Herpes Simplex Virus - HSV

Indications for Testing

Persons with signs or symptoms of HSV infection should be tested. Additionally, type-specific testing should be performed in persons with recurrent genital symptoms. If a patient has active lesion(s), PCR testing should be performed on a sample from a lesion. Serology testing is used in the absence of active lesions. It can take days to weeks after initial exposure for immunoglobulin G (IgG) antibodies to develop and up to 6 months for HSV type-specific antibodies to form. Serologic testing performed too early in the infection can result in false-negative results. In these cases, patients can be retested 6-12 months later. Some patients never develop type-specific antibodies. 

Per the U.S. Preventive Services Task Force (USPSTF), screening of asymptomatic individuals in the general population for HSV-1 and HSV-2 is not indicated, including during pregnancy.  HSV testing may be considered in patients being evaluated for a sexually transmitted infection (STI).

Laboratory Testing

Diagnosis

Genital Herpes

Genital herpes is a chronic, lifelong infection. HSV-2 is the primary cause of genital herpes; however, HSV-1 is responsible for a growing number of cases. HSV can be transmitted easily and the virus can be shed even when symptoms are mild or not apparent. Most people positive for HSV-1 or HSV-2 have not been diagnosed with genital herpes and may not realize they have it.

Antivirals agents can reduce the severity and frequency of symptoms and transmission of the virus but are not curative. When indicated, treatment for HSV-1 and HSV-2 is the same. However, HSV-1 is less likely to manifest with recurrent episodes and shedding; treatment may not be indicated in some patients, and treatment decisions should be based on clinical evaluation.  Infection with HSV-2 also increases the risk of acquiring HIV infection (refer to the ARUP Consult Human Immunodeficiency Virus topic and Human Immunodeficiency Virus in Adults and Adolescents Testing Algorithm).

Clinical suspicion for genital herpes should be confirmed by laboratory testing. The presentation is not often classic and may be similar to the presentation of other conditions, including syphilis and chancroid. Confirming the diagnosis is important for proper patient management. 

Virologic testing of samples from active lesions is the best way to confirm HSV diagnosis. PCR has been shown to be more sensitive than culture and is the preferred diagnostic testing method. Sensitivity decreases as the disease progresses, as lesions heal, and in recurrences. A negative test in the presence of active lesions does not rule out HSV because viral shedding is intermittent. 

If there are no active lesions but exposure to HSV is suspected, serologic testing may be used. IgG to HSV-1/2 develops before type-specific IgG to HSV-1 and HSV-2 glycoproteins, which take an average of 2-3 weeks and up to 6 months to develop. If the suspected exposure was particularly recent, IgG to HSV-1/2 should be tested first, with reflex to the type-specific antibodies. If the exposure was in the past, type-specific testing for IgG to HSV-1 and HSV-2 glycoproteins alone can be performed. If suspicion is high but results are negative, testing should be repeated 6-12 months later, given that false-negative results can occur, especially early in the disease. Some patients never develop type-specific antibodies. A positive IgG result cannot determine the exact time of exposure or the site of infection. IgM testing is not recommended because it is unreliable for acute infection and has been shown to cross-react with other herpes viruses.  

Neonatal HSV

HSV can be transmitted from an infected mother to the neonate during pregnancy, during delivery, or after delivery. The risk is highest during delivery, especially if the mother acquired genital herpes near the time of delivery. All pregnant individuals should be asked whether they have a history of genital herpes, and at the onset of labor, they should be questioned about symptoms and examined for lesions. Those with genital lesions at the onset of labor should deliver by cesarean birth to reduce the risk of transmission. Although routine screening of mothers for HSV is not recommended, serologic testing can be used to assess risk in patients with a sex partner who has a known HSV diagnosis. Women are counseled to abstain from vaginal intercourse during the third trimester with partners who are known to have or suspected of having genital herpes. 

Neonatal herpes infection can present as disseminated infection involving multiple organ systems, with central nervous system involvement, or with only mucocutaneous involvement. If there is clinical suspicion for HSV, specimens should be obtained for viral culture from the conjunctivae, mouth, nasopharynx, rectum, and any lesions. Viral culture is still recommended for these specimens because there are not enough data relating to use of PCR testing in this population. CSF and blood samples, however, should be tested using PCR. Serologic testing in neonates is not helpful, given that detected HSV IgG antibodies are most likely transplacentally acquired maternal antibodies. 

HSV Encephalitis

HSV is the most common cause of nonepidemic, sporadic, acute focal encephalitis in the U.S. The majority of cases are caused by HSV-1 in adults. Without treatment, these cases of encephalitis have a mortality rate of approximately 70%. The clinical presentation is nonspecific and the differential diagnosis includes St. Louis encephalitis, Eastern equine encephalitis, and Epstein-Barr viruses, among others. Thus, early identification of HSV and appropriate treatment are important to the clinical course. 

The recommended test for HSV encephalitis is PCR on a CSF sample obtained by lumbar puncture. Viral culture lacks sensitivity in CSF, and the previous gold standard, brain biopsy, is invasive and slow. PCR can be falsely negative, especially in children and early in the disease course. If PCR is negative and there is clinical suspicion for HSV, a second lumbar puncture should be performed within 3-7 days and the CSF should be tested. Serologic testing on CSF is available but often not clinically useful. 

Screening

According to the USPSTF, screening of asymptomatic individuals for HSV-1 and HSV-2 in the general population is not indicated, including during pregnancy.  HSV testing may be considered for patients presenting for an STI evaluation.

Immunocompromised Patients

Immunocompromised patients, including those positive for HIV and those who have undergone transplants, can be at higher risk for more severe HSV infections. When the immune system is weakened, the ability to maintain HSV in the latent state is decreased, which results in increased frequency and severity of mucocutaneous recurrences as well as the possibility of dissemination of the disease to other organ systems. In these cases, antibody testing will not be helpful and PCR testing should be used. 

Antiviral Susceptibility Testing

HSV may become resistant to the first-line treatment, acyclovir, especially in patients infected with HIV. Foscarnet can be used to treat acyclovir-resistant HSV in these cases. Resistance to foscarnet can also occur, mostly in patients with previous exposure to the drug. Susceptibility testing for acyclovir and foscarnet is available to help guide treatment when patients are not responding to these medications.