhoids.

Patients may develop strictures and fistulous tracts secondary to repeated tissue scarring and repair.

Enlargement, thickening, and fibrosis of the labia may occur in women, a condition termed esthiomene.

Chronic lymphatic obstruction may lead to elephantiasis of the genitals.

Penile and scrotal edema and distortion have been termed saxophone penis.

Causes

The L1, L2, and L3 serovars of C trachomatis cause LGV. Risk factors include residing in or visiting endemic areas, practicing anal-receptive intercourse, eschewing condoms, and working in the commercial sex trade.

Complications

Bubo rupture may lead to fistulas and sinus tracts. This complication typically occurs during the first stage (primary LGV) of infection.

Proctocolitis may lead to fissures, fistulas, abscess, scarring, and strictures.

Laboratory Studies

Laboratory diagnosis ultimately depends on detecting C trachomatis– specific DNA, followed by genotyping to identify serovars L1, L2, or L3 found in LGV.

Diagnosis is based primarily on clinical findings, with increasing evidence supporting the use of nucleic acid amplification tests (NAATs) for confirmation. Serologic testing is problematic because of the difficulty in culturing the organism and cross-reactivity of the many different serotypes.

Needle aspiration of an involved bubo is the best method to obtain tissue for culture.

Culture of C trachomatis, while definitive diagnostically, is technically demanding and expensive and yields an isolate only 30% of the time.

Because of its systemic nature, the disease produces a strong immunologic response that is readily evident on complement fixation testing.

Cross-reactivity between various chlamydial infections occurs on complement fixation testing.

Chlamydial urethritis, cervicitis, or conjunctivitis rarely produces titers greater than 1:16. LGV titers are usually more than 1:1024.

A complement fixation titer greater than 1:64, when coupled with the appropriate clinical scenario, is considered diagnostic of LGV.

Immunofluorescent testing with monoclonal antibodies and polymerase chain reaction (PCR) testing are also reported to be effective; however, these tests are not widely available for commercial use.[25]

NAATs have shown significant promise in revealing the presence of Chlamydia. Several commercially available NAATS used to identify the presence of Chlamydia in urine demonstrated an increased sensitivity and specificity that ranged from 96-100% and 99.1-100%, respectively.[26] These assays are cleared for use by the US Food and Drug Administration (FDA) with cervical swabs, male urethral swabs, and urine specimens.

Procedures

Needle aspiration of involved buboes may be performed to ease discomfort or to obtain tissue for culture.

Histologic Findings

Histologic findings of lymph node biopsies performed in the second and third stages of the disease typically reveal stellate abscesses.

Medical Care

The complete treatment of patients with LGV includes appropriate antimicrobial coverage and drainage of infected buboes.

The recommended medical treatment for LGV involves one of the following antibiotic regimens:

Doxycycline is the drug of choice in patients who are not pregnant. Pregnant and lactating females should be treated with erythromycin. HIV-positive patients should be treated the same as HIV-negative patients, although they may require prolonged treatment, with longer resolution of symptoms.

Infected patients should abstain from sexual intercourse until antibiotic therapy is completed and symptoms resolve.

Sex partners who have had contact with the patient within the past 60 days should be evaluated and treated if symptomatic. If no symptoms are present, they should be treated for exposure as follows:

Surgical Care

Needle aspiration or incision and drainage of involved inguinal nodes may be required for pain relief and prevention of ulcer formation. Some of the late complications of the third stage of LGV may require surgical repair.

Consultations

Surgical consultation for lymphadenopathy is generally not required unless extensive buboes require further exploration. For tertiary disease, appropriate surgical consultation is indicated.

Activity

No restrictions to physical activities are required; however, patients should abstain from sexual contact until the infection resolves completely.

Prevention

No vaccine is available to prevent LGV.

Condom use may reduce the risk of LGV transmission but does not prevent transmission from ulcerated areas not covered by the condom.

The emergence of cases of LGV among MSM in developed countries supports the need for careful screening of these patients. High rates of asymptomatic rectal chlamydia infection found in the MSM attending HIV/GUM clinics in UK should prompt the clinician to routinely screen for rectal chlamydia in MSM, even in the absence of symptoms. This aids in the diagnosis of a subset of patients with LGV before symptoms are present. Treatment of this group of patients is essential in the attempt to eradicate the disease.[28]

Patients, especially those traveling to endemic areas, should be counseled about safe-sex practices, including condom use. Advise the patient to refrain from intercourse with high-risk individuals.

Inform patients that recovery from infection does not confer immunity against future infection.

Further Outpatient Care

For patients who have had incision and drainage of buboes, appropriate outpatient follow-up care may be required to ensure complete healing and to prevent secondary infections.

WHO Guidelines on the Treatment of Lymphogranuloma Venereum

WHO recommendations for the treatment of lymphogranuloma venereum (LGV) are as follows:[29]

Medication Summary

The goal of therapy is to eradicate the organism.

Doxycycline (Bio-Tab, Doxy, Doryx, Vibramycin, Vibra-Tabs)

Clinical Context:  Inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Erythromycin (E.E.S., E-Mycin, Eryc, Ery-Tab, Erythrocin)

Clinical Context:  Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest. For treatment of staphylococcal and streptococcal infections. In children, age, weight, and severity of infection determine proper dosage. When bid dosing is desired, half of the total daily dose may be taken q12h. For more severe infections, double the dose.

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Totally eradicate the causative organism or organisms.

What is lymphogranuloma venereum (LGV)?What is the pathophysiology of lymphogranuloma venereum (LGV)?What is the prevalence of lymphogranuloma venereum (LGV) in the US?What is the global prevalence of lymphogranuloma venereum (LGV)?What is the mortality and morbidity associated with lymphogranuloma venereum (LGV)?What are the racial predilections of lymphogranuloma venereum (LGV)?What are the sexual predilections of lymphogranuloma venereum (LGV)?Which age groups have the highest prevalence of lymphogranuloma venereum (LGV)?What is the prognosis of lymphogranuloma venereum (LGV)?What is included in patient education about lymphogranuloma venereum (LGV)?Which clinical history findings are characteristic of primary lymphogranuloma venereum (LGV)?Which clinical history findings are characteristic of secondary lymphogranuloma venereum (LGV)?What conditions are associated with systemic spread of lymphogranuloma venereum (LGV)?Which clinical history findings are characteristic of tertiary lymphogranuloma venereum (LGV)?What are the signs and symptoms of tertiary lymphogranuloma venereum (LGV)?Which physical findings are characteristic of lymphogranuloma venereum (LGV)?Which physical findings are characteristic of primary lymphogranuloma venereum (LGV)?Which physical findings are characteristic of secondary lymphogranuloma venereum (LGV)?Which physical findings are characteristic of tertiary lymphogranuloma venereum (LGV)?What causes lymphogranuloma venereum (LGV)?What are the possible complications of lymphogranuloma venereum (LGV)?What are the differential diagnoses for Lymphogranuloma Venereum (LGV)?What is the role of lab testing in the diagnosis of lymphogranuloma venereum (LGV)?What is the role of needle aspiration in the workup of lymphogranuloma venereum (LGV)?Which histologic findings are characteristic of lymphogranuloma venereum (LGV)?How is lymphogranuloma venereum (LGV) treated?What is the role of doxycycline in the treatment of lymphogranuloma venereum (LGV)?What treatment should sex partners of patients with lymphogranuloma venereum (LGV) undergo?What is the role of surgery in the treatment of lymphogranuloma venereum (LGV)?Which specialist consultations are beneficial to patients with lymphogranuloma venereum (LGV)?Which activity modifications are used in the treatment of lymphogranuloma venereum (LGV)?How is lymphogranuloma venereum (LGV) prevented?What is included in long-term monitoring of lymphogranuloma venereum (LGV)?What are the WHO recommendations for the treatment of lymphogranuloma venereum (LGV)?What is the goal of therapy for lymphogranuloma venereum (LGV)?Which medications in the drug class Antibiotics are used in the treatment of Lymphogranuloma Venereum (LGV)?

Author

Pamela Arsove, MD, FACEP, Associate Residency Director, Department of Emergency Medicine, Hofstra Northshore Long Island Jewish School of Medicine; Attending Physician, Department of Emergency Medicine, Long Island Jewish Medical Center; Assistant Professor, Department of Emergency Medicine, Northshore Long Island Jewish School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Barbara Edwards, MD, Associate Physician, Division of Infectious Diseases, Department of Medicine, Long Island Jewish Medical Center; Assistant Professor, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Charles V Sanders, MD, Edgar Hull Professor and Chairman, Department of Internal Medicine, Professor of Microbiology, Immunology and Parasitology, Louisiana State University School of Medicine at New Orleans; Medical Director, Medicine Hospital Center, Charity Hospital and Medical Center of Louisiana at New Orleans; Consulting Staff, Ochsner Medical Center

Disclosure: Received royalty from Baxter International for other.

Chief Editor

Pranatharthi Haran Chandrasekar, MBBS, MD, Professor, Chief of Infectious Disease, Department of Internal Medicine, Wayne State University School of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Kenneth C Earhart, MD Deputy Head, Disease Surveillance Program, United States Naval Medical Research Unit #3

Kenneth C Earhart, MD is a member of the following medical societies: American College of Physicians, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, and Undersea and Hyperbaric Medical Society

Disclosure: Nothing to disclose.

Alexandre F Migala, DO Staff Physician, Department of Emergency Medicine, Denton Regional Medical Center

Disclosure: Nothing to disclose.

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