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Approach to the patient with genital ulcers

Approach to the patient with genital ulcers
Literature review current through: May 2024.
This topic last updated: Nov 28, 2022.

INTRODUCTION — The majority of genital ulcers are caused by sexually transmitted infections (STIs), although there are noninfectious etiologies that should be considered once STIs have been ruled out.

In the United States, the most common cause of genital ulcer disease (GUD) is herpes simplex virus, followed by syphilis. Outbreaks of lymphogranuloma venereum (LGV) have also been reported, mainly in populations of men who have sex with men. Other sexually transmitted pathogens causing genital ulcers are less common in the United States but may be more prevalent in other parts of the world. The presence of genital ulcers is a risk factor for the transmission of HIV.

The challenge for the clinician is to determine the cause of the genital ulcer in order to institute appropriate therapy and to decrease the risk of transmission to others. However, determining the etiology can be complicated due to limitations of current diagnostic testing modalities and the fact that more than one infection may coexist.

The approach to the patient with genital ulcers is discussed below. More detailed information regarding the individual infections can be found in the relevant topic reviews:

(See "Syphilis: Screening and diagnostic testing".)

(See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV".)

(See "Syphilis: Treatment and monitoring".)

(See "Chancroid".)

(See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection".)

(See "Treatment of genital herpes simplex virus infection".)

(See "Lymphogranuloma venereum".)

ETIOLOGIES — Genital ulcers can result from infectious as well as noninfectious causes.

Infectious etiologies — Infectious pathogens that cause genital ulcers are usually sexually transmitted; however, on occasion, genital ulcers may be a manifestation of non-sexually transmitted infections as well.

Sexually transmitted — Sexually transmitted pathogens that cause genital ulcers include [1-3]:

Herpes simplex virus types I and II (HSV-1 and HSV-2)

Treponema pallidum (the causative agent of syphilis)

Chlamydia trachomatis serovars L1-3 (the causative agents of lymphogranuloma venereum [LGV])

Haemophilus ducreyi (the causative agent of chancroid)

Klebsiella (Calymmatobacterium) granulomatis (the causative agent of granuloma inguinale; also known as "donovanosis")

Occasionally, primary infection with HIV can present with genital ulcers [4]. In addition, some epidemiologic studies suggest that Epstein-Barr virus (EBV) may be sexually transmitted and, rarely, EBV can lead to genital ulceration [5,6]. (See "Acute and early HIV infection: Clinical manifestations and diagnosis", section on 'Rash' and "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Primary infection'.)

Patients with monkeypox can also present with genital lesions [7-9]. During the outbreak of monkeypox in nonendemic countries that was first reported in May 2022, it appears that transmission can occur through close contact during sexual activity. Monkeypox is discussed in detail in separate topic reviews. (See "Epidemiology, clinical manifestations, and diagnosis of mpox (monkeypox)" and "Treatment and prevention of mpox (monkeypox)".)

Non-sexually transmitted infections — On rare occasion, non-sexually transmitted infections have been reported to cause genital ulcerations [10,11]. These include tuberculosis, amebiasis, and leishmaniasis. (See "Cutaneous manifestations of tuberculosis" and "Extraintestinal Entamoeba histolytica amebiasis", section on 'Cutaneous infection' and "Cutaneous leishmaniasis: Clinical manifestations and diagnosis", section on 'Mucosal leishmaniasis'.)

Lipschütz ulcer — Non-sexually acquired acute genital ulceration (NAGU), also referred to as "Lipschütz ulcer," is a rare vulvar skin condition that is thought to be an immune response to a recent infection (eg, EBV, cytomegalovirus, mycoplasma, and Lyme disease) [11,12], although the exact etiology is unknown. This condition occurs most often in adolescent girls and young women [13,14]. Patients can present with one or multiple ulcers, which are frequently bilateral and are often painful. In addition, they frequently report prodromal symptoms, such as fever, malaise, tonsillitis, lymphadenopathy, and increased levels of liver enzymes. A more detailed discussion of NAGU is found elsewhere. (See "Acute genital ulceration (Lipschütz ulcer)".)

Noninfectious etiologies — Noninfectious etiologies of genital ulcers include fixed drug reactions (picture 1), Behçet syndrome, neoplasms, Crohn's disease, and trauma [11,15]. (See "Vulvar lesions: Differential diagnosis of vesicles, bullae, erosions, and ulcers" and "Drug eruptions" and "Clinical manifestations and diagnosis of Behçet syndrome" and "Vulvar lesions: Differential diagnosis of vesicles, bullae, erosions, and ulcers", section on 'Vesicles and bullae'.)

GENERAL APPROACH — During the initial assessment of a patient with genital ulcers, individuals should be evaluated for the presence of a sexually transmitted infection (STI). These infections are the most common cause of genital ulcer disease (GUD), and can be transmitted to others. In addition, genital ulcers increase the risk of acquiring HIV.

The initial evaluation should include:

A careful history (including sexual and travel history). (See 'History' below and 'Geographic location and travel' below.)

A physical examination. (See 'Physical examination' below.)

Diagnostic testing (eg, testing for herpes simplex virus and syphilis). (See 'Diagnostic testing' below.)

Empiric treatment is often initiated based upon the history and physical examination since results of testing are often not immediately available and/or some assays have low sensitivity (algorithm 1). (See 'Empiric Treatment' below.)

Some patients will have a negative evaluation and/or will not respond to empiric therapy. For such patients, further evaluation for less common sexually transmitted causes of GUD and non-sexually acquired causes of GUD may be needed. (See 'Patient counseling and follow-up' below.)

CLINICAL EVALUATION — In patients with genital ulcers, the clinical evaluation is important in guiding the approach to diagnosis and empiric therapy (algorithm 1). (See 'Diagnostic testing' below and 'Empiric Treatment' below.)

History — When obtaining the history from a patient with genital ulcers, it is important to assess their sexual risk behaviors, where they (or their sexual contacts) reside or travel, any history of new medications (whether systemically or topically applied), and information regarding pertinent clinical signs and symptoms (eg, the number of lesions, whether the lesions are painful, the presence of lymphadenopathy, constitutional symptoms).

Sexual history — A thorough sexual history should be obtained from any patient who presents with a genital ulcer. When obtaining a sexual history, the clinician should ask about:

Any recent sexual exposure (within the last 90 days) to a partner with a known sexually transmitted infection (STI). (See 'When to initiate empiric treatment' below.)

Gender of the sexual contacts (men, women, or both).

Number of sexual contacts within the past month and past six months.

Use of barrier protection (consistent or inconsistent).

Sites of sexual contact (oral, genital, rectal).

Geographic location of the sexual contact. (See 'Geographic location and travel' below.)

Timing of sexual contact with respect to onset of symptoms (to assess potential incubation period) (table 1).

Past history of other STIs and prior HIV testing.

The use of drugs (eg, methamphetamine) and/or heavy alcohol use that are associated with increased high-risk sexual behaviors.

In light of the 2022 outbreak of monkeypox reported in nonendemic countries, questions specific to identifying epidemiologic criteria for monkeypox should be asked as well (table 2) [8,16]. These are discussed in detail elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of mpox (monkeypox)", section on 'Evaluation and diagnosis'.)

The sexual history can help dictate the type of diagnostic testing that should be performed, as well as the need/choice of agent for empiric therapy. As an example, in the United States, syphilis should be considered in all men who have sex (MSM) who present with a genital ulcer since the majority of new cases occur in this population [17]. Similarly, lymphogranuloma venereum (LGV) should be considered in HIV-infected MSM, as outbreaks of LGV have been concentrated in this group.

Geographic location and travel — The evaluation of a patient with genital ulcers should include a thorough travel history, including questions about sexual activity with new partners and involvement in sex tourism. Understanding the relative prevalence of various pathogens in a particular geographic area also helps to inform the selection of appropriate diagnostic tests and the choice of empiric therapy.

In the United States, genital herpes related to herpes simplex virus (HSV-1 or HSV-2) is the most common ulcerative STI followed by syphilis. Outbreaks of LGV have been reported amongst MSM [18]. Chancroid is rare and, when it is reported, has usually been in the context of small, focused outbreaks [19].

Outside the United States, genital herpes and syphilis also cause the majority of genital ulcers [20-25]. The prevalence of other pathogens can vary from one geographic area to another. As examples:

LGV is typically found in areas of East and West Africa, India, parts of Southeast Asia, and the Caribbean. This infection has rarely been reported in resource-rich countries, except in the context of localized outbreaks that were reported among MSM in urban areas in North America and Europe (eg, Amsterdam, London). (See "Lymphogranuloma venereum", section on 'Epidemiology'.)

Historically, chancroid has been considered an important cause of genital ulcer disease (GUD) in many countries in Africa, Asia, Latin America, and the Caribbean. However, there are indications that rates of H. ducreyi as a cause of GUD may be declining in many areas [26,27]. (See "Chancroid", section on 'Epidemiology'.)

Granuloma inguinale, an uncommon infection caused by Klebsiella (Calymmatobacterium) granulomatis, has been recognized in parts of India, South Africa, and South America [28].

In May 2022, an outbreak of monkeypox was reported, in which some patients presented with genital lesions or proctitis among other clinical features. This outbreak has a worldwide distribution and to date primarily involves MSM [29]. Patients should be asked about recent travel to endemic countries (Central or West Africa), as well as nonendemic countries where monkeypox has been reported [30]. (See "Epidemiology, clinical manifestations, and diagnosis of mpox (monkeypox)", section on 'Geographic distribution'.)

Medication history — Patients should be questioned about medication use since reactions to medications, systemically or locally (eg, boric acid or over-the-counter products such as antibacterial ointments), may cause genital ulcers.

Symptoms — Although the clinical manifestations of genital ulcers are variable, there are certain characteristic signs and symptoms associated with specific etiologies.

Painless versus painful ulcer – When formulating a differential diagnosis, it is helpful to know if an ulcer is painless or painful. Ulcers associated with syphilis, LGV, and granuloma inguinale are usually painless, while painful ulcers tend to be more typical of HSV and chancroid. Limited data suggest the lesions associated with monkeypox also appear to be painful [8]. (See 'Infectious etiologies' above.)

However, a diagnosis made solely on the presence or absence of pain may be misleading and, in the absence of obvious vesicles that strongly suggest genital herpes, is unreliable for making an etiologic diagnosis. (See 'Limitations of a clinical diagnosis' below.)

Urinary symptoms – Genital ulcers can be associated with dysuria, and patients may incorrectly be evaluated and treated only for a urinary tract infection, missing a treatable STI [31]. As examples:

A complaint of dysuria may be due to the anatomic location of a genital ulcer, and painful urination may be the chief complaint in a female with an ulcerative labial or urethral lesion, or in a male with an ulcer at the urethral meatus or on the glans.

Dysuria may also suggest a concurrent diagnosis of a sexually transmitted urethritis (eg, Chlamydia trachomatis or Neisseria gonorrhoeae urethritis). (See "Clinical manifestations and diagnosis of Chlamydia trachomatis infections in adults and adolescents", section on 'Urethritis' and "Clinical manifestations and diagnosis of Neisseria gonorrhoeae infection in adults and adolescents", section on 'Urethritis'.)

The presence of urinary retention would be strongly suggestive of a complicated HSV infection with the development of sacral radiculitis. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection".)

Constitutional symptoms – Constitutional symptoms can be seen with certain STIs that cause GUD, such as HSV, secondary syphilis, and LGV. As examples:

Some patients with primary HSV infection present with systemic symptoms, such as fever, malaise, and myalgias. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Clinical features'.)

Fever, headache, and malaise can occur in patients with secondary syphilis. Although the chancre has usually resolved by the time these symptoms become apparent, the two stages can sometimes overlap. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV".)

Systemic symptoms can be seen in the second stage of LGV, when the patient presents with inguinal lymphadenopathy. However, this often occurs two to four weeks after the ulcer, and may be delayed for up to six months in some cases [32]. (See "Lymphogranuloma venereum", section on 'Clinical manifestations'.)

Patients with monkeypox may present with a prodrome of fever, chills, rash, and/or new lymphadenopathy before the rash develops; however, perianal or genital lesions in the absence of subjective fever/prodromal symptoms have been reported [16,29]. (See "Epidemiology, clinical manifestations, and diagnosis of mpox (monkeypox)", section on 'Clinical manifestations'.)

Frequency of episodes – A history of recurrent ulcers would suggest HSV infection. However, if diagnostic testing does not support this, a history of recurrent ulcers may also suggest less common etiologies, such as Behçet syndrome or fixed drug eruption. (See 'Etiologies' above.)

In patients with a known history of herpetic outbreaks, providers should also consider a new or alternative infectious diagnosis. Patients can present with genital ulcers due to more than one agent (eg, HSV and syphilis).

Evidence of other symptoms – For patients who present with GUD, certain associated symptoms may support a diagnosis of a specific STI or noninfectious cause. As an example, the presence of aseptic meningitis can be seen in the setting of HSV, whereas the presence of arthritis may suggest an autoimmune disorder.

Physical examination — Although the history gives important information as to the potential etiologic agent, the physical exam provides other key clues to the diagnosis. However, as with the history, diagnostic testing should be performed to support/confirm the diagnosis. (See 'Limitations of a clinical diagnosis' below.)

Appearance of ulcers — The number of lesions as well as their appearance may suggest one diagnosis over the other. As an example, infection due to HSV or H. ducreyi (chancroid) typically presents as multiple ulcers, whereas syphilis usually presents as a single lesion (picture 2).

Other identifying features include:

Herpetic lesions classically begin as one or more grouped vesicles on an erythematous base (picture 3 and picture 4). These vesicles subsequently open, resulting in shallow ulcerations. In areas under the foreskin or around the labia and rectum, vesicles often break prior to being noticed. Occasionally, atypical manifestations such as pustular lesions may be seen. In severely immunosuppressed patients, such as those with untreated HIV, chronic lesions can develop and form large, crusted erosions. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Clinical features'.)

The syphilitic chancre is classically a single, indurated, well-circumscribed painless ulcer (picture 2). (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Primary syphilis (chancre)'.)

LGV often begins as a single papule or a shallow ulcer (picture 5 and picture 6). (See "Lymphogranuloma venereum", section on 'Clinical manifestations'.)

The ulcers associated with chancroid begin as papules that go on to ulcerate (picture 7). The ulcers are characteristically deep and ragged with a purulent, yellow-gray base, and an undermined, violaceous border. (See "Chancroid", section on 'Genital ulcers'.)

Granuloma inguinale can present as one or more nodular lesions that ulcerate. The ulcers, which slowly enlarge, are often friable and have raised, rolled margins. "Kissing" lesions may occur from autoinoculation on adjacent skin.

The rash associated with monkeypox involves deep-seated and well-circumscribed lesions that may umbilicate (figure 1) [33]. Characteristically, the lesions of monkeypox progress through specific sequential stages (macules, then papules, then vesicles, then pustules, and finally scabs that eventually fall off) [34]. The lesions are often described as painful until the healing phase when they become itchy [35]. (See "Epidemiology, clinical manifestations, and diagnosis of mpox (monkeypox)", section on 'Clinical manifestations'.)

Lymphadenopathy — Inguinal lymphadenopathy is commonly seen in patients with infectious causes of genital ulcers.

The lymph nodes are often tender in patients with HSV, chancroid, and LGV.

Rubbery, non-tender nodes are often seen in late primary syphilis.

Matting or suppuration of the lymph nodes, or the development of a "buboe" (unilateral painful inguinal lymph nodes), may occur with chancroid or LGV.

Lymphadenopathy is common in monkeypox. (See "Epidemiology, clinical manifestations, and diagnosis of mpox (monkeypox)", section on 'Clinical manifestations'.)

Lymphadenopathy is less common with granuloma inguinale, though nodular lesions may appear as pseudo buboes.

Significant inguinal, cervical, and/or axillary lymphadenopathy may also raise concern for concomitant HIV infection. (See "Acute and early HIV infection: Clinical manifestations and diagnosis", section on 'Adenopathy'.)

Other findings — It is important to assess whether the patient may have other findings suggestive of a specific STIs, such as rectal pain, discharge or bleeding (eg, HSV, LGV, gonorrhea, chlamydia, and monkeypox), urethral or cervical discharge (eg, gonorrhea, chlamydia), thrush (eg, HIV infection), or hepatomegaly (eg, hepatitis B or C, secondary syphilis).

Limitations of a clinical diagnosis — Determining the etiology of a genital ulcer based only upon the history and physical exam may lead to a mistaken diagnosis and inappropriate treatment in some settings [19,20,36-38]. Thus, it is important to perform diagnostic testing to support a suspected diagnosis. (See 'Diagnostic testing' below.)

The signs, symptoms, and appearance of genital ulcers due to individual pathogens can vary, and coinfection with multiple organisms can also occur [20]. In addition, patients who are immunocompromised may have atypical clinical presentations, including more widespread and severe disease. As examples:

Patients with primary genital HSV can occasionally present as a single ulcer or a fissure in the genital area. In addition, there are a wide range of symptoms. For many patients, initial infection is associated with painful ulcers, dysuria, fever, tender inguinal lymphadenopathy, and/or headache; however, other patients may have only mild symptoms or may be entirely asymptomatic. Herpetic ulcers can also manifest as a sensation of pruritus rather than pain, which, in women, may be misdiagnosed as a vaginal yeast infection. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Clinical features'.)

In patients with syphilis, making a diagnosis based only upon the classic presentation of a single painless ulcer can also be misleading. As an example, up to 30 percent of patients with primary syphilis may present with painful ulcers [39]. In addition, multiple syphilis lesions have occasionally been reported in patients with HIV [40]. (See "Syphilis in patients with HIV", section on 'Clinical manifestations' and "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Primary syphilis (chancre)'.)

There have been case reports of painful, persistent LGV ulcers [41], despite the classic description of the initial LGV lesion as a painless ulcer. (See "Lymphogranuloma venereum".)

DIAGNOSTIC TESTING — Although the history and physical examination may give important clues to the diagnosis, it is important that diagnostic testing be obtained in an effort to support/confirm the infectious agent.

General approach — Sexually transmitted infections (STIs) are the most likely cause of genital ulcer disease (GUD).

Patients should be tested for common STIs regardless of the clinical presentation. (See 'Baseline testing' below.)

Testing for less common STIs depends upon the specific exposure. (See 'Additional evaluation' below.)

We typically test for non-sexually transmitted infections and noninfectious causes if initial testing for STIs is negative. (See 'Patient counseling and follow-up' below.)

Some patients may have a known cause for their STI (eg, a known exposure or recurrent herpes simplex virus [HSV] infection). For such patients, we still test for other common STIs because more than one infection may be present. As an example, a patient with recurrent genital HSV could acquire syphilis, and small studies have found syphilis to be a co-pathogen in up to 10 percent of patients with chancroid. (See "Chancroid".)

Baseline testing — Patients who present with genital ulcers should undergo testing for common causes of GUD, such as HSV and syphilis, as well as other STIs (eg, HIV, gonorrhea, and chlamydia). During the initial evaluation, we typically test for HSV and syphilis, even if the patient does not endorse being at risk, since patients may not be aware of their exposure and/or may not feel comfortable disclosing sensitive information.

Herpes simplex virus (HSV) – During the workup of a patient with new genital ulcers, we obtain testing for herpes simplex. However, repeat HSV testing is generally not necessary in a patient with prior laboratory-confirmed genital HSV and with clinical manifestations consistent with recurrent disease.

To test for HSV, the lesion should be swabbed and directly tested for HSV. Nucleic acid amplification methods (NAATs), including polymerase chain reaction (PCR) assays, are now commercially available and are the test of choice, as they have a higher sensitivity than culture or direct immunofluorescent antibody testing [28,42].

If HSV PCR is not available, a viral culture of the base of the ulcer can be obtained. If a vesicle is present, vesicular fluid is preferred because of its higher diagnostic yield.

Other types of tests are also available, but these are less sensitive and generally not recommended. These include direct fluorescent antibody testing performed on a scraping of the base of an ulcer and cytologic evaluation for cellular changes associated with HSV infection (ie, Tzanck preparation) [28]. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Diagnosis'.)

Serology is not routinely used for diagnosis of HSV since the performance characteristics of commercially available tests vary (eg, the IgM is unreliable and not recommended, and there can be false-positive IgG tests at low index values requiring confirmatory testing) [28]. In addition, tests for HSV-1 cannot distinguish between oral and genital infections. However, obtaining HSV serologies may be considered in select clinical scenarios. As an example, if no active lesions are present, the presence of HSV-2 serum antibodies in someone with recurrent genital ulcers is highly suggestive of the diagnosis. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Serologic testing'.)

Syphilis – Serologic testing for syphilis should be performed during the initial evaluation of a patient who presents with a genital ulcer. However, serologies may be negative in 5 to 25 percent of primary syphilis, and the decision to treat is based upon the likelihood of infection. (See 'When to initiate empiric treatment' below.)

Treponemal tests may be somewhat more sensitive than nontreponemal tests for primary syphilis [43,44], and many laboratories now perform stepwise "reverse sequence algorithm" testing beginning with a T. pallidum antibody screen (syphilis IgG). Positive or equivocal test results are followed by a reflex nontreponemal test, such as a rapid plasma reagin. (See "Syphilis: Screening and diagnostic testing", section on 'Serologic testing algorithms'.)

The use of darkfield microscopy to visualize T. pallidum directly from the lesion had been the gold standard for diagnosing syphilis for many years, but it is rarely available outside of specialized clinics. However, if available, a swab of the ulcer should be obtained and direct visualization should be attempted by someone experienced with this technique.

Other than darkfield microscopy, there are no established methods to detect the organism. Some laboratories provide locally developed PCR tests for the detection of T. pallidum DNA, but none are commercially available. In addition, direct fluorescent antibody tests for T. pallidum may be available in some settings. (See "Syphilis: Screening and diagnostic testing".)

Other STIs – Patients with an ulcerative sexually transmitted infection (STI) are at increased risk for coinfection with other STIs. Thus, individuals should also be tested for HIV, gonorrhea, and chlamydia. In certain populations, testing for hepatitis B and hepatitis C may also be considered. STI screening recommendations for select populations are reviewed in detail elsewhere and summarized in the table (table 3). (See "Screening for sexually transmitted infections".)

Additional evaluation — Testing for lymphogranuloma venereum, chancroid, or granuloma inguinale should be performed during the initial evaluation if the patient had a known exposure to one of these pathogens or if there is a high suspicion for infection. (See 'Clinical evaluation' above.)

Lymphogranuloma venereum (LGV) – Nucleic acid amplification tests (NAATs) for chlamydia will be positive if LGV is present. In the United States, FDA-cleared NAATs for chlamydia trachomatis will detect the LGV serovars but will not distinguish LGV serovars from the more typical D-K serovars. Molecular tests that are specific for LGV (eg, PCR-based genotyping) are not widely available.

Serological tests for LGV are available, but are of limited utility because they lack standardization, especially in the setting of proctitis. However, they may be used in the setting of isolated inguinal or femoral lymphadenopathy to support a diagnosis of LGV [28].

A more detailed discussion of how to diagnose LGV is found elsewhere. (See "Lymphogranuloma venereum", section on 'Diagnosis'.)

Granuloma inguinale – A biopsy specimen of the ulcer or tissue crush prep looking for Donovan bodies is necessary to make the diagnosis of granuloma inguinale.

Chancroid – Specialized cultures can be used to diagnose chancroid. Some laboratories have developed locally validated PCR tests for chancroid as well. Additional information on how to diagnose chancroid is presented in a separate topic review. (See "Chancroid", section on 'Diagnosis'.)

Monkeypox – If a patient is suspected of having monkeypox (table 2), isolation precautions and workup for monkeypox should be initiated immediately. (See "Epidemiology, clinical manifestations, and diagnosis of mpox (monkeypox)", section on 'Evaluation and diagnosis' and "Treatment and prevention of mpox (monkeypox)", section on 'Infection prevention and control'.)

In such patients, work-up/management for other causes of GUD should continue concomitantly (algorithm 1).

EMPIRIC TREATMENT — In most clinical settings, there are few reliable point-of-care diagnostic tests (eg, rapid serum rapid plasma reagin [RPR] or darkfield microscopy for syphilis). Thus, most results will not be immediately available, and empiric therapy may need to be initiated while awaiting results (algorithm 1). (See 'When to initiate empiric treatment' below.)

In addition, despite testing, approximately 25 percent of all patients with genital ulcers may not have a specific etiologic agent identified [37]. Some of the assays have low sensitivity (eg, viral culture for herpes simplex virus [HSV], syphilis IgG during primary syphilis) [40]. More sensitive assays, such as real-time HSV polymerase chain reaction (RT-PCR), are more costly to perform and are often unavailable in emergency rooms, sexually transmitted infection (STI) clinics, and resource-limited settings, though this may change in the future.

Empiric treatment decisions are based primarily upon the clinical evaluation and sexual history. Knowledge of the local epidemiology of the agents that cause genital ulcers in a given geographic area can also be instructive, particularly in the setting of an outbreak. Public health departments can often provide helpful information since syphilis, chancroid, and lymphogranuloma venereum (LGV) are reportable infections in most jurisdictions. (See 'Geographic location and travel' above and 'Notification and treatment of contacts' below.)

This section will review the use of empiric therapy in patients who have genital ulcers. The approach to empiric therapy in asymptomatic patients after a potential exposure to a patient with genital ulcer disease is discussed below. (See 'Notification and treatment of contacts' below.)

When to initiate empiric treatment — We initiate empiric therapy for certain patients with genital ulcers rather than waiting for diagnostic test results. These include patients with:

A known exposure to an STI; the choice of agent depends upon the pathogen. (See 'Sexual history' above and 'Treatment regimens' below.)

Genital ulcers suggestive of HSV, since antiviral therapy can lessen the severity and duration of symptoms compared with untreated disease. (See "Treatment of genital herpes simplex virus infection".)

Genital ulcers suggestive of syphilis (single or painless ulcer) in patients who are at high risk for infection, such as:

Sexually active men who have sex with men (MSM)

Commercial sex workers

Individuals who exchange sex for drugs

We also treat patients with genital ulcers suggestive of syphilis if they are unlikely to return for follow-up and/or abstain from sexual contact until the diagnostic workup is completed. Treatment of primary syphilis is important to both prevent transmission and the development of secondary, tertiary, and neurosyphilis. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV".)

We do not routinely initiate empiric treatment for LGV; however, it is reasonable to provide empiric therapy in an outbreak setting if the patient has appropriate risk factors (eg, HIV-infected MSM), particularly if the patient has significant inguinal lymphadenopathy. It is also reasonable to initiate empiric therapy in patients with genital ulcers and significant inguinal lymphadenopathy if they engaged in high-risk sexual behaviors in an area where LGV is endemic. (See "Lymphogranuloma venereum", section on 'Epidemiology' and "Lymphogranuloma venereum", section on 'Treatment of LGV'.)

In cases where the presentation is atypical, treatment of more than one infection may be needed. Diagnostic uncertainty may be related to dual infections or atypical manifestations in an immunocompromised host (eg, multiple lesions secondary to syphilis in the HIV-infected patient). (See 'Geographic location and travel' above.)

Treatment regimens — Treatment regimens for STIs associated with genital ulcers are summarized below and discussed in detail in the specific topic reviews.

Syphilis – The drug of choice for primary syphilis is a single dose of penicillin G benzathine (2.4 million units), administered via the intramuscular (IM) route (table 4). Prior to initiating treatment, all patients should have serologic testing. Although serology may be negative in the setting of primary syphilis, if positive, nontreponemal tests are used to monitor the response to therapy. (See "Syphilis: Screening and diagnostic testing", section on 'Serologic tests'.)

Herpes simplex virus (HSV) – In patients with suspected primary clinical genital HSV, clinical trials have demonstrated comparable efficacy of acyclovir (400 mg three times daily), famciclovir (250 mg three times daily), and valacyclovir (1000 mg twice daily). Valacyclovir has the convenience of twice-daily dosing, while acyclovir is less expensive than the other two medications. The usual duration of treatment is 7 to 10 days. (See "Treatment of genital herpes simplex virus infection".)

For patients with recurrent disease, treatment options include chronic suppression, episodic therapy, or no intervention. These management strategies are discussed in detail in a separate topic review. (See "Treatment of genital herpes simplex virus infection", section on 'Treatment of recurrent infection'.)

Lymphogranuloma venereum (LGV) – The preferred treatment for LGV in nonpregnant patients is doxycycline 100 mg orally twice daily for 21 days. (See "Lymphogranuloma venereum", section on 'Treatment of LGV'.)

Chancroid – In a patient with suspected chancroid, empiric single-dose therapy should be administered with either azithromycin (1 gram orally) or ceftriaxone (250 mg IM). Both are effective, although azithromycin is more expensive. We typically treat patients with suspected chancroid empirically for syphilis as well, particularly if the patient is at high risk for acquiring syphilis (eg, sexually active MSM) and may not return for timely follow-up. Additional information on the treatment of chancroid is presented elsewhere. (See "Chancroid", section on 'Treatment'.)

Granuloma inguinale – Azithromycin (1 g once weekly, or 500 mg daily) is the preferred agent. The duration of treatment is a minimum of three weeks, and should be continued until all lesions have completely healed [28].

For nonpregnant patients, alternative agents include doxycycline (100 mg twice a day), erythromycin (500 mg four times a day), or trimethoprim-sulfamethoxazole (one double-strength tablet twice a day) [28,45]. These agents should be given for the same duration as azithromycin. If no clinical improvement occurs within the first few days, an aminoglycoside can be added [28].

Pregnant persons should be treated with erythromycin or azithromycin.

Monkeypox – Antiviral therapy is indicated for certain patients with monkeypox (eg, those with severe disease, involvement of anatomic areas which might result in serious sequelae such as scarring or strictures, persons with severe immunocompromise). Treatment of monkeypox is discussed in detail separately. (See "Treatment and prevention of mpox (monkeypox)", section on 'Clinical Management'.)

PATIENT COUNSELING AND FOLLOW-UP — All patients should be advised to refrain from sexual activity while awaiting test results and, if empiric therapy was initiated, for at least seven days after both the patient and his/her partner(s) are treated. Counseling regarding partner/contact testing and condom use is key to decreasing transmission. (See 'Notification and treatment of contacts' below.)

Follow-up should be arranged within one week of the initial visit to assess the clinical response to therapy and review results of diagnostic testing. If the patient's symptoms are worsening or constitutional symptoms develop, more testing may be required.

Repeat testing for syphilis can be performed two to four weeks after the initial test in patients who were not empirically treated if there is a high suspicion of infection. A negative initial treponemal or nontreponemal test for syphilis does not rule out the possibility of infection in a patient with genital ulcers. (See "Syphilis: Screening and diagnostic testing", section on 'Negative nontreponemal test in early syphilis'.)

Patients should be reassessed for risk factors for other less common sexually transmitted causes of genital ulcer disease (GUD) (eg, lymphogranuloma venereum, chancroid, granuloma inguinale) and evaluated as appropriate. (See 'Additional evaluation' above.)

Patients should also be evaluated for non-sexually transmitted infection-related causes of GUD. As an example, recurrent painful genital lesions with repeated negative herpes simplex virus testing should raise the possibility of Behçet syndrome. (See 'Non-sexually transmitted infections' above and 'Lipschütz ulcer' above and 'Noninfectious etiologies' above and "Clinical manifestations and diagnosis of Behçet syndrome".)

The follow-up patient encounter is also an opportunity to review other test results, including serologic testing for HIV and viral hepatitis. Patients who have not been vaccinated or exposed to hepatitis B virus in the past (as determined by serologic testing) should receive hepatitis B vaccine. Hepatitis A immunization is also indicated for men who have sex with men and injection drug users. The human papillomavirus vaccine should also be recommended when appropriate. (See "Prevention of sexually transmitted infections", section on 'Vaccines'.)

NOTIFICATION AND TREATMENT OF CONTACTS — Sexual contacts of patients who are diagnosed with a sexually transmitted infection should be notified, screened, and treated, depending upon the pathogen and the timing of exposure. Partner notification for reportable infections, such as syphilis, is usually accomplished through the local public health department.

As examples, the following patients should be evaluated and treated, even if asymptomatic:

Someone who has had sexual contact with a patient with early syphilis (primary, secondary, early latent syphilis) if the contact occurred within the 90 days preceding the index case's diagnosis or before the index patient was appropriately treated. Treatment should be administered even if the contact's serologic testing for syphilis is negative. (See "Syphilis: Treatment and monitoring", section on 'Treatment after an exposure'.)

A person who had sexual contact with someone diagnosed with chancroid if the contact occurred within the 10 days preceding the diagnosis or before the index case was adequately treated. (See "Chancroid", section on 'Sex partners'.)

Sexual contacts of a patient with lymphogranuloma venereum if the contact occurred within the 60 days preceding the diagnosis or before the index case was appropriately treated. (See "Lymphogranuloma venereum", section on 'Management of sex partners'.)

Contacts of a patient with granuloma inguinale if the contact occurred within the 60 days before the index case was diagnosed with granuloma inguinale or before the index patient was appropriately treated [28].

We do not empirically treat contacts of patients with genital herpes simplex virus (HSV). However, such patients should be counseled and educated about the symptoms and presentation of HSV. Type-specific antibody testing can be offered to contacts to assess their HSV status and potential risk for HSV transmission. (See "Prevention of genital herpes virus infections".)

Persons exposed to a patient with monkeypox in the preceding 21 days should be closely monitored. Post-exposure vaccination may be indicated after certain exposures in addition to monitoring. Post-exposure management is discussed in detail separately. (See "Treatment and prevention of mpox (monkeypox)", section on 'Post-exposure management'.)

PUBLIC HEALTH IMPLICATIONS — Knowledge of prevalence rates of the various etiologies of genital ulcers in a given area can be helpful in making a diagnosis, particularly when the clinical picture is not clear. If surveillance data are inaccurate, certain infections can be under-recognized and undertreated [19,46]. However, even with a thorough evaluation, more than 25 percent of patients who have genital ulcers have no laboratory-confirmed diagnosis [28].

Accurate diagnoses are also important from a public health standpoint, since treatment of sexual contacts of patients with syphilis, chancroid, and lymphogranuloma venereum is important in curbing the spread of these infections. Diagnosis and treatment of herpes simplex virus (HSV) decreases viral shedding and, subsequently, the risk of HSV transmission. However, treatment of HSV has not been shown to decrease the risk of HIV transmission from patients who are coinfected with both HSV and HIV. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus in patients with HIV".)

It is important that patients have a confidential, easily accessible setting where they can go for screening and treatment of sexually transmitted infections (STIs). Many STI clinics offer services for no fee as part of their mission to diagnose and control the spread of infection. Introduction of even a modest clinic fee of USD $15 for Denver residents during a budget shortfall led to 3250 fewer STI clinic visits in 2003 (a decline of 29 percent) compared with the previous year [47].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sexually transmitted infections" and "Society guideline links: HIV screening and diagnostic testing".)

SUMMARY AND RECOMMENDATIONS

Etiologies of genital ulcer disease – Genital ulcers can result from infectious as well as noninfectious causes. There are five sexually transmitted pathogens that cause most genital ulcer disease (GUD): herpes simplex virus types I and II (HSV-1, HSV-2); Treponema pallidum (the causative agent of syphilis); Haemophilus ducreyi (the causative agent of chancroid); Chlamydia trachomatis serovars L1-3 (the causative agents of lymphogranuloma venereum [LGV]); and Klebsiella (Calymmatobacterium) granulomatis (the causative agent of granuloma inguinale, also known as "donovanosis"). (See 'Etiologies' above.)

Initial evaluation – The initial evaluation of a patient with genital ulcers should assess for the presence of a sexually transmitted infection (STI) (table 1); such infections can be transmitted to others and can increase the risk of acquiring HIV. Evaluation for non-sexually acquired causes of GUD as part of the initial evaluation should be determined on a case by case basis. (See 'General approach' above.)

When obtaining a history from patients with genital ulcers, it is important to assess their sexual risk behaviors and where they (or their sexual contacts) reside, as well as pertinent clinical signs and symptoms (eg, if the lesions are painful, the presence of constitutional symptoms). (See 'History' above.)

On physical examination, the number of lesions, their appearance, and the presence of adenopathy may suggest one diagnosis over another. However, the clinician may be mistaken if the diagnosis is made solely on this basis. (See 'Physical examination' above and 'Limitations of a clinical diagnosis' above.)

Most patients with genital ulcers should have a diagnostic evaluation for HSV and syphilis, regardless of their symptoms. They should also be tested for HIV, gonorrhea, and chlamydia, since patients with an ulcerative STI are at increased risk for coinfection with other STIs. Additional testing for chancroid, LGV, or granuloma inguinale will depend upon the patient's risk factors. (See 'Diagnostic testing' above.)

Empiric therapy – Clinicians are often faced with lack of diagnostic test results at the initial patient encounter and concerns regarding patient follow-up. We initiate empiric therapy for the following patients with genital ulcers, rather than waiting for diagnostic test results: patients with a known exposure to an STI; patients with genital ulcers suggestive of HSV; and patients with an ulcer suggestive of syphilis (eg, painless ulcer) if they are at high risk for syphilis or may not follow up. (See 'When to initiate empiric treatment' above and 'Treatment regimens' above.)

Follow-up – A follow-up evaluation is essential for patients to review the results of initial testing and be certain a clinical response has been obtained if empiric therapy was initiated. If the patient continues to have ulcerative lesions or constitutional symptoms develop, further evaluation for less common sexually transmitted causes of GUD and non-sexually acquired causes of GUD may be needed. (See 'Patient counseling and follow-up' above.)

Management of sexual contacts – Sexual contacts of patients who are diagnosed with an STI should be notified, screened, and treated, depending on the pathogen and the timing of the exposure. Partner notification for reportable infections, such as syphilis, is usually accomplished through the local public health department. (See 'Notification and treatment of contacts' above and 'Public health implications' above.)

ACKNOWLEDGMENTS — The editorial staff at UpToDate acknowledge Sonia Chimienti, MD, and Donna Felsenstein, MD, who contributed to an earlier version of this topic review.

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Topic 7592 Version 42.0

References

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