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Screening for Asymptomatic Genital Herpes: Is Serologic Testing Worth It?
Screening for Asymptomatic Genital Herpes: Is Serologic Testing Worth It? Leia Raphaelidis, FNP ABSTRACT
Genital herpes is very common, but most people who have it are not aware of their status because they do not have symptoms. Serologic testing can be used to identify asymptomatic herpes, but the benefit of screening is not clear-cut. Clinicians should be aware of the issues surrounding herpes screening to help their patients decide if they should be tested and to counsel those who test positive. Keywords: asymptomatic herpes, genital herpes, sexually transmitted infection screening Ó 2014 Elsevier, Inc. All rights reserved.
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enital herpes is one of the most common sexually transmitted infections (STIs) in the United States and is lifelong and incurable, yet only a small fraction of individuals with herpes are symptomatic or aware of their infection.1 Historically, the gold standard for the diagnosis of genital herpes has been via a physical examination and direct testing of mucocutaneous lesions during an outbreak, thereby limiting the diagnosis to symptomatic individuals. However, over the past decade, developments in testing technology have made it possible to accurately detect herpes antibodies in serum (Table 1), thus providing a way to diagnose herpes regardless of the presence or absence of lesions. Based on a surface protein called glycoprotein G, these tests reliably differentiate between antibodies to herpes simplex virus type 1 (HSV-1) immunoglobulin G (IgG) and herpes simplex virus type 2 (HSV-2) IgG.2 Screening asymptomatic individuals via serology has emerged as a widely available and relatively affordable testing option, leading to the following question: Should clinicians be screening their patients for asymptomatic herpes? Arguments have been made for and against screening, and the subject remains controversial.3-6 The US Preventive Services Task Force and the Centers for Disease Control and Prevention (CDC) recommend against routine serologic screening in the general population, citing a lack of evidence that screening reduces herpes transmission and expressing concern that the potential harms of screening 194
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outweigh the potential benefits.7 However, the 2010 Sexually Transmitted Diseases Treatment Guidelines from the CDC state that some experts believe that clinicians should perform herpes serology for highrisk individuals presenting for STI evaluation.8 This article discusses the clinical complexities of asymptomatic herpes and the issues surrounding screening for this highly stigmatized infection. Clinicians ordering herpes serology need to be well versed in the subject of asymptomatic herpes and be prepared to counsel those patients who are deciding whether or not to get tested and those who do test positive. ASYMPTOMATIC GENITAL HERPES: MORE COMMON THAN YOU THINK
Most genital herpes is associated with HSV-2, and it is uncommon for HSV-2 to take hold outside the anogenital region. Therefore, the presence of HSV-2 antibodies in serum can be taken as an indicator of genital herpes.2(pS176) According to the most recent data from the CDC, seroprevalence of HSV-2 in the US was estimated to be 16.2%, with a prevalence of 20.9% among women and 11.5% among men.9 To further complicate the diagnostic picture, an increasing number of new cases of genital herpes are caused by HSV-1, the virus usually associated with herpes labialis.10 Because a positive HSV-1 IgG does not identify the site of infection, the test cannot be used to specifically screen for asymptomatic genital HSV-1. Therefore, the total prevalence of genital Volume 10, Issue 3, March 2014
Table 1. Type-specific Herpes Serology Test Name
Manufacturer
AtheNA Multi-Lyte HSV 1 & 2 IgG Plus
ZEUS Scientific
BioPlex 2200 HSV-1 & HSV -2 IgG
Bio-Rad
Captia HSV-1 & HSV-2 IgG
Trinity Biotech
EuroImmun anti-HSV-1 and anti-HSV-2 ELISA (IgG)
EuroImmun US
HerpeSelect 1&2 ELISA IgG
Focus Diagnostics
HerpeSelect 1 & 2 Immunoblot IgG
Focus Diagnostics
HSV-2 Rapid Test (also marketed as SureVue HSV-2 Rapid Test by Fisher HealthCare)
Biokit USA
Wampole HSV gG-2 ELISA II
Alere
HSV-1 ¼ herpes simplex virus type 1; HSV-2 ¼ herpes simplex virus type 2; IgG ¼ immunoglobulin G. Note: Available type-specific herpes serology tests are listed in the table. All these rely on glycoprotein-G to distinguish between HSV-1 and HSV-2. Clinicians ordering HSV serology should verify that the laboratory is using a type-specific test (www.ashasexualhealth.org/uploads/pdfs/HerpesBloodTestGuide.pdf). The rapid tests are Clinical Laboratory Improvement Amendments nonwaived and of moderate complexity.
HSV (ie, type 1 and type 2) is presumed to be even higher than the CDC’s 16.2%. ASYMPTOMATIC SHEDDING AND TRANSMISSION
Somewhat surprisingly, more than 80% of HSV-2 infections are asymptomatic, subtle enough that they remain unrecognized, or misdiagnosed because genital ulcers are absent.9(p458) Even in the absence of any clinical manifestations, herpes can reactivate from its usual dormant state and be transmitted via skin to skin contact to sexual partners through a process called asymptomatic shedding. In fact, the majority of new HSV cases are transmitted from source individuals who have no apparent lesions.11 By means of sensitive DNA amplification tests conducted on anogenital swabs, HSV has been detected in almost all asymptomatic seropositive individuals about 20%-25% of days.12 The minimum amount of detectable HSV needed for transmission to occur to a sexual partner has not yet been established. Therefore, it is not known if each instance of detectable HSV necessarily represents potential infectivity.13 The rate of shedding appears to decrease with time elapsed since primary infection by up to 70% after 10 years.12(p S20) Given these findings, experts advise that all seropositive www.npjournal.org
individuals should be considered potentially infectious to their sexual partners, even if the risk of transmission cannot be quantified.14 HERPES AND ITS RISKS: CAN SCREENING MAKE A DIFFERENCE?
From a physiologic standpoint, asymptomatic herpes is largely harmless to immunocompetent individuals. Although HSV can carry rare but serious complications such as ocular herpes, herpes encephalitis, and neonatal herpes, most individuals infected with the virus will suffer no adverse physical sequelae. Furthermore, there is no evidence that screening reduces the risk of such complications. The American College of Obstetricians and Gynecologists recommends against routine serologic screening of pregnant women because of a lack of evidence for a costeffective strategy that prevents neonatal herpes.15 However, genital herpes can increase the risk of human immunodeficiency virus (HIV) acquisition by 3-fold because the inflammation associated with HSV activation facilitates HIV entry into the body.16 Nevertheless, there is no evidence at this time that this risk can be decreased by treating the HSV infection with antivirals.17 In 1 double-blind, randomized, placebo-controlled study, suppressive therapy with the antiviral acyclovir taken daily had no effect on the risk of HIV acquisition despite significantly reducing the number of herpes outbreaks.18 TO SCREEN OR NOT TO SCREEN?
The usual purpose of medical screenings, including STI screening, is the early identification of a disease in order to maximize health outcomes. For example, screening for chlamydia and promptly treating this STI can help prevent pelvic inflammatory disease, reduce the risk of subsequent ectopic pregnancy, and preserve women’s fertility.19 However, in the case of HSV, early detection does not alter health outcomes for identified individuals nor does it affect the natural history of the infection. Regardless of when it is detected, herpes cannot be cured. At best, positive serology may help provide an alternate explanation for genital symptoms previously misidentified as yeast infections, urinary tract infections, razor burn, insect bites, friction rubs, allergic reactions, or any other of the myriad misdiagnoses given for subtle, atypical, The Journal for Nurse Practitioners - JNP
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but not wholly asymptomatic genital HSV. At worst, positive HSV serology may produce significant psychological distress, with repercussions for relationships, emotional health, and sexual well-being.20 If screening cannot change outcomes for affected individuals, can it at least help prevent transmission to others? Although the US Preventive Services Task Force has concluded that there is no evidence that screening reduces transmission, there is limited evidence that knowledge of a partner’s positive HSV status does help protect against HSV acquisition. In a 1996 study by Wald et al,21 researchers found that among initially discordant couples, the median time to HSV-2 acquisition was longer for participants whose partners disclosed their HSV status. The behaviors that produced that delay in transmission were not clear, although interestingly, consistent condom use was not one of them.21 Further research is needed to establish whether individuals who are made aware of their asymptomatic herpes can take effective measures to reduce transmission to others, perhaps by limiting their number of sexual partners, taking antiviral therapy, or committing to consistent condom use.
Herpes can be transmitted in the absence of symptoms. Most herpes infections are transmitted this way.1 Antibodies to herpes can be detected as early as 2-3 weeks after initial infection, although detectable antibodies can take up to 16 weeks.2(pS175) Herpes is a highly stigmatized infection. Being diagnosed with herpes can be distressing. Clinicians should explore their patients’ motivation for testing and should probe how being diagnosed with HSV might affect the way they approach intimate relationships. Would a diagnosis of genital herpes affect their sexual behaviors? Would they be willing to disclose their status to current and future sexual partners? Would they consider using daily medications to reduce the risk of transmission? Although this discussion will take up valuable office time, it may be helpful for clinicians to bear in mind that in the near future, they will likely be notifying about 1 in 6 of the patients whom they have screened that they have been found to have genital herpes. The time spent on education before testing will have laid the groundwork for the delivery of that result.
PRETEST COUNSELING STRATEGIES
Given the lack of strong evidence that HSV-2 screening reduces harm, the decision whether or not to screen asymptomatic individuals is not clear-cut. The clinician and patient have to carefully consider the decision and its implications. A negative HSV-2 IgG may come as a huge relief, especially to someone with a known exposure to herpes. However, anyone who chooses to be tested needs to be prepared to cope with a positive result. There are no clear guidelines about what HSV pretest counseling should include. The following key points about asymptomatic herpes can correct common misunderstandings and help patients decide if finding out their HSV status is the right decision for them. Herpes is common and a lack of symptoms or known exposures cannot be taken as proof that a person is not infected. Most people with herpes have no symptoms.1 Herpes serology is a test that does come back positive in individuals who have no suspicion at all that they may be infected. 196
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COPING WITH POSITIVE HSV-2 SEROLOGY
Because of the stigma that we as a society have attached to herpes and to all STIs, receiving the diagnosis of HSV-2 via positive serology can be emotionally overwhelming. The clinician needs to set aside time to help the individual diagnosed with asymptomatic herpes understand and cope with the result. If in-office rapid testing has been used, then the clinician or other qualified personnel will have to find time at that very same visit to initiate that counseling process. The patient’s first reaction may be anger, grief, or disbelief, and a return visit for more patient education may be warranted. Here are some of the key messages to convey at that time. Although the initial diagnosis usually comes a shock, over time people with herpes learn how to live with it and how to talk about it. You may have had this infection for a long time. You did not necessarily acquire this infection from your current or most recent sexual partner. Volume 10, Issue 3, March 2014
Even if you have no symptoms, it is possible that you could pass this infection to your sexual partner. Using condoms consistently can reduce the transmission of genital herpes. Some people with asymptomatic genital herpes choose to go on suppressive therapy with antiviral medicine. There are no studies to date that tell us to what extent this treatment can reduce transmission to others in people with no symptoms, but experts believe it may help. Much more information is available online (Table 2). Studies have shown that the negative response to HSV-2 diagnosis, although intense at the time of the initial diagnosis, generally gets better with time, with little lasting psychosocial impact or long-term deterioration in mental health.22,23 Although there are limited data about how the newly diagnosed adjust, there is ample anecdotal evidence that people learn how to cope with genital herpes, successfully disclose their status to prospective or current partners, and enjoy healthy, satisfying sexual relationships despite their infection. CONFIRMATORY TESTING
Although the diagnosis of asymptomatic genital herpes made via type-specific serology may be met with incredulity, the tests have a high degree of accuracy. For example, the HerpeSelect test by Focus
Diagnostics, one of the most widely used technologies, has a sensitivity of 96% and a specificity of 97% for HSV-2.24 The manufacturer has disclosed that most false positives are associated with test specimens that have values at the bottom of the reference range (index values between 1.1 and 3.5). Index values over 3.5 are highly unlikely to be false positives. Even test manufacturers recommend that additional testing be performed before accepting the diagnosis if the probability of a true positive is low.25 It is known that the positive predictive value of the test is low in a low prevalence population. One study found it to be no higher than 37.5%.26 Given that the Web is loaded with message boards urging those diagnosed via serology to seek confirmatory testing, it should be expected that patients who have gone online to do more research may ask for it. One option for confirmatory testing would be to order a different type-specific test.27 However, the best and most accurate option is to order an HSV Western blot. This test is only available via the University of Washington’s Clinical Virology Laboratory (1-800-713-5198). Some Quest Diagnostics sites may be able to facilitate this testing. Otherwise, samples are mailed directly to the Virology Lab in Seattle for processing. The Western blot, with sensitivity and specificity of greater than 99%, is considered the definitive test for the diagnosis of herpes via serology.28 TREATMENT FOR TRANSMISSION REDUCTION
Table 2. Patient Resources Herpes Resource Center from the American Sexual Health Association, http://www.ashasexualhealth.org/ std-sti/Herpes.html Information, referrals STI Resource Center Hotline, 1-800-227-8922 Information, referrals Warren T. The Updated Herpes Handbook. Portland, OR: The Portland Press; 2010, http://westoverheights.com/ herpes_handbook/final_HH_for_2010_revision_1.pdf Easy to understand, comprehensive information Ebel C, Wald A. Managing Herpes: Living and Loving With HSV. Research Triangle Park, NC: American Sexual Health Association; 2007 Comprehensive guide with several chapters on the psychosocial impact of the herpes simplex virus
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An area of needed study is to determine whether daily suppressive therapy with antiviral medications such as acyclovir or valacyclovir can help reduce the risk of transmitting asymptomatic herpes. In a landmark 2009 article, Corey et al29 showed that daily therapy with valacyclovir produced a 48% reduction in HSV transmission in couples with discordant HSV-2 status in which 1 partner had outbreaks and the other partner was initially seronegative. The Corey study prompted the Food and Drug Administration to approve the reduction of transmission in heterosexual partners as a new indication for valacyclovir.30 Whether this prevention strategy can be expected to succeed for asymptomatic seropositive people remains an unanswered question. A small 2008 study by Sperling et al31 found that daily The Journal for Nurse Practitioners - JNP
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valacyclovir reduced viral shedding in asymptomatic individuals by 71% although the authors caution that further research is needed to demonstrate whether this effect can be expected to produce a comparable reduction in transmission. Recent findings indicate that even high doses of daily acyclovir and valacyclovir do not completely suppress shedding.32 Current pharmacologic options ultimately may be proven to reduce but not entirely prevent transmission from asymptomatic seropositive individuals. Without citing sources, the CDC posits in its 2010 guidelines that suppressive antiviral therapy is likely to reduce transmission when used by HSV-2 seropositive people without a history of genital outbreaks.8(p22) Clinicians should certainly discuss this option with patients, emphasizing, however, that the evidence about efficacy for this measure is still limited. When patients opt for suppressive therapy, there are 3 available options: acyclovir, valacyclovir, and famciclovir. The standard dosing is acyclovir 400 mg twice a day, valacyclovir 500-1,000 mg every day, or famciclovir 250 mg twice a day. All 3 are available in generic versions, but acyclovir is by far the most affordable choice and can often be found on pharmacies’ low-cost formularies.33,34 These medications have been shown to have a favorable safety profile for long-term use with minimal microbial resistance.35 For some patients, serologic testing for sexual partners may help determine whether suppressive therapy would be of potential benefit. If 2 asymptomatic monogamous partners are both HSV-2 IgG positive, the need for suppressive therapy to reduce transmission is obviated. In a different clinical situation, if the partner of a seropositive person is pregnant and is herself seronegative, clinicians should counsel regarding the prevention of primary maternal herpes, which carries a higher risk for perinatal transmission and neonatal complications.11(p1491-1492) HERPES AND CONDOMS
In addition to the potential benefit of suppressive therapy with daily antivirals, another prevention strategy is condoms. Condom use has been shown to protect against HSV transmission.36,37 However, although herpes cannot cross a latex barrier, 198
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transmission can occur via vulvar or perineal inoculation even with a correctly used condom.38,39 One large pooled analysis found only a 30% lower risk of HSV acquisition with consistent condom use compared with no condom use.40 More studies are needed to specifically study the degree of protection afforded by condoms in serologically discordant partners. CONCLUSION
Clearly, the decision as to whether to screen for asymptomatic genital herpes must be individualized. HSV-2 IgG is a test that should not be ordered without the patient making an informed decision and understanding the potential benefits and repercussions of being tested. Some patients may decide that they would rather not know their status, whereas others may feel that knowing their status with certainty so as to be able to notify prospective partners and take measures to prevent transmission is the only ethical approach to take. Whether testing for herpes or not, clinicians should reinforce the importance of safer sex with all patients at risk for STI acquisition. References 1. Centers for Disease Control and Prevention. Genital Herpes. Centers for Disease Control and Prevention Web site. http://www.cdc.gov/std/herpes. Accessed October 22, 2013. 2. 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. 3. Wald A. Knowledge is power: a case for wider herpes simplex virus serologic testing. JAMA Pediatr. 2013;167(8):689-690. 4. Hayley M. Asymptomatic sexually active adolescents and young adults should not be screened for herpes simplex virus. JAMA Pediatr. 2013;167(8):691-692. 5. Patrick DM, Money D. Debate: the argument for. Should every STD clinic patient be considered for type-specific serological screening for HSV? Herpes. 2002;9(2):32-34. 6. Mindel A, Taylor J. Debate: the argument against. Should every STD clinic patient be considered for type-specific serological screening for HSV? Herpes. 2002;9(2):35-37. 7. US Preventive Services Task Force. Screening for genital herpes simplex recommendation statement. US Preventive Services Task Force Web site. http://www.uspreventiveservicestaskforce.org/uspstf05/herpes/herpesrs.htm. Accessed June 1, 2013. 8. Division of STD Prevention National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010;59(RR-12):1-110. 9. Centers for Disease Control and Prevention. Seroprevalence of herpes simplex virus type 2 among persons aged 14-49 years—United States, 20052008. MMWR Morb Mortal Wkly Rep. 2010;59(15):456-459. 10. Wald A. Genital HSV-1 infections. Sex Transm Infect. 2006;82(3):189-190. 11. Mertz GJ. Asymptomatic shedding of herpes simplex virus 1 and 2: implications for prevention of transmission. J Infect Dis. 2008;198(8):1098-1100. 12. Sacks SL, Griffiths PD, Corey L, et al. HSV shedding. Antiviral Res. 2004;63(suppl 1):S19-S26. 13. Tronstein E, Johnston C, Huang ML, et al. Genital shedding of herpes simplex virus among symptomatic and asymptomatic persons with HSV-2 infection. JAMA. 2011;305(14):1441-1449. 14. Wald A, Zeh J, Selke S, et al. Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N Engl J Med. 2000;342(12):844-850.
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15. ACOG Practice Bulletin. Clinical management guidelines for obstetriciangynecologists. No. 82 June 2007. Management of herpes in pregnancy. Obstet Gynecol. 2007;109(6):1489-1498. 16. Freeman E, Weiss H, Glynn J, Cross P, Whitworth J, Hayes R. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS. 2006;20(1):73-83. 17. Barnabas RV, Celum C. Infectious co-factors in HIV-1 transmission herpes simplex virus type-2 and HIV-1: new insights and interventions. Curr HIV Res. 2012;10(3):228-237. 18. Celum C, Wald A, Hughes J, et al. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;371(9630):2109-2119. 19. Centers for Disease Control and Prevention. ChlamydiaeCDC Fact Sheet. Centers for Disease Control and Prevention Web site. http://www.cdc.gov/std/ chlamydia/STDFact-chlamydia-detailed.htm. Accessed October 22, 2013. 20. Melville J, Sniffen S, Crosby R, Salazar L, et al. Psychosocial impact of serological diagnosis of herpes simplex virus type 2: a qualitative assessment. Sex Transm Infect. 2003;79(4):280-285. 21. Wald A, Krantz E, Selke S, Lairson E, Morrow RA, Zeh J. Knowledge of partners’ genital herpes protects against herpes simplex virus type 2 acquisition. J Infect Dis. 2006;194(1):42-52. 22. Provenzale A, Evans K, Russell J, Hoory T, Mark H. Psychosocial impact of a positive HSV-2 diagnosis on adults with unrecognized HSV-2 infection. Public Health Nurs. 2001;28(4):325-334. 23. Brookes JL, Haywood S, Green J. Adjustment to the psychological and social sequelae of recurrent genital herpes simplex infection. Genitourin Med. 1993;69(5):384-387. 24. Focus Diagnostics. HerpeSelect 2 ELISA IgG. Focus Diagnostics Web site. www.focusdx.com/pdfs/pi/US/EL0920G.pdf. Accessed September 10, 2013. 25. Focus Diagnostics. Herpes testing Information for healthcare providers. HerpeSelect Web site. http://www.herpeselect.com/healthcare_counseling.py. Accessed September 10, 2013. 26. Mark HD, Nanda JP, Roberts J, et al. Performance of Focus ELISA tests for HSV-1 and HSV-2 antibodies among university students with no history of genital herpes. Sex Transm Dis. 2007;34(9):681-685. 27. Morrow RA, Friedrich D, Meier A, Corey L. Use of "biokit HSV-2 Rapid Assay" to improve the positive predictive value of Focus HerpeSelect HSV-2 ELISA. BMC Infect Dis. 2005;5:84. 28. University of Washington. Herpes serologies. Department of Laboratory Medicine Web site. http://depts.washington.edu/labweb/Divisions/Viro/ Herpes_sero.htm. Accessed June 1, 2013. 29. Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004;350(1):11-20. 30. Drugs.com. FDA Advisory Committee votes in favor of Valtrex for the reduction of genital herpes transmission. Drugs.com. http://www.drugs.com/
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31.
32.
33. 34. 35.
36. 37.
38.
39. 40.
news/fda-advisory-committee-votes-favor-valtrex-reduction-genital-herpestransmission-3282.html. Accessed October 24, 2013. Sperling RS, Fife KH, Warren TJ, Dix LP, Brennan CA. The effect of daily valacyclovir suppression on herpes simplex virus type 2 viral shedding in HSV-2 seropositive subjects without a history of genital herpes. Sex Transm Dis. 2008;35(3):286-290. Johnston C, Saracino M, Kuntz S, et al. Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: three randomised, open-label, cross-over trials. Lancet. 2012;379(9816): 641-647. Target Brands Inc. $4 generics. Target Pharmacy Web site. http://www.target .com/pharmacy/generics-alphabetic. Accessed October 22, 2013. Wal-Mart Stores Inc. $4 Prescriptions. Wal-Mart Web site. http://www. walmart.com/cp/PI-4-Prescriptions/1078664. Accessed October 22, 2013. Tyring SK, Baker D, Snowden W. Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years’ experience with acyclovir. J Infect Dis. 2002;186(suppl 1):S40-S46. Casper C, Wald A. Condom use and the prevention of genital herpes acquisition. Herpes. 2002;9(1):10-14. Stanaway JD, Wald A, Martin ET, Gottlieb SL, Magaret AS. Case-crossover analysis of condom use and herpes simplex virus type 2 acquisition. Sex Transm Dis. 2012;39(5):388-393. Martin ET, Krantz A, Gottlieb SL, et al. A pooled analysis of the effect of condoms in preventing HSV-2 acquisition. Arch Intern Med. 2009;169(13):1233-1240. Conant MA, Spicer DW, Smith CD. Herpes simplex virus transmission: condom studies. Sex Transm Dis. 1984;11(2):94-95. Wald A, Langenberg AG, Link K, et al. Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women. JAMA. 2001;285(24):3100-3106.
Leia Raphaelidis, FNP, is a nurse practitioner at Planned Parenthood of the Southern Finger Lakes in Ithaca, NY, and can be reached at leia.raphaelidis@ppsfl.org. In compliance with national ethical guidelines, the author reports no relationships with business or industry that would pose a conflict of interest. 1555-4155/14/$ see front matter © 2014 Elsevier, Inc. All rights reserved. http://dx.doi.org/10.1016/j.nurpra.2013.12.008
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Genital herpes is very common, but most people who have it are not aware of their status because they do not have symptoms. Serologic testing can be used to identify asymptomatic herpes, but the benefit of screening is not clear-cut. Clinicians should be aware of the issues surrounding herpes screening to help their patients decide if they should be tested and to counsel those who test positive. Keywords: asymptomatic herpes, genital herpes, sexually transmitted infection screening Ó 2014 Elsevier, Inc. All rights reserved.
G
enital herpes is one of the most common sexually transmitted infections (STIs) in the United States and is lifelong and incurable, yet only a small fraction of individuals with herpes are symptomatic or aware of their infection.1 Historically, the gold standard for the diagnosis of genital herpes has been via a physical examination and direct testing of mucocutaneous lesions during an outbreak, thereby limiting the diagnosis to symptomatic individuals. However, over the past decade, developments in testing technology have made it possible to accurately detect herpes antibodies in serum (Table 1), thus providing a way to diagnose herpes regardless of the presence or absence of lesions. Based on a surface protein called glycoprotein G, these tests reliably differentiate between antibodies to herpes simplex virus type 1 (HSV-1) immunoglobulin G (IgG) and herpes simplex virus type 2 (HSV-2) IgG.2 Screening asymptomatic individuals via serology has emerged as a widely available and relatively affordable testing option, leading to the following question: Should clinicians be screening their patients for asymptomatic herpes? Arguments have been made for and against screening, and the subject remains controversial.3-6 The US Preventive Services Task Force and the Centers for Disease Control and Prevention (CDC) recommend against routine serologic screening in the general population, citing a lack of evidence that screening reduces herpes transmission and expressing concern that the potential harms of screening 194
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outweigh the potential benefits.7 However, the 2010 Sexually Transmitted Diseases Treatment Guidelines from the CDC state that some experts believe that clinicians should perform herpes serology for highrisk individuals presenting for STI evaluation.8 This article discusses the clinical complexities of asymptomatic herpes and the issues surrounding screening for this highly stigmatized infection. Clinicians ordering herpes serology need to be well versed in the subject of asymptomatic herpes and be prepared to counsel those patients who are deciding whether or not to get tested and those who do test positive. ASYMPTOMATIC GENITAL HERPES: MORE COMMON THAN YOU THINK
Most genital herpes is associated with HSV-2, and it is uncommon for HSV-2 to take hold outside the anogenital region. Therefore, the presence of HSV-2 antibodies in serum can be taken as an indicator of genital herpes.2(pS176) According to the most recent data from the CDC, seroprevalence of HSV-2 in the US was estimated to be 16.2%, with a prevalence of 20.9% among women and 11.5% among men.9 To further complicate the diagnostic picture, an increasing number of new cases of genital herpes are caused by HSV-1, the virus usually associated with herpes labialis.10 Because a positive HSV-1 IgG does not identify the site of infection, the test cannot be used to specifically screen for asymptomatic genital HSV-1. Therefore, the total prevalence of genital Volume 10, Issue 3, March 2014
Table 1. Type-specific Herpes Serology Test Name
Manufacturer
AtheNA Multi-Lyte HSV 1 & 2 IgG Plus
ZEUS Scientific
BioPlex 2200 HSV-1 & HSV -2 IgG
Bio-Rad
Captia HSV-1 & HSV-2 IgG
Trinity Biotech
EuroImmun anti-HSV-1 and anti-HSV-2 ELISA (IgG)
EuroImmun US
HerpeSelect 1&2 ELISA IgG
Focus Diagnostics
HerpeSelect 1 & 2 Immunoblot IgG
Focus Diagnostics
HSV-2 Rapid Test (also marketed as SureVue HSV-2 Rapid Test by Fisher HealthCare)
Biokit USA
Wampole HSV gG-2 ELISA II
Alere
HSV-1 ¼ herpes simplex virus type 1; HSV-2 ¼ herpes simplex virus type 2; IgG ¼ immunoglobulin G. Note: Available type-specific herpes serology tests are listed in the table. All these rely on glycoprotein-G to distinguish between HSV-1 and HSV-2. Clinicians ordering HSV serology should verify that the laboratory is using a type-specific test (www.ashasexualhealth.org/uploads/pdfs/HerpesBloodTestGuide.pdf). The rapid tests are Clinical Laboratory Improvement Amendments nonwaived and of moderate complexity.
HSV (ie, type 1 and type 2) is presumed to be even higher than the CDC’s 16.2%. ASYMPTOMATIC SHEDDING AND TRANSMISSION
Somewhat surprisingly, more than 80% of HSV-2 infections are asymptomatic, subtle enough that they remain unrecognized, or misdiagnosed because genital ulcers are absent.9(p458) Even in the absence of any clinical manifestations, herpes can reactivate from its usual dormant state and be transmitted via skin to skin contact to sexual partners through a process called asymptomatic shedding. In fact, the majority of new HSV cases are transmitted from source individuals who have no apparent lesions.11 By means of sensitive DNA amplification tests conducted on anogenital swabs, HSV has been detected in almost all asymptomatic seropositive individuals about 20%-25% of days.12 The minimum amount of detectable HSV needed for transmission to occur to a sexual partner has not yet been established. Therefore, it is not known if each instance of detectable HSV necessarily represents potential infectivity.13 The rate of shedding appears to decrease with time elapsed since primary infection by up to 70% after 10 years.12(p S20) Given these findings, experts advise that all seropositive www.npjournal.org
individuals should be considered potentially infectious to their sexual partners, even if the risk of transmission cannot be quantified.14 HERPES AND ITS RISKS: CAN SCREENING MAKE A DIFFERENCE?
From a physiologic standpoint, asymptomatic herpes is largely harmless to immunocompetent individuals. Although HSV can carry rare but serious complications such as ocular herpes, herpes encephalitis, and neonatal herpes, most individuals infected with the virus will suffer no adverse physical sequelae. Furthermore, there is no evidence that screening reduces the risk of such complications. The American College of Obstetricians and Gynecologists recommends against routine serologic screening of pregnant women because of a lack of evidence for a costeffective strategy that prevents neonatal herpes.15 However, genital herpes can increase the risk of human immunodeficiency virus (HIV) acquisition by 3-fold because the inflammation associated with HSV activation facilitates HIV entry into the body.16 Nevertheless, there is no evidence at this time that this risk can be decreased by treating the HSV infection with antivirals.17 In 1 double-blind, randomized, placebo-controlled study, suppressive therapy with the antiviral acyclovir taken daily had no effect on the risk of HIV acquisition despite significantly reducing the number of herpes outbreaks.18 TO SCREEN OR NOT TO SCREEN?
The usual purpose of medical screenings, including STI screening, is the early identification of a disease in order to maximize health outcomes. For example, screening for chlamydia and promptly treating this STI can help prevent pelvic inflammatory disease, reduce the risk of subsequent ectopic pregnancy, and preserve women’s fertility.19 However, in the case of HSV, early detection does not alter health outcomes for identified individuals nor does it affect the natural history of the infection. Regardless of when it is detected, herpes cannot be cured. At best, positive serology may help provide an alternate explanation for genital symptoms previously misidentified as yeast infections, urinary tract infections, razor burn, insect bites, friction rubs, allergic reactions, or any other of the myriad misdiagnoses given for subtle, atypical, The Journal for Nurse Practitioners - JNP
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but not wholly asymptomatic genital HSV. At worst, positive HSV serology may produce significant psychological distress, with repercussions for relationships, emotional health, and sexual well-being.20 If screening cannot change outcomes for affected individuals, can it at least help prevent transmission to others? Although the US Preventive Services Task Force has concluded that there is no evidence that screening reduces transmission, there is limited evidence that knowledge of a partner’s positive HSV status does help protect against HSV acquisition. In a 1996 study by Wald et al,21 researchers found that among initially discordant couples, the median time to HSV-2 acquisition was longer for participants whose partners disclosed their HSV status. The behaviors that produced that delay in transmission were not clear, although interestingly, consistent condom use was not one of them.21 Further research is needed to establish whether individuals who are made aware of their asymptomatic herpes can take effective measures to reduce transmission to others, perhaps by limiting their number of sexual partners, taking antiviral therapy, or committing to consistent condom use.
Herpes can be transmitted in the absence of symptoms. Most herpes infections are transmitted this way.1 Antibodies to herpes can be detected as early as 2-3 weeks after initial infection, although detectable antibodies can take up to 16 weeks.2(pS175) Herpes is a highly stigmatized infection. Being diagnosed with herpes can be distressing. Clinicians should explore their patients’ motivation for testing and should probe how being diagnosed with HSV might affect the way they approach intimate relationships. Would a diagnosis of genital herpes affect their sexual behaviors? Would they be willing to disclose their status to current and future sexual partners? Would they consider using daily medications to reduce the risk of transmission? Although this discussion will take up valuable office time, it may be helpful for clinicians to bear in mind that in the near future, they will likely be notifying about 1 in 6 of the patients whom they have screened that they have been found to have genital herpes. The time spent on education before testing will have laid the groundwork for the delivery of that result.
PRETEST COUNSELING STRATEGIES
Given the lack of strong evidence that HSV-2 screening reduces harm, the decision whether or not to screen asymptomatic individuals is not clear-cut. The clinician and patient have to carefully consider the decision and its implications. A negative HSV-2 IgG may come as a huge relief, especially to someone with a known exposure to herpes. However, anyone who chooses to be tested needs to be prepared to cope with a positive result. There are no clear guidelines about what HSV pretest counseling should include. The following key points about asymptomatic herpes can correct common misunderstandings and help patients decide if finding out their HSV status is the right decision for them. Herpes is common and a lack of symptoms or known exposures cannot be taken as proof that a person is not infected. Most people with herpes have no symptoms.1 Herpes serology is a test that does come back positive in individuals who have no suspicion at all that they may be infected. 196
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COPING WITH POSITIVE HSV-2 SEROLOGY
Because of the stigma that we as a society have attached to herpes and to all STIs, receiving the diagnosis of HSV-2 via positive serology can be emotionally overwhelming. The clinician needs to set aside time to help the individual diagnosed with asymptomatic herpes understand and cope with the result. If in-office rapid testing has been used, then the clinician or other qualified personnel will have to find time at that very same visit to initiate that counseling process. The patient’s first reaction may be anger, grief, or disbelief, and a return visit for more patient education may be warranted. Here are some of the key messages to convey at that time. Although the initial diagnosis usually comes a shock, over time people with herpes learn how to live with it and how to talk about it. You may have had this infection for a long time. You did not necessarily acquire this infection from your current or most recent sexual partner. Volume 10, Issue 3, March 2014
Even if you have no symptoms, it is possible that you could pass this infection to your sexual partner. Using condoms consistently can reduce the transmission of genital herpes. Some people with asymptomatic genital herpes choose to go on suppressive therapy with antiviral medicine. There are no studies to date that tell us to what extent this treatment can reduce transmission to others in people with no symptoms, but experts believe it may help. Much more information is available online (Table 2). Studies have shown that the negative response to HSV-2 diagnosis, although intense at the time of the initial diagnosis, generally gets better with time, with little lasting psychosocial impact or long-term deterioration in mental health.22,23 Although there are limited data about how the newly diagnosed adjust, there is ample anecdotal evidence that people learn how to cope with genital herpes, successfully disclose their status to prospective or current partners, and enjoy healthy, satisfying sexual relationships despite their infection. CONFIRMATORY TESTING
Although the diagnosis of asymptomatic genital herpes made via type-specific serology may be met with incredulity, the tests have a high degree of accuracy. For example, the HerpeSelect test by Focus
Diagnostics, one of the most widely used technologies, has a sensitivity of 96% and a specificity of 97% for HSV-2.24 The manufacturer has disclosed that most false positives are associated with test specimens that have values at the bottom of the reference range (index values between 1.1 and 3.5). Index values over 3.5 are highly unlikely to be false positives. Even test manufacturers recommend that additional testing be performed before accepting the diagnosis if the probability of a true positive is low.25 It is known that the positive predictive value of the test is low in a low prevalence population. One study found it to be no higher than 37.5%.26 Given that the Web is loaded with message boards urging those diagnosed via serology to seek confirmatory testing, it should be expected that patients who have gone online to do more research may ask for it. One option for confirmatory testing would be to order a different type-specific test.27 However, the best and most accurate option is to order an HSV Western blot. This test is only available via the University of Washington’s Clinical Virology Laboratory (1-800-713-5198). Some Quest Diagnostics sites may be able to facilitate this testing. Otherwise, samples are mailed directly to the Virology Lab in Seattle for processing. The Western blot, with sensitivity and specificity of greater than 99%, is considered the definitive test for the diagnosis of herpes via serology.28 TREATMENT FOR TRANSMISSION REDUCTION
Table 2. Patient Resources Herpes Resource Center from the American Sexual Health Association, http://www.ashasexualhealth.org/ std-sti/Herpes.html Information, referrals STI Resource Center Hotline, 1-800-227-8922 Information, referrals Warren T. The Updated Herpes Handbook. Portland, OR: The Portland Press; 2010, http://westoverheights.com/ herpes_handbook/final_HH_for_2010_revision_1.pdf Easy to understand, comprehensive information Ebel C, Wald A. Managing Herpes: Living and Loving With HSV. Research Triangle Park, NC: American Sexual Health Association; 2007 Comprehensive guide with several chapters on the psychosocial impact of the herpes simplex virus
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An area of needed study is to determine whether daily suppressive therapy with antiviral medications such as acyclovir or valacyclovir can help reduce the risk of transmitting asymptomatic herpes. In a landmark 2009 article, Corey et al29 showed that daily therapy with valacyclovir produced a 48% reduction in HSV transmission in couples with discordant HSV-2 status in which 1 partner had outbreaks and the other partner was initially seronegative. The Corey study prompted the Food and Drug Administration to approve the reduction of transmission in heterosexual partners as a new indication for valacyclovir.30 Whether this prevention strategy can be expected to succeed for asymptomatic seropositive people remains an unanswered question. A small 2008 study by Sperling et al31 found that daily The Journal for Nurse Practitioners - JNP
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valacyclovir reduced viral shedding in asymptomatic individuals by 71% although the authors caution that further research is needed to demonstrate whether this effect can be expected to produce a comparable reduction in transmission. Recent findings indicate that even high doses of daily acyclovir and valacyclovir do not completely suppress shedding.32 Current pharmacologic options ultimately may be proven to reduce but not entirely prevent transmission from asymptomatic seropositive individuals. Without citing sources, the CDC posits in its 2010 guidelines that suppressive antiviral therapy is likely to reduce transmission when used by HSV-2 seropositive people without a history of genital outbreaks.8(p22) Clinicians should certainly discuss this option with patients, emphasizing, however, that the evidence about efficacy for this measure is still limited. When patients opt for suppressive therapy, there are 3 available options: acyclovir, valacyclovir, and famciclovir. The standard dosing is acyclovir 400 mg twice a day, valacyclovir 500-1,000 mg every day, or famciclovir 250 mg twice a day. All 3 are available in generic versions, but acyclovir is by far the most affordable choice and can often be found on pharmacies’ low-cost formularies.33,34 These medications have been shown to have a favorable safety profile for long-term use with minimal microbial resistance.35 For some patients, serologic testing for sexual partners may help determine whether suppressive therapy would be of potential benefit. If 2 asymptomatic monogamous partners are both HSV-2 IgG positive, the need for suppressive therapy to reduce transmission is obviated. In a different clinical situation, if the partner of a seropositive person is pregnant and is herself seronegative, clinicians should counsel regarding the prevention of primary maternal herpes, which carries a higher risk for perinatal transmission and neonatal complications.11(p1491-1492) HERPES AND CONDOMS
In addition to the potential benefit of suppressive therapy with daily antivirals, another prevention strategy is condoms. Condom use has been shown to protect against HSV transmission.36,37 However, although herpes cannot cross a latex barrier, 198
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transmission can occur via vulvar or perineal inoculation even with a correctly used condom.38,39 One large pooled analysis found only a 30% lower risk of HSV acquisition with consistent condom use compared with no condom use.40 More studies are needed to specifically study the degree of protection afforded by condoms in serologically discordant partners. CONCLUSION
Clearly, the decision as to whether to screen for asymptomatic genital herpes must be individualized. HSV-2 IgG is a test that should not be ordered without the patient making an informed decision and understanding the potential benefits and repercussions of being tested. Some patients may decide that they would rather not know their status, whereas others may feel that knowing their status with certainty so as to be able to notify prospective partners and take measures to prevent transmission is the only ethical approach to take. Whether testing for herpes or not, clinicians should reinforce the importance of safer sex with all patients at risk for STI acquisition. References 1. Centers for Disease Control and Prevention. Genital Herpes. Centers for Disease Control and Prevention Web site. http://www.cdc.gov/std/herpes. Accessed October 22, 2013. 2. 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. 3. Wald A. Knowledge is power: a case for wider herpes simplex virus serologic testing. JAMA Pediatr. 2013;167(8):689-690. 4. Hayley M. Asymptomatic sexually active adolescents and young adults should not be screened for herpes simplex virus. JAMA Pediatr. 2013;167(8):691-692. 5. Patrick DM, Money D. Debate: the argument for. Should every STD clinic patient be considered for type-specific serological screening for HSV? Herpes. 2002;9(2):32-34. 6. Mindel A, Taylor J. Debate: the argument against. Should every STD clinic patient be considered for type-specific serological screening for HSV? Herpes. 2002;9(2):35-37. 7. US Preventive Services Task Force. Screening for genital herpes simplex recommendation statement. US Preventive Services Task Force Web site. http://www.uspreventiveservicestaskforce.org/uspstf05/herpes/herpesrs.htm. Accessed June 1, 2013. 8. Division of STD Prevention National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010;59(RR-12):1-110. 9. Centers for Disease Control and Prevention. Seroprevalence of herpes simplex virus type 2 among persons aged 14-49 years—United States, 20052008. MMWR Morb Mortal Wkly Rep. 2010;59(15):456-459. 10. Wald A. Genital HSV-1 infections. Sex Transm Infect. 2006;82(3):189-190. 11. Mertz GJ. Asymptomatic shedding of herpes simplex virus 1 and 2: implications for prevention of transmission. J Infect Dis. 2008;198(8):1098-1100. 12. Sacks SL, Griffiths PD, Corey L, et al. HSV shedding. Antiviral Res. 2004;63(suppl 1):S19-S26. 13. Tronstein E, Johnston C, Huang ML, et al. Genital shedding of herpes simplex virus among symptomatic and asymptomatic persons with HSV-2 infection. JAMA. 2011;305(14):1441-1449. 14. Wald A, Zeh J, Selke S, et al. Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N Engl J Med. 2000;342(12):844-850.
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15. ACOG Practice Bulletin. Clinical management guidelines for obstetriciangynecologists. No. 82 June 2007. Management of herpes in pregnancy. Obstet Gynecol. 2007;109(6):1489-1498. 16. Freeman E, Weiss H, Glynn J, Cross P, Whitworth J, Hayes R. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS. 2006;20(1):73-83. 17. Barnabas RV, Celum C. Infectious co-factors in HIV-1 transmission herpes simplex virus type-2 and HIV-1: new insights and interventions. Curr HIV Res. 2012;10(3):228-237. 18. Celum C, Wald A, Hughes J, et al. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;371(9630):2109-2119. 19. Centers for Disease Control and Prevention. ChlamydiaeCDC Fact Sheet. Centers for Disease Control and Prevention Web site. http://www.cdc.gov/std/ chlamydia/STDFact-chlamydia-detailed.htm. Accessed October 22, 2013. 20. Melville J, Sniffen S, Crosby R, Salazar L, et al. Psychosocial impact of serological diagnosis of herpes simplex virus type 2: a qualitative assessment. Sex Transm Infect. 2003;79(4):280-285. 21. Wald A, Krantz E, Selke S, Lairson E, Morrow RA, Zeh J. Knowledge of partners’ genital herpes protects against herpes simplex virus type 2 acquisition. J Infect Dis. 2006;194(1):42-52. 22. Provenzale A, Evans K, Russell J, Hoory T, Mark H. Psychosocial impact of a positive HSV-2 diagnosis on adults with unrecognized HSV-2 infection. Public Health Nurs. 2001;28(4):325-334. 23. Brookes JL, Haywood S, Green J. Adjustment to the psychological and social sequelae of recurrent genital herpes simplex infection. Genitourin Med. 1993;69(5):384-387. 24. Focus Diagnostics. HerpeSelect 2 ELISA IgG. Focus Diagnostics Web site. www.focusdx.com/pdfs/pi/US/EL0920G.pdf. Accessed September 10, 2013. 25. Focus Diagnostics. Herpes testing Information for healthcare providers. HerpeSelect Web site. http://www.herpeselect.com/healthcare_counseling.py. Accessed September 10, 2013. 26. Mark HD, Nanda JP, Roberts J, et al. Performance of Focus ELISA tests for HSV-1 and HSV-2 antibodies among university students with no history of genital herpes. Sex Transm Dis. 2007;34(9):681-685. 27. Morrow RA, Friedrich D, Meier A, Corey L. Use of "biokit HSV-2 Rapid Assay" to improve the positive predictive value of Focus HerpeSelect HSV-2 ELISA. BMC Infect Dis. 2005;5:84. 28. University of Washington. Herpes serologies. Department of Laboratory Medicine Web site. http://depts.washington.edu/labweb/Divisions/Viro/ Herpes_sero.htm. Accessed June 1, 2013. 29. Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004;350(1):11-20. 30. Drugs.com. FDA Advisory Committee votes in favor of Valtrex for the reduction of genital herpes transmission. Drugs.com. http://www.drugs.com/
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news/fda-advisory-committee-votes-favor-valtrex-reduction-genital-herpestransmission-3282.html. Accessed October 24, 2013. Sperling RS, Fife KH, Warren TJ, Dix LP, Brennan CA. The effect of daily valacyclovir suppression on herpes simplex virus type 2 viral shedding in HSV-2 seropositive subjects without a history of genital herpes. Sex Transm Dis. 2008;35(3):286-290. Johnston C, Saracino M, Kuntz S, et al. Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: three randomised, open-label, cross-over trials. Lancet. 2012;379(9816): 641-647. Target Brands Inc. $4 generics. Target Pharmacy Web site. http://www.target .com/pharmacy/generics-alphabetic. Accessed October 22, 2013. Wal-Mart Stores Inc. $4 Prescriptions. Wal-Mart Web site. http://www. walmart.com/cp/PI-4-Prescriptions/1078664. Accessed October 22, 2013. Tyring SK, Baker D, Snowden W. Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years’ experience with acyclovir. J Infect Dis. 2002;186(suppl 1):S40-S46. Casper C, Wald A. Condom use and the prevention of genital herpes acquisition. Herpes. 2002;9(1):10-14. Stanaway JD, Wald A, Martin ET, Gottlieb SL, Magaret AS. Case-crossover analysis of condom use and herpes simplex virus type 2 acquisition. Sex Transm Dis. 2012;39(5):388-393. Martin ET, Krantz A, Gottlieb SL, et al. A pooled analysis of the effect of condoms in preventing HSV-2 acquisition. Arch Intern Med. 2009;169(13):1233-1240. Conant MA, Spicer DW, Smith CD. Herpes simplex virus transmission: condom studies. Sex Transm Dis. 1984;11(2):94-95. Wald A, Langenberg AG, Link K, et al. Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women. JAMA. 2001;285(24):3100-3106.
Leia Raphaelidis, FNP, is a nurse practitioner at Planned Parenthood of the Southern Finger Lakes in Ithaca, NY, and can be reached at leia.raphaelidis@ppsfl.org. In compliance with national ethical guidelines, the author reports no relationships with business or industry that would pose a conflict of interest. 1555-4155/14/$ see front matter © 2014 Elsevier, Inc. All rights reserved. http://dx.doi.org/10.1016/j.nurpra.2013.12.008
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