The Scarlet H

(See the major article by Bradley et al on pages 325–33.) On 2 August 1982, TIME magazine published a cover story titled “The New Scarlet Letter,” with the word “Herpes” emblazoned in blood-red font above a picture of a young couple. The article effectively described the silent epidemic of genital herpes, providing a warning siren to alert millions of Americans of a significant risk associated with the sexual revolution of the 1960s and 1970s. It was a great example of investigative journalism at its best. And then … nothing. To my knowledge, herpes has not appeared on a cover of any of the major news magazines since. To understand why, one need look no further than the letters H.I.V. The destinies of human immunodeficiency virus (HIV) and herpes simplex virus (HSV) have been inextricably linked. This is true at the biologic level, where the genital ulcerative disease caused by HSV type 2 (HSV-2) enhances HIV transmission [1]. It also is true at the interface of health and the public, where the (legitimately) scary prospects of the global HIV epidemic rapidly overtook public awareness of virtually all other infectious diseases during the 1980s. As the scientific community, and eventually the American public, came to recognize the manner by which HIV is spread, terms such as “safe sex” entered the public lexicon. The success of public campaigns to educate the citizens of the world and, thereby, limit the spread of HIV are irrefutable. As with all good things, though, there have been unintended consequences. One of these has been the embrace of the notion that oral sex is “safe” because it does not involve penile-vaginal or penile-anal penetration. Although oral sex is safer in the sense that it cannot result in an unintended pregnancy, it nevertheless carries its own significant risk of transmission of sexually transmitted infections, including transmission of HSV type 1 (HSV-1) from the mouth to genital mucosa. Against this backdrop, Bradley and colleagues, in this issue of the Journal of Infectious Diseases, have produced yet another remarkable study in the long-running series of National Health and Nutrition Examination Survey (NHANES) publications. Dating back almost 50 years, the National Center for Health Statistics (NCHS) has used these serial surveys to describe the health and nutritional status of adults and children in the United States. Beginning in the mid-1970s, NHANES specimens have been evaluated for HSV-1 and HSV-2 seroprevalence. Previous NHANES publications have documented the increase in HSV-2 seroprevalence among adolescents and adults of childbearing age during the early and mid-1980s [2, 3]. Indeed, NHANES data substantially drove the budding awareness of genital herpes that culminated in the TIME cover story in 1982. The article by Bradley et al [4] continues in the outstanding tradition of NHANES HSV publications. Their key finding is that HSV-1 seroprevalence among 14- to 19-year-olds has declined by nearly 23% from 1999–2004 to 2005–2010, from 39.0% to 30.1% for an absolute difference of about 9% [4]. Stated differently, almost 1 in 10 adolescents who 10 years ago already would have acquired HSV-1 earlier in life now are vulnerable to getting a primary infection as they enter their sexually active years. This is occurring at the same time in which sexual practices have substantially shifted, with increases in oral sex reported in adults over the past 20 years [5–7]. In 2007–2010, almost half of 15- to 19-year-olds and more than four-fifths of 20- to 24-year-olds had engaged in oral sex practices [8]. This produces the perfect storm of serosusceptible adolescents engaging in sexual behavior that increases the likelihood that their first exposure to HSV-1 will be on their genitalia, and, thus, that they will develop HSV-1 genital herpes. Increasing rates of genital HSV-1 infection already are being seen in several studies published over the past decade [9–11], and Bradley and colleagues' data give reason to be concerned that this trend will accelerate. Why should we care? It appears that HSV-1 is less likely than HSV-2 to reactivate in the genital tract of men and nonpregnant women [12]. Additionally, most genital HSV shedding occurs from reactivation of viral infection, rather than from primary HSV disease [13–15]. Thus, it is possible that genital herpes could actually decline over the longer time period if a larger proportion of primary genital herpes infections are due to the serotype that is less likely to reactivate and result in clinically apparent or inapparent recurrent viral shedding. However, this possibility of fewer recurrent genital HSV infections years down the road is dwarfed by the current risk of an explosion in genital HSV-1 primary infections as serosusceptible adolescents engage in oral sex practices that expose them to HSV-1 for the first time on their genitalia. This is likely, as 50%–60% of Americans in their 20s and 30s currently are infected with HSV-1 [4], with the overwhelming majority of them having oral infection that they acquired earlier in their lives. We saw an epidemic of genital herpes caused by HSV-2 in the 1980s when 15%–20% of the population had HSV-2 infections. Imagine the consequences with >50% of the population intermittently shedding virus orally and also engaging in oral sex practices with seronegative partners. The most serious consequence of genital herpes is transmission of HSV to an infant at the time of delivery [16]. Both HSV-1 and HSV-2 can be of devastating consequence to neonates, because they lack a mature immune system to battle the virus [17]. Up to 30% of infected infants will die from this infection if they have the most severe form of the disease (disseminated disease) [18]. Among infants with central nervous system disease, approximately 30% will be left with lifelong neurologic sequelae from their neonatal brain infections, even with optimal therapy [19]. The infants at highest risk of acquiring neonatal herpes are those born to women with first-episode primary infections, with almost 60% of them developing neonatal disease if exposed to the virus at delivery as they pass through an infected birth canal [15]. These infants also are the ones who are more likely to develop disseminated neonatal HSV disease, as they lack the protection of maternal antibodies passed across the placenta [20]. If we begin to see more primary (and possibly even recurrent [21]) genital HSV-1 infections, especially among young women acquiring it as they emerge from adolescence, it is logical to hypothesize that we will see neonatal herpes more frequently over the next decade, and that it will be more severe. It is ironic that the destinies of HSV and HIV remain so intertwined in the United States. Three decades ago, HIV displaced HSV-2 as the principal virus competing for the attention of the public health community at a time when public awareness of genital herpes was just beginning to rise. Furthermore, the “safe sex” educational advances that have contributed significantly to limiting the spread of HIV since then have contributed to modifications in sexual practices that now are poised to contribute to a resurgence in genital herpes, although this time with HSV-1. As a result, today we find ourselves once again confronting a scarlet letter, and the lives of many infants yet to be born may hang in the balance.