Diagnosis

Genital herpes infection is common, afflicting more than 50 million people in the United States (Xu et al, 2006). It is caused by HSV type 2 (HSV-2) in 85% to 90% of cases and HSV type 1 (HSV-1) in 10% to 15% of cases. HSV-1 is responsible for common cold sores but can be transmitted via oral secretions during oral-genital sex. Silent infection is common and may account for more than 75% of viral transmission (Langenberg et al, 1999). Up to 80% of women with HSV-2 antibodies have no history of clinical infection (White and Wardropper, 1997). The incubation period ranges from 1 to 26 days but is usually short, approximately 4 days. Nongenital infection of HSV-1 during childhood may be protective to some extent against subsequent genital HSV-2 infection in adults. When exposed to HSV-2, women with negative HSV-1 antibodies had a 32% risk of infection per year whereas women with positive antibodies had a 10% risk of infection per year (Baker, 1997).

Primary infection manifests as painful ulcers of the genitalia or anus and bilateral painful inguinal adenopathy. The initial presentations for HSV-1 and HSV-2 are the same. A group of vesicles on an erythematous base that does not follow a neural distribution is pathognomonic (Figs. 11-1 to 11-3). The differential diagnosis includes other STIs, such as primary syphilis and chancroid, as well as noninfectious disorders such as Crohn disease, trauma, contact dermatitis, erythema multiforme, Reiter syndrome, psoriasis, and lichen planus.

Figure 13–1 Typical vesicular eruption of herpes simplex virus.

Figure 13–2 Herpes simplex virus infection on the penis.

Figure 13–3 Vulvovaginal herpes simplex virus infection.

The initial infection is often associated with constitutional flulike symptoms. Sacral radiculomyelopathy is a rare manifestation of primary infection that has a greater association with primary anal HSV. Genital lesions, especially urethral lesions, may cause transient urinary retention in women. Recurrent episodes are usually less severe, involving only ulceration of the genital or anal area. Severe disease and complications of herpes include pneumonitis, disseminated infection, hepatitis, meningitis, and encephalitis. Asymptomatic viral shedding can take place for up to 3 months after clinical presentation, thereby perpetuating the risk of transmission (Baker, 1997).

The diagnosis of genital herpes should not be made on clinical suspicion alone because the classic presentation of the ulcer occurs in only a small percentage of patients. Women especially may present with atypical lesions such as abrasions, fissures, or itching (ACOG Practice Bulletin, 2004). Viral culture with subtyping has been the gold standard of diagnosis of herpes infection. Viral subtype should be determined in every patient because it is important for prognosis and counseling. Women with HSV-2 have an average of four recurrences within the first year, and women with HSV-1 have one recurrence in the first year. After the first year, HSV-1 rarely recurs whereas the rate of HSV-2 decreases but slowly (Bendedetti et al, 1994). Viral culture can generally isolate the virus in 5 days, is relatively inexpensive, and is highly specific. However, the sensitivity of viral culture ranges from 30% to 95%, depending on the stage of the lesion and whether it is the primary infection or a recurrence. Viral load is highest when the lesion is vesicular and during primary infection. Therefore, viral culture has the highest sensitivity at these times and declines sharply as the lesion heals.

There are currently three U.S. Food and Drug Administration (FDA)-approved type-specific antibody assays (HerpeSelect HSV-1 and HSV-2 ELISA, HerpeSelect HSV-1 and HSV-2 Immunoblot, and Captia ELISA). These tests identify antibodies to HSV glycoproteins G-1 and G-2, which evoke a type-specific antibody response (Wald and Ashley-Morrow, 2002). These tests may also be able to identify recently acquired versus established HSV infection based on antibody avidity (Morrow et al, 2004).

Antigen detection kits are available but cannot distinguish reliably between HSV-1 and HSV-2. PCR testing has been shown to be 1.5 to 4 times as sensitive as viral culture. Samples are easy to attain and more stable than samples for viral culture. PCR testing will most likely replace viral culture as its availability increases and cost decreases.

Treatment

Antiviral therapies approved for treatment include those using oral acyclovir, valacyclovir, and famciclovir (Table 13–2). Topical antiviral medications are not effective. Recurrences can be treated with an episodic or suppressive approach. When used for episodic treatment, medication must be initiated during the prodrome or within 1 day of the onset of lesions. Daily suppressive therapy has been shown to prevent 80% of recurrences and is an option for patients who suffer from frequent recurrences. It has been shown to decrease the frequency and duration of recurrences as well as viral shedding and therefore reduce the rate of transmission. The safety and efficacy of daily suppressive therapy has been well documented.

Table 13–2 Recommended Oral Treatment for Genital Herpes Simplex Virus Infection

Diagnosis

Chancroid, caused by Haemophilus ducreyi, is the most common ulcerative STI worldwide but is rare in the United States. It affects men three times more often than women. The incubation period ranges from 1 to 21 days. It causes a painful, nonindurated ulcer on the penis or vulvovaginal area. The ulcer has a friable base covered with a gray or yellow purulent exudate and a shaggy border. It can spread laterally by apposition to inner thighs and buttocks, especially in women. It is associated with inguinal adenopathy that is typically unilateral and tender with a tendency to become suppurative and fistulize (Figs. 13-4 and 13-5). H. ducreyi is fastidious and difficult to culture. The special culture media is not widely available, and sensitivity of culture remains less than 80%. Gram stain of a specimen obtained from the undermined edge of the ulcer may be more helpful in identifying the short, fine, gram-negative streptobacilli, which are usually arranged in short, parallel chains. Recently, PCR assays have been shown to be a sensitive and specific means of detecting H. ducreyi. Although no PCR test is currently FDA approved, testing can be performed by commercial agencies. HIV and syphilis screening should be performed at the time of diagnosis and 3 months after treatment if initial results are negative.

Figure 13–4 Chancroid with regional adenopathy.

Figure 13–5 Chancroid lesion.

Treatment

Single-dose treatments consist of azithromycin, 1 g orally, or ceftriaxone, 250 mg intramuscularly. Alternative regimens include ciprofloxacin, 500 mg twice daily for 3 days, or erythromycin base, 500 mg by mouth three times daily for 7 days. However, antibiotic susceptibility varies geographically. Resistance has been reported to ciprofloxacin and erythromycin in some regions. Ciprofloxacin is contraindicated during pregnancy and lactation. Subjective improvement should be noted within 3 days, and ulcers generally heal completely in 7 to 14 days. Healing may be slower in uncircumcised men with ulcers below the foreskin and in patients with HIV (Schmid, 1999). Patients should be reexamined in 5 to 7 days. Sexual partners should be examined and treated if sexual relations were held within 2 weeks before or during the eruption of the ulcer. Symptomatic relief of inguinal tenderness can be provided by needle aspiration or incision and drainage of the buboes.

Diagnosis

Syphilis is caused by the spirochete Treponema pallidum. Incubation periods range between 10 and 90 days. It is spread through contact with infectious lesions or body fluids. It can also be acquired in utero and through blood transfusion. Syphilis has been categorized into overlapping stages based on clinical signs and symptoms to guide diagnosis and treatment. Primary syphilis is characterized by a single painless, indurated ulcer occurring at the site of inoculation that appears about 3 weeks after inoculation and persists for 4 to 6 weeks (Figs. 13-6 and 13-7). The ulcer is typically found on the glans, corona, or perianal area on men and on the labial or anal area on women. It is often associated with bilateral, nontender inguinal or regional lymphadenopathy. Because the ulcer and adenopathy are painless and heal without treatment, primary syphilis often goes unnoticed.

Figure 13–6 Syphilis with vulvar chancre.

Figure 13–7 Syphilis with penile chancre.

Secondary syphilis usually begins 4 to 10 weeks after the appearance of the ulcer but may present as long as 24 months after the initial infection. Secondary syphilis manifests as mucocutaneous, constitutional, and parenchymal signs and symptoms (Figs. 13-8 and 13-9). Frequent early manifestations consist of maculopapular rash, which is commonly seen on the trunk and arms, and generalized nontender lymphadenopathy. After several days or weeks, a papular rash may accompany the primary rash. These papular lesions are associated with endarteritis and may therefore become necrotic and pustular. The distribution widens and commonly affects the palms and soles. In the intertriginous areas these papules may enlarge and erode to produce condyloma lata, which are particularly infectious. Less common manifestations of secondary syphilis include hepatitis and immune complex–induced glomerulonephritis (Goldmeier and Guallar, 2003).

Figure 13–8 Secondary syphilis affecting the genitalia.

Figure 13–9 Secondary syphilis affecting the soles of the feet.

Approximately one third of untreated patients will develop tertiary syphilis. It is very rare in industrialized countries, except for occasional cases reported in HIV patients. Syphilis is a systemic disease that can affect almost any organ or system, especially the cardiovascular, skeletal, and central nervous systems, and skin. Neurosyphilis can occur at any stage. Aortitis, meningitis, uveitis, optic neuritis, general paresis, tabes dorsalis, and gummas of the skin and skeleton are just some of the sequelae associated with tertiary syphilis.

Latent syphilis is defined as seroreactivity with no clinical evidence of disease. Early latent syphilis is latent syphilis acquired within the past year. All other latent syphilis is either referred to as late latent syphilis or latent syphilis of unknown duration.

Darkfield microscopy and direct fluorescent antibody (DFA) tests can be performed on specimens obtained from primary or secondary lesions. Darkfield microscopy is not widely available, but DFA testing of a fixed smear from a lesion can be performed at many commercial laboratories. Nontreponemal serologic testing with rapid plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL) are the most common methods of screening suspected individuals. Sensitivity is 78% and 86% for RPR and VDRL, respectively, in primary syphilis, 100% for both in secondary syphilis, and over 95% in tertiary syphilis (Hart, 1986). The false-positive rate is 1% to 2% and may be secondary to a large variety of causes (Golden et al, 2003). Therefore, all positive tests should be confirmed with treponemal testing using T. pallidum particle agglutination (TP-PA) or fluorescent treponemal antibody absorbed (FTA-ABS) testing. HIV can cause false-negative results by both treponemal and nontreponemal methods (Hicks et al, 1987; Erbelding et al, 1997). Positive treponemal antibody tests usually remain positive for life and do not correlate with disease activity. Nontreponemal antibody titers, RPR and VDRL, correlate with disease activity. These tests usually become negative 1 year after treatment. A low percentage of patients remain “serofast,” never regaining a negative titer. A fourfold difference in titer is reflective of a clinically significant difference. A fourfold increase after therapy is indicative of ineffective therapy or reinfection (Johnson and Farnie, 1994). A fourfold decrease represents successful treatment. Following disease activity, the same test, either RPR or VDRL, should be performed at the same laboratory because the results are not interchangeable and may vary from laboratory to laboratory.

The U.S. Preventive Services Task Force recommends that pregnant women and people who are at higher risk for syphilis infection receive screening tests for the disease (Calonge, 2004). People at higher risk for syphilis include men who have sex with men and engage in high-risk sexual behavior, commercial sex workers, persons who exchange sex for drugs, and those in adult correctional facilities. The CDC recommends that HIV testing should be considered in the initial evaluation of all patients with syphilitic infection and that screening for hepatitis B and C, gonorrhea, and chlamydial infection also should be considered. The presence of chancres increases the risk of HIV acquisition twofold to fivefold (Greenblatt et al, 1988; Stamm et al, 1988).

Treatment

Benzathine penicillin G (2.4 million units intramuscularly as a single dose) remains the treatment of choice for adults with primary, secondary, or early latent syphilis. Other parenteral preparations or oral penicillin are not acceptable substitutes. The Jarisch-Herxheimer reaction is a reaction consisting of headache, myalgia, fever, tachycardia, and increased respiratory rate that occurs within the first 24 hours after treatment with penicillin. Patients should be warned about the reaction, and it is usually managed with bed rest and nonsteroidal anti-inflammatory agents. It may cause fetal distress and preterm labor in pregnant women. If the patient has penicillin allergy, doxycycline, 100 mg by mouth twice daily for 14 days, or tetracycline, 500 orally for 14 days, have been used as alternatives. Close follow-up of patents receiving alteratives to the recommended benzathine penicillin regimen is critical.

For late latent syphilis, latent syphilis of unknown duration, or tertiary syphilis with no evidence of neurosyphilis, benzathine penicillin, 2.4 million units intramuscular injection should be repeated weekly for a total of three doses (total dose of 7.2 million units) or doxycycline therapy extended for a total of 4 weeks. In pregnancy, the alternative regimens of doxycycline and tetracycline should not be used and desensitization to penicillin is recommended if the patient has a penicillin allergy. Small studies have shown that azithromycin or ceftriaxone may be potential alternatives for early syphilis, but insufficient data are available to make definitive recommendations (Augenbraun and Workowski, 1999; Gruber et al, 2000; Hook et al, 2002).

Neurosyphilis and syphilitic eye disease are treated with aqueous crystalline penicillin G, 3 to 4 million units intravenously every 4 hours for 10 to 14 days, or with procaine penicillin G, 2.4 million units intramuscularly once daily, plus probenecid, 500 mg orally four times daily, with both drugs given for 10 to 14 days. Probenecid cannot be used in patients with an allergy to sulfa. The CDC recommends consideration of treatment with benzathine penicillin, 2.4 million units intramuscularly once a week for 3 weeks after completion of the neurosyphilis treatment regimen, to provide total duration of therapy comparable to that of late syphilis.

Patients should be followed with nontreponemal antibody titers at 6 and 12 month. Patients with HIV should be followed at 3, 6, 9, 12, and 24 months. A fourfold decrease in antibody titer is usually reflective of cure. The rate of treatment failure ranges from 4% to 21% (Parkes et al, 2004

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