Is it herpes, syphilis, or something else?

Genital ulcers could be one of many sexually transmitted diseases or an infection that is not transmitted by sex. An expert walks you through a case.

This is the first of a three-part series on sexually transmitted diseases. Part 2 will appear in the June issue.

A 30-year-old man presents with mildly painful sores that have been present on his penis for three days. He had no symptoms before the lesions appeared, and he has never had similar genital lesions before. The patient has no other symptoms and otherwise feels well. He has no significant medical history and no drug allergies.

Examination of the penile shaft reveals multiple shallow ulcerations with some exudate. Minimal bilateral inguinal lymphadenopathy is nontender. The remainder of his genital exam is unremarkable.

Q: What patient information should be obtained to assist in making a diagnosis?
A complete sexual history is particularly important in patients presenting with genital complaints. This patient reveals that his partners are male and that in the past three months he has had sex with three men, two of whom are new partners. He gives and receives oral sex and engages in insertive anal sex. He uses condoms for anal sex, but not with his primary boyfriend. Results of his latest HIV test four months ago were negative. His only prior sexually transmitted disease (STD) was gonorrhea (urethral) five years ago. His boyfriend is HIV negative and doesn’t have any STD symptoms. The patient denies any drug use and occasionally uses alcohol.

Q: Given your patient’s sexual history and genital findings, should you perform further examination?
Yes. All patients being evaluated for STDs should have an exam that includes: skin, oral cavity, lymph nodes, and genitals. An anal exam should be done if there is a history of any type of anal sex. Any patient with lesions suspicious for syphilis should have a neurologic exam focusing on cranial nerves and motor and sensory deficits. This patient’s history of receptive oral sex and multiple partners accompanied by genital lesions, possibly from an STD, necessitate further physical exam.

Examination of the patient’s skin is unremarkable and without rash. Oropharyngeal exam is within normal limits; no mucous patches or ulcerative lesions are found. There is no lymphadenopathy.

Q: What is your differential diagnosis?
The differential for genital ulcers is broad and includes genital herpes, syphilis, and chancroid, along with other less common STD causes of genital ulcer (lymphogranuloma venereum, granuloma inguinale, and acute HIV infection) and non-STD causes of genital ulcer (including candidiasis, psoriasis, trauma, Reiter’s syndrome, Behçet’s syndrome, fixed-drug eruption, and scabies). Co-infections can occur. In approximately 25% of patients, no etiology is found. Based on this patient’s sexual history, he is at high risk for a sexually transmitted infection.

Q: What laboratory tests should be done?
Tests for herpes and syphilis are warranted. Herpes viral culture of the lesion(s) is recommended. Polymerase chain reaction (PCR), which is more sensitive, can also be used, but it is more expensive and is not FDA-approved for diagnosing genital lesions. If neither culture nor PCR testing is available, a direct fluorescent antibody test can be used. (Other antigen detection methods do not distinguish between herpes simplex virus [HSV]-1 and HSV-2 and are not recommended.) Type-specific glycoprotein G serologic testing for HSV-2 can be considered if genital lesions are crusted or if direct testing of the lesion is negative. Keep in mind that it may take up to four months for any of these serologic tests to be positive after initial infection.

With regard to syphilis, direct assessment of the genital ulcer(s) with darkfield microscopy exam or direct fluorescent antibody toTreponema pallidum is reliable, though access to these tests is frequently limited. Serologic testing with a nontreponemal syphilis test, a rapid plasma reagin test (RPR), or a Venereal Disease Research Laboratory (VDRL) test, are also acceptable alternatives. Both tests are nonspecific and measure an antibody to a cardiolipin that is present in other inflammatory conditions.

A specific treponemal test, such as the T. pallidum agglutination assay (TP-PA) or the fluorescent treponemal antibody absorption test (FTA-ABS), is necessary to confirm a syphilis diagnosis when using RPR or VDRL as the first screening test. Most laboratories will automatically perform the treponemal tests on all positive RPR or VDRL samples. The sensitivity of RPR or VDRL tests in early primary syphilis is 74%-87%, so a negative test does not rule out syphilis, particularly if the lesion has been present for only a few days.

Additional testing to assess for chancroid is not necessary in this case. This would be considered if the patient had traveled to an endemic area or exchanged sex for drugs or money.

Q: Are there other laboratory tests that should be done?
Sexually active men who have sex with men (MSM) should be screened for urethral gonorrhea and chlamydia, rectal gonorrhea and chlamydia (if engaging in receptive anal sex), and pharyngeal gonorrhea (if engaging in oral receptive sex). An HIV test should be performed even though his latest test was just four months ago. Presentation with a new STD indicates possible concurrent HIV exposure.

Q: What is your presumptive diagnosis?
This case of an MSM with multiple mildly painful, shallow genital ulcers and nontender inguinal lymphadenopathy demonstrates the challenges of diagnosing the cause of genital ulcers. The presentation is consistent with herpes, which classically appears as multiple shallow lesions with exudate. However, if these were primary lesions, one would expect them to be more painful and accompanied by tender regional lymphadenopathy and systemic symptoms. Recurrent herpes is another possibility, though it typically has fewer lesions.

This patient’s lesions are not classic for syphilis, which typically presents as a solitary, painless indurated ulcer with nontender, bilateral lymphadenopathy. Atypical presentations of syphilis (and herpes) do occur, particularly in HIV-infected persons. The lesions are not consistent with chancroid, which classically presents as painful deep ulcer(s) with ragged edges and tender, inguinal lymphadenopathy that may suppurate. A non-STD etiology can be considered, although given this man’s sexual history, STDs should first be excluded.

Q: Does the current epidemiology of herpes, syphilis, and chancroid influence your presumptive diagnosis?
Yes. In the United States, genital herpes is the most common cause of STD-related genital ulcers among sexually active adults, followed by syphilis. Chancroid is rare in this country. Even though syphilis is not as common as herpes, rates of primary and secondary syphilis among MSM have been increasing since 2001. Factors associated with high rates of syphilis among MSM are HIV coinfection, high-risk sexual behavior, methamphetamine use, and meeting sexual partners via the Internet. The fact that this patient is an MSM engaging in high-risk sex should raise your suspicion of syphilis.

Q: What is your management strategy?
Presumptive treatment for syphilis, herpes, or both is often necessary for patients with genital ulcers. In general, patients with classic syphilis lesions or those at high risk for syphilis should be offered presumptive syphilis treatment. Those with a classic presentation of vesicles or prodrome consistent with herpes should be offered herpes treatment. Also, patients at risk for being lost to follow-up should be treated for syphilis, given the serious sequelae of untreated syphilis and risk of transmission to partners. In this patient, empiric treatment for syphilis is recommended despite the atypical presentation. He is at sufficient risk for syphilis given his sexual orientation and high-risk behavior. Penicillin G benzathine (Bicillin L-A) is the only recommended regimen for early syphilis. Errors in use of other preparations of penicillin G benzathine (particularly Bicillin C-R) have been documented, so caution to avoid such errors should be exercised. The patient is told that malaise, fever, arthralgias, and other flulike reactions can occur within 24 hours. He is also warned that syphilis can be transmitted orally as well as ano-genitally, and he is encouraged to consistently use condoms.

Q: Should you contact your local health department to report this possible syphilis case?
Yes. Nationally, syphilis is a reportable condition, and presumptive cases generally should be reported. For specifics, check with your locality. Your local health department will generally provide assistance in partner management for confirmed cases.

Q: Is there any further follow-up necessary for this patient?
Yes. The patient returns one week later and his lesions are resolving. His lab results reveal a reactive RPR with titer of 1:256 and a reactive confirmatory TP-PA. All other tests (i.e., herpes culture, gonorrhea, chlamydia, and HIV) are negative. The health department has already contacted him to obtain information on his partners so they can be evaluated and treated.

This patient should have repeat RPR tests at six and 12 months to ensure adequate response to treatment, which is reflected by a fourfold drop in his RPR titer.

Annual screening with a nontreponemal serology test (RPR or VDRL) is recommended after adequate treatment response. MSM with ongoing risk for syphilis should have more frequent screening, with some experts recommending intervals of three to six months. The patient in this case was counseled about his risk for STDs and the importance of STD screening.

This case demonstrates both an atypical presentation of syphilis that could be easily misdiagnosed as herpes and the importance of syphilis testing for all patients with genital ulcers. The case also shows that knowledge of current STD epidemiology is important when assessing patients with genital ulcers and why clinicians should have a low threshold for presumptive treatment of syphilis in MSM with such lesions.

For more about genital ulcer disease and syphilis, visit the National Network of Prevention Training Centers’ (NNPTC) online case series (www.stdhivtraining.org/nnptc). To find out about STD training, go to the NNPTC Web site (www.depts.washington.edu/nnptc).

For a list of references used in this article, contact the editor via e-mail (editor@clinicaladvisor.com) or telephone (646.638.6077).

Dr. Adler, a family physician by training, is a clinical instructor at the California STD/HIV Prevention Training Center in Oakland. She would like to thank colleagues Heidi Bauer, MD, MS, MPH, Helene Calvet, MD, and Linda Creegan, MS, FNP, for their assistance.

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