Box 6.1 MAJOR CAUSATIVE AGENTS IN STDS

THE ULCERATIVE STDS

In the United States, HSV and syphilis are the most common causes of genital ulcers, with chancroid occurring infrequently. Outbreaks of lymphogranuloma venereum have been reported recently among men who have sex with men (MSM) in large US and European cities. For evaluating a patient with genital ulcers, the history and physical (table 6.1) are essential but often misleading, and diagnostic testing is important. All patients presenting with genital ulcers should undergo testing for herpes and syphilis, whereas testing for chancroid (Haemophilus ducreyi culture of the leading edge of the lesion) and lymphogranuloma venereum should be reserved for individuals at increased risk. However, given limitations of testing modalities, providers should consider empirical treatment of the most likely diagnosis while awaiting laboratory test results; despite comprehensive evaluation, it is estimated that at least 25% of patients with genital ulcers never have a laboratory-confirmed diagnosis. Ulcerative STDs are also cofactors for HIV transmission. Routine HIV screening is now recommended for all adult and sexually active adolescent patients; however, regardless of prior testing all patients newly diagnosed with syphilis or chancroid should undergo HIV testing, and HIV testing should also be strongly considered for those diagnosed with genital herpes infections.

Table 6.1 FEATURES OF GENITAL ULCERS BY ETIOLOGY

GENITAL HSV

Epidemiology

It is estimated that 50 million adolescents and adults in the United States— approximately 16% of all US residents 14–49 years of age—were infected with HSV-2, the most common cause of genital herpes infections. These estimates are based on serologic testing for HSV-2 and do not include genital HSV-1 infections, although recent data suggests that HSV-1 accounts for a growing number of genital HSV infections and may be at least as common as HSV-2 in genital infections. Large epidemiologic surveys suggest that as many as 70–90% of HSV-2–seropositive individuals are not aware of their infection yet and may still transmit the infection to others. Risk factors for HSV-2 infections in the United States include female gender, duration of sexual experience, African-American ethnicity, and history of prior genital infections. Other risk factors may include number of sex partners and socioeconomic status. A previous HSV-1 infection in an individual does not affect the likelihood of HSV-2 acquisition, but it does decrease the likelihood of developing a symptomatic infection with HSV-2.

Etiology and Pathogenesis

HSV is a double-stranded DNA virus. There are two human HSV types, which are distinguished based on their envelope glycoproteins: HSV-1 (glycoprotein G1) and HSV-2 (glycoprotein G2). Most genital HSV infections are caused by HSV-2, although the proportion of HSV-1 as the cause for genital HSV among adolescents and young women is increasing over time, and in young American women HSV-1 may now account for the majority of newly acquired genital HSV infections.

    Initial genital HSV infection occurs through direct contact of the virus with the genital mucosa or nonintact skin in the genital area. Primary infection occurs when an individual acquires HSV-1 or HSV-2 without previously having antibodies to either viral type. A nonprimary first episode occurs when an individual who has antibodies to one viral type (e.g., HSV-1) acquires the other viral type (e.g., HSV-2) for the first time. During primary infection, HSV infects cells in the epidermis and dermis and then becomes latent in the sensory neuron. Reactivation of viral replication in the sensory ganglia may result in subclinical viral shedding or in symptomatic outbreaks. A recurrent infection occurs when an HSV-1 or HSV-2 lesion develops in an individual with preexisting antibodies to the same HSV type. Subclinical shedding occurs when HSV can be isolated from a patient without symptoms. Recurrence and subclinical shedding are more common with HSV-2 than HSV-1 genital infection and in immunocompromised hosts. In patients with HSV-2 infection, viral shedding occurs at roughly the same rate for those who are symptomatic as for those who are asymptomatic.

Clinical Manifestations

The classic presentation of genital herpes, present in about 60–70% of patients, is painful, clustered vesicular lesions. However, symptoms of primary genital HSV infections may range from asymptomatic infection to a severe systemic illness. Severe illness presents with multiple, bilateral, painful, or pruritic genital lesions. The lesions are vesicular, pustular, or ulcerated. Common associated symptoms include fever, myalgias, malaise, headache, dysuria, and inguinal lymphadenopathy. Nonprimary first episodes are more likely to have less severe symptoms or be asymptomatic.

    Symptoms of recurrent HSV infections are less severe than primary or nonprimary first episodes, and the duration of symptoms and viral shedding are typically shorter. Lesions of recurrent HSV are usually unilateral, and systemic symptoms are infrequent. Approximately 50% of patients with recurrent episodes describe a typical prodrome of neuropathic symptoms in the nerve distribution of the skin lesions, such as pruritus, tingling, or shooting pains. Recurrent genital herpes episodes are more common with HSV-2 than HSV-1, although the frequency is variable for both. Recurrences are earlier and more frequent in patients with more severe primary infection and in immunocompromised hosts.

    Atypical presentations of genital HSV include vulvovaginitis or proctitis, often with fissures, urethritis, and cervicitis. HSV-2, the major cause of genital HSV, may also cause extragenital syndromes. These may include other skin or mucosal sites (e.g., erythema multiforme, herpes labialis), meningitis (often recurrent), hepatitis, and disseminated skin and visceral infections (which are more common in the immunocompromised host).

Diagnosis

Viral culture of the lesion remains the preferred diagnostic method for HSV disease, but the sensitivity of this method varies by the features of the disease. Rates of isolation of HSV are higher for primary lesions as compared to those of recurrent disease and decline as lesions begin to heal and crust over. More rapid testing for viral antigen by direct fluorescent antibody (DFA) may be performed within several hours. Polymerase chain reaction (PCR) testing for HSV DNA is the preferred test for diagnosis of HSV in the cerebrospinal fluid (CSF); it is currently not approved for testing of genital specimens.

    Serologic testing for antibodies to HSV type-specific glycoproteins (GP-G1 and GP-G2 for HSV-1 or HSV-2) has a sensitivity of 80–98% and specificity of >96%. Serologic testing may be helpful in evaluating culture-negative ulcers and is potentially helpful in identifying asymptomatic carriers, assessing and counseling partners of infected individuals, and STD screening. However, serologic testing is limited by a lag time to the development of antibodies after initial exposure and the fact that a positive result only indicates a previous exposure and may not be diagnostic of concurrent lesions.

Treatment

Treatment of genital HSV disease is usually aimed at control of symptoms, prevention of symptomatic outbreaks, and prevention of shedding and transmission. Treatment does not eradicate the latent virus. Systemic antiviral agents are the treatment of choice; topical therapy has minimal effect on shedding and symptoms. Specific regimens, based on the clinical syndrome, are outlined in table 6.2. Treatment of a first episode decreases symptom duration and shedding. Episodic therapy for outbreaks will decrease symptoms if administered during the prodrome, at the onset of an outbreak, or within 1 day of the appearance of a lesion. Daily suppressive therapy may reduce the frequency of outbreaks by 70–80% for patients who experience frequent (e.g., more than six annually) anogenital HSV outbreaks. Abstinence during outbreaks and routine condom use should be discussed as measures to reduce transmission to others, although condoms provide incomplete protection against transmission of HSV. Suppressive therapy may be given to HSV-2–infected individuals to reduce transmission to seronegative partners.

Pregnancy

Genital HSV infection during pregnancy poses a risk to both the developing fetus and the newborn. Approximately 10% of HSV-2–seronegative pregnant women have partners who are HSV-2 seropositive. The overall rate of HSV-1 or HSV-2 seroconversion during pregnancy in the United States is about 2%. Most new infections in pregnant women are asymptomatic, and most neonatal HSV disease is in infants born to asymptomatic mothers. The risk of transmission is highest during primary infection (30–50%), followed by nonprimary first episode and then recurrent disease (<1%). Pregnant women should be treated with systemic antiviral medications for active outbreaks. Cesarean section is offered to women with symptoms of genital HSV or visible lesions at the time of delivery in order to reduce the risk of neonatal HSV disease.

Immunocompromised Hosts

Atypical clinical presentations of anogenital HSV, including more severe and prolonged symptoms, are more common in immunocompromised patients, and HSV viral shedding is more common in HIV-infected individuals. The treatment of HSV in immunocompromised patients is outlined in table 6.3. For severe HSV disease in immunocompromised patients, acyclovir, 5 mg/kg intravenously every 8 hours, should be considered. HSV acyclovir resistance is rare. However, in immunocompromised hosts HSV resistance to acyclovir may be seen, and foscarnet should be considered in the treatment of acyclovir-resistant HSV disease.

SYPHILIS

Background and Epidemiology

Syphilis is caused by the spirochete bacteria Treponema pallidum. Between 1990 and 2000 rates of early syphilis in the United States had declined, but since 2001 rates increased each year, only reaching a plateau in 2010. In 2011 more than 70% of new diagnoses of early syphilis were in MSM. In 2010, in response to the high incidence of syphilis among MSM, the CDC instituted a recommendation for annual syphilis screening by serologic test among all MSM who are sexually active. Rates among women have recently begun to decrease, and rates of congenital syphilis continue to decline.

Transmission and Clinical Manifestations

Early syphilis includes all stages of syphilis within the first year after infection. This includes primary infection, secondary infection, and early latent infection. Late syphilis includes all stages of syphilis after the first year since acquisition. This includes late latent infection and tertiary syphilis. Latent syphilis includes any case of asymptomatic syphilis infection: early within the first year of acquisition and late thereafter.

    Sexual transmission of T. pallidum occurs through direct exposure to an open lesion during primary and secondary infection. The incubation period before the development of primary syphilis is up to 90 days. Primary infection is characterized by a painless ulcer or chancre at the site of inoculation. The painless nature of the lesion often helps to distinguish it from the lesions of chancroid and genital herpes; however, the painless chancre often goes unnoticed. Secondary infection results from systemic dissemination and occurs 2 to 8 weeks after the appearance of the chancre in about 25% of untreated patients. Rarely, the primary chancre is still present when secondary infection develops. The most common presentation is a generalized skin rash. Lesions are usually discrete pink or red macules or pustules, beginning on the trunk and bilateral proximal extremities. Any surface of the body may be involved and, although their involvement suggests the diagnosis, the palms (see Figure 6.1) and soles are not always involved. Systemic symptoms of fever, headache, myalgia, malaise, and lymphadenopathy are common. Other common skin manifestations include mucocutaneous lesions, condylomata lata, and alopecia. Other organ involvement may lead to hepatitis, ulcerative gastroenteritis, synovitis, immune-mediated glomerulonephritis, and nephrotic syndrome. Tertiary infection may involve any organ system, but the most common form in the United States is neurosyphilis followed by cardiac manifestations and gummatous lesions. Neurosyphilis can occur at any stage of infection. When symptomatic, symptoms may include cognitive, motor, or sensory deficits; ophthalmic disease (e.g., uveitis or optic neuritis); auditory symptoms; cranial nerve palsies; or symptoms of meningitis. Tabes dorsalis is the slow degeneration and demyelination of the dorsal column of the spinal cord associated with neurosyphilis, leading to a variety of deficits including weakness, diminished reflexes, gait disturbances, and paresthesias (e.g., formication).

Diagnosis

The definitive diagnostic tests for early syphilis are direct visualization of the spirochete by dark field microscopy or DFA testing of exudate from a lesion. However, these require expertise and are often not attainable. The most commonly used diagnostic tool for syphilis is serology, with tests falling into two categories: the nontreponemal tests and the treponemal tests (see table 6.4). The nontreponemal tests are the Venereal Disease Research Laboratory (VDRL) and the rapid plasma reagin (RPR). They are used primarily as screening tools, and their titers are used to follow response to therapy. The two tests are equally valid, but the results of both tests cannot be directly compared so only one should be followed over time in a single patient. Nontreponemal tests may be negative in 20–30% of patients with a primary chancre. The tests may also be negative in approximately 2% of patients with secondary syphilis due to a prozone phenomenon, in which a high antigen burden in undiluted serum leads to a false positive result. In this case, dilution of the sample will correct the results. Negative results are also seen in a proportion of patients with late untreated or previously treated syphilis. The treponemal tests are qualitative assays using T. pallidum antigens; they include the fluorescent treponemal antibody-absorption (FTA-abs) test and the T. pallidum particle agglutination (TP-PA) test. These tests are more specific and are used to confirm infection. The treponemal tests may be negative in a proportion of patients with primary syphilis but remain positive for life, despite treatment, in >90% of patients. Several newer tests are available including the T. pallidum enzyme immunoassays (CAPTIA, using native T. pallidum antigens; and ICE, using recombinant T. pallidum antigens) and the T. pallidum Western blot. The T. pallidum enzyme immunoassays (EIA) tests have a high sensitivity and may be automated, so are useful for high-volume screening but are not widely used at present. All patients diagnosed with syphilis should also be tested for HIV.

    Nontreponemal serologic tests may be negative in as many as 25% of patients with neurosyphilis. The diagnosis of neurosyphilis is made by CSF analysis. CSF analysis is recommended for patients with suspected neurosyphilis; patients with known syphilis and neurologic, ophthalmic, or otic symptoms; patients with active tertiary disease; and patients with treatment failure. Many authorities recommend CSF examination for all HIV-infected patients with latent syphilis or syphilis of unknown duration. It remains controversial whether CSF analysis should be performed for all patients with latent syphilis and a nontreponemal titer of 1:32 or greater. CSF analysis should include a cell count, protein level, and CSF-VDRL titer. The CSF protein and CSF white blood cell (WBC) count are usually elevated, but these findings are nonspecific. The CSF-VDRL is specific but not sensitive for diagnosing neurosyphilis. When positive, titers are used for follow-up. When neurosyphilis is suspected clinically, empirical treatment should be strongly considered even when the CSF-VRDL is negative.

Treatment

The preferred treatment for syphilis at any stage of disease is parenterally administered penicillin G (benzathine, aqueous procaine, or aqueous crystalline, but not combination benzathine-procaine). For nonpregnant patients who are allergic to penicillin, alternative therapy may include doxycycline and tetracycline. Azithromycin (2 g orally once) may be considered for early syphilis, but resistance mutations and treatment failures have been documented with this regimen. Ceftriaxone may also be considered at a dose of 1 g intramuscularly or intravenously daily for 10–14 days for primary or secondary syphilis, but the data to support its use are lacking. Pregnant women with syphilis should always be treated with penicillin-based regimens, even if this requires desensitization in the case of a penicillin allergy. Penicillin-based therapies are the only regimens that have clearly been shown to be effective during pregnancy, including prevention of transmission to the fetus. Treatment regimens depend on the stage of infection (see table 6.5).

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