62. Genital ulcer adenopathy syndrome Allan Ronald The control and prevention of genital ulcer disease (GUD) is an important public health priority. Ulcerative lesions may produce significant genital pain, some pathogens are transmitted during birth from mothers to their infants, and genital lesions increase the risk of human immunodeficiency virus (HIV) acquisition and transmission during sexual intercourse. Table 62.1 lists the infectious and noninfectious etiologies that may produce genital ulcerations with or without adenopathy. The most commonly transmitted GUD diagnosis and etiologies are syphilis (Treponema pallidum), herpes simplex (HSV-1 and-2), chancroid (Haemophilus ducreyi), lymphogranuloma venereum (LGV), L1, L2, and L3 serovars of Chlamydia trachomatis; and granuloma inguinale or donovanosis (Calymmatobacterium granulomatis). Trauma, erosive balanitis, and fixed drug eruptions are the most common nontransmissible causes of GUD. Neoplasia, fungi, and mycobacteria, if suspected, should be excluded by biopsy. Because of the limitations of diagnostic tests, a specific etiology is obtained in only 50% to 80% of patients. Major geographic variation exists in the etiology and prevalence of GUD (Table 62.2). In Europe and North America, fewer than 5% of patients who present to sexually transmitted disease (STD) clinics, have a genital ulcer compared with 20% to 30% of patients presenting to similar clinics in Africa and Asia. Herpes simplex virus (HSV) is the most common cause of genital ulcerations in Europe and North America, whereas chancroid has been the common cause elsewhere. However, herpetic ulcers are now more common, particularly in patients coinfected with HIV, whereas chancroid is unusual.. LGV is endemic in some areas of the tropics and has reappeared as an epidemic among men in developed countries who have sex with men, many of whom are HIV positive. Donovanosis was endemic in New Guinea, India, and Southern Africa but is now rare. Syphilis remains endemic and has become more common with clusters among men who have sex with men. Males who are circumcised have a reduced probability of acquiring chancroid, herpes or syphilis following heterosexual intercourse. Table 62.1 Etiologies of genital ulcer disease Infectious Bacterial Haemophilus ducreyi (chancroid) Treponema pallidum (syphilis) Chlamydia trachomatis (lymphogranuloma venereum) Calymmatobacterium granulomatis (donovanosis) Balanitis (often polymicrobial but Candida albicans is often present) Viral Herpes simplex Varicella zostera Epstein–Barr virus Cytomegalovirusa Parasitic Sarcoptes scabieia Phthirus pubisa Entamoeba histolyticaa Trichomonas vaginalisa Noninfectious Trauma Fixed drug eruptions Pyoderma gangrenosuma Behçet’s diseasea Reiter’s syndromea Wegener’s granulomatosisa Neoplasmsa Unknown a Unusual. Table 62.2 Geographic variation in the prevalence of genital ulcer diseases Southeast Asia/India Africa North America/ Europe Chancroid +/– +/– +/– Syphilis +++ +++ ++ Genital herpes ++++ ++++ ++++ Lymphogranuloma venereum + + + Donovanosis +/– +/– +/– Table 62.3 Clinical characteristics of genital ulcer adenopathy syndromes Syphilis Herpes simplex virus Chancroid Lymphogranuloma venereum Donovanosis Incubation period 9–90 d 2–7 d 1–14 d 7–21 d 8–80 d Primary lesion Papule Vesicle Papule or pustule Papule, pustule, or vesicle Papule Number of lesions Usually solitary Multiple Multiple Usually solitary Variable Classical ulcer characteristics Size (mm) 5–15 1–10 2–20 2–10 Variable Margins Well demarcated Elevated Round or oval Erythematous Ragged, irregular Undetermined Elevated Round or oval Variable Elevated, irregular Depth Superficial or deep Superficial Excavated Superficial or deep Elevated Base Red, smooth, nonpurulent Red, smooth, serous discharge Purulent exudate Variable “Beefy” red, rough Induration ++ – – – ++ Pain – ++ ++ ± – Lymphadenopathy ++B ++B ++U ++U – P Characteristics of lymphadenopathy Consistency Firm Firm Fluctuant Fluctuant – Tenderness – ++ ++ ++ – B Bilateral;U unilateral;P pseudolymphadenopathy. CLINICAL PRESENTATIONS Clinical features of GUD are listed in Table 62.3. The incubation period is usually less than 1 week for genital herpes and chancroid, 1 to 3 weeks for LGV, and 2 to 6 weeks for syphilis and donovanosis. Depending on the etiology, the initial lesion can be a papule, pustule, or vesicle which erodes to form an ulcer. In men the ulcers are often located on the coronal sulcus but may also be found on the glans, prepuce, and shaft of the penis or less often on the scrotum or surrounding skin. Herpes and chancroid have a predilection for involving the frenulum. In women, the ulcers may occur on the labia, in the vagina, on the cervix, on the fourchette, or on the perianal area. Perianal and intrarectal ulcers are common among men who have sex with men. Genital herpes HSV-1 is transmitted primarily by oral contact and in the developing world, the initial infection occurs in infancy and genital HSV-1 infections are uncommon. However, in the developed world most adolescents have not acquired HSV-1, and this virus is frequently transmitted sexually particularly with oral–genital sex. In all societies, HSV-2 is almost always transmitted by sex. Genital herpes due to both viruses presents as multiple, small vesicles that rapidly become superficial ulcers with erythematous margins. Urethral, gynecologic or cutaneous symptoms may predominate depending on the site of vesicles. Systemic symptoms of fever, myalgias, and headache can occur with an initial infection. A prodrome of paresthesias 12 to 48 hours before the appearance of vesicles is often reported with recurrences. Painful lymphadenopathy can be present. Following the initial infection, both HSV-1 and HSV-2 remain latent in the sensory ganglion but recur unpredictably. Recurrences are usually less severe. However, they tend to be severe and persistent in HIV-infected individuals and large, painful, often single, ulcers are common, particularly in the perianal area. Figure 62.1 Chancroid; note penile lesion (green arrow) and inguinal adenopathy (red arrow). (Public Health Image Library; content provider CDC/Susan Lindsley.) Syphilis The ulcer of primary syphilis is classically solitary, painless or minimally tender with elevated, well-demarcated margins and an indurated non-purulent base. Multiple ulcers are common in women. Lymphadenopathy, if present, is usually bilateral with firm, nontender nodes. Secondary syphilis can have many cutaneous features, including condyloma and superficial ulcers and these frequently occur in the genital area. Chancroid Chancroid typically produces painful, excavated ulcers with irregular, undetermined margins and a purulent base (Figure 62.1). The ulcers can be superficial and may resemble herpetic ulcers. Approximately 50% of the patients will develop painful inguinal lymphadenopathy, which can be unilateral. Lymph nodes may become fluctuant (buboes) and rupture. Untreated ulcers or buboes may persist for months. Lymphogranuloma venereum The ulcer of LGV is transient, usually superficial and painless. It precedes the development of inguinal lymphadenopathy by 7 to 30 days and fewer than a third of the patients recall having had an ulcer. The lymph nodes are tender and may become fluctuant with eventual rupture and formation of draining sinuses. A “groove” sign may be present if nodes above and below Poupart’s ligament are involved. Women and homosexual men may have involvement of perianal and perirectal tissues and present with proctitis. Complications of untreated infection include genital elephantiasis, rectal strictures, and perianal fistulas. Other manifestations include meningoencephalitis, hepatitis, erythema nodosum, and erythema multiforme. Donovanosis Patients present with a slowly progressive painless ulceration of the genital area characterized by heaped-up granulomatous tissue. Local extension, healing, and fibrosis may occur simultaneously. Lymphadenopathy is unusual, but “pseudobuboes” caused by subcutaneous extension of the granulomatous process into the inguinal area are common. Systemic spread with involvement of liver, thorax, and bones has been reported but is rare. LABORATORY DIAGNOSIS OF GUD Clinical diagnosis of GUD is imprecise because of overlap between the clinical syndromes, the presence of mixed infections, and atypical presentations. Because of these limitations, the diagnosis must be confirmed whenever possible using the relevant laboratory tests (Table 62.4). Specimens should be collected for H. ducreyi, C. trachomatis, and herpes simplex cultures and, if available, DNA identification with polymerase chain reaction (PCR). If possible, a dark-field examination should be performed in all patients presenting with GUD unless classical vesical lesions in clusters provide definite evidence of herpes genitalis. The ulcer base is washed with saline, dried with a cotton gauze, and squeezed between the thumb and forefinger until an exudate appears. This can be collected directly onto a coverslip for dark-field microscopy. Vesicles and pustules should be aspirated with a fine-gauge needle or de-roofed and swabbed for viral culture. Fluctuant lymph nodes should be aspirated for H. ducreyi and C. trachomatis culture. Both Treponema pallidum particle agglutination (TPPA) and non-treponemal rapid plasma reagin (RPR), serologic tests should be obtained in all patients with GUD to exclude syphilis. LGV diagnosis is confirmed by PCR or by rising antibody titers or a single titer of 1:64 by complement fixation or 1:512 by microimmunofluorescence. Table 62.4 Recommended tests for diagnosing genital ulcer diseases Recommended tests Other tests Chancroid Culture Gram stain/PCR Syphilis Dark-field examination PCR Direct fluorescent antibody test Serology (e.g., RPR/VDRL, FTA- ABS, MHA-TP) Genital herpes Viral culture Antigen detection (ELISA), PCR, Serology Lymphogranuloma venereum PCR Chlamydia culture Serology (complement fixation, microimmunofluorescence) Donovanosis Giemsa or Wright stains of tissue smears Histopathology Abbreviations: PCR = polymerase chain reaction; RPR = rapid plasma reagin; VDRL = Venereal Disease Research Laboratories; FTA-ABS = fluorescent treponemal antibody absorption; MHA-TP = microhemagglutination test for Treponema pallidum; ELISA = enzyme-linked immunosorbent assay. APPROACH TO THE PATIENT WITH GUD An algorithm for investigating a patient with genital ulceration is given in Figure 62.2. The history is crucial. Information should be collected about sexual risks, demographics, medication, and travel. Risk factors such as sex work or recent prostitute contact are associated with syphilis and chancroid. Travel may suggest the diagnosis of an otherwise uncommon diagnosis such as donovanosis. Self-medication with topical or systemic antibiotics may lead to a false-negative dark-field examination. TREATMENT The drug regimens currently recommended for treating GUD are given in Table 62.5. Treatment traditionally has been initiated only once a laboratory diagnosis has been established; however, the delay inherent in obtaining laboratory results makes it necessary to initiate empiric syndromic therapy at the time of the initial visit. Syndromic therapy should usually be effective for syphilis. Fluctuant buboes should be incised or aspirated. All patients with GUD should be tested for HIV infection. Patients should be reassessed at 7 days to assess response to therapy. Most patients will show improvement; failure of the lesions to respond should prompt a search for an alternative diagnosis. The RPR as well as a treponemal test should be repeated in all patients as erology can be negative in 30% of patients when they first present with primary syphilis. Specific treatment recommendations for the common causes of GUD are given in the following sections. Syphilis A single intramuscular (IM) injection of benzathine penicillin G, 2.4 million U, is the treatment of choice for both HIV-infected and -uninfected patients with primary or secondary syphilis. Doxycycline or tetracycline for 14 days can be used in patients with a documented penicillin allergy. Azithromycin resistance is now widespread and the macrolides are no longer recommended. All patients should be followed with a quantitative RPR or VDRL at 3, 6, 12, and 24 months after treatment. Treatment failure is diagnosed if clinical signs persist or recur, a sustained 4-fold rise in titer occurs, or an initially high titer (>1/8) fails to decline by at least 4-fold at 6 months. Patients who fail treatment as determined by these criteria should undergo a lumbar puncture. If the cerebrospinal fluid (CSF) is normal, they should be treated with benzathine penicillin G, 2.4 million U IM weekly for 3 weeks. Patients with CSF abnormalities should be treated for neurosyphilis. Because tetracyclines are contraindicated in pregnancy, pregnant patients with a proven penicillin allergy must be desensitized and treated with penicillin. All persons who had sexual contact during the preceding 90 days should be treated and followed with serology. Chancroid Trimethoprim–sulfamethoxazole (TMP–SMX) is no longer recommended for the treatment of chancroid because H. ducreyi are generally resistant. Erythromycin, 250 mg three times daily for 7 days, is effective in both HIV-infected and -uninfected patients. A single dose of azithromycin, 2 g or ciprofloxacin, 500 mg, is also effective, with cure rates of over 95%. All chancroid patients with initially negative serologies for HIV and syphilis should have these tests repeated at 3 months. All persons who had sexual contact with the patient in the preceding 3 weeks should be treated regardless of evidence of infection. Erythromycin can be prescribed in pregnant patients. Figure 62.2 Diagnostic algorithm for patients with genital ulcer disease. Lymphogranuloma venereum Doxycycline for 21 days is the treatment of choice for LGV, but treatment failures may occur, especially in the presence of proctitis, and repeated longer courses should be prescribed. Pregnant patients should be treated with erythromycin. All sexual contacts within the last 30 days should be investigated for rectal, urethral, or cervical chlamydial infection and treated regardless of laboratory confirmation. Donovanosis Doxycycline remains the treatment of choice for donovanosis, although treatment failures occur. When therapy fails, patients can be treated with TMP–SMX or ciprofloxacin. Genital herpes Acyclovir, valacyclovir, or famciclovir should be used to treat the initial clinical episode of genital herpes, and for severe cases, intravenous acyclovir therapy may be required. Prophylaxis is indicated for patients with concomitant HIV infection or frequent recurrences. Acyclovir, 400 mg twice daily, famciclovir, 250 mg twice daily, or valacyclovir, 1 g once daily, each prevents 90% or more of recurrences. See Chapter 187, Herpes simplex viruses 1 and 2, for more details of treatment. Table 62.5 Treatment regimens for infectious causes of the genital ulcer adenopathy syndrome Disease Recommended regimen Alternative regimens Comments Primary syphilis Benzathine penicillin G (2.4 million U IM) Doxycycline (100 mg PO BID × 14 days) or Tetracycline (500 mg PO QID × 14 days) The Jarisch–Herxheimer (J-H) reaction (acute onset of fever accompanied by headache, myalgia, malaise, nausea, and tachycardia) may occur 2–24 h after initiating therapy for syphilis. Although the J-H reaction may produce fetal distress or premature labor in a pregnant woman, this is not an indication to delay therapy Chancroid Erythromycin (250 mg PO QID × 7 days) Erythromycin (500 mg PO QID × 7 days) Azithromycin (1 g PO × 1 dose) or Ciprofloxacin (500 mg PO × 1 dose) or Amoxicillin-clavulanic acid (500/125 mg PO TID × 7 days) Single-dose regimens are contraindicated in HIV-seropositive patients because of unexpectedly high failure rates Lymphogranuloma venereum Doxycycline (100 mg PO BID × 21 days) Erythromycin (500 mg PO QID × 21 days) or Sulfisoxazole (500 mg PO QID × 21 days) Contacts may require treatment Donovanosis Doxycycline (100 mg PO BID) TMP–SMX (160/800 mg PO BID) Ciprofloxacin (500 mg PO BID) Tetracycline (500 mg PO QID) Treat until all lesions are healed (may take up to 4 wk) Genital herpes (primary) Acyclovir (200 mg PO 5 × daily × 10 days) Famciclovir (250 mg PO TID × 5–10 days) Valacyclovir (1 g PO BID × 5–10 days) Recurrences require treatment only if severe Abbreviations: HIV = human immunodeficiency virus; IM = intramuscularly; PO = orally; BID = twice a day; QID = four times a day; TID = three times a day; TMP–SMX = trimethoprim–sulfamethoxazole. 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