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Serologic Testing to Diagnose Herpes Simplex Virus Infections
JNP
Serologic Testing to Diagnose
Herpes Simplex Virus Infections Terri Warren
Keywords: STD, herpes simplex virus, HSV1, HSV2, HSV serology, HSV polymerase chain reaction, HerpeSelect ELISA test
Herpes simplex virus (HSV) is an increasingly common infection seen in primary care. More sophisticated testing is now available that allows the type of infection to be classified as either HSV1 or HSV2. When patients should be tested and the implications of the results are of importance not only to clinicians but also to the patients who will live with this chronic infection.
CASE Carolyn, 26, comes to your clinic and requests testing for sexually transmitted diseases (STDs). She had contact with a new partner that she met on a cruise 3 weeks ago.They had intercourse four times. Upon taking a thorough history, you learn that she received oral sex from him all four times and gave him oral sex twice. No condoms were used for any encounters. She has never had a cold sore on her face or lip but does have a history of recurring yeast infections that sometimes cause cracks on her labia. She has no symp84
toms now and comes only for screening. She read on the Internet about a new blood test for herpes and wants you to include that in your STD screen. If her test is positive for herpes, she wants to know if this is the partner who gave it to her. For many years, herpes experts asked clinicians not to use herpes antibody tests because the available tests could not accurately distinguish herpes simplex virus 1 (HSV1) from HSV2.1 Now, the use of new and better blood tests for HSV is enthusiastically encouraged.These tests can accurately identify those who are infected and September 2005
When using this test, it is important to keep in mind that people who have very little risk of herpes infection will have a higher percentage of false positives than those who have more risk.
WHICH PATIENTS SHOULD BE OFFERED THIS BLOOD TEST? As with any test, many factors go into deciding whether to use it or not.When using this test, it is important to keep in mind that people who have very little risk of herpes infection will have a higher percentage of false positives than those who have more risk. For example, in the setting of a sexual health clinic, one would expect a high percentage of patients to be infected with HSV2, so the positive predictive value for this test would be very good.3 However, if testing is conducted on a group of incoming college freshmen, the number who are actually infected with HSV2 would be much lower4; therefore, the positive predictive value for this test would be poorer. When selecting candidates for testing, the clinician may include the following groups of people. Patients Requesting STD Testing
Failure to include a blood test for the most prevalent STD in the United States5 may be a poor decision from both a clinical and legal perspective. Patients requesting STD testing are not asking the clinician to test just for infections that can be cured or infections for which testing is inexpensive.They are asking to be tested for STDs and assume that includes a screen for herpes.6-9 Patients Who Have Had a Partner With Herpes in the Past or a Current Partner With Herpes
do not know it.2 However, technicalities about HSV serology need to be clearly understood before clinicians begin ordering serologic testing for herpes. WHY SHOULD WE DIAGNOSE HERPES The patient who has HSV2 infection is at double the risk of acquiring HIV infection, should they be exposed. This factor alone may motivate clinicians to identify those infected, so that patients may recognize their increased HIV risk and be more rigorous about practicing safer sex.Women who have genital herpes can infect their babies at birth and women newly infected in the third timester have a high rate of infecting their neonates.This is an outcome we would all like to avoid. People who have herpes can infect their sexual partners, even when they have no symptoms present. Unless they are aware that they are infected, they will do nothing to reduce the risk of transmission to partners. For these reasons, testing for herpes should be considered more often than it has been in the past. www.npjournal.org
A common scenario involves a patient who gets a phone call about a previous partner who has recently been diagnosed with herpes.Your patient wants to know whether the partner has infected him or her. Or perhaps the patient indicates that she has met a great new guy, but he has revealed to her that he has genital herpes, and she is asking how to prevent transmission to her. Because about 1 in 4 adults older than 18 years have HSV2 and almost 90% do not know it,8 your patient could easily be infected and be unaware.Why take all the precautions to avoid transmission when it may not be necessary? If both partners have HSV1 or HSV2, they no longer need to worry about herpes affecting their sexual behavior. Patients Who Have Recurrent Genital Symptoms That Cannot Be Explained by Some Other Positive Laboratory Test
Herpes does not always present with multiple painful genital sores. It often presents as vague, recurrent genital symptoms that patients do not associate at all with having herpes.10 Patients may simply have recurrent genital itching (and a negative potassium hydroxide test). Many 85
JNP
RESOURCES FOR PATIENTS WITH HSV Many resources are available for patients seeking information about herpes.The following is a list of accurate information sources for patients who have been diagnosed with genital herpes. Information
• American Social Health Association booklets, books, handouts,The Helper, 1.800.230.6039; herpes patient toll-free hotline 1.888.411-4377 Books
• Managing Herpes: How to Live and Love With a Chronic STD by Charles Ebel and Anna Wald • The Truth About Herpes by Stephen Sacks • Understanding Herpes by Lawrence Stanberry Internet Sites
• www.webmd.com, questions and answers • www.ashastd.org, reading materials • www.herpesdiagnosis.com, diagnostic information • www.westoverheights.com, free handbook and DVD • www.healthchecksusa.com, patient-ordered IgG tests • www.herpeshomepage.com, medications and networking • www.ihmf.org, international perspective on HSV Financial Assistance with Prescriptions
• GlaxoSmithKline: 1.800.TALK2GW, www.IPP.GSK.com • Novartis: 1.800.277.2254
misdiagnosed herpes infections have mistakenly been treated repeatedly with antifungal medication. Herpetic urethritis can get mixed up with urinary tract infection. In those cases, patients may have dysuria and pyuria but no growth on urine cultures and no remarkable frequency and urgency. When herpes lesions are in the urethra, patients experience dysuria, and these lesions add white cells that can be detected on a urine dipstick. Women may complain of a variety of problems: allergies to condoms, spermicides, sperm, tampons, sanitary pads, douching products, toilet paper, lubricants, or even sexual partners. Men may complain of bug bites, human bites, irritation from intercourse or masturbation without adequate lubrication, jock itch, normal itch, getting their penis caught in their zipper, and irritation from condoms or sexual partners. Many of these complaints are actually due to undiagnosed genital herpes infections. People are not necessarily deluding themselves; they really do not know what is causing these symptoms. It is up to clinicians to help determine what is happening, and herpes should be included in the differential diagnosis. Patients Who Have Had Negative Herpes Culture From a Suspicious Skin Lesion
There are two kinds of swab tests available to diagnose herpes now—a herpes culture and a herpes PCR (polymerase chain reaction). HSV PCR is four times more sensitive than HSV culture.11 Both culture and PCR are collected in exactly the same way—a swab from a suspicious area of skin—but when the sample is sent to the laboratory, a PCR is requested instead of a culture. A negative herpes swab test simply means that no virus was isolated in a sample, not that the person has no infection. If something is suspicious enough that swab testing is done and the test is negative, a blood test should be done as follow-up.This test should be drawn 3 to 4 months after the last sexual exposure. Patients Who Have Been Diagnosed by Clinical Examination Only but Have Never Had a Typed, Positive Laboratory Test
A clinical examination alone, without laboratory confirmation, can lead to errors in the diagnosis of herpes.12,13 In addition, a visual examination cannot differentiate between HSV1 and HSV2. Both infections look identical, and the type can only be distinguished with a type 86
September 2005
Figure 1. Serologic Testing in Pregnancy HSVserologyat18-weekvisit
MomHSV1andHSV2seronegative
PartnerHSV1positive
Avoidgivingoralsextomom Suppressionforpartner Abstinence Condoms
MomHSV1positiveonly
PartnerHSV2positive
Suppressionat36weeks EducationaboutHSV Avoidinvasiveproceduresatdelivery
Abstinence Suppressionforpartner Condoms
specific blood test or typed swab test (either culture or PCR). Patients with a positive swab test that were never typed may benefit from a blood test to determine which type of infection they have. Why does it matter what type of virus a patient has? HSV1 genital infection recurs, on average, about 0.7 times per year, whereas HSV2 genital infection recurs about 4-6 times per year,14,15 so the prognosis for the two genital infections is very different. Why else does this matter? In a monogamous relationship in which both people believe the other has never had sexual contact with anyone else and genital herpes is diagnosed in one partner, it matters very much. If you are able to type the virus from genital herpes as HSV1 and the couple practices oral sex, that is a parsimonious explanation for the origin of the infection. HSV1 is more often transmitted from mouth to genital than genital to genital.16,17 But if you did not type the virus, they may assume that another partner has been involved. Relationships can end unhappily and unnecessarily over this issue. People need not have an active cold sore to transmit virus from their mouth to the genitals of their partner. Both HSV1 and HSV2 can be given from the body in the absence of symptoms.18-21 There is a third reason to type the virus.The person with HSV1 can still get HSV2, but the person with HSV2 is highly unlikely to get new HSV1 after already having HSV2 infection.22,23 This matters in the situation in which a person diagnosed with genital herpes seeks another partner with herpes with whom to have sexual contact (or it just happens coincidentally that both partners have herpes).The person who does not know that www.npjournal.org
MomHSV2positive
he or she has HSV1 genitally can still acquire HSV2 in the same location and end up with a very different kind of infection. But unless someone is aware that he or she has HSV1 genitally (versus HSV2), he or she cannot make an intelligent and informed decision about whether to take the risk of having sexual contact with someone with HSV2. Pregnant Patients
Approximately 60% of neonatal herpes occurs as a result of primary maternal infection in the third trimester of pregnancy with either HSV1 or HSV2.Transmission to the neonate occurs during delivery when the mother is actively shedding virus.22 Most of the other 40% of neonatal herpes happens when women who do not know that they have herpes transmit virus to their babies during delivery. No one is looking for symptoms of HSV in women who deny a history of herpes, and subtle presentations are easy to miss. In addition, asymptomatic shedding does occur in these women, as well as women who know they have genital herpes. How can we begin to diagnose and track the numbers in either of these two populations without serologic testing in pregnancy? The pregnancy testing algorithm (Figure 1) will give you some guidelines about how to institute serologic testing in pregnancy. The flow chart also describes what to do about partners, should they also need testing. Sometimes pregnancy care providers indicate that they cannot test male partners of pregnant women because the men are not their patients. But semen analysis is routinely ordered by obstetric clinicians without a problem; it is likely that 87
JNP Table 1. Serologic Test Characteristics Serologic test
Sensitivity %
Specificity %
Cost $
Contact information
Western blot HSV1, HSV2
>99
>99
~110
Herpesdiagnosis.com
Immunoblot HSV1, HSV2
97–100
98
~40–120
Herpeselect.com
ELISA HSV1, HSV2
96–100
97–100
~80–140
Herpeselect.com
Biokit HSV2
93–100
94–97
~20–50
Biokitusa.com
Table 2. Codes for Ordering Serologic Tests From 2 National Laboratories Laboratory
HSV1
HSV2
HSV1 and HSV2
Confirmatory test for HSV2
Quest
3636X
3640X
6447X
17170X
LabCorp
164897
163147
164905
NA
NA indicates not applicable.
Table 3. Interpreting the Index Value on HerpeSelect ELISA Tests Index value
Interpretation
<0.9
Negative, if patient waited long enough from exposure to be tested.
0.9–1.1
Equivocal. Repeat if testing too soon. If long enough, likely negative.
1.1–3.5
Low positive. Repeat or retest if too soon or confirm with another test.
>3.5
Positive. Very likely to be accurate. Confirmation rarely needed.
obstetricians could also order HSV testing for partners without difficulty. Pregnancy clinicians routinely order tests for many things that are much less common than genital and neonatal herpes, such as syphilis and rubella. Herpes testing is not yet part of routine prenatal screening, although herpes infections in mothers are much more common than either of the above-mentioned conditions: this may provide rationale for ordering the tests. Testing for herpes in pregnancy is a controversial issue for some clinicians. Reasons why clinicians may not be willing to order herpes tests during pregnancy include concerns about payment (although an insurance company rejecting that claim is very uncommon), causing mothers unnecessary anxiety about having herpes, discomfort with the interpretation of results, too much time needed for counseling positives, and an increase in the rate of Cesarean sections (appropriate in the woman with symptomatic herpes at the time of delivery). CHOOSING AND IMPLEMENTING SEROLOGIC TESTS The first key to successful serologic testing is to use only the newest, type-specific tests. Four tests are currently available that can separate HSV1 from HSV2 accurately. The first is the HSV Western blot, done in the United 88
States only at the University of Washington.The second test is the HerpeSelect enzyme-linked immunosorbent assay (ELISA), made by Focus Diagnostics.The third test, also made by Focus Diagnostics, is called the HerpeSelect Immunoblot. And the fourth test is called the Biokit, a point-of-care test that looks for HSV2 only.Table 1 lists some of the characteristics associated with each blood test. HerpeSelect ELISA test.Table 2 lists the national test codes clinicians should use for ordering these tests from those laboratories. In addition, the Quest list includes a code for a confirmatory test, called an inhibition assay, that can be used should clinicians desire a “second opinion” for any reason. The ELISA test result will be a number, called an index value.Table 3 contains information about how to interpret the index value.The ELISA test for HSV2 has a specificity of about 97%.This means that every 100 times we tell someone she has HSV2 based on this test, we will be wrong 3 times.23 Herpes is a highly stigmatized, emotionally upsetting, potentially problematic infection during pregnancy (or almost any time). Clinicians would rather not tell people they have herpes when they really do not. Recent studies have looked at the patients who are truly uninfected but serologically positive on this test.What has been found so September 2005
far is that the person most likely to have a false positive on the ELISA Focus test is someone who has an index value of 1.1 to 3.5. Not everyone in this low-positive range is falsely positive, of course.There are very few false positives in people whose index value is above 3.5. Three tests are available to confirm HSV2 positive values.The one commercially available is called an inhibition assay.This test can be ordered after obtaining a lowpositive value, or, alternatively, the entire testing experience could be set up reflexively. So on the laboratory form, testing could be described as HSV2 immunoglobulin G (IgG) serology: if the value obtained is 1.1 to 3.5, inhibition assay is to be performed.This would automatically ensure confirmatory testing for all low-positive values.The other two tests that could be used to confirm a low-positive ELISA are Western blot or Biokit. When interpreting laboratory test results for herpes serology, it is important to combine a clinical and sexual history with the index value. For example, a clinician sees a patient who had a new sexual partner 3 weeks ago.The patient is concerned about some irritation that she has had on the labia since that time and requests a blood test for herpes. An HSV2 ELISA is drawn, and the index value comes back at 1.2.To better understand the meaning of this index value, the clinician looks back at the sexual history that has been obtained.This woman had a new partner 3 weeks ago. She may well be in the process of developing antibody and is on her way up the scale from 0 to greater than 5. Her blood was drawn in the middle of this transition. If her blood is redrawn 3 months from her infection, she may well have a value greater than 5. If, however, she still has a value at that time of around 1.2, confirmation might be useful. By about 3 weeks from infection, 50% of people will be positive by blood test. At about 6 weeks, 70% will be positive, and by 4 months, most people who are going to make antibody will have done so.24 So a blood test drawn too soon after infection could yield a false-negative result. The key diagnostic message to remember is that antibody is something people make, not something they get from someone else, and they need to be allowed enough time for antibodies to be made prior to a blood draw. This concept is familiar when thinking about HIV blood testing. Conversely, if someone has a positive HSV2 serology, it is not currently possible to know exactly how long he or she has been infected. A procedure called avidity testwww.npjournal.org
ing will help with that information in the future.18 Levels of antibody (ie, the index value) do not tell anything about the herpes infection—not necessarily how long a person has had it, the virulence of the strain, or the ability of the immune system to deal with the infection. Levels of antibody simply vary from person to person. IgM tests for herpes should not be used at all. Currently available IgM tests show crossreactivity between HSV1 and HSV2, as well as crossreactivity with other members of the herpes virus family. Also about one third of people experiencing a reactivation of an established infection will have a positive IgM response, so IgM cannot necessarily sort out new from old infection.18 Blood tests do not tell where an infection is, only that someone is infected. For this reason, HSV1 positive test results can be confusing. Although it is known that almost all HSV2 infection is genital,21 it is less clear about HSV1. Probably most HSV1 infection is still oral, but with HSV1 causing about a third of all new genital infections,17 a positive HSV1 blood test in the absence of a history of cold sores can be confusing for both clinician and patient.What can be said is that the patient is infected with HSV1 somewhere, and if she or he develops symptoms in either location, she or he should come back and have the symptoms evaluated. Sometimes clinicians opt to do only HSV2 serologic testing for STD screening. Because 95% of genital herpes recurrences are caused by HSV2, it is the most important infection to be recognized. COUNSELING THE PATIENT POSITIVE FOR HSV When a patient has a positive antibody test for HSV2, what does that mean? In a study done by Wald et al,20 subjects were identified who were HSV2 positive but had never had any symptoms of genital herpes.Those people were asked to swab their genitalia in a systematic and standardized method, using herpes culture, every day for about 3 months. A similar population of people who had known herpes outbreaks and were HSV2 positive were asked to do the same. It was found that people who simply test positive for HSV2 by blood test but have no recognized symptoms shed virus, on asymptomatic days, at the same rate as those having 1 to 12 recognized outbreaks per year.This finding shows that people who are HSV2 positive are both infected and infectious.20 When diagnosing someone with HSV2, it is important to understand that this is not only a medical diagno89
JNP sis but also a psychological, emotional, and relationship diagnosis. One of the biggest concerns experienced by people with herpes is transmitting their infection to a sexual partner.26 One study found that 75% of people find out they have herpes by infecting someone else.25 Patients who take antiviral therapy daily can reduce the risk of transmitting herpes to a sexual partner by almost half 13 and also shed virus significantly less at the end of pregnancy.27 Condoms can also reduce the risk of HSV transmission and will be valuable tools for the person with recognized herpes.28 Although infection with genital herpes is not something that people want to hear, it is undoubtedly better to find out that one is infected with HSV2 by a blood test than by infecting a sexual partner or, worse, a newborn.The use of type specific blood tests can facilitate this diagnosis.
12. 13.
14. 15.
16.
17.
18.
19.
20.
21. 22.
References 1. Morrow RA, Friedrich D. Inaccuracy of certain commercial enzyme immunoassays in diagnosing genital infections with herpes simplex virus types 1 or 2. Am J Clin Pathol. 2003;120(6):839-844. 2. Corey L. Challenges in genital herpes simplex virus management. J Infect Dis. 2002;186(suppl 1):S29-S33. 3. Cherpes TL, Ashley RL, Meyn LA, Hillier SL. Longitudinal reliability of focus glycoprotein G-based type-specific enzyme immunoassays for detection of herpes simplex virus types 1 and 2 in women. J Clin Microbiol. 2003;41(2):671-674. 4. Gibson J, Hornung CA, Alexander GR, Lee FK, Potts WA, Nahmias AJ. A cross-sectional study of herpes simplex virus types 1 and 2 in college students: occurrence and determinants of infection. J Infect Dis. 1990;162(2):306-312. 5. Centers for Disease Control and Prevention. Tracking the hidden epidemics: trends in STDs in the United States 2000:1-31. 6. Edmiston N, O’Sullivan M, Charters D, Chuah J, Pallis L. Study of knowledge of genital herpes infection and attitudes to testing for genital herpes among antenatal clinic attendees. Aust N Z J Obstet Gynaecol. 2003;43(5):351-353. 7. Wald A, Ashley-Morrow R. Serological testing for herpes simplex virus (HSV)-1 and HSV-2 infection. Clin Infect Dis. 2002;35(suppl 2):S173-S182. 8. Leone P, Fleming DT, Gilsenan AW, Li L, Justus S. Seroprevalence of herpes simplex virus-2 in suburban primary care offices in the United States. Sex Transm Dis. 2004;31(5):311-316. 9. Zimet GD, Rosenthal SL, Fortenberry JD, et al. Factors predicting the acceptance of herpes simplex virus type 2 antibody testing among adolescents and young adults. Sex Transm Dis. 2004;31:665-669. 10. Ashley RL, Wald A. Genital herpes: review of the epidemic and potential use of type-specific serology. Clin Microbiol Rev. 1999;12:1-8. 11. Wald A, Huang M, Carrell D, Selke S, Corey L. Polymerase chain reaction for detection of herpes simplex virus (HSV) DNA on mucosal surfaces:
90
23. 24.
25.
26.
27.
28.
comparison with HSV isolation in cell culture. J Infect Dis. 2003;188:13451351. Centers for Disease Control and Prevention. STD treatment guidelines, 2002. MMWR Recom Rep. 2002:51(RR-6):1-78. Corey L, Wald A, Patel R, Sacks SL, Tyring SK, Warren T; Valacyclovir HSV Transmission Study Group. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004;350(1):11-20. Engelberg R, Carrell D, Krantz E, Corey L, Wald A. Natural history of genital herpes simplex virus type 1 infection. Sex Transm Dis. 2003;30:174-177. Wald A, Zeh J, Selke S, Ashley RL, Corey L. Virologic characteristics of subclinical and symptomatic genital herpes infections. N Engl J Med. 1995;333:770-775. Roberts CM, Pfizer JR, Spear SO. Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students. Sex Transm Dis. 2003;30:797-800. Cherpes TL, Meyn LA, Hillier SL. Cunnilingus and vaginal intercourse are risk factors for herpes simplex virus type 1 acquisition in women. Sex Transm Dis. 2005;32(2):84-89. Morrow RA, Friedrich D, Krantz E, Wald A. Development and use of a typespecific antibody avidity test based on herpes simplex virus type 2 glycoprotein G. Sex Transm Dis. 2004;31(8):508-515. Benedetti J, Zeh J, Corey L. Clinical reactivation of genital herpes simplex virus infection decreases in frequency over time. Ann Intern Med. 1999;131:14-20. Wald A, Zeh J, Selke S, et al. Reactivation of genital herpes simplex virus type 2 infections in asymptomatic seropositive persons. N Engl J Med. 2000;342:844-850. Wald A, Ericsson M, Krantz E, Selke S, Corey L. Oral shedding of herpes simplex virus type 2. Sex Transm Infect. 2004;80:272-276. Brown ZA, Wald A, Morrow RA, Selke S, Zeh J, Corey L. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA. 2003;289:203-209. Ashley RL. Sorting out the new HSV type specific antibody test. Sex Transm Infect. 2001:77:232-237. Ashley-Morrow R, Krantz E, Wald A. Time course of seroconversion by HerpeSelect ELISA after acquisition of genital herpes simplex virus type 1 or HSV 2. Sex Transm Dis. 2003;30:310-314. Mertz GJ, Schmidt O, Jourden JL, et al. Frequency of acquisition of firstepisode genital infection with herpes simplex virus from symptomatic and asymptomatic source contacts. Sex Transm Dis. 1985;12(1):33-39. Melville J, Sniffen S, Crosby R, et al. Psychosocial impact of serological diagnosis of HSV 2: a qualitative assessment. Sex Transm Infect. 2003;79:280-285. Watts DH, Brown ZA, Money D, et al. A double-blind, randomized, placebocontrolled trial of acyclovir in late pregnancy for the reduction of herpes simplex virus shedding and cesarean delivery. Am J Obstet Gynecol. 2003;188:836-843. Wald A, Langenberg AG, Link K, et al. Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women. JAMA. 2001;285:3100-3106.
Terri Warren, RN, MS, ANP, MEd, has owned and operated a private clinic,Westover Heights Clinic, specializing in sexually transmitted disease in Portland, Ore., for 23 years. 1555-4155/05/$ see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1067/j.nurpra.2005.08.015
September 2005
Serologic Testing to Diagnose
Herpes Simplex Virus Infections Terri Warren
Keywords: STD, herpes simplex virus, HSV1, HSV2, HSV serology, HSV polymerase chain reaction, HerpeSelect ELISA test
Herpes simplex virus (HSV) is an increasingly common infection seen in primary care. More sophisticated testing is now available that allows the type of infection to be classified as either HSV1 or HSV2. When patients should be tested and the implications of the results are of importance not only to clinicians but also to the patients who will live with this chronic infection.
CASE Carolyn, 26, comes to your clinic and requests testing for sexually transmitted diseases (STDs). She had contact with a new partner that she met on a cruise 3 weeks ago.They had intercourse four times. Upon taking a thorough history, you learn that she received oral sex from him all four times and gave him oral sex twice. No condoms were used for any encounters. She has never had a cold sore on her face or lip but does have a history of recurring yeast infections that sometimes cause cracks on her labia. She has no symp84
toms now and comes only for screening. She read on the Internet about a new blood test for herpes and wants you to include that in your STD screen. If her test is positive for herpes, she wants to know if this is the partner who gave it to her. For many years, herpes experts asked clinicians not to use herpes antibody tests because the available tests could not accurately distinguish herpes simplex virus 1 (HSV1) from HSV2.1 Now, the use of new and better blood tests for HSV is enthusiastically encouraged.These tests can accurately identify those who are infected and September 2005
When using this test, it is important to keep in mind that people who have very little risk of herpes infection will have a higher percentage of false positives than those who have more risk.
WHICH PATIENTS SHOULD BE OFFERED THIS BLOOD TEST? As with any test, many factors go into deciding whether to use it or not.When using this test, it is important to keep in mind that people who have very little risk of herpes infection will have a higher percentage of false positives than those who have more risk. For example, in the setting of a sexual health clinic, one would expect a high percentage of patients to be infected with HSV2, so the positive predictive value for this test would be very good.3 However, if testing is conducted on a group of incoming college freshmen, the number who are actually infected with HSV2 would be much lower4; therefore, the positive predictive value for this test would be poorer. When selecting candidates for testing, the clinician may include the following groups of people. Patients Requesting STD Testing
Failure to include a blood test for the most prevalent STD in the United States5 may be a poor decision from both a clinical and legal perspective. Patients requesting STD testing are not asking the clinician to test just for infections that can be cured or infections for which testing is inexpensive.They are asking to be tested for STDs and assume that includes a screen for herpes.6-9 Patients Who Have Had a Partner With Herpes in the Past or a Current Partner With Herpes
do not know it.2 However, technicalities about HSV serology need to be clearly understood before clinicians begin ordering serologic testing for herpes. WHY SHOULD WE DIAGNOSE HERPES The patient who has HSV2 infection is at double the risk of acquiring HIV infection, should they be exposed. This factor alone may motivate clinicians to identify those infected, so that patients may recognize their increased HIV risk and be more rigorous about practicing safer sex.Women who have genital herpes can infect their babies at birth and women newly infected in the third timester have a high rate of infecting their neonates.This is an outcome we would all like to avoid. People who have herpes can infect their sexual partners, even when they have no symptoms present. Unless they are aware that they are infected, they will do nothing to reduce the risk of transmission to partners. For these reasons, testing for herpes should be considered more often than it has been in the past. www.npjournal.org
A common scenario involves a patient who gets a phone call about a previous partner who has recently been diagnosed with herpes.Your patient wants to know whether the partner has infected him or her. Or perhaps the patient indicates that she has met a great new guy, but he has revealed to her that he has genital herpes, and she is asking how to prevent transmission to her. Because about 1 in 4 adults older than 18 years have HSV2 and almost 90% do not know it,8 your patient could easily be infected and be unaware.Why take all the precautions to avoid transmission when it may not be necessary? If both partners have HSV1 or HSV2, they no longer need to worry about herpes affecting their sexual behavior. Patients Who Have Recurrent Genital Symptoms That Cannot Be Explained by Some Other Positive Laboratory Test
Herpes does not always present with multiple painful genital sores. It often presents as vague, recurrent genital symptoms that patients do not associate at all with having herpes.10 Patients may simply have recurrent genital itching (and a negative potassium hydroxide test). Many 85
JNP
RESOURCES FOR PATIENTS WITH HSV Many resources are available for patients seeking information about herpes.The following is a list of accurate information sources for patients who have been diagnosed with genital herpes. Information
• American Social Health Association booklets, books, handouts,The Helper, 1.800.230.6039; herpes patient toll-free hotline 1.888.411-4377 Books
• Managing Herpes: How to Live and Love With a Chronic STD by Charles Ebel and Anna Wald • The Truth About Herpes by Stephen Sacks • Understanding Herpes by Lawrence Stanberry Internet Sites
• www.webmd.com, questions and answers • www.ashastd.org, reading materials • www.herpesdiagnosis.com, diagnostic information • www.westoverheights.com, free handbook and DVD • www.healthchecksusa.com, patient-ordered IgG tests • www.herpeshomepage.com, medications and networking • www.ihmf.org, international perspective on HSV Financial Assistance with Prescriptions
• GlaxoSmithKline: 1.800.TALK2GW, www.IPP.GSK.com • Novartis: 1.800.277.2254
misdiagnosed herpes infections have mistakenly been treated repeatedly with antifungal medication. Herpetic urethritis can get mixed up with urinary tract infection. In those cases, patients may have dysuria and pyuria but no growth on urine cultures and no remarkable frequency and urgency. When herpes lesions are in the urethra, patients experience dysuria, and these lesions add white cells that can be detected on a urine dipstick. Women may complain of a variety of problems: allergies to condoms, spermicides, sperm, tampons, sanitary pads, douching products, toilet paper, lubricants, or even sexual partners. Men may complain of bug bites, human bites, irritation from intercourse or masturbation without adequate lubrication, jock itch, normal itch, getting their penis caught in their zipper, and irritation from condoms or sexual partners. Many of these complaints are actually due to undiagnosed genital herpes infections. People are not necessarily deluding themselves; they really do not know what is causing these symptoms. It is up to clinicians to help determine what is happening, and herpes should be included in the differential diagnosis. Patients Who Have Had Negative Herpes Culture From a Suspicious Skin Lesion
There are two kinds of swab tests available to diagnose herpes now—a herpes culture and a herpes PCR (polymerase chain reaction). HSV PCR is four times more sensitive than HSV culture.11 Both culture and PCR are collected in exactly the same way—a swab from a suspicious area of skin—but when the sample is sent to the laboratory, a PCR is requested instead of a culture. A negative herpes swab test simply means that no virus was isolated in a sample, not that the person has no infection. If something is suspicious enough that swab testing is done and the test is negative, a blood test should be done as follow-up.This test should be drawn 3 to 4 months after the last sexual exposure. Patients Who Have Been Diagnosed by Clinical Examination Only but Have Never Had a Typed, Positive Laboratory Test
A clinical examination alone, without laboratory confirmation, can lead to errors in the diagnosis of herpes.12,13 In addition, a visual examination cannot differentiate between HSV1 and HSV2. Both infections look identical, and the type can only be distinguished with a type 86
September 2005
Figure 1. Serologic Testing in Pregnancy HSVserologyat18-weekvisit
MomHSV1andHSV2seronegative
PartnerHSV1positive
Avoidgivingoralsextomom Suppressionforpartner Abstinence Condoms
MomHSV1positiveonly
PartnerHSV2positive
Suppressionat36weeks EducationaboutHSV Avoidinvasiveproceduresatdelivery
Abstinence Suppressionforpartner Condoms
specific blood test or typed swab test (either culture or PCR). Patients with a positive swab test that were never typed may benefit from a blood test to determine which type of infection they have. Why does it matter what type of virus a patient has? HSV1 genital infection recurs, on average, about 0.7 times per year, whereas HSV2 genital infection recurs about 4-6 times per year,14,15 so the prognosis for the two genital infections is very different. Why else does this matter? In a monogamous relationship in which both people believe the other has never had sexual contact with anyone else and genital herpes is diagnosed in one partner, it matters very much. If you are able to type the virus from genital herpes as HSV1 and the couple practices oral sex, that is a parsimonious explanation for the origin of the infection. HSV1 is more often transmitted from mouth to genital than genital to genital.16,17 But if you did not type the virus, they may assume that another partner has been involved. Relationships can end unhappily and unnecessarily over this issue. People need not have an active cold sore to transmit virus from their mouth to the genitals of their partner. Both HSV1 and HSV2 can be given from the body in the absence of symptoms.18-21 There is a third reason to type the virus.The person with HSV1 can still get HSV2, but the person with HSV2 is highly unlikely to get new HSV1 after already having HSV2 infection.22,23 This matters in the situation in which a person diagnosed with genital herpes seeks another partner with herpes with whom to have sexual contact (or it just happens coincidentally that both partners have herpes).The person who does not know that www.npjournal.org
MomHSV2positive
he or she has HSV1 genitally can still acquire HSV2 in the same location and end up with a very different kind of infection. But unless someone is aware that he or she has HSV1 genitally (versus HSV2), he or she cannot make an intelligent and informed decision about whether to take the risk of having sexual contact with someone with HSV2. Pregnant Patients
Approximately 60% of neonatal herpes occurs as a result of primary maternal infection in the third trimester of pregnancy with either HSV1 or HSV2.Transmission to the neonate occurs during delivery when the mother is actively shedding virus.22 Most of the other 40% of neonatal herpes happens when women who do not know that they have herpes transmit virus to their babies during delivery. No one is looking for symptoms of HSV in women who deny a history of herpes, and subtle presentations are easy to miss. In addition, asymptomatic shedding does occur in these women, as well as women who know they have genital herpes. How can we begin to diagnose and track the numbers in either of these two populations without serologic testing in pregnancy? The pregnancy testing algorithm (Figure 1) will give you some guidelines about how to institute serologic testing in pregnancy. The flow chart also describes what to do about partners, should they also need testing. Sometimes pregnancy care providers indicate that they cannot test male partners of pregnant women because the men are not their patients. But semen analysis is routinely ordered by obstetric clinicians without a problem; it is likely that 87
JNP Table 1. Serologic Test Characteristics Serologic test
Sensitivity %
Specificity %
Cost $
Contact information
Western blot HSV1, HSV2
>99
>99
~110
Herpesdiagnosis.com
Immunoblot HSV1, HSV2
97–100
98
~40–120
Herpeselect.com
ELISA HSV1, HSV2
96–100
97–100
~80–140
Herpeselect.com
Biokit HSV2
93–100
94–97
~20–50
Biokitusa.com
Table 2. Codes for Ordering Serologic Tests From 2 National Laboratories Laboratory
HSV1
HSV2
HSV1 and HSV2
Confirmatory test for HSV2
Quest
3636X
3640X
6447X
17170X
LabCorp
164897
163147
164905
NA
NA indicates not applicable.
Table 3. Interpreting the Index Value on HerpeSelect ELISA Tests Index value
Interpretation
<0.9
Negative, if patient waited long enough from exposure to be tested.
0.9–1.1
Equivocal. Repeat if testing too soon. If long enough, likely negative.
1.1–3.5
Low positive. Repeat or retest if too soon or confirm with another test.
>3.5
Positive. Very likely to be accurate. Confirmation rarely needed.
obstetricians could also order HSV testing for partners without difficulty. Pregnancy clinicians routinely order tests for many things that are much less common than genital and neonatal herpes, such as syphilis and rubella. Herpes testing is not yet part of routine prenatal screening, although herpes infections in mothers are much more common than either of the above-mentioned conditions: this may provide rationale for ordering the tests. Testing for herpes in pregnancy is a controversial issue for some clinicians. Reasons why clinicians may not be willing to order herpes tests during pregnancy include concerns about payment (although an insurance company rejecting that claim is very uncommon), causing mothers unnecessary anxiety about having herpes, discomfort with the interpretation of results, too much time needed for counseling positives, and an increase in the rate of Cesarean sections (appropriate in the woman with symptomatic herpes at the time of delivery). CHOOSING AND IMPLEMENTING SEROLOGIC TESTS The first key to successful serologic testing is to use only the newest, type-specific tests. Four tests are currently available that can separate HSV1 from HSV2 accurately. The first is the HSV Western blot, done in the United 88
States only at the University of Washington.The second test is the HerpeSelect enzyme-linked immunosorbent assay (ELISA), made by Focus Diagnostics.The third test, also made by Focus Diagnostics, is called the HerpeSelect Immunoblot. And the fourth test is called the Biokit, a point-of-care test that looks for HSV2 only.Table 1 lists some of the characteristics associated with each blood test. HerpeSelect ELISA test.Table 2 lists the national test codes clinicians should use for ordering these tests from those laboratories. In addition, the Quest list includes a code for a confirmatory test, called an inhibition assay, that can be used should clinicians desire a “second opinion” for any reason. The ELISA test result will be a number, called an index value.Table 3 contains information about how to interpret the index value.The ELISA test for HSV2 has a specificity of about 97%.This means that every 100 times we tell someone she has HSV2 based on this test, we will be wrong 3 times.23 Herpes is a highly stigmatized, emotionally upsetting, potentially problematic infection during pregnancy (or almost any time). Clinicians would rather not tell people they have herpes when they really do not. Recent studies have looked at the patients who are truly uninfected but serologically positive on this test.What has been found so September 2005
far is that the person most likely to have a false positive on the ELISA Focus test is someone who has an index value of 1.1 to 3.5. Not everyone in this low-positive range is falsely positive, of course.There are very few false positives in people whose index value is above 3.5. Three tests are available to confirm HSV2 positive values.The one commercially available is called an inhibition assay.This test can be ordered after obtaining a lowpositive value, or, alternatively, the entire testing experience could be set up reflexively. So on the laboratory form, testing could be described as HSV2 immunoglobulin G (IgG) serology: if the value obtained is 1.1 to 3.5, inhibition assay is to be performed.This would automatically ensure confirmatory testing for all low-positive values.The other two tests that could be used to confirm a low-positive ELISA are Western blot or Biokit. When interpreting laboratory test results for herpes serology, it is important to combine a clinical and sexual history with the index value. For example, a clinician sees a patient who had a new sexual partner 3 weeks ago.The patient is concerned about some irritation that she has had on the labia since that time and requests a blood test for herpes. An HSV2 ELISA is drawn, and the index value comes back at 1.2.To better understand the meaning of this index value, the clinician looks back at the sexual history that has been obtained.This woman had a new partner 3 weeks ago. She may well be in the process of developing antibody and is on her way up the scale from 0 to greater than 5. Her blood was drawn in the middle of this transition. If her blood is redrawn 3 months from her infection, she may well have a value greater than 5. If, however, she still has a value at that time of around 1.2, confirmation might be useful. By about 3 weeks from infection, 50% of people will be positive by blood test. At about 6 weeks, 70% will be positive, and by 4 months, most people who are going to make antibody will have done so.24 So a blood test drawn too soon after infection could yield a false-negative result. The key diagnostic message to remember is that antibody is something people make, not something they get from someone else, and they need to be allowed enough time for antibodies to be made prior to a blood draw. This concept is familiar when thinking about HIV blood testing. Conversely, if someone has a positive HSV2 serology, it is not currently possible to know exactly how long he or she has been infected. A procedure called avidity testwww.npjournal.org
ing will help with that information in the future.18 Levels of antibody (ie, the index value) do not tell anything about the herpes infection—not necessarily how long a person has had it, the virulence of the strain, or the ability of the immune system to deal with the infection. Levels of antibody simply vary from person to person. IgM tests for herpes should not be used at all. Currently available IgM tests show crossreactivity between HSV1 and HSV2, as well as crossreactivity with other members of the herpes virus family. Also about one third of people experiencing a reactivation of an established infection will have a positive IgM response, so IgM cannot necessarily sort out new from old infection.18 Blood tests do not tell where an infection is, only that someone is infected. For this reason, HSV1 positive test results can be confusing. Although it is known that almost all HSV2 infection is genital,21 it is less clear about HSV1. Probably most HSV1 infection is still oral, but with HSV1 causing about a third of all new genital infections,17 a positive HSV1 blood test in the absence of a history of cold sores can be confusing for both clinician and patient.What can be said is that the patient is infected with HSV1 somewhere, and if she or he develops symptoms in either location, she or he should come back and have the symptoms evaluated. Sometimes clinicians opt to do only HSV2 serologic testing for STD screening. Because 95% of genital herpes recurrences are caused by HSV2, it is the most important infection to be recognized. COUNSELING THE PATIENT POSITIVE FOR HSV When a patient has a positive antibody test for HSV2, what does that mean? In a study done by Wald et al,20 subjects were identified who were HSV2 positive but had never had any symptoms of genital herpes.Those people were asked to swab their genitalia in a systematic and standardized method, using herpes culture, every day for about 3 months. A similar population of people who had known herpes outbreaks and were HSV2 positive were asked to do the same. It was found that people who simply test positive for HSV2 by blood test but have no recognized symptoms shed virus, on asymptomatic days, at the same rate as those having 1 to 12 recognized outbreaks per year.This finding shows that people who are HSV2 positive are both infected and infectious.20 When diagnosing someone with HSV2, it is important to understand that this is not only a medical diagno89
JNP sis but also a psychological, emotional, and relationship diagnosis. One of the biggest concerns experienced by people with herpes is transmitting their infection to a sexual partner.26 One study found that 75% of people find out they have herpes by infecting someone else.25 Patients who take antiviral therapy daily can reduce the risk of transmitting herpes to a sexual partner by almost half 13 and also shed virus significantly less at the end of pregnancy.27 Condoms can also reduce the risk of HSV transmission and will be valuable tools for the person with recognized herpes.28 Although infection with genital herpes is not something that people want to hear, it is undoubtedly better to find out that one is infected with HSV2 by a blood test than by infecting a sexual partner or, worse, a newborn.The use of type specific blood tests can facilitate this diagnosis.
12. 13.
14. 15.
16.
17.
18.
19.
20.
21. 22.
References 1. Morrow RA, Friedrich D. Inaccuracy of certain commercial enzyme immunoassays in diagnosing genital infections with herpes simplex virus types 1 or 2. Am J Clin Pathol. 2003;120(6):839-844. 2. Corey L. Challenges in genital herpes simplex virus management. J Infect Dis. 2002;186(suppl 1):S29-S33. 3. Cherpes TL, Ashley RL, Meyn LA, Hillier SL. Longitudinal reliability of focus glycoprotein G-based type-specific enzyme immunoassays for detection of herpes simplex virus types 1 and 2 in women. J Clin Microbiol. 2003;41(2):671-674. 4. Gibson J, Hornung CA, Alexander GR, Lee FK, Potts WA, Nahmias AJ. A cross-sectional study of herpes simplex virus types 1 and 2 in college students: occurrence and determinants of infection. J Infect Dis. 1990;162(2):306-312. 5. Centers for Disease Control and Prevention. Tracking the hidden epidemics: trends in STDs in the United States 2000:1-31. 6. Edmiston N, O’Sullivan M, Charters D, Chuah J, Pallis L. Study of knowledge of genital herpes infection and attitudes to testing for genital herpes among antenatal clinic attendees. Aust N Z J Obstet Gynaecol. 2003;43(5):351-353. 7. Wald A, Ashley-Morrow R. Serological testing for herpes simplex virus (HSV)-1 and HSV-2 infection. Clin Infect Dis. 2002;35(suppl 2):S173-S182. 8. Leone P, Fleming DT, Gilsenan AW, Li L, Justus S. Seroprevalence of herpes simplex virus-2 in suburban primary care offices in the United States. Sex Transm Dis. 2004;31(5):311-316. 9. Zimet GD, Rosenthal SL, Fortenberry JD, et al. Factors predicting the acceptance of herpes simplex virus type 2 antibody testing among adolescents and young adults. Sex Transm Dis. 2004;31:665-669. 10. Ashley RL, Wald A. Genital herpes: review of the epidemic and potential use of type-specific serology. Clin Microbiol Rev. 1999;12:1-8. 11. Wald A, Huang M, Carrell D, Selke S, Corey L. Polymerase chain reaction for detection of herpes simplex virus (HSV) DNA on mucosal surfaces:
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comparison with HSV isolation in cell culture. J Infect Dis. 2003;188:13451351. Centers for Disease Control and Prevention. STD treatment guidelines, 2002. MMWR Recom Rep. 2002:51(RR-6):1-78. Corey L, Wald A, Patel R, Sacks SL, Tyring SK, Warren T; Valacyclovir HSV Transmission Study Group. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004;350(1):11-20. Engelberg R, Carrell D, Krantz E, Corey L, Wald A. Natural history of genital herpes simplex virus type 1 infection. Sex Transm Dis. 2003;30:174-177. Wald A, Zeh J, Selke S, Ashley RL, Corey L. Virologic characteristics of subclinical and symptomatic genital herpes infections. N Engl J Med. 1995;333:770-775. Roberts CM, Pfizer JR, Spear SO. Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students. Sex Transm Dis. 2003;30:797-800. Cherpes TL, Meyn LA, Hillier SL. Cunnilingus and vaginal intercourse are risk factors for herpes simplex virus type 1 acquisition in women. Sex Transm Dis. 2005;32(2):84-89. Morrow RA, Friedrich D, Krantz E, Wald A. Development and use of a typespecific antibody avidity test based on herpes simplex virus type 2 glycoprotein G. Sex Transm Dis. 2004;31(8):508-515. Benedetti J, Zeh J, Corey L. Clinical reactivation of genital herpes simplex virus infection decreases in frequency over time. Ann Intern Med. 1999;131:14-20. Wald A, Zeh J, Selke S, et al. Reactivation of genital herpes simplex virus type 2 infections in asymptomatic seropositive persons. N Engl J Med. 2000;342:844-850. Wald A, Ericsson M, Krantz E, Selke S, Corey L. Oral shedding of herpes simplex virus type 2. Sex Transm Infect. 2004;80:272-276. Brown ZA, Wald A, Morrow RA, Selke S, Zeh J, Corey L. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA. 2003;289:203-209. Ashley RL. Sorting out the new HSV type specific antibody test. Sex Transm Infect. 2001:77:232-237. Ashley-Morrow R, Krantz E, Wald A. Time course of seroconversion by HerpeSelect ELISA after acquisition of genital herpes simplex virus type 1 or HSV 2. Sex Transm Dis. 2003;30:310-314. Mertz GJ, Schmidt O, Jourden JL, et al. Frequency of acquisition of firstepisode genital infection with herpes simplex virus from symptomatic and asymptomatic source contacts. Sex Transm Dis. 1985;12(1):33-39. Melville J, Sniffen S, Crosby R, et al. Psychosocial impact of serological diagnosis of HSV 2: a qualitative assessment. Sex Transm Infect. 2003;79:280-285. Watts DH, Brown ZA, Money D, et al. A double-blind, randomized, placebocontrolled trial of acyclovir in late pregnancy for the reduction of herpes simplex virus shedding and cesarean delivery. Am J Obstet Gynecol. 2003;188:836-843. Wald A, Langenberg AG, Link K, et al. Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women. JAMA. 2001;285:3100-3106.
Terri Warren, RN, MS, ANP, MEd, has owned and operated a private clinic,Westover Heights Clinic, specializing in sexually transmitted disease in Portland, Ore., for 23 years. 1555-4155/05/$ see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1067/j.nurpra.2005.08.015
September 2005