What are the differences in causative agents, laboratory diagnosis, and management of genital ulcers in pregnant and non-pregnant patients, including those with a history of sexually transmitted infections (STIs)?

Genital Ulcers: Causative Agents, Laboratory Diagnosis, and Management

Overview of Common Genital Ulcer Etiologies

In the United States, genital herpes (HSV) is the most common cause of genital ulcers, accounting for approximately 49% of cases, followed by syphilis and chancroid, with 3-10% of patients having co-infections with multiple pathogens. 1, 2, 3

Primary Infectious Causes

Genital Herpes (HSV-1 and HSV-2)

• Clinical presentation: Multiple shallow, tender ulcers that may be preceded by vesicles; HSV-2 is the dominant causative agent, though HSV-1 genital infections are rising in proportion 1, 3, 4
• Key features: Vesicles burst forming shallow erosions that crust and heal spontaneously in less than 10 days; recurrent episodes are common with HSV-2 but less frequent with HSV-1 1, 4

Primary Syphilis (Treponema pallidum)

• Clinical presentation: Classically presents as a painless, indurated chancre with a clean base, though this classic presentation occurs in only 31% of cases 5, 3
• Key features: Single ulcer (typically), firm borders, non-tender unless secondarily infected; associated with regional lymphadenopathy 1

Chancroid (Haemophilus ducreyi)

• Clinical presentation: One or more painful genital ulcers with ragged, undermined edges and purulent bases 1, 3
• Key features: Tender inguinal adenopathy in one-third of patients; when accompanied by suppurative inguinal adenopathy, this combination is almost pathognomonic 1

Lymphogranuloma Venereum (LGV)

• Clinical presentation: Self-limited genital ulcer at inoculation site, though most patients present after this has resolved with inguinal/femoral lymphadenopathy 3

Granuloma Inguinale (Donovanosis)

• Clinical presentation: Progressive, painless, beefy-red ulcers that bleed easily on contact; rare in the United States 3

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Laboratory Diagnosis

Mandatory Testing for All Genital Ulcers

Serologic testing for syphilis is required in all patients presenting with genital ulcers, with 90% of primary syphilis cases showing positive titers. 2, 5

• Nontreponemal tests (RPR or VDRL): Mandatory initial screening, though sensitivity in primary syphilis is only 62-78% 5
• Treponemal tests (FTA-ABS, TP-PA, or EIA): Confirm true infection versus biological false-positive if nontreponemal test is positive 5
• Critical timing: Serologic tests become reliably positive by 4-6 weeks after infection; if initial serology is negative but clinical suspicion remains high, repeat testing at least 7 days after ulcer onset 1, 5

HSV Testing

HSV culture or PCR from the ulcer base is essential because genital herpes is the most common cause of genital ulcers. 2, 5

• Specimen collection: Open vesicles with sterile needle, collect content with swab, and introduce into transport media for viral culture or nucleic acid amplification tests (NAATs) 1
• Alternative methods: Direct immunofluorescence staining on microscope slides 1

Syphilis-Specific Testing

Darkfield examination or direct immunofluorescence testing for T. pallidum provides immediate diagnosis when available. 1, 5

• Specimen source: Ulcer exudate examined directly 1
• Limitation: Not widely available in most clinical settings 5

Chancroid Testing

• Culture for H. ducreyi: Requires special culture media not widely available commercially; sensitivity is ≤80% even with optimal media 1
• Probable diagnosis criteria: Patient has one or more painful genital ulcers AND no evidence of T. pallidum infection by darkfield or serology performed at least 7 days after ulcer onset AND clinical presentation typical for chancroid with negative HSV test 1

HIV Testing

HIV testing should be performed in all patients with genital ulcers caused by T. pallidum or H. ducreyi, and strongly considered for those with HSV ulcers, as genital ulcers facilitate HIV transmission. 1, 2, 3

• Repeat testing: If initially negative, repeat at 3 months 2, 5
• Rationale: Genital ulcers are established co-factors for HIV acquisition; chancroid and syphilis are particularly strong cofactors for HIV transmission 1

Diagnostic Pitfalls

• Do not rely solely on clinical appearance: Diagnosis based only on history and physical examination is often inaccurate, with at least 25% of genital ulcers having no laboratory-confirmed diagnosis even after complete testing 1, 5
• Co-infection is common: 3-10% of patients have multiple pathogens present; up to 10% of chancroid patients are co-infected with T. pallidum or HSV 1, 2, 3
• HIV affects test interpretation: In HIV-infected patients, serologic tests for syphilis may show atypical responses with unusually low, high, or fluctuating titers 5

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Management Strategies

Empiric Treatment Approach

When diagnosis is unclear, treat for the most likely diagnosis based on clinical presentation and local epidemiology; many experts recommend treating for both syphilis and chancroid in communities where H. ducreyi is significant, especially when diagnostic capabilities are not ideal. 1, 2

Treatment by Etiology

Genital Herpes (HSV)

Initial episode:

• Acyclovir 400 mg orally 5 times daily for 10 days 2
• Alternative: Valacyclovir or famciclovir per standard dosing 6, 7

Recurrent episodes:

• Episodic or suppressive therapy depending on frequency 8

Primary Syphilis

• Benzathine penicillin G 2.4 million units IM in a single dose 2
• This regimen is effective for primary, secondary, or early latent syphilis 2

Chancroid

Recommended regimens (choose one):

• Azithromycin 1 g orally in a single dose 1, 2
• Ceftriaxone 250 mg IM in a single dose 1, 2
• Ciprofloxacin 500 mg orally twice daily for 3 days 1
• Erythromycin base 500 mg orally 4 times daily for 7 days 1

Critical contraindication: Ciprofloxacin is contraindicated in pregnant and lactating women and persons aged <18 years 1

Special Populations

HIV-Positive Patients

• HIV-positive patients with genital ulcers have slower healing, higher treatment failure rates, and may require prolonged therapy courses. 2
• For chancroid: Use erythromycin 500 mg orally 4 times daily for 7 days with close follow-up 2
• Uncircumcised HIV-infected patients may not respond as well to standard therapy 1

Pregnant Patients

HSV in pregnancy:

• The risk of neonatal HSV infection varies from 30% to 50% for genital HSV acquired in late pregnancy (third trimester), whereas with HSV acquisition in early pregnancy, the risk is about 1%. 6, 7
• Valacyclovir and acyclovir have not shown drug-associated risk of major birth defects based on clinical data over several decades 6
• Famciclovir has no identified drug-associated risk of major birth defects or adverse maternal/fetal outcomes 7
• Primary herpes during first trimester has been associated with neonatal chorioretinitis, microcephaly, and skin lesions 6, 7

Chancroid in pregnancy:

• Avoid ciprofloxacin (contraindicated) 1
• Use azithromycin 1 g orally single dose or ceftriaxone 250 mg IM single dose 1, 2

Syphilis in pregnancy:

• Benzathine penicillin G remains the treatment of choice 2

Follow-Up Protocol

Patients should be re-examined at 3-7 days after initiating therapy to assess for symptomatic and objective improvement. 2

• Large ulcers may require more than 2 weeks for complete healing, even with appropriate therapy 2
• Repeat HIV and syphilis testing at 3 months if initial results are negative 2, 5
• Patients should avoid sexual contact until ulcers are completely healed and treatment is completed 2

Partner Management

All sexual contacts within 10 days before symptom onset should be treated empirically, regardless of whether symptoms are present, to prevent further transmission. 2

• For syphilis: Evaluate and treat sexual contacts from the past 3 months 5

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Critical Management Considerations

When to Cover Multiple Pathogens

In high-risk patients (sex workers, MSM, multiple partners) presenting with genital ulcers, empiric treatment should cover multiple pathogens while awaiting test results, as co-infections occur in 10% of cases. 2, 3

• Treat for both syphilis and HSV when presentation is atypical 2
• Add chancroid coverage if endemic in the area or patient has epidemiologic risk factors 1, 2

Common Clinical Pitfalls

• Painless ulcers are not always syphilis: The classic painless chancre presentation occurs in only 31% of primary syphilis cases, and HSV can occasionally present with relatively painless ulcers 5
• Multiple ulcers do not exclude syphilis: While HSV typically causes multiple ulcers, syphilis can occasionally present with multiple chancres 5
• Negative initial serology does not exclude early primary syphilis: If the chancre appeared recently, repeat testing is mandatory 5

Risk Stratification Factors

• Sex workers, MSM, or recent travel to endemic areas increase risk for all STIs including chancroid and LGV 3
• Immunocompromised states (HIV, diabetes) are associated with atypical presentations and slower healing 3
• Multiple sexual partners or partners with known STIs increase likelihood of co-infections 3