On the case...
Challenges of testing for  genital herpes
By Melanie A. Deal, MS, WHNP-BC, FNP-BC
Genital herpes is a common, chronic sexually transmitted infection (STI).1 It is caused by herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). HSV is a lifelong infection characterized by periodic eruption of painful lesions in the genital area.2 Approximately 1 in 8 individuals between the ages of 13 and 49 years has a genital infection with HSV-2 in the United States.1,3 The proportion of genital infections caused by HSV-1 versus HSV-2 is increasing, especially among young persons.4 The Centers for Disease Control and Prevention (CDC) estimates that 776,000 people in the United States become infected with genital herpes each year.1 
Although severe sequelae are rare, genital herpes fosters a strong sense of fear, shame, and stigma among individuals. Because infections with HSV-1 and -2 have a wide spectrum of manifestation (from classic herpetic sores to recurrent genital irritation to no symptoms at all), infectious status is often underestimated. Studies consistently report 65% to 90% of those with genital HSV infection are unaware of its presence.5 Further, many individuals may assume they have been tested as part of routine STI testing, which is rarely the case. 
Testing for herpes does present challenges for clinicians. There are direct testing options (ie, sampling of active lesions to detect the virus) and indirect testing options (ie, serology to assess for the presence of HSV antibodies). Each kind of test has its own set of indications and limitations. Clinicians can use appropriately ordered and interpreted tests to guide the counseling messages they provide. 
The following three cases are used to explain the indications for and interpretation of the various test types.
Case 1. Primary genital HSV infection 
MN is a 23-year-old college student (female assigned at birth). She presents to the student health center with a complaint of painful urination for the past 2 days. She describes the pain as worst when the urine touches her skin: “It is getting so bad, it hurts to walk.” MN is afebrile and has no back pain, nausea, or vomiting. Her urinalysis is normal.
On examination, the clinician notes multiple tender, shallow ulcerations on the labia bilaterally and confluent tender vesicles on the posterior vestibule. There is an enlarged, tender left inguinal lymph node. MN is unable to tolerate a speculum or bimanual exam due to the painful lesions. The clinician suspects a genital herpes infection.   
A direct test using a sample from a lesion is needed for this patient. With any of the direct test types, it is important to consider the stage of a lesion. The viral load of any given lesion decreases with time.6,7 If a lesion is dry or crusted over, it is more likely to test negative, even if it is a true herpes infection.7 In the case of MN, several lesions are moist and open, so it is likely the viral load will be adequate.
The CDC recommends two direct test types as first-line diagnostics: polymerase chain reaction (PCR) assay for HSV DNA and HSV viral culture. PCR has superior sensitivity, from 98% to 99%, compared to culture and is increasingly available.6 Viral culture was previously the gold standard. Although it is still a recommended option, sensitivity varies greatly between primary infections (80%) and recurrent lesions (25%–50%).7 Also, the sensitivity declines rapidly. Culture of vesicular fluid has a sensitivity of more than 90%, but sensitivity of a crusted herpetic lesion is only about 25%.7 Whether using PCR or viral culture, a type-specific test should be ordered. The expected natural course of the infection varies by type. Although both virus types can cause genital infection, recurrences and asymptomatic shedding are generally more frequent with HSV-2 than with HSV-1.5
An older test type, the Tzanck preparation (which assesses cellular changes associated with HSV infections), is insensitive and nonspecific and is not recommended.2 Similarly, the direct immunofluorescence assay using fluorescein-labeled monoclonal antibodies that detect HSV antigen lacks sensitivity and is not recommended.2
Should the clinician order herpes serology?
Serology is not appropriate in this case. This occurrence is suspicious for a primary outbreak in someone previously uninfected, and if so, antibodies are not going to be present. It takes 3 weeks to several months after exposure to the herpes virus for antibodies to be detectable in the blood.7 
It is important, however, to remember that first clinical presentations can occur long after the primary infection.8 The clinician should not assume that what appears to be a primary outbreak indicates the patient has been recently infected or counsel the patient that they must have been infected by their current partner. There is no way to determine when the patient was initially exposed.
Clinicians may be tempted to test for herpes immunoglobulin M (IgM) in an effort to determine if this is a new infection. In the case of HSV, however, IgM is not exclusively produced with initial infections. It can reappear with recurrences years after initial infection. The presence of herpes IgM cannot help differentiate between initial and established infections.7
Should the clinician offer antiviral treatment to MN without a test result?
Given that the patient’s symptoms and the characteristics of the lesions are consistent with herpes, the clinician recommends presumptive treatment with an antiviral medication and reviews other comfort measures. Antiviral medications should be started within 72 hours of an outbreak to offer the most relief.6 The clinician discusses the suspected diagnosis and treatment options with the patient. 
What are the key messages in this first counseling session?
The clinician provides short, clear messages about herpes in an effort not to overload the patient, especially if distraught over the potential diagnosis, with too much information:  
Herpes is a common infection. 
Recurrences will happen, although the frequency usually decreases over time. 
Transmission can occur even when there are no genital sores.
Herpes is a lifelong infection that is not curable, but it is very manageable with medication and self-care.
Transmission reduction strategies include: avoid oral and genital sex during an outbreak, use condoms and dental dams at all other times to decrease transmission, and consider suppressive therapy to decrease frequency of outbreaks and transmissibility.
Many people feel embarrassment and shame. Adapting to this diagnosis is a process. A patient’s feelings should not be dismissed by telling them herpes is not a serious medical problem. 
If the patient is emotionally upset, she may not absorb all of the important information the clinician wants to convey. Provide written information and consider scheduling a follow-up appointment in 1 to 2 weeks when the patient will be better able to organize questions. Mental health referrals should be provided as appropriate. 
The PCR test result for MN is positive for HSV-1 and negative for HSV-2. How does this diagnosis affect further counseling?
Years ago, HSV-1 was commonly considered the strain that caused oral herpes (“cold sores”), whereas HSV-2 was considered the “genital” virus. The proportion of new cases of genital herpes among young adults is increasingly due to HSV-1.8 This increase is the result of lowered prevalence of oral HSV infection during childhood. Many patients with a history of cold sores do not know that they are at risk for transmitting this virus with oral/genital sexual activity. Many patients are also unaware of their infection with HSV-1 (oral or genital).8 
Again, treatment options are the same for HSV-1 as for HSV-2, but cases tend to be milder. There are fewer recurrences and fewer days of asymptomatic shedding. 
If the PCR test had been negative for HSV, the clinician could consider testing for HSV-1 and HSV-2 serology in 6 to 8 weeks. Serologic testing for HSV-1 can be ordered with the caveat that a positive HSV-1 serology could indicate the patient’s genital lesions were due to a herpes infection or that the patient had a previous oral HSV-1 infection. It is not possible to confirm location of an HSV-1 infection with serology.
Case 2. Asymptomatic and low risk for HSV
MD is a 30-year-old patient (female assigned at birth). She has had 3 lifetime sexual partners, all male assigned at birth. Neither she nor her sexual partners have ever been diagnosed with an STI. She is getting married in 6 months, and she and her partner want comprehensive STI testing: “I want to be tested for everything.” She specifically requests herpes testing. Neither she nor her partner have had any symptoms of genital or oral herpes nor any known exposures. 
Should the clinician order herpes serology?
Generally, no. Routine screening of asymptomatic patients is not recommended. In fact, serologic testing may lead to more questions than answers. Serologic testing is significantly limited by low sensitivity and specificity.9 This is especially true in low-risk individuals, in whom there is a higher likelihood of a false-positive.9 The likelihood that a positive result indicates a true infection is called the positive predictive value. In low-prevalence populations, the positive predictive value for herpes serologic tests can be as low as 50%, meaning that half of the positive herpes results are false-positives.9 Unfortunately, no confirmatory test is commercially available. 
Further, in the case of HSV-1, even if the test result were a true positive, serologic tests cannot determine site of infection (oral or genital). For these reasons, the US Preventive Services Task Force has given routine screening for herpes a grade D, that is, not recommended.9  
The clinician explains to MD what STI screening is recommended and the rationale for not testing for herpes. MD says she thought that when she had her regular well-woman examination, she was routinely tested for all STIs. This is a common misconception. Clinicians should always inform patients what STI screening tests are recommended and being performed. As well, they should inform patients of risks and symptoms that may indicate an STI and the need to seek testing.
When are type-specific serologic tests for HSV useful?
According to the CDC, serologic  testing is useful in the following  scenarios2: 
Recurrent genital symptoms or atypical symptoms with negative HSV PCR or culture 
Clinical diagnosis of genital herpes without laboratory confirmation
A patient whose partner has genital herpes 
Persons presenting for an STI evaluation (especially those with multiple sex partners), persons with human immunodeficiency virus (HIV) infection, and MSM [men who have sex with men] at increased risk for HIV acquisition. 
Case 3. Recurrent genital itching 
DT is an 18-year-old new patient (female assigned at birth) who presents with “yet another yeast infection” and recurrent genital itching. Her previous provider gave her refills of oral fluconazole to be used as needed.
On examination, the clinician sees generalized mild erythema at the introitus and perineum with some slit-like fissures at the posterior vestibule. The speculum exam was negative. The wet prep showed no pseudohyphae or yeast buds. The clinician collects specimens for a fungal culture and a type-specific HSV PCR test.
Why is it important to consider testing for herpes for this patient?  
Clinicians need to expand their differential diagnoses when investigating chronic or recurrent vulvar concerns. Genital herpes, especially recurrent episodes, often does not manifest as classic painful, shallow ulcers on an erythematous base. Many individuals with recurrent genital herpes are unaware of having had a typical primary infection episode.8  
The PCR is positive for HSV-2 and negative for HSV-1. The fungal culture is negative. The clinician contacts the patient, discusses the test results, and provides education about recurrences, the importance of partner notification, and strategies to reduce the risk for infection transmission. The CDC recommends type-specific serologic testing of the asymptomatic partner(s) of persons with genital herpes to determine whether such partners are already HSV seropositive or whether risk for acquiring HSV exists.2
The clinician provides information about the use of antiviral medication to be initiated when genital itching or lesions occur. Because HSV-2 infection is more likely than HSV-1 infection to have recurrences and to be transmitted to sexual partners through asymptomatic shedding, the clinician also discusses suppressive therapy.  
Conclusion
Genital herpes is very common, yet it is often not an easy diagnosis to make.
Many people are unaware of their infection status or risk.
There are two types of tests: direct (swab collected from a lesion) or indirect (a serologic test that assesses for HSV antibodies).
PCR is the most sensitive direct test.
When obtaining a specimen from a lesion, clinicians should remember that the viral load drops over time.
Given that the course of infection varies by HSV type, clinicians should order type-specific tests.
Routine screening of asymptomatic individuals is not recommended because the risk of a false-positive is high in low-prevalence populations.
IgM testing does not necessarily connote a new herpes infection and is never recommended.
The diagnostic tests for HSV are not perfect. Similarly, the clinical presentation of genital herpes is not always straightforward. Clinicians can use direct and indirect HSV tests to improve diagnostic certainty  and to guide patient counseling.  It is important to understand the  indications and limitations for these  tests. 	=
Melanie A. Deal is a women’s health and a family nurse practitioner at University Health Services, University of California, Berkeley, in Berkeley, California. The author has no actual or potential conflicts of interest in relation to the contents of this article.
References
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