How Should I manage This Young Woman's Painful Genital Ulcers

A 29-year-old female accountant is seen by you for painful lesions in the vulva. Her past medical history is notable only for the use of the hormonal contraceptive patch. She has been married for one year and denies a past history of herpes. Examination reveals two mildly tender grouped ulcerative lesions on the left labia.

What is the differential diagnosis?

Ulcerative lesions of the genitals can have both infectious and non-infectious etiologies. Infectious causes predominate, with Herpes Simplex Virus (HSV) being by far the most common cause. Since syphilis (Treponema pallidum) is the second most common cause of infectious ulcers, it should be considered in the differential.

Less frequent infectious causes include chancroid ( Haemophilus ducreyi), lymphogranuloma venereum (Chlamydia trachomatis, serovars L1-3), and granuloma inguinale (Calymmatobacterium granulomatis).

Noninfectious causes include Behcet’s syndrome, psoriasis, and neoplasms. These etiologies may be considered based on the presence of other associated findings (e.g. history of recurrent aphthous ulcers are indicative of Behcet’s) or if an infectious agent is not found after diagnostic testing.

What clinical findings are helpful in differentiating the possible etiologies?

Clinical findings that may aid in guiding the differential include the number and morphology of ulcers, the presence or absence of pain, and the presence or absence of lymphadenopathy.

Painful ulcers are described with herpes and chancroid, while the ulcers in primary syphilis, lymphogranuloma venereum, and granuloma inguinale are classically painless. Genital HSV typically occurs as multiple vesicles within the labia, vagina, or rectum that eventually open to form superficial ulcers.

Primary syphilis typically begins as a single well-demarcated ulcer with a clean base (chancre). Like herpes, chancroid lesions occur with multiple tender ulcers, but have a friable base covered with a necrotic exudate. Painful, unilateral lymphadenopathy accompanies about half of chancroid cases. While empiric treatment based on historical factors and clinical features is recommended, the history and exam findings are not adequately sensitive or specific for an accurate diagnosis. Confirmation should always be made through laboratory testing.

What laboratory tests would you order?

My recommendation for initial diagnostic testing includes virologic testing for herpes and serologic testing for syphilis. Virologic tests for herpes are indicated when lesions are present and include both cell culture and PCR. Culture for HSV is widely available and less costly than PCR. Culture is also highly specific but lacks sensitivity, particularly when specimens are sampled from healing or recurrent (non-primary) lesions.

Two PCR-based tests are now FDA approved for the detection of herpes in symptomatic anogenital lesions. Specimens for PCR are collected in a similar fashion as culture specimens, have a lower false negative rate than culture, and are becoming increasingly used in clinical practice.

Type-specific serologic tests for HSV are also available and may be useful for diagnostic confirmation of genital herpes when lesions are not present at the time of presentation or when prior attempts at laboratory confirmation, like culture and PCR, are negative and clinical suspicion persists.

All patients with anogenital ulcers should have syphilis serologic testing, which includes non-treponemal (VDRL, RPR) and treponemal (FTA-ABS, TP-PA) tests. Traditionally, screening was initiated with a non-treponemal test and, if positive, followed by a confirmatory treponemal test. Some clinicians and/or labs now reverse that order. Negative non-treponemal tests with a high index of clinical suspicion for primary syphilis can be followed with a repeat test in a month, since the false negative rate of these tests with primary syphilis infection may be as high as 30%.

The CDC recommends that all patients with anogenital ulcers have HIV screening. Additional testing for sexually transmitted infections, including Chlamydia trachomatis, Neisseria gonorrhea, and Hepatitis B and C should be individualized.

You make the diagnosis of herpes genitalis. Her husband states he has never had herpes in the past. Both the patient and husband deny any instances of infidelity.

Does the diagnosis of herpes mean that one of them is being untruthful?

Most patients with a new diagnosis of herpes will want to know if they acquired the infection from a former or current partner. The chronicity of the HSV infection, the variability of symptomatology, and the overall pervasiveness of the virus can complicate the possibility of a definitive answer. As few as 10% of infected individuals are aware of their positivity; therefore, the patient’s partner may be unknowingly infected and for an unknown length of time and from any previous partner. Negative serologic testing in this patient’s partner could only confirm that the partner was not the source of the patient’s infection.

The patient inquires whether she has herpes genitalis type 1 or 2.

Is there any value to making this differentiation?

Though HSV-1 is usually associated with oral infections and HSV-2 with anogenital infections, both viral types may cause anogenital herpes. The value to differentiating between the two is to counsel the patient with regard to the likelihood of recurrence and the risk of transmission to seronegative partners. While both viral types establish latency in the dorsal root ganglion innervating areas involved in the initial infection, the probability of recurrent clinical episodes is much higher with HSV-2 infections.

Rates of subclinical shedding and infectivity are also much greater for HSV-2 than HSV-1 infected individuals. Both virologic (culture and PCR) and serologic (IgG) type-specific testing for HSV is available. Serologic IgM testing for HSV 1 or 2 should not be used because it is not type-specific and it may be positive during recurrent as well as primary outbreaks.

All patients with a first-episode HSV infection should be treated with a systemic antiviral. Recommended regimens include acylovir, valacylovir, or famciclovir for 7-10 days (or longer if healing is incomplete after 10 days of treatment). All three are CDC-recommended regimens for HSV infection (per the 2010 published recommendations) and each has been demonstrated to decrease the severity and duration of symptoms. Choice of medication depends on cost and convenience of dosing. The CDC discourages use of topical antivirals due to a lack of clinical benefit.

Patients should be counseled that the goal of antiviral treatment is to relieve and shorten the duration of symptoms but is not curative and will neither affect the natural course of the infection nor decrease the risk of recurrence upon completion.

The patient responds to treatment but over the next six months has two additional outbreaks.

How would you manage recurrences?

The majority of patients with one symptomatic episode of HSV-2 (and a minority of patients with a first clinical-episode of HSV-1) will experience at least one symptomatic recurrence. Recurrent episodes may be treated with shortened courses of the same antivirals recommended for initial genital infection. Episodic treatment for recurrent genital herpes can assist with relieving or shortening the duration of lesions but must be initiated within one day of lesion prodome or onset for maximum effectiveness. Patients should therefore be provided with a supply or advanced prescription of antiviral medications and instructed to initiate treatment at symptom onset.

What options are available for preventing recurrences?

Daily systemic antiviral regimens are also available for suppression of recurrences. Treatment has demonstrated efficacy in patients with frequent, meaning more than 6 outbreaks per year, and infrequent outbreaks. Treatment options for both suppressive and episodic therapy should, therefore, be discussed and offered to all patients.

Safety of continuous use has been demonstrated in acyclovir for up to 6 years of use, and valacylovir and famciclovir for up to one year. Decisions regarding suppressive therapy should be based on patient preference as well as recurrence frequency and severity. Since patients with HSV experience viral shedding during asymptomatic periods, partner susceptibility should also be taken into consideration as an indication for suppressive treatment.

Daily valacylcovir 500mg in HSV seropositive individuals has demonstrated efficacy in reducing HSV-2 transmission to seronegative partners. In addition to suppressive therapy, consistent condom use and avoidance of sexual activity during symptomatic recurrences are other strategies to prevent transmission. Since the frequency of recurrences decreases with time, physicians should consider and discuss the need for continued therapy at least yearly.

Three years later the patient becomes pregnant.

How does her history of herpes impact the management of her pregnancy?

The risk of neonatal herpes transmission is greatest in neonates whose mothers acquire the infection near the time of delivery (any time within the third trimester). Universal screening of pregnant women to assess HSV serostatus is not recommended; however, women who are not clinically known to have HSV-2 but have known HSV infected partners (genital/oral) should abstain from intercourse and/or receptive oral — genital contact during the third trimester.

Herpes is less problematic for women who acquire herpes prior to, or even during the first half of, pregnancy, with the rate of neonatal transmission from these women being less than 1%. In our patient, prevention of neonatal transmission would depend on avoidance of infant exposure to herpetic lesions during the time of delivery. Our patient should be evaluated through history and physical exam for signs of infection at the onset of labor, with a plan for Cesarean section only if prodromal symptoms or lesions are present.

Pregnant women with one or more recurrences during pregnancy could be offered oral acyclovir (400 mg 3 times daily) starting at 36 weeks of gestation and continuing through delivery. This strategy effectively reduces the rate of cesarean section in women with recurrent genital herpes.