Essentials of Diagnosis

  • Most individuals with genital herpes are unaware of the infection but are able to transmit it to others.
  • Type-specific serology allows reliable differentiation of chronic type 1 from type 2 infection.
  • Clinical diagnosis should be confirmed by diagnostic testing of the genital lesion (culture or polymerase chain reaction [PCR]) or a type-specific serologic assay.

General Considerations

Herpes simplex virus (HSV) infections are endemic in the United States and are a cause of recurrent genital and oral ulcerative disease. Genital herpes infection can be caused by type 2 virus (HSV-2), or less frequently by type 1 (HSV-1). Although most infections are asymptomatic, genital HSV infection, whether type 1 or 2, can cause vesicular and ulcerative disease in adults and severe systemic disease in neonates and immunocompromised individuals. Genital HSV infection increases the risk of HIV acquisition in infected persons.

HSV-2 transmission is almost always sexual, whereas HSV-1 is usually transmitted through nonsexual skin-to-skin contact. Current estimates place the incidence of HSV-2 infection at more than 1.5 million cases annually. In the general population, HSV-2 seroprevalence is low for persons younger than 12 years of age, rises sharply following onset of sexual activity, and peaks by the early 40s. HSV-2 seroprevalence in the United States rose 30% between 1978 and 1991 to 21.7%. The overwhelming majority of individuals with genital HSV infection have undiagnosed initial infections and unrecognized recurrences. Orolabial HSV-2 infection is rare and is almost always associated with genital infection.

HSV-1 infection frequently occurs as orolabial infection in childhood, and approximately 20% of children younger than 5 years of age are seropositive. The seroprevalence of HSV-1 rises almost linearly with increasing age to approximately 70%. In the general population over the past decade, HSV-1 has become an increasingly common cause of genital infection, with an estimated 50% of newly acquired genital herpes attributable to it in some populations.

Pathogenesis

Primary HSV infection occurs at mucosal sites of inoculation, with retrograde infection propagating to sensory nerve ganglia. Following resolution of primary infection, HSV enters a latent state in sensory nerve ganglia from which reactivation may occur to cause active infection at any mucosal sites innervated by the nerve ganglia.

During primary HSV infection, natural killer cells are important effectors of immunity. Their activation depends on the production of several cytokines in response to the infection. These cytokines also have direct and indirect effects that are important for limiting replication of the virus. As the immune response matures, HSV clearance from infected tissues is T-cell mediated, involving cytokine-mediated effector mechanisms and direct cytolysis of virus-infected cells. In mice and humans, both CD4 and CD8 T cells are important in resolution of infection. Antibody may play a limited role in controlling HSV infection as well.

The efficiency of the immune response appears to influence the quantity of virus establishing latency in the ganglia. Although the elements contributing to this control are incompletely known, interferon- (IFN-) is likely to be important. IFN- activates antiviral genes that inhibit HSV replication and may be required for early decrease in local HSV viral titers. However, it appears from murine models that both IFN- and T-cell response can maintain viral latency and clear peripheral infections.

Prevention

There are multiple proven ways to prevent the acquisition and transmission of genital herpes. There are no “right” answers for prevention, and each patient must determine those best suited for his or her lifestyle. All patients diagnosed with genital herpes should be educated to recognize genital herpes outbreaks and given the option of daily suppressive therapy as a means to reduce genital herpes transmission. Measures for reducing transmission and acquisition of genital herpes include:

  1. 1. Disclosure of genital herpes infection to new partners. Although it may be difficult at first for patients to inform new partners that they have genital herpes, medical providers should encourage this important and necessary step to allow sex partners to make informed choices and, if appropriate, modify sexual practices to reduce the risk of transmission.
  2. 2. Abstinence during outbreaks. Once educated about the typically mild signs and symptoms of outbreaks, most patients are able to recognize symptomatic outbreaks.
  3. 3. Correct and consistent condom use. Male latex condom use can reduce transmission, especially during the first 6–12 months after initial infection.
  4. 4. Selection of partners with similar HSV serologic status or a history of genital herpes.
  5. 5. Chronic suppressive therapy. A recent major study demonstrated a 70% reduction in HSV transmission by infected patients using daily suppressive therapy. The reduction in disease and infection transmission may be attributable to both reduction of genital herpes recurrences and reduction of subclinical shedding.

Genital Herpes: Clinical Findings

Symptoms and Signs

Genital infection with HSV can be differentiated into five categories: first recognized episode, primary first episode, nonprimary first episode, recurrent episode, and subclinical shedding. Symptoms and signs characteristic of each are described below.

First Recognized Episode

The clinical diagnosis of a first episode versus recurrent episodes is unreliable. For the patient, the first recognized episode is an “initial” infection, whether it is a first episode or recurrent infection. The only way to classify a first episode with certainty is to document serologic conversion, but such classification usually serves little clinical purpose. All first recognized episodes can be safely managed as a newly acquired infection given the safety profile of currently recommended oral antiviral medications for HSV. Although both increased frequency of outbreaks and viral shedding are more likely with recent acquisition of infection, recommendations for daily suppressive therapy are based on the patient’s desire to control disease (ie, outbreaks) or reduce the risk of transmission, or both.

Primary First Episode

This refers to infection with either HSV-1 or HSV-2 in an individual who has never had infection with a herpes simplex virus. In immunocompetent hosts, this event often goes unrecognized.

After an incubation period of several days (average, 4 days; range, 1–14 days), a small papule appears that quickly evolves into a vesicle within 24 hours. Vesicles can be clear or pustular, are multiple, and rapidly evolve into shallow, nonindurated, painful ulcers. The appearance of lesions can be associated with dysuria, inguinal lymphadenitis, vaginal discharge, and cervicitis. In primary infection, systemic symptoms including myalgias, malaise, fever, and other “flu-like” symptoms may be associated with the appearance of genital lesions. In the typical presentation, signs or symptoms are minimal and usually are not recognized as primary genital herpes.

Crops of lesions may occur over 1–2 weeks, and crusting and healing of lesions requires an additional 1–2 weeks.

Nonprimary First Episode

This refers to infection in individuals who have had a previous infection with either HSV type. The typical scenario is an individual with prior HSV-1 orolabial infection who subsequently acquires new genital HSV-2 infection. Typically, the first genital herpes outbreak tends to be less severe clinically than a true primary episode due to an existing, partial humoral and cellular immunity. Fewer lesions appear, pain and systemic symptoms are less, and lesion resolution is more rapid than with a primary first episode. The first episode usually resolves within 5–7 days. Nonprimary first episodes are clinically similar to recurrent disease and are often mistaken for recurrent genital herpes, if they are recognized at all.

Recurrent Episode

Recurrent genital herpes refers to the second or subsequent episodes of genital herpes with the same virus type. HSV-2 is much more likely to recur then HSV-1 and accounts for more than 90% of recurrent genital herpes. The median number of recurrences is four per year, but up to 38% of individuals have six or more recurrences per year. Recurrences are, in general, clinically fairly mild and are often unrecognized. The outbreak usually is not associated with systemic symptoms but may be preceded by a prodrome of local paresthesia or dysesthesia.

Recurrent genital herpes may occur as a cluster of localized vesiculopustular or ulcerative lesions. Lesions tend to lateralize to one side of the midline. “Atypical” lesions are common and may be mistaken for excoriation or irritation. The predominant locations of lesions are on the glans penis or penile shaft in men, the vaginal introitus or labia in women, and the buttocks and anal area in both sexes. A neuropathic prodrome characterized by pain or a burning sensation may occur 6–24 hours prior to the appearance of lesions.

Subclinical Shedding

Subclinical shedding refers to the detection of virus in the absence of visible lesions. Our understanding of the natural history of genital herpes has shifted from that of intermittent outbreaks to one of low-grade frequent shedding of virus that can be detected by viral antigen detection methods (culture or PCR) of the genital tract on 5–20% of days. Subclinical shedding is most common during the first 6–12 months following acquisition of infection, approaching 40% of days. Subclinical shedding of HSV-2 occurs in almost all infected individuals, is of equivalent frequency in both women and men, and tends to diminish in frequency over time. About 50% of shedding episodes are temporarily associated around clinically recognized outbreaks, with virus detected one to several days proceeding or following resolution of lesions. Conversely, and of particular import, 50% of subclinical shedding events are more than 7 days removed from outbreaks. Patients who are counseled about the mild signs and symptoms of recurrent outbreaks may be able to recognize some of those periods when they are at greater risk of transmitting HSV to partners. HSV-1 subclinical shedding is much less common then HSV-2, occurring on 3–5% of days.

Diagnostic Tests

Until recently, viral culture was the “gold standard” for herpes diagnosis. Culture allows definitive diagnosis and permits distinction of HSV-1 from HSV-2, which is important for prognosis and counseling. Cultures are most sensitive while lesions are in the vesicularpustular stage. Sensitivity rapidly declines as lesions ulcerate and crust.

PCR is three to five times more sensitive than viral culture, is offered by most reference laboratories, and is quickly replacing viral culture as the “gold standard.” It is important to note that a negative culture for HSV does not rule out genital herpes.

Type-specific antibody testing based on HSV glycoprotein G is the most important and reliable diagnostic tool for chronic HSV infection. Antibody tests based on complement fixation, indirect immunofluorescence, or neutralization technologies do not reliably distinguish antibodies to HSV-1 from those to HSV-2. A negative result on an antibody test can be reassuring in that it excludes the diagnosis in a patient who has symptoms suggestive of long-standing or recurrent herpes. A positive result on a test that is not HSV glycoprotein G based is of little diagnostic value, because these serologic assays do not reliably distinguish between type 1 and type 2 infections. Because more then half of US adults are seropositive for HSV-1 as a result of herpes labialis infection, a positive test for HSV-1 antibody does not provide useful diagnostic information for the evaluation of genital ulcer disease. IgM antibody is often present during recurrent HSV outbreaks and does not indicate recent infection.

The newer type-specific serologic assays have specificities of more than 98% for the detection of HSV-2 antibody and sensitivities of more than 90%. One assay is a rapid, office-based test that can be run on serum or a whole blood specimen collected by a fingerstick and can provide results in less then 10 minutes. It is imperative to specify and request a glycoprotein G–based test when ordering an HSV serologic test. The following type-specific assays have been cleared by the Food and Drug Administration (FDA): Western immunoblot, HerpeSelect HSV-1 and HSV-2 ELISA (Focus Diagnostics, Cypress, CA), HerpeSelect HSV-1 and HSV-2 immunoblot (Focus Diagnostics, Cypress, CA), BioKit HSV-2 Rapid Assay (Biokit USA, Lexington, MA), and Captia HSV-1 and HSV-2 (Trinity Biotech, Wicklow, Ireland).

Other diagnostic tests for possible herpetic lesions include the following:

  1. 1. Direct immunofluorescent antibody testing for HSV antigen. Although more rapid (4–6 hours) than culture, this test may not differentiate HSV-1 and HSV-2.
  2. 2. Enzyme-linked immunosorbent assay (ELISA) testing for HSV antigens in clinical specimens. This test offers a rapid alternative to culture (results are available in 3–4 hours), but its use is generally confined to large reference laboratories and teaching institutions.
  3. 3. Microscopy of Papanicolaou smears or Giemsa staining (Tzanck test). These tests, although inexpensive, are insensitive, nonspecific, and not recommended.

Differential Diagnosis

Discreet genital or anal ulcers in sexually active young adults have a relatively narrow differential diagnosis. A complete differential diagnosis of genital herpes should include the following infectious etiologies: syphilis, primary HIV, chancroid, lymphogranuloma venereum, and donovanosis. Chancroid is currently rare in the United States and syphilis had been, until recently, at an historic low and is highly concentrated in geographic areas and certain groups. Thus, most genital ulcers (>90%) are caused by HSV.

The chancre of primary syphilis is classically nontender, indurated, and nonpurulent. Those findings can distinguish a syphilitic chancre from other infectious genital ulceration with some certainty. Other ulcer characteristics are less helpful in distinguishing infectious etiologies, but given the far greater prevalence of herpes, most genital ulcer disease is likely due to herpes. Thus, it is critical that diagnostic testing for HSV be performed on all genital lesions whenever possible to prevent missing a diagnosis for other treatable causes of genital ulcer disease, such as syphilis.

In general, genital lesions should always be evaluated by obtaining a “swab” test. This generally means obtaining a specimen for darkfield examination for Treponema pallidum and obtaining a specimen for HSV culture or PCR. Serologic screening for syphilis should accompany the diagnostic evaluation for genital lesions. HIV testing is encouraged for all individuals presenting with a genital lesion.

Complications

A primary first episode infection can be severe and may be associated with symptoms and signs of meningitis. On analysis, cerebrospinal fluid is aseptic and usually shows a predominance of lymphocytes. Antiviral therapy will speed the resolution of the clinical illness.

Long-term sequelae from genital herpes infection in adults are rare. Reactivation of HSV-1 infection, usually orolabial infection, in adults can cause keratitis or encephalitis. Genital herpes infection can increase the risk of HIV transmission and possibly the acquisition of other viral infections (eg, hepatitis C). In newborns, herpes infection can be devastating, resulting in permanent neurologic disability or death.

Treatment of Genital Herpes

Appropriate management of genital herpes is predicated on addressing the following critical areas: accurate etiologic diagnosis (see Clinical Findings, earlier), treatment of disease, reduction of transmission risk, and emotional counseling. The latter is all too often ignored by providers or, if acknowledged, is trivialized. There is an undeserved stigma attached to genital herpes, and most patients require reassurance concerning their sexual well-being, reproductive health, and ability to reduce the risk of transmission of disease and infection to partners. Patients should be encouraged to inform sex partners of their infection but may need help in learning how to disclose their status to partners.

Pharmacotherapy

Table Recommended Treatment Regimens for Genital Herpes Based on Type of Infection outlines pharmacologic treatment, based on the 2006 guidelines from the Centers for Disease Control and Prevention (CDC).

Table Recommended Treatment Regimens for Genital Herpes Based on Type of Infection

Indication Regimen
Initial infection Acyclovir, 400 mg PO 3 times daily for 7–10 d
  or
Valacyclovir, 1 g PO twice daily for 7–10 d
  or
Famciclovir, 250 mg PO 3 times daily for 7–10 d
Recurrent infection Acyclovir, 400 mg PO 3 times daily for 5 d
  or
Acyclovir, 800 mg PO 3 times daily for 2 d
  or
Acyclovir, 800 mg PO twice daily for 5 d
  or
Valacyclovir, 500 mg PO twice daily for 3 da
  or
Valacyclovir, 1 g PO daily for 5 d
  or
Famciclovir, 125 mg PO twice daily for 5 d
  or
Famciclovir, 1000 mg PO twice daily for 1 d
Suppressive therapy Acyclovir, 400 mg PO twice daily
  or
Valacyclovir, 500 mg PO daily (increased to 1.0 g daily in patients with >9 outbreaks per year)
  or
Famciclovir, 250 mg PO twice daily.

a Clinicians can order the 1-g dose and order it scored or split, at a cost (for 3-day supply) that is less than or comparable to acyclovir (5-day supply).

Antiviral therapy for initial genital herpes prevents new lesion formation and rapidly reduces viral shedding, infectivity, and the risk of autoinfection. However, it has no effect on the frequency of subsequent recurrences. Episodic treatment shortens the duration of recurrences by 20–30%. Taken daily, antiviral therapy effectively suppresses HSV recurrences and reduces subclinical shedding. Episodic therapy is most effective when started immediately upon the earliest sign or symptom of an outbreak. Self-initiation of therapy is an important element of episodic therapy to prevent delays. Patients, therefore, should be given a prescription for medication to be-filled and kept easily accessible.

All currently recommended oral regimens for genital herpes therapy are well tolerated and associated with few adverse effects. Dosing frequency is the main difference among the current therapies. It should be noted that acyclovir can be given three times daily. Limited clinical trial data exist for this dosing schedule, but considerable clinical experience justifies administering the drug in this manner. All three oral agents are renally excreted and thus can accumulate when renal function is impaired (requiring a reduction in dosage). Acyclovir, valacyclovir, and famciclovir are not approved for the use in pregnancy but are FDA category B drugs and are probably safe for pregnant women and fetuses. Some experts recommend the use of suppressive acyclovir therapy during the last month of pregnancy for women with a history of recurrent genital herpes. Suppressive therapy has been shown to reduce the likelihood of genital herpes recurrences at term and, thus, the need for cesarean delivery.

Daily suppressive therapy reduces the frequency of recurrences and viral shedding. Suppressive therapy should be offered to all patients with frequent recurrences, those with psychological distress related to genital herpes, and those wishing to reduce the risk of transmission. A recent study involving heterosexual monogamous couples discordant for HSV-2 evaluated use of daily suppressive therapy to reduce risk of transmission. The study demonstrated a 48% reduction of transmission of infection and a 75% reduction in development of clinical genital herpes in susceptible partners. Consideration of suppressive therapy is equally justified to control recurrences as well as to reduce the risk of transmission. Ultimately, patents must decide what their goals for treatment are and make decisions about episodic versus suppressive therapy.

Topical lidocaine jelly 2% is sometimes a useful adjunct to oral antiviral agents for managing severe first episodes in women. It should be applied frequently, and especially before voiding, but for no longer than 24–36 hours. There is a theoretical risk of sensitization, but this is very rarely seen in practice.

Other Treatment Measures

There is no evidence that salt baths, topical antiseptics, lysine, vitamins, or the multitude of over-the-counter herpes remedies are any more effective than placebo in the treatment or prevention of genital herpes.

Optimal Evaluation and Treatment

First Episodes

Specimens from clinical lesions should be obtained for diagnosis, depending on tests available and stage of presentation of the patient. Viral culture or PCR testing permits distinction of HSV-1 from HSV-2 and allows a definitive etiologic diagnosis for the genital ulcer. Culture yield diminishes quickly as lesions begin to heal, with the highest yield being at the vesiculopustular stage. The need for further immediate tests should be assessed if there is risk behavior or clinical suspicion of syphilis, chancroid, primary HIV, or other sexually transmitted disease. Such tests include darkfield examination, rapid plasma reagin evaluation of serum, Venereal Disease Research Laboratory (VDRL), T pallidum particle agglutination (TP-PA) tests, and HIV RNA or HIV antibody testing. Type-specific serologic assays for HSV-1 and HSV-2 can be used as part of the initial evaluation for HSV culture- or PCR-negative lesions. Seroconversion for newly acquired HSV infection may take 8–12 weeks with the use of the current type-specific serologic assays.

An oral antiviral agent should be prescribed for 7–10 days. The patient can expect symptoms to resolve in 3–4 days. If symptoms do not resolve, the patient should be reexamined and the possibility of secondary infection or an alternative diagnosis considered. Persistence of lesions for more then 14 days should prompt consideration of HIV coinfection.

All patients with genital ulcer disease should be reevaluated at 1 week. The clinician should consider repeat serologic testing for syphilis and examination for other genital infections. If the results of initial HSV virologic tests were negative, HSV type-specific serology can be obtained at least 6 weeks and preferably 3 months after presentation. All patients should be counseled about treatment options, with the purpose of obtaining desired outcomes such as controlling disease and reducing transmission of HSV.

Recurrent Episodes

Virologic specimens should be obtained from active lesions, if the diagnosis has not been confirmed earlier. Consideration should be given to obtaining type-specific serology in patients with atypical-appearing lesions, negative results on virologic tests, or lesions that cannot be tested for the presence of HSV.

HIV testing should be strongly encouraged for patients in whom HIV status has not recently been obtained.

Episodic treatment with an oral antiviral agent should be offered. All patients should be counseled about full treatment options (ie, continued episodic therapy that may be started at the first signs or symptoms of an outbreak or suppressive therapy to prevent recurrences and reduce the risk of transmission).

Counseling

Firstly, and most importantly, the medical provider must give accurate information about all aspects of the disease. Newly diagnosed genital herpes can be an emotionally traumatic event for some patients, making comprehension and retention of information difficult at the time of diagnosis. Important information to be discussed at the first visit is listed in Table Recommended Counseling Messages for Persons Newly Diagnosed with Genital Herpes.

Table Recommended Counseling Messages for Persons Newly Diagnosed with Genital Herpes.

Many sexually active adults (> 20%) have genital herpes infection, and most (90%) are unaware of the infection.
Effective therapy is available for initial episodes and recurrences, as well as for suppression.
Daily suppressive therapy can prevent transmission.
Recurrent episodes tend to be milder than the initial episode.
Transmission of herpes usually occurs from a partner who was not aware of the infection or did not believe he or she was infectious when exposure occurred.
Genital herpes simplex virus type 2 (HSV-2) infection is associated with an increased risk of HIV acquisition, and with an increased risk of HIV transmission in those dually infected with HSV-2 and HIV.
Genital herpes does not affect fertility, but there is a substantial risk of neonatal transmission in women with infections acquired during pregnancy, particularly the third trimester.

Time should be offered at a follow-up visit to address the patient’s concerns and to provide appropriate counseling. Patients may be given written information and referred to Internet web sites (see listing at end of chapter) and telephone hotlines (eg, the American Social Health Association national herpes hotline, at 919-361-8488, or the CDC national STD hotline, at 800-227-8922 or 800-342-2427 [English] and 800-344-7432 [Spanish]).

When to Refer to a Specialist

Although acyclovir-resistant genital herpes infection is rare, it has occurred in immunocompromised patients whose adherence to antiviral therapy was intermittent. If resistant infection is suspected, consultation with an infectious disease specialist is warranted to confirm the diagnosis and obtain appropriate antiviral therapy.

Prognosis

An outbreak of genital herpes will resolve on its own; however, the frequency of recurrent outbreaks is quite variable. Over a prolonged period, recurrences decline but in some patients, episodic outbreaks continue. Fortunately, antiviral treatment is safe and well-tolerated, and clinical outcomes in patients with recurrent disease can be improved with daily suppressive therapy.

Practice Points

All patients diagnosed with genital herpes should be educated to recognize genital herpes outbreaks and given the option of daily suppressive therapy as a means to reduce genital herpes transmission.

Episodic therapy is most effective when started immediately upon the earliest sign or symptom of an outbreak.

Relevant Web Sites

[American Sexual Health Association:]

http://www.ashastd.org

[CDC Division of Sexually Transmitted Diseases:]

http://www.cdc.gov/std

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