The Journal of Pediatrics
Volume 151, Issue 4 , Pages 336-338, October 2007

Rethinking Herpes Simplex Virus Infections in Children and Adolescents

  • Kathleen M. Gutierrez, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Kathleen M. Gutierrez, MD, Division of Pediatric Infectious Diseases, Stanford University School of Medicine, 300 Pasteur Drive, Room G312, Stanford, CA 94305.

Division of Pediatric Infectious Diseases, Stanford University School of Medicine, Stanford, California

Article Outline

HSV, Herpes simplex virus, NHANES, National Health and Nutrition Examination Survey

 

“In all affairs, it’s a healthy thing now and then to hang a question mark on the things you have taken for granted.” —Bertrand Russell

See related article, p 374

Most physicians have learned that herpes simplex virus (HSV) infections involving the genital tract are caused predominantly by HSV-2 and that infections of the lips and mouth are usually caused by HSV-1. Recent studies show that HSV-1 is an increasingly frequent cause of genital infection.1

Even though it is possible for HSV-1 to infect genital sites, this is not its preferred location for replication and establishment of latency. Animal models suggest that preference of anatomic sites may be associated with sequence differences in the latency-associated transcript of HSV-1 and HSV-2.2 As a result, clinical differences are noted when HSV-1 infects the genital area or HSV-2 infects the mouth. Symptomatic recurrence and asymptomatic viral shedding occur less often with HSV-1 genital infection compared with HSV-2 genital infection.3 Similarly, although shedding of HSV-2 from oral secretions has been reported, the virus is shed less frequently and in lower amounts than HSV-1 from oral mucosa.4

Despite anatomic preferences of the virus for establishment of latency and reactivation, epidemiologic studies show that in some countries and in certain populations in the United States, HSV-1 is becoming an increasingly important cause of genital herpes infection.5 Studies from Scandinavia and the United Kingdom indicate that HSV-1 is responsible for a substantially higher proportion or even the majority of first clinical episodes of genital herpes in young women.1 A retrospective study in the United Kingdom found HSV-1 to be the cause of primary genital infection in 71% of individuals presenting to a genitourinary medicine clinic. The high prevalence of HSV-1 infection was most marked in women.6 HSV-1 accounted for 64% of primary genital HSV infections between 1995 and 1999 at a sexually transmitted infection clinic in Sweden.7 A study of college students in the midwestern United States found that the proportion of genital herpes infections caused by HSV-1 increased from 31% to 78% between 1993 and 2001.5 Whether this occurred because there is a larger pool of HSV-1–susceptible adolescents and adults, because of changing sexual practices, or both remains to be determined.

The study by Xu et al8 in this issue of The Journal provides some support for the hypothesis that a decline in oral HSV-1 infections in children may play a role in the increasing proportion of cases of genital HSV-1 infection. The study was designed to explore the epidemiology of HSV-1 infections in the United States. Sera from 2989 children who participated in recent National Health and Nutrition Examination Surveys (NHANES) were tested for antibody to HSV-1.

The NHANES project, conducted by the National Center for Health Statistics, was implemented in the early 1960s to monitor the health and diet of the US population. Individuals who participate in NHANES are selected in a manner so as to be representative of the noninstitutionalized general civilian population. Previous NHANES studies have addressed the seroepidemiology of HSV infection in adolescents and adults.9, 10 The most recent study of HSV-1 and HSV-2 seroprevalence in this older age group, published in 2006, showed, in contrast to earlier surveys, a downward trend in HSV-2 seroprevalence in adolescents and young adults in the United States, as well as an overall decrease in HSV-1 seroprevalence. However, a higher percentage of persons with serologic evidence of HSV-1 but not HSV-2 infection gave a history of being diagnosed with genital herpes compared with previous surveys, suggesting an increase in genital HSV-1 infections compared with previous years.9

Xu et al focus on children age 6 to 13 years enrolled in NHANES from 1999 to 2002. Sera were tested for antibodies to HSV-1 in all age groups. In addition, HSV-1 seroprevalence in 12- to 13-year-old children enrolled in the 1999-2002 NHANES and in a previous NHANES study (1988-1994) were compared. The authors found that HSV-1 seroprevalence increased with age and varied by race and socioeconomic status. Non-Hispanic white children were significantly less likely to be HSV-1 seropositive over all age groups (24.7% positive) compared with non-Hispanic black children (47.8% positive). Children who lived below the poverty level were more likely to be seropositive than those above the poverty line (51.8 vs 24%). The point estimate of HSV-1 seroprevalence in children age 12 to 13 years decreased from 40.3% in NHANES 1988-1994 to 36.1% in NHANES 1999-2002. The decrease in HSV-1 seroprevalence is nonsignificant; however, the authors conclude that with changes in living and hygiene conditions, HSV-1 acquisition in young children is expected to continue to decline. Future studies within the NHANES framework will be needed to substantiate this conclusion. Nonetheless, this study is important in that it gives an overview of HSV-1 seroprevalence in a young population in the United States. Only a few studies in the United States have specifically addressed HSV-1 seroprevalence in very young children, and these studies have targeted unique patient populations.11

The variability of HSV-1 seroprevalence is not unexpected. Cross-sectional seroprevalence studies in 8 European countries showed significant variations in HSV-1 and HSV-2 seropositivity among them.12 In countries in which serum from young children (age 0 to 9 years) was evaluated, seropositivity for HSV-1 varied from approximately 8% (Finland) to 62% (Bulgaria) in the younger age groups. There was a steady increase in seroprevalence to HSV-1 with age. The European studies confirm the relationship between socioeconomic status and seroprevalence, finding an inverse correlation between age-standardized seroprevalence of HSV-1 and national gross domestic product.12

If the hypothesis that improved hygiene and living conditions will facilitate a continuing decline in childhood oral HSV-1 infection is correct, then it is likely that the proportion of genital infections caused by HSV-1 will increase as adolescents and young adults susceptible to both HSV-1 and HSV-2 become sexually active. We will need to evaluate and reframe how we think about (1) the clinical presentation of genital herpes and how it is acquired (eg, changing sexual practices, particularly the practice of oral-genital sex), (2) the role of HSV-1 versus HSV-2 as a co-factor in the acquisition of HIV-1 infection, (3) the impact of increasing HSV-1 genital infection during child-bearing years on neonatal HSV infection, and (4) the influence of baseline HSV-1 and HSV-2 seroprevalence on the efficacy of future HSV vaccines.

Although the clinical presentation of HSV-1 and HSV-2 genital infections is similar, the natural history of disease differs between the 2 viruses. Persons with genital infection caused by HSV-1 are less likely to have symptomatic or asymptomatic recurrence,3 but persons who develop genital HSV-2 infection but lack antibody to HSV-1 may have more prominent symptoms. This is because antibody to HSV-1 seems to attenuate the severity of HSV-2 disease in some cases, although it does not prevent infection with HSV-2.

Clinicians need to be familiar with the differences in the clinical course of genital infection between HSV-1 and HSV-2 to provide appropriate counseling and treatment. For example, patients with HSV-1 genital infection may be more appropriately treated with episodic rather than long-term suppressive antiviral therapy. HSV-2 genital infection may be prevented by consistent use of condoms, but oral-genital sexual practices will possibly increase the incidence of genital HSV-1 infection.

Factors that put adolescents and young adults at risk for genital ulcer disease must be clearly defined. Clinically apparent and microscopic genital ulcer disease caused by HSV-2 is a risk factor for acquisition of HIV.13 An increase in local CD4 lymphocytes resulting from HSV infection and reactivation offers a greater number of target cells for HIV attachment and entry. All patients with HSV-2 genital infection appear to be at higher risk for acquiring HIV infection; however, those with recent HSV-2 seroconversion seem to be more susceptible.14 Theoretically, HSV-2, by virtue of its propensity to cause more frequent recurrence, may be more likely than HSV-1 to enable HIV acquisition; however, the relative risk of HSV-1 versus HSV-2 in facilitating HIV infection has not been studied.

The impact of an increasing number of genital HSV-1 infections on transmission of HSV to the neonate remains unknown. A recent study shows that when HSV-1 is present in the genital tract at delivery, it appears to be more readily transmissible to the neonate than HSV-2.15 However, the possible increased risk of transmissibility of genital HSV-1 may be offset by the relative infrequency of viral shedding compared with HSV-2. HSV-1 and HSV-2 cause similar clinical disease in the neonate. Both types of HSV infection are associated with substantial morbidity and mortality; however, central nervous system infection with HSV-1 appears to be less severe than that caused by HSV-2.

The study by Xu et al8 provides important information for determining which populations of children and adolescents can most likely benefit from a future HSV vaccine. Unfortunately, the development of vaccines against HSV infection has been complicated by the virus’ unique properties of rapid replication and its ability to evade recognition by the immune system.16 One candidate vaccine appeared to have efficacy against genital herpes, but only in women who were seronegative for both HSV-1 and 2 at baseline; it was not effective in women who had previous infection with HSV-1.17 Because vaccine efficacy may be affected by baseline seroprevalence, the information provided by Xu et al and future studies like this, will help target groups in the United States who could benefit most from the current vaccines in development.

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References 

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  2. Yoshikawa T, Hill JM, Stanberry LR, Bourne N, Kurawadwala JF, Krause PR. The characteristic site-specific reactivation phenotypes of HSV-1 and HSV-2 depend upon the latency-associated transcript region. J Exp Med. 1996;184:659–664
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  9. Xu F, Sternberg MR, Kottiri BJ, McQuillan GM, Lee FK, Nahmias AJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA. 2006;296:964–973
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  15. Brown EL, Gardella C, Malm G, Prober CG, Forsgren M, Krantz EM, et al. Effect of maternal herpes simplex virus (HSV) serostatus and HSV type on risk of neonatal herpes. Acta Obstet Gynecol Scand. 2007;86:523–529
  16. Rouse BT, Kaistha SD. A tale of 2 alpha-herpesviruses: lessons for vaccinologists. Clin Infect Dis. 2006;42:810–817
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PII: S0022-3476(07)00556-2

doi:10.1016/j.jpeds.2007.05.052

Refers to article:

  • Seroprevalence of Herpes Simplex Virus Type 1 in Children in the United States , 13 August 2007

    Fujie Xu, Francis K. Lee, Rhoda A. Morrow, Maya R. Sternberg, Kristina E. Luther, Gary Dubin, Lauri E. Markowitz
    The Journal of Pediatrics October 2007 (Vol. 151, Issue 4, Pages 374-377)

The Journal of Pediatrics
Volume 151, Issue 4 , Pages 336-338, October 2007

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