Herpes Simplex Virus Infections in Neonates and Early Childhood

Herpes Simplex Virus Infections in Neonates and Early Childhood David W. Kimberlin, MD Of the commonly considered congenital infections, those caused by cytomegalovirus (CMV), syphilis, and herpes simplex virus (HSV) are frequently (CMV, HSV) or exclusively (syphilis) acquired sexually by the mother, with subsequent transmission to the developing fetus. Of the other commonly considered congenital infections, including rubella and toxoplasma infections, the mother is exposed to the infectious agent via interpersonal or environmental contacts. Unlike each of these other pathogens, which are transmitted transplacentally to the developing fetus following maternal infection though, HSV usually is transmitted perinatally as the neonate is exposed to the virus during passage through an infected birth canal. This difference in timing of acquisition of infection has had important consequence in the therapeutic advances achieved during the last 30 years in the management of neonatal HSV infections. Because the time period between the acquisition of infection and initiation of effective antiviral therapy is shorter in neonatal herpes than in congenital toxoplasmosis or CMV infections, the outcomes of therapy have the potential to be markedly different. This article will summarize the current state of neonatal HSV disease presentation, diagnosis, and management. Semin Pediatr Infect Dis 16:271-281 © 2005 Elsevier Inc. All rights reserved.

M

ost of the advancements in understanding the pathogenesis and epidemiology of neonatal herpes simplex virus (HSV) disease have occurred in the antiviral era. This progress has been made in part because effective antiviral agents provide the means by which to interfere with the natural course of infection, thereby illumining key aspects related to the host-virus interactions. Studies of antiviral therapeutics also provide opportunities to investigate the natural history of infections within the context of larger, expensive therapeutic drug trials. The earliest antiviral agents with in vitro activity against HSV, including 5-iodo-2=-deoxyuridine (IDU) and 1-␤-Darabinofuranosylcytosine (ara-C), proved too toxic in humans to be useful.1,2 Vidarabine (1-␤-D-arabinofuranosyladenine, ara-A) was the first systemically administered antiviral

Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL. Supported under contract with the Virology Branch, Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases (NIAID) (NO1-AI-30025, NO1-AI-65306, NO1-AI15113, NO1-AI-62554), and by grants from the General Clinical Research Center Program (M01-RR00032) and the State of Alabama. Address reprint requests to David W. Kimberlin, MD, Associate Professor of Pediatrics, Division of Pediatric Infectious Diseases, The University of Alabama at Birmingham, 1600 Seventh Avenue South, CHB 303, Birmingham, AL 35233. E-mail: [email protected]

1045-1870/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.spid.2005.06.007

medication with activity against HSV for which therapeutic efficacy outweighed toxicity for the management of lifethreatening HSV disease. Because of toxicity when administered systemically, intravenous vidarabine was restricted by the Food and Drug Administration (FDA) to use in lifethreatening HSV and varicella-zoster virus (VZV) infections when it was licensed for use in the United States in 1977. Multicenter collaborative clinical trials conducted by The National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Antiviral Study Group (CASG) established the efficacy of vidarabine in the treatment of neonatal HSV infections.3,4 Further developments in the management of neonatal HSV disease occurred in the 1980s and the 1990s, initially with a comparison of vidarabine and a lower dose of acyclovir (30 mg/kg/d administered intravenously in 3 divided doses for 10 days)5 and then with an investigation of a higher dose of acyclovir (60 mg/kg/d administered intravenously in 3 divided doses for 21 days).6 Ultimately, acyclovir proved to be less toxic and easier to administer than was vidarabine, with improved outcomes observed with the higher dose of acyclovir. Additional improvements in the outcomes of neonates with HSV disease have been achieved through advances in the diagnostics available to clinicians, the most powerful of which is the application of the polymerase chain reaction (PCR) to patients with neonatal HSV disease.7,8 This powerful diagnostic tool has 271

D.W. Kimberlin

272 enhanced the ability to diagnose neonatal HSV infections correctly, and it has proven to be especially beneficial in those patients without overt manifestations of HSV disease such as skin vesicles. It also has provided an additional means by which response to therapy can be assessed. Despite these diagnostic and therapeutic advances, though, mortality and morbidity rates from neonatal HSV disease remain unacceptably high, and the ultimate answer to the problem of neonatal herpes likely resides in prevention. Recent developments in the manufacture and testing of a genetically engineered subunit HSV vaccine show promise for this approach,9 as do recent advances in preventing genital transmission of HSV to a susceptible partner in a serodiscordant relationship through antiviral suppression of the infected partner.10 This article will summarize the recent developments in neonatal HSV disease management, focusing on enhanced therapeutic interventions, improved diagnostic modalities, and possible means of preventing viral transmission to newborns in the future.

Epidemiology of Neonatal HSV Definitions A first-episode primary HSV infection occurs when a person with no prior HSV-1 or -2 antibody acquires either virus in the genital tract. If a person with preexisting HSV-1 antibody acquires HSV-2 genital infection, a first-episode nonprimary infection ensues. Viral reactivation from latency and subsequent antegrade translocation of virus back to skin and mucosal surfaces produces a recurrent infection.

Risk of Maternal Infection and Disease During Pregnancy Recurrent genital herpes infections are the most common form of genital HSV during pregnancy.11 However, women with primary genital HSV infections who are shedding HSV at delivery are 10 to 30 times more likely to transmit the virus to their babies compared with women with a recurrent infection,12 as discussed herein. Approximately 10 percent of HSV-2-seronegative pregnant women have an HSV-2-seropositive sexual partner and thus are at risk of contracting a primary HSV-2 infection during the pregnancy,13 with the ensuing high risk of then transmitting the virus to their babies during delivery. Furthermore, women seronegative for both HSV-1 and HSV-2 who are in relationships with partners who are seropositive for HSV-1 also can acquire HSV-1 genital infection during oral-genital sex, with equally devastating consequences for the neonate. Among discordant couples in which the woman is seronegative for both HSV-1 and HSV-2, the chance that the woman will acquire either virus during the pregnancy is estimated to be 3.7 percent.14 For women who already are seropositive for HSV-1, the estimated chance of acquiring HSV-2 during the pregnancy is 1.7 percent.14 Approximately two-thirds of women who acquire genital herpes during pregnancy have no symptoms to suggest they have a genital HSV infection.14 This rate is consistent with the finding that 60 to 80 percent of women who

deliver an HSV-infected infant have no evidence of having genital HSV infection at the time of delivery and have neither a past history of genital herpes nor a sexual partner reporting a history of genital HSV.15-17

Risk of Neonatal Infection Neonatal HSV disease is acquired in one of three distinct times: intrauterine (in utero), peripartum (perinatal), and postpartum (postnatal). The vast majority (85%) of infected infants acquire their infections during birth, in the peripartum period. An additional 10 percent of infected neonates acquire the virus postnatally (eg, from someone shedding HSV from the mouth who then kisses the baby, from exposure to HSV from a breast lesion, or from an herpetic whitlow exposure in the nursery). The final 5 percent of infants are infected with HSV in utero. The five factors known to influence transmission of HSV from mother to neonate are type of maternal infection (primary versus recurrent),12,18-21 maternal antibody status,12,17,22,23 duration of rupture of membranes,21 integrity of mucocutaneous barriers (eg, use of fetal scalp electrodes),12,24,25 and mode of delivery (cesarean versus vaginal).12 As mentioned previously, infants born to mothers who have a first episode of genital HSV infection near term are at much greater risk of developing neonatal herpes than are those whose mothers have recurrent genital herpes.12,18-21 This increased risk is the result of both lower concentrations of transplacentally passaged HSV-specific antibodies (which also are less reactive to expressed polypeptides) in women with primary infection and the higher quantities of HSV that are shed for longer periods of time in the maternal genital tract when compared with women with recurrent genital HSV infection. In the largest trial to date spanning almost 20 years, 57 percent of babies delivered to women shedding HSV with first episode primary infection developed neonatal HSV disease compared with 25 percent of babies delivered to shedding women with first episode nonprimary infection and 2 percent of babies delivered to shedding women with recurrent HSV disease (Fig. 1).12 Directly related to type of maternal infection, neonates with higher neutralizing antibody titers are less likely to become infected with HSV during perinatal exposure in an infected birth canal,22 illustrating the protective effects of preexisting antibody in preventing neonatal HSV disease. Similarly, the amount of anti-HSV neutralizing antibody in an infected baby correlates with the extent of the disease: infants with higher neutralizing antibody titers and higher levels of antibodies that promote antiHSV antibody-dependent cellular cytotoxicity are more likely to have localized disease (and less likely to have disseminated disease) once they are infected.26,27 The duration of rupture of membranes and mode of delivery also impact the risk for acquisition of neonatal infection. A small study involving just 26 women published in 1971 demonstrated that cesarean delivery in a woman with active genital lesions can reduce the infant’s risk of acquiring HSV if performed within 4 hours of rupture of the membrane.21 Despite the extremely small sample size, these data led to the

HSV infections in neonates and early childhood

273

Women delivered (n=58,288) Cultured within 48 hrs (n=39,949) (69%) Subclinical shedding (n=128) (0.3%) Serologies available (n=121) (95%) First episode genital HSV (n=23) (19%)

Recurrent genital HSV (n=98) (81%)

1º HSV-1 (n=3) (13%)

1º HSV-2 (n=4) (17%)

Non-1º HSV-1 (n=1) (4%)

Non-1º HSV-2 (n=15) (65%)

HSV-1 (n=8) (8%)

HSV-2 (n=90) (92%)

Infant with HSV (n=3)

Infant with HSV (n=1)

Infant with HSV (n=0)

Infant with HSV (n=4)

Infant with HSV (n=2)

Infant with HSV (n=0)

57%

25%

2%

Figure 1 Type of maternal infection and risk of HSV transmission to the neonate. A total of 39,949 women without clinical evidence of genital HSV infection were cultured within 48 hours of delivery, with 121 found to be shedding and for whom sera were available for serologic analysis. Outcomes for these 121 women are illustrated. Data from Brown et al.12

standard practice over the ensuing decades to deliver women by cesarean with active genital lesions at the time of onset of labor.28 However, it was not until 2003 that cesarean delivery was proven to be effective in the prevention of HSV transmission to the neonate from a mother actively shedding virus from the genital tract.12 In this study, which began in 1982, there was a seven-fold reduction in the rate of neonatal HSV infections among women who had cesarean delivery (1 of 85) versus those with vaginal delivery (9 of 117 was noted). Importantly, neonatal infection has occurred despite cesarean delivery performed before the rupture of membranes.15,29

Incidence of Neonatal HSV Currently, neonatal HSV disease in the United States occurs in approximately one in 3200 deliveries,12 resulting in an estimated 1500 cases of neonatal HSV infection annually. As the baseline prevalence of HSV-2 genital infection increases in the overall population30,31 and the incidence of HSV-1 genital disease rises,32,33 a gravid woman will be increasingly more likely to acquire HSV for the first time during her pregnancy through sexual contact with a partner with a genital HSV-2 or an oral HSV-1 infection. Hence, the incidence of neonatal HSV disease may increase in the years to come. Fortunately, neonatal HSV disease occurs much less frequently in other countries of the world, although the reasons for these geographic disparities are not fully understood.34

Epidemiology of Non-Neonatal HSV in Early Childhood Orolabial HSV in Early Childhood Orolabial HSV-1 infections serve as the largest reservoir for HSV of either type (HSV-1 or HSV-2). HSV-1 is distributed

worldwide, with infection occurring in both developed and underdeveloped countries. Virus is transmitted from infected to susceptible individuals during close personal contact. No seasonal variation in the incidence of infection exists. Because infection rarely is fatal and HSV establishes latency, more than one-third of the world’s population has recurrent HSV-1 infections and, therefore, the capability of transmitting HSV during episodes of productive infection. The seroprevalence of HSV-1 infections in the United States has been determined utilizing sera obtained from the randomized National Health and Nutrition Examination Survey (NHANES).35,36 By the age of 5 years, more than 35 percent of black children versus 18 percent of white children are infected by HSV-1. Through adolescence, blacks have approximately a two-fold higher prevalence of antibodies to HSV-1 than do whites, and girls have a slightly higher prevalence of antibody than do boys. By 60 years of age, however, both African-Americans and Caucasians have a similarly high prevalence of HSV-1 antibodies (as much as 90 percent). At any given time, 1 percent of normal children and 1 to 5 percent of normal adults asymptomatically shed HSV-1 and, therefore, are capable of transmitting HSV to susceptible contacts.

Genital HSV in Early Childhood The presence of HSV lesions on the genitalia of a young child always should raise suspicion of sexual abuse, especially if these lesions are caused by HSV-2. Although autoinoculation from an orolabial source can be the source of HSV-1 genital infection, one must consider orogenital sexual abuse in this case as well. It is important to remember, though, that neonatal HSV lesions caused by both HSV-1 (perinatally or postnatally acquired) and HSV-2 (perinatally acquired) sometimes can occur on the genitalia of a neonate,37,38 with or without the presence of cutaneous lesions elsewhere, and

D.W. Kimberlin

274

Figure 2 Illustration of viral latency and reactivation. Adapted from the CIBA Collection of Medical Illustrations. (Color version of figure is available online.)

thus can reactivate on the genitalia during early childhood. Therefore, while genital HSV lesions in very young children should lead to consideration of sexual abuse, and in most cases evaluation for possible abuse, they are not definitive proof in and of themselves that sexual abuse has occurred.

Microbiology/ Molecular Microbiology As with all herpesviruses, HSV-1 and HSV-2 are large, enveloped virions with an icosahedral nucleocapsid consisting of 162 capsomeres, arranged around a linear, double-stranded DNA core. The genome consists of two covalently linked components, designated as L (long) and S (short). Each component consists of a unique sequence flanked by inverted repeats. Additionally, the unique L and S components can invert relative to one another, yielding four linear isomers. Each intact HSV virion contains only one of these four isomers, and all four are equally virulent (functionally equivalent) in the host cell. The DNAs of HSV-1 and HSV-2 are largely colinear, and considerable homology exists between the HSV-1 and HSV-2 genomes. These homologous sequences are distributed over the entire genomic map. Most of the polypeptides specified by one viral type are antigenically related to polypeptides of the other viral type, resulting in considerable cross-reactivity between the HSV-1 and HSV-2 glycoproteins, although unique antigenic determinants exist for each virus. Viral surface glycoproteins mediate attachment and penetration of HSV into cells and provoke host immune responses. Eleven glycoproteins of HSV have been

identified (gB, gC, gD, gE, gG, gH, gI, gJ, gK, gL, and gM), with a twelfth being predicted (gN). Glycoprotein D is the most potent inducer of neutralizing antibodies and appears to be related to viral entry into a cell, and gB also is required for infectivity. Antigenic specificity is provided by gG, with the resulting antibody response allowing for the distinction between HSV-1 (gG-1) and HSV-2 (gG-2). Two biologic properties of HSV that directly influence human disease are neurovirulence and latency. Neurovirulence refers to the affinity with which HSV is drawn to and propagated in neuronal tissue, which can result in profound disease with severe neurologic sequelae, as is the case with herpes simplex encephalitis and neonatal HSV central nervous system (CNS) disease. Latency perpetuates the virus within the host in an “inactive” state. During primary HSV infection, virions are transported by retrograde flow along axons that connect the point of entry into the body to the nuclei of sensory neurons (Fig. 2).39 Viral multiplication occurs in a small number of sensory neurons, and the viral genome then remains in a latent state for the life of the host. With periodic reactivation brought on by events such as physical or emotional stress, fever, ultraviolet light, and tissue damage, the virus is transported back down the axon to replicate again at or near the original point of entry into the body (Fig. 2). Such reactivation can result in clinically apparent disease (lesions) or clinically inapparent (asymptomatic, or subclinical) infection. Transmission can occur regardless of whether the infection is symptomatic or asymptomatic. Indeed, because asymptomatic shedding occurs much more frequently than does symptomatic disease, most experts agree that most cases

HSV infections in neonates and early childhood

275

of transmission of genital herpes are a consequence of asymptomatic shedding.40

the result of the severe coagulopathy, liver dysfunction, and pulmonary involvement of the disease.

Pathology of Mucocutaneous HSV Lesions

CNS Disease

Cutaneous HSV infection causes ballooning of infected epithelial cells, with nuclear degeneration and loss of intact cellular membranes. Infected epithelial cells either lyse or fuse to form multinucleated giant cells. With cell lysis, clear fluid containing large quantities of virus, cellular debris, and inflammatory cells accumulates between the epidermal and dermal layers. Multinucleated giant cells usually are present at the base of the vesicle. An intense inflammatory response extends from the base of the vesicle into the dermis. As the lesions heal, vesicular fluid becomes purulent as more inflammatory cells are recruited to the site of infection. The formation of scabs then follows. Scarring seldom occurs. When infection involves mucous membranes, shallow ulcers occur more commonly than do vesicles because of rapid rupture of the very thin cornified epithelium present at mucosal sites. The histopathologic findings of mucosal lesions are similar to those of skin lesions.

Clinical Presentations of Neonatal HSV HSV infections acquired either peripartum or postpartum can be classified as: (1) disseminated disease involving multiple visceral organs, including lung, liver, adrenal glands, skin, eye, and the brain (disseminated disease); (2) CNS disease, with or without skin lesions; and (3) disease limited to the skin, eyes, and/or mouth (SEM disease). This classification system is predictive of both morbidity and mortality.3,5,6,41,42 Patients with disseminated or SEM disease generally present to medical attention at 10 to 12 days of life, whereas patients with CNS disease on average present somewhat later at 16 to 19 days of life.41

Disseminated Disease Historically, disseminated HSV infections have accounted for approximately one-half to two-thirds of all children with neonatal HSV disease. However, this figure has been reduced to approximately 25 percent since the development and utilization of antiviral therapy, likely the consequence of recognizing and treating SEM infection before it progresses to more severe disseminated disease.15 Involvement of the CNS is a common component of this category of infection, occurring in approximately 60 to 75 percent of infants with disseminated disease.11 Although the presence of a vesicular rash can greatly facilitate establishing the diagnosis of HSV infection, more than 20 percent of neonates with disseminated HSV disease will not develop cutaneous vesicles during the course of their illness.15,41,43,44 Patients present in a sepsislike state. Presentation of disease usually is around day 10 to 12 of life. Hepatitis and pneumonitis are common findings. Death from disseminated neonatal HSV infection usually is

Almost one-third of all neonates with HSV infection are categorized as having CNS disease (with or without SEM involvement).15 Clinical manifestations of CNS disease include seizures (both focal and generalized), lethargy, irritability, tremors, poor feeding, temperature instability, and bulging fontanelle. Disease presentation is usually around day 16 to 19 of life. Between 60 and 70 percent of babies classified as having CNS disease have associated skin vesicles at any point in the disease course.41,43 In the absence of skin lesions and frank CNS signs, the initial presentation can be indistinguishable from other viral and bacterial infections that lead clinicians to suspect possible sepsis in neonates. HSV should be considered in young infants evaluated for sepsis when bacterial cultures are negative at 48 to 72 hours and the infant has experienced a worsening or lack of improvement clinically.41 With CNS neonatal HSV disease, mortality usually is the product of devastating brain destruction, with resulting acute neurologic and autonomic dysfunction. Neonatal HSV can involve any and often multiple parts of the brain, in contrast with the typical temporal lobe predilection seen with herpes simplex encephalitis that has onset beyond the neonatal period.

Disease Limited to the Skin, Eyes, and/or Mouth (SEM Disease) Infection localized to the skin, eye, and/or mouth (SEM disease) historically has accounted for approximately 20 percent of all cases of neonatal HSV disease. With the introduction of early antiviral therapy, this frequency has increased to approximately 45 percent.15 By definition, babies with SEM disease have limited infection, and 80 to 85 percent of them have associated vesicular lesions apparent on physical examination.41

Clinical Presentations of Non-Neonatal HSV in Early Childhood Orolabial HSV in Early Childhood Primary oropharyngeal infection with HSV-1 occurs most commonly in young children between 1 and 3 years of age. It usually is asymptomatic. The incubation period ranges from 2 to 12 days, with an average of 4 days. Symptomatic disease is characterized by fever to 104° F, oral lesions, sore throat, fetor oris, anorexia, cervical adenopathy, and mucosal edema. Oral lesions initially are vesicular but rapidly rupture, leaving 1- to 3-mm shallow gray–white ulcers on erythematous bases. These lesions are distributed on the hard palate, the anterior portion of the tongue, along the gingiva, and around the lips. In addition, the lesions may extend down the chin and neck due to drooling. Total duration of illness is 10 to 21 days. Primary gingivostomatitis results in viral shedding in oral secretions for an average of 7 to 10 days. Virus

D.W. Kimberlin

276 can be isolated from the saliva of asymptomatic children as well. Recurrences of herpes labialis may be associated with physical or emotional stress, fever, exposure to ultraviolet light, tissue damage, and immune suppression. Recurrent orolabial HSV lesions frequently are preceded by a prodrome of pain, burning, tingling, or itching. These symptoms generally last for less than six hours, followed within 24 to 48 hours by the appearance of painful vesicles, typically at the vermillion border of the lip. Lesions usually crust within three to four days, and healing is complete within 8 to 10 days. Recurrences occur only rarely in the mouth or on the skin of the face of immunocompetent patients. As with primary HSV-1 infection, recurrent infection may occur in the absence of clinical symptoms.

Differential Diagnosis for Neonatal Herpes Numerous other conditions, both infectious and noninfectious, can mimic neonatal HSV infection. They include hyaline membrane disease, intraventricular hemorrhage, necrotizing enterocolitis, and various ocular or cutaneous disorders. Bacterial pathogens of newborns with systemic and/or cutaneous manifestations that can be confused with neonatal HSV disease include group B Streptococcus, Staphylococcus aureus, Listeria monocytogenes, and gram-negative bacteria. Exanthemous viral agents that can be confused for neonatal HSV infection include varicella-zoster virus infection, enteroviral disease, and disseminated CMV infection. Other infectious pathogens on the differential diagnosis list include toxoplasmosis, rubella, and syphilis. Noninfectious cutaneous disorders that also should be considered include erythema toxicum, neonatal melanosis, acrodermititis, and incontinentia pigmenti.

Approach to Diagnosis of HSV Infections Serologic Testing Until recently, the commercially available serologic assays were unable to distinguish between HSV-1 and HSV-2 antibodies, severely limiting their utility. However, in the past few years, two type-specific antibody assays manufactured by Focus Technologies, Inc.,45 have received FDA approval: the HerpeSelect® HSV-1 and HSV-2 ELISA and the HSV-1 and HSV-2 Immunoblot tests. Another type-specific serologic assay originally manufactured by Diagnology and known as POCkit HSV-246-48 received FDA approval for the rapid typespecific detection of HSV-2 IgG. This assay is now available in the United States under the new names of “biokitHSV-2,” marketed by biokit USA (Lexington, MA), and “Sure-Vue HSV-2,” from Fisher Health Care. Several additional tests that claim to distinguish between HSV-1 and HSV-2 antibody are commercially available, but high cross-reactivity rates due to their use of crude antigen preparations limit their

utility to documentation of primary seroconversion, rather than distinguishing between viral types.49 In contrast to its benefit in other congenital and neonatal infections, serologic diagnosis of neonatal HSV infection is not of great clinical value. With the availability of reliable type-specific assays, one barrier to interpreting serologic results in babies with suspected HSV disease has been removed. However, the presence of transplacentally acquired maternal IgG still confounds the assessment of the neonatal antibody status during acute infection, especially given the large proportion of the adult American population that is HSV-1- and HSV-2-seropositive. As a result, serologic studies generally play no role in the diagnosis of neonatal HSV disease.

Viral Culture Isolation of HSV by culture remains the definitive diagnostic method of documenting an HSV infection, including establishing neonatal HSV disease. Skin or mucous membrane lesions are scraped and transferred in appropriate viral transport media on ice to a diagnostic virology laboratory.50 Such specimens are inoculated into cell culture systems, which then are monitored for cytopathic effects characteristic of HSV replication. Typing of an HSV isolate then may be performed by using one of several techniques. Other sites from which virus may be isolated in neonatal HSV disease include the cerebrospinal fluid (CSF), urine, blood, stool or rectum, oropharynx, and conjunctivae.50 Specimens for viral culture from multiple body sites (with the exception of CSF) of babies suspected of having neonatal herpes may be combined before plating in cell culture to decrease costs because, with the exception of CNS involvement, the important information gathered from such cultures is the presence or absence of replicating virus, rather than its precise location.

Polymerase Chain Reaction The diagnosis of neonatal HSV infections has been revolutionized by the application of PCR to clinical specimens, including CSF7,8,51-55 and blood.8,55-59 Because of the very power of the technology, however, the variability in performance of PCR among laboratories warrants brief consideration. Interlaboratory standards that assure that identical specimens processed in two different laboratories will yield identical results are lacking. Furthermore, the performance of PCR is highly dependent on the manner in which the specimen is collected and maintained before reaching the laboratory for PCR analysis.60 Given these caveats, interpretation of PCR results, either positive or negative, must be correlated with the patient’s clinical presentation and disease course in determining their ultimate clinical or diagnostic significance. A negative PCR result does not in and of itself rule out neonatal HSV disease. In two relatively large reports of PCR in neonatal herpes, 76 to 78 percent of neonates with CNS HSV disease had HSV detected in their CSF by PCR.7,8 Overall sensitivities of CSF PCR in neonatal HSV disease have ranged from 75 to 100 percent,7,52,55 with overall specificities ranging from 71 to 100 percent.7,52,55 In comparison, PCR of blood components

HSV infections in neonates and early childhood has been evaluated to a much lesser extent, with only six relatively small studies reported to date in the literature.8,55-59 Further study of blood PCR in neonatal HSV infection is needed, as illustrated by one recent report questioning the sensitivity of serum PCR analysis from neonates with disseminated HSV disease.61

Treatment of Neonatal HSV Neonates with HSV disease should be treated with intravenous acyclovir at 60 mg/kg/d divided every 8 hours.6,50 The dosing interval of intravenous acyclovir may need to be increased in premature infants, based on their creatinine clearance.62 Duration of therapy is 21 days for patients with disseminated or CNS neonatal HSV disease and 14 days for patients with HSV infection limited to the SEM.63 All patients with CNS HSV involvement should undergo a repeat lumbar puncture at the end of intravenous acyclovir therapy to determine that the specimen is PCR-negative in a reliable laboratory and to document the end-of-therapy CSF indices.41 Those persons who remain PCR-positive should continue to receive intravenous antiviral therapy until PCR-negativity is achieved.7,41 Absolute neutrophil counts should be followed during the course of therapy.6

Treatment of Non-Neonatal HSV in Early Childhood Treatment of primary gingivostomatitis in pediatric patients using oral acyclovir at 600 mg/m2/dose administered four times per day for 10 days decreases time to cessation of symptoms by 30 to 50 percent, and time to lesion healing by 20 to 25 percent.64 Oral acyclovir has a more modest effect in the treatment of recurrent herpes labialis,65-67 and treatment of these patients should be individualized.68 Topical acyclovir cream69,70 and topical penciclovir, or Denavir®,70-72 for the treatment of recurrent herpes labialis reduces time to healing and duration of pain by approximately half a day. Recently, the use of valaciclovir (2 g orally twice a day for 1 day) also has demonstrated efficacy in the treatment of recurrent herpes labialis, reducing the overall duration of the episode by approximately one day.73 In general, therapeutic benefit in recurrent herpes labialis is enhanced if treatment is initiated as soon as possible after onset of symptoms, preferably within 24 to 48 hours of onset of the recurrence. Prophylactic acyclovir also has been used to prevent reactivation of herpes labialis after exposure to ultraviolet radiation, facial surgery, or exposure to sun and wind while skiing.74-76 Topical acyclovir cream also is effective in preventing recurrent herpes labialis in skiers77 and in persons with a history of frequent recurrences of herpes labialis.78 Longterm suppressive therapy with oral acyclovir or valaciclovir reduces the number of recurrences of oral infection in those with histories of frequent recurrences.79-81

277

Prognosis/ Outcomes of Neonatal HSV Mortality In the preantiviral era, 85 percent of patients with disseminated neonatal HSV disease died by 1 year of age, as did 50 percent of patients with CNS neonatal HSV disease.3 With current antiviral therapy, the 12-month mortality rate has been reduced to 29 percent for disseminated neonatal HSV disease and to 4 percent for CNS HSV disease (Figs. 3 and 4, respectively).6 Lethargy and severe hepatitis are associated with mortality among patients with disseminated disease, as are prematurity and seizures in patients with CNS disease.41

Morbidity Improvements in morbidity rates with antiviral therapies have not been as dramatic as with mortality. The proportion of survivors of disseminated neonatal HSV disease who have normal neurologic development has increased from 50 percent in the preantiviral era3 to 83 percent today.6 In the case of CNS neonatal HSV disease, no change at all has occurred, with 33 percent of patients in the preantiviral era and 31 percent of patients today having normal neurologic development (Fig. 5).3,6 Seizures that occur at or before the time of initiation of antiviral therapy are associated with increased risk of morbidity both in patients with CNS disease and in patients with disseminated infection.41 In contrast to disseminated or CNS neonatal HSV disease, the rate of morbidity after having SEM disease has improved dramatically during the antiviral era. Before the development of vidarabine or acyclovir, 38 percent of patients with SEM disease experienced developmental difficulties at 12 months of age.3 Today, fewer than 2 percent of acyclovir recipients

Figure 3 Mortality in patients with disseminated neonatal HSV disease by daily dosage of acyclovir. Dosage was divided every eight hours. Recipients of the 45 mg/kg/d and 60 mg/kg/d dosing were treated for 21 days, whereas recipients of the 30 mg/kg/d dosing (*) were from a historical cohort treated for 10 days. Reprinted with permission from Kimberlin et al.6

278

D.W. Kimberlin HSV disease, however, cesarean delivery has a number of drawbacks, including the fact that 60 to 80 percent of babies who develop neonatal HSV disease are born to women without a history of genital herpes,15-17 and thus will not be prevented with this approach. Furthermore, neonatal infections have occurred despite cesarean delivery performed before the rupture of membranes.15,29

Antiviral Suppression of Seropositive Man in Discordant Relationship Involving a Gravid Seronegative Woman

Figure 4 Mortality in patients with CNS neonatal HSV disease by daily dosage of acyclovir. Dosage was divided every 8 hours. Recipients of the 45 mg/kg/d and 60 mg/kg/d dosing were treated for 21 days, whereas recipients of the 30 mg/kg/d dosing (*) were from a historical cohort treated for 10 days. Reprinted with permission from Kimberlin et al.6

have developmental delays following recovery from SEM disease (Fig 5).5,6

Follow-Up of Neonatal HSV The most significant sequelae of neonatal HSV disease is neurologic impairment. Survivors of neonatal HSV infections should be followed closely for the achievement of developmental milestones and should undergo developmental assessments as needed. Early intervention programs, including physical therapy, occupational therapy, and speech therapy, should be employed at the first sign of the potential for or risk of impairment. Cutaneous recurrences, although not of the same significance as neurologic sequelae, nonetheless are common occurrences5 and oftentimes are quite disruptive to the lives of the patients and their families, including impacting child care arrangements. The role of suppressive oral acyclovir82 currently is being evaluated in randomized controlled trials being conducted by the NIAID CASG. However, pending these results, data are insufficient for one to recommend routine utilization of suppression therapy after the management of acute neonatal HSV disease.83

Approximately 10 percent of HSV-2-seronegative pregnant women have an HSV-2-seropositive sexual partner and thus are at risk of contracting a primary HSV-2 infection.13 As noted previously, women acquiring genital HSV infection for the first time during pregnancy are at highest risk of transmitting the virus to their neonates during delivery. Hence, preventing maternal genital infection in the first place is of paramount importance. However, the optimal approach to preventing the transmission of HSV to uninfected persons in practice remains uncertain. The use of condoms is one useful and effective strategy. A recent study of 528 monogamous couples discordant for HSV-2 infection found that when condoms were used during more than 70 percent of sexual encounters between an HSV-2-positive man and an HSV-2negative woman, transmission was reduced by more than 60 percent.84 The means by which to achieve more consistent condom use by discordant couples, however, remains to be determined. Another approach is the use of antiviral suppressive therapy in the seropositive partner, which in this case would be the male partner of the seronegative gravid woman.10 In a recent report, suppressive therapy with valaciclovir 500 mg once daily for 8 months decreased the rate of symptomatic HSV infection in the seronegative partner by 75 percent and reduced the likelihood of acquisition of genital HSV-2 infection (symptomatic or asymptomatic) by 48 percent.10 With either use of condoms or antiviral suppression of

Prevention of Neonatal HSV Cesarean Delivery As noted previously, cesarean delivery in a woman with active genital lesions can reduce the infant’s risk of acquiring HSV.12,21 In 1999, the American College of Obstetricians and Gynecologists updated its management guidelines for genital herpes in pregnancy.28 To prevent the acquisition of neonatal HSV disease, cesarean delivery should be performed if genital HSV lesions or prodromal symptoms are present at the time of delivery. As a method to reduce the incidence of neonatal

Figure 5 Morbidity among patients with known outcomes after 12 months of life. The 2 groups represent those treated with acyclovir at 30 mg/kg/d for 10 days versus those treated with 60 mg/kg/d for 21 days. Mild impairment was defined as ocular sequelae without blindness, speech delay, or mild motor delay without hemiparesis. Moderate impairment was defined as hemiparesis, persistent seizure disorder, or less than 3 months’ developmental delay. Severe impairment was defined as microcephaly, spastic quadriplegia, blindness or chorioretinitis, or more than 3 months’ developmental delay. Reprinted with permission from Kimberlin et al.6

HSV infections in neonates and early childhood the seropositive male partner, however, one must understand that some risk of transmission to the seronegative woman remains, and thus neonatal transmission is possible.

Antiviral Prophylaxis During Pregnancy Because of acyclovir’s safety record in pregnancy,85 along with a desire to decrease the incidence of neonatal HSV disease and reduce the number of cesarean deliveries performed for the indication of herpes, utilization of oral acyclovir near the end of pregnancy to suppress genital HSV recurrences has become increasingly common in clinical practice. Several small studies suggest that the administration of suppressive acyclovir therapy during the last weeks of pregnancy decreases the occurrence of clinically apparent genital HSV disease at the time of delivery,86-88 with an associated decrease in cesarean section rates for the indication of genital HSV.86,87 However, because viral shedding still occurs (albeit with reduced frequency),88,89 the potential for neonatal infection likely is not completely avoided. Additional studies are needed to establish more definitively the safety and effectiveness of late pregnancy maternal HSV suppressive therapy, including the potential for development of neutropenia in neonates born to women receiving antiviral suppressive therapy.82,90,91 Data currently do not support the routine utilization of suppressive oral acyclovir or valaciclovir in gravid women with a history of recurrent genital herpes.33

Vaccine Development Recently, a candidate HSV-2 glycoprotein D subunit vaccine adjuvanted with alum combined with 3-deacylated monophosphoryl lipid A (MPL) has demonstrated promising results. In two large Phase III studies, the vaccine has been demonstrated to be safe and, in a subset of volunteers, effective in preventing HSV-1 or -2 genital herpes disease (vaccine efficacy, ⬃75%) and HSV-2 infection (vaccine efficacy, ⬃40%).9 In both studies, efficacy was limited to women who were HSV-1 and -2 seronegative before vaccination, with no evidence of vaccine efficacy in men or in women who were HSV-1-positive and HSV-2-negative before receiving vaccination. Because these earlier trials were neither designed nor powered to assess efficacy in women who were negative for HSV-1 and -2, another Phase III trial is being undertaken by GlaxoSmithKline (GSK) and NIAID.

Implications of Diagnosis Despite the advances in our understanding of genital herpes, considerable shame, embarrassment, and stigma remain among infected persons.92 For many patients, the psychological impact is far more severe than are the physical consequences of the disease.93 Shock, anger, guilt, low self-esteem, fear of transmission of the infection to others, and impaired sexual function are common responses and can interfere substantially with relationships.92 Anecdotal experience suggests that the diagnosis of neonatal herpes has a similar negative impact on the parents’ relationship, with guilt and anger over

279 the baby’s illness and its association with genital herpes often leading to separation and divorce.

Future Directions Although tremendous advances have occurred in the understanding and management of neonatal herpes during the last several decades, many questions remain regarding the epidemiology of neonatal HSV infections in the United States and around the world. To develop strategies to facilitate the recognition of neonatal HSV disease and thereby initiate antiviral therapy in a timely fashion, discrepancies from country to country in rates of genital herpes, type of genital infections (HSV-2 versus. HSV-1), and rates of neonatal HSV disease must be better understood.34 One way to improve our understanding of the epidemiology of neonatal HSV infection in the United States is to make it a reportable disease, as has recently been considered by the IHMF and suggested by U.S. investigators (Handsfield, HH, Waldo, AB, Brown, ZA, et al. Neonatal herpes should be a reportable disease. Submitted). However, additional epidemiologic studies of mother-tochild transmission of HSV are required in both developed and developing countries. Efforts such as these will then allow for development of country- or region-specific obstetrical practice guidelines that fit the medical needs of the locale. Ultimately, identifying mothers at the time of delivery who are actively shedding HSV from the genital tract could lead to management algorithms designed to minimize neonatal exposure to the virus, thereby preventing neonatal infection in the first place. Development of a bedside nucleic acid detection kit for real-time detection of HSV DNA in the maternal genital tract at the time of delivery, as has been explored for the detection of group B Streptococcus colonization,94 would have the potential to revolutionize management and should be encouraged. Finally, ultimate elimination of neonatal HSV likely will require development of an effective HSV vaccine that protects against genital HSV-2 and HSV-1 infection and/or disease. The cooperative effort between GSK and NIAID to investigate the most promising vaccine available at this time is a model that should be expanded as appropriate to facilitate development of additional vaccine candidates.

References 1. Boston Interhospital Virus Study Group: An NIAI: D-sponsored cooperative antiviral clinical study: Failure of high dose 5-iodo-2=-deoxyuridine in the therapy of herpes simplex virus encephalitis. Evidence of unacceptable toxicity. N Engl J Med 292:599-603, 1975 2. Stevens DA, Jordan GW, Waddell TF, et al: Adverse effect of cytosine arabinoside on disseminated zoster in a controlled trial. N Engl J Med 289:873-878, 1973 3. Whitley RJ, Nahmias AJ, Soong SJ, et al: Vidarabine therapy of neonatal herpes simplex virus infection. Pediatrics 66:495-501, 1980 4. Whitley RJ, Yeager A, Kartus P, et al: Neonatal herpes simplex virus infection: Follow-up evaluation of vidarabine therapy. Pediatrics 72: 778-785, 1983 5. Whitley R, Arvin A, Prober C, et al: A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. N Engl J Med 324:444-449, 1991 6. Kimberlin DW, Lin CY, Jacobs RF, et al: Safety and efficacy of high-dose

D.W. Kimberlin

280

7.

8.

9.

10. 11.

12.

13.

14. 15. 16.

17.

18.

19.

20.

21.

22.

23.

24. 25.

26.

27.

28.

29.

intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics 108:230-238, 2001 Kimberlin DW, Lakeman FD, Arvin AM, et al: Application of the polymerase chain reaction to the diagnosis and management of neonatal herpes simplex virus disease. J Infect Dis 174:1162-7, 1996 Malm G, Forsgren M: Neonatal herpes simplex virus infections: HSV DNA in cerebrospinal fluid and serum. Arch Dis Child Fetal Neonatal Ed 81:F24-9, 1999 Stanberry LR, Spruance SL, Cunningham AL, et al: Glycoprotein-Dadjuvant vaccine to prevent genital herpes. N Engl J Med 347:1652-61, 2002 Corey L, Wald A, Patel R, et al: Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 350:11-20, 2004 Whitley RJ: Herpes simplex virus infections, in Remington JS, Klein JO (eds): Infectious Diseases of the Fetus and Newborn Infants (ed 3). Philadelphia, W.B. Saunders Company, 1990, pp 282-305 Brown ZA, Wald A, Morrow RA, et al: Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA 289:203-209, 2003 Kulhanjian JA, Soroush V, Au DS, et al: Identification of women at unsuspected risk of primary infection with herpes simplex virus type 2 during pregnancy. N Engl J Med 326:916-920, 1992 Brown ZA, Selke S, Zeh J, et al: The acquisition of herpes simplex virus during pregnancy. N Engl J Med 337:509-515, 1997 Whitley RJ, Corey L, Arvin A, et al: Changing presentation of herpes simplex virus infection in neonates. J Infect Dis 158:109-116, 1988 Whitley RJ, Nahmias AJ, Visintine AM, et al: The natural history of herpes simplex virus infection of mother and newborn. Pediatrics 66: 489-494, 1980 Yeager AS, Arvin AM: Reasons for the absence of a history of recurrent genital infections in mothers of neonates infected with herpes simplex virus. Pediatrics 73:188-193, 1984 Brown ZA, Benedetti J, Ashley R, et al: Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor. N Engl J Med 324:1247-1252, 1991 Brown ZA, Vontver LA, Benedetti J, et al: Effects on infants of a first episode of genital herpes during pregnancy. N Engl J Med 317:12461251, 1987 Corey L, Wald A: Genital herpes, in Holmes KK, Sparling PF, Mardh PA, et al (eds): Sexually Transmitted Diseases (ed 3). New York, McGraw-Hill, 1999, pp 285-312 Nahmias AJ, Josey WE, Naib ZM, et al: Perinatal risk associated with maternal genital herpes simplex virus infection. Am J Obstet Gynecol 110:825-37, 1971 Prober CG, Sullender WM, Yasukawa LL, et al: Low risk of herpes simplex virus infections in neonates exposed to the virus at the time of vaginal delivery to mothers with recurrent genital herpes simplex virus infections. N Engl J Med 316:240-4, 1987 Yeager AS, Arvin AM, Urbani LJ, et al: Relationship of antibody to outcome in neonatal herpes simplex virus infections. Infect Immun 29:532-8, 1980 Parvey LS, Ch’ien LT: Neonatal herpes simplex virus infection introduced by fetal-monitor scalp electrodes. Pediatrics 65:1150-3, 1980 Kaye EM, Dooling EC: Neonatal herpes simplex meningoencephalitis associated with fetal monitor scalp electrodes. Neurology 31:1045-7, 1981 Sullender WM, Miller JL, Yasukawa LL, et al: Humoral and cell-mediated immunity in neonates with herpes simplex virus infection. J Infect Dis 155:28-37, 1987 Kohl S, West MS, Prober CG, et al: Neonatal antibody-dependent cellular cytotoxic antibody levels are associated with the clinical presentation of neonatal herpes simplex virus infection. J Infect Dis 160: 770-6, 1989 Anonymous: ACOG practice bulletin. Management of herpes in pregnancy. Number 8 October 1999. Clinical management guidelines for obstetrician-gynecologists. Int J Gynaecol Obstet 68:165-173, 2000 Peng J, Krause PJ, Kresch M: Neonatal herpes simplex virus infection after cesarean section with intact amniotic membranes. J Perinatol 16: 397-399, 1996

30. Fleming DT, McQuillan GM, Johnson RE, et al: Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 337:11051111, 1997 31. Xu, F, McQuillan GM, Kottiri, BJ, et al: Trends in Herpes Simplex Virus Type 2 Infection in the United States, 42nd Annual Meeting of the Infectious Diseases Society of America. Boston, MA; Abstract 739, 2004 32. Lafferty WE, Downey L, Celum C, et al: Herpes simplex virus type 1 as a cause of genital herpes: impact on surveillance and prevention. J Infect Dis 181:1454-1457, 2000 33. Kimberlin DW, Rouse DJ: Genital herpes. N Engl J Med 350:19701977, 2004. 34. Kimberlin DW: Neonatal HSV infections: the global picture. HERPES 11:31-32, 2004 35. Johnson RE, Nahmias AJ, Magder LS, et al: A seroepidemiologic survey of the prevalence of herpes simplex virus type 2 infection in the United States. N Engl J Med 321:7-12, 1989 36. Nahmias AJ, Lee FK, Beckman-Nahmias S: Sero-epidemiological and -sociological patterns of herpes simplex virus infection in the world. Scand J Infect Dis Suppl 69:19-36, 1990 37. Rubin LG, Lanzkowsky P: Cutaneous neonatal herpes simplex infection associated with ritual circumcision. Pediatr Infect Dis J 19:266268, 2000 38. Distel R, Hofer V, Bogger-Goren S, et al: Primary genital herpes simplex infection associated with Jewish ritual circumcision. Israel Med Assoc J (IMAJ) 5:893-894, 2003 39. Stevens JG, Cook ML: Latent herpes simplex virus in spinal ganglia of mice. Science 173:843-845, 1971 40. Mertz GJ, Benedetti J, Ashley R, et al: Risk factors for the sexual transmission of genital herpes. Ann Intern Med 116:197-202, 1992 41. Kimberlin DW, Lin CY, Jacobs RF, et al: Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics 108:223229, 2001 42. Whitley R, Arvin A, Prober C, et al: Predictors of morbidity and mortality in neonates with herpes simplex virus infections. N Engl J Med 324:450-454, 1991 43. Sullivan-Bolyai JZ, Hull HF, Wilson C, et al: Presentation of neonatal herpes simplex virus infections: Implications for a change in therapeutic strategy. Pediatr Infect Dis 5:309-314, 1986 44. Arvin AM, Yeager AS, Bruhn FW, et al: Neonatal herpes simplex infection in the absence of mucocutaneous lesions. J Pediatr 100:715-721, 1982 45. Prince HE, Ernst CE, Hogrefe WR: Evaluation of an enzyme immunoassay system for measuring herpes simplex virus (HSV) type 1-specific and HSV type 2-specific IgG antibodies. J Clin Lab Anal 14:13-16, 2000 46. Kinghorn GR: Type-specific serological testing for herpes simplex infection. Int J STD AIDS 9:497-500, 1998 47. Ashley RL, Eagleton M: Evaluation of a novel point of care test for antibodies to herpes simplex virus type 2. Sex Transm Infect 74:228229, 1998 48. Ashley RL, Wald A, Eagleton M: Premarket evaluation of the POCkit HSV-2 type-specific serologic test in culture-documented cases of genital herpes simplex virus type 2. Sex Transm Dis 27:266-269, 2000 49. Ashley RL: Sorting out the new HSV type specific antibody tests. Sex Transm Infect 77:232-237, 2001 50. American Academy of Pediatrics: Herpes simplex, in Pickering LK (ed): 2003 Red Book: Report of the Committee on Infectious Diseases (ed 26). Elk Grove Village, IL, American Academy of Pediatrics, 2003, pp 344-353 51. Rowley AH, Whitley RJ, Lakeman FD, et al: Rapid detection of herpessimplex-virus DNA in cerebrospinal fluid of patients with herpes simplex encephalitis. Lancet 335:440-441, 1990 52. Troendle-Atkins J, Demmler GJ, Buffone GJ: Rapid diagnosis of herpes simplex virus encephalitis by using the polymerase chain reaction. J Pediatr 123:376-380, 1993 53. Anderson NE, Powell KF, Croxson MC: A polymerase chain reaction assay of cerebrospinal fluid in patients with suspected herpes simplex encephalitis. J Neurol Neurosurg Psychiatry 56:520-525, 1993 54. Schlesinger Y, Storch GA: Herpes simplex meningitis in infancy. Pediatr Infect Dis J 13:141-144, 1994

HSV infections in neonates and early childhood 55. Kimura H, Futamura M, Kito H, et al: Detection of viral DNA in neonatal herpes simplex virus infections: Frequent and prolonged presence in serum and cerebrospinal fluid. J Infect Dis 164:289-293, 1991 56. Barbi M, Binda S, Primache V, et al: Use of Guthrie cards for the early diagnosis of neonatal herpes simplex virus disease. Pediatr Infect Dis J 17:251-252, 1998 57. Diamond C, Mohan K, Hobson A, et al: Viremia in neonatal herpes simplex virus infections. Pediatr Infect Dis J 18:487-489, 1999 58. Lewensohn-Fuchs I, Osterwall P, Forsgren M, et al: Detection of herpes simplex virus DNA in dried blood spots making a retrospective diagnosis possible. J Clin Virol 26:39-48, 2003 59. Kimura H, Ito Y, Futamura M, et al: Quantitation of viral load in neonatal herpes simplex virus infection and comparison between type 1 and type 2. J Med Virol 67:349-353, 2002 60. Atkins JT: HSV PCR for CNS infections: pearls and pitfalls. Pediatr Infect Dis J 18:823-824, 1999 61. Kimberlin D, Cloud G, Lakeman F, et al: Serum polymerase chain reaction (PCR) may not diagnose neonatal herpes simplex virus (HSV) disease, 42nd Annual Meeting of the Infectious Diseases Society of America. Boston, Massachusetts; Abstract 992, 2004 62. Englund JA, Fletcher CV, Balfour HH Jr: Acyclovir therapy in neonates. J Pediatr 119:129-135, 1991 63. American Academy of Pediatrics: Herpes simplex, in Pickering LK (ed): 2000 Red Book: Report of the Committee on Infectious Diseases (ed 25). Elk Grove Village, IL, American Academy of Pediatrics, 2000, pp 309-318 64. Aoki FY, Law BJ, Hammond GW, et al: Acyclovir (ACV) suspension for treatment of acute herpes simplex virus (HSV) gingivostomatitis in children: A placebo (PL) controlled, double blind trial., 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy. New Orleans, LA, 1993, pp 399, Abstract #1530 65. Raborn GW, McGaw WT, Grace M, et al: Treatment of herpes labialis with acyclovir. Review of three clinical trials. Am J Med 85:39-42, 1988 66. Raborn GW, McGaw WT, Grace M, et al: Oral acyclovir and herpes labialis: a randomized, double-blind, placebo-controlled study. J Am Dent Assoc 115:38-42, 1987 67. Spruance SL, Stewart JC, Rowe NH, et al: Treatment of recurrent herpes simplex labialis with oral acyclovir. J Infect Dis 161:185-190, 1990 68. Kimberlin DW, Prober CG: Antiviral agents, in Prober CG (ed): Principles and Practice of Pediatric Infectious Diseases (ed 2). Philadelphia, Churchill Livingstone, 2003, pp 1527-1547 69. Spruance SL, Nett R, Marbury T, et al: Acyclovir cream for treatment of herpes simplex labialis: Results of two randomized, double-blind, vehicle-controlled, multicenter clinical trials. Antimicrob Agents Chemother 46:2238-2243, 2002 70. Lin L, Chen XS, Cui PG, et al: Topical application of penciclovir cream for the treatment of herpes simplex facialis/labialis: A randomized, double-blind, multicentre, aciclovir-controlled trial. J Dermatol Treatment 13:67-72, 2002 71. Boon R, Goodman JJ, Martinez J, et al: Penciclovir cream for the treatment of sunlight-induced herpes simplex labialis: A randomized, double-blind, placebo-controlled trial. Penciclovir Cream Herpes Labialis Study Group. Clin Ther 22:76-90, 2000 72. Spruance SL, Rea TL, Thoming C, et al: Penciclovir cream for the treatment of herpes simplex labialis. A randomized, multicenter, double-blind, placebo-controlled trial. Topical Penciclovir Collaborative Study Group. JAMA 277:1374-1379, 1997 73. Spruance SL, Jones TM, Blatter MM, et al: High-dose, short-duration, early valacyclovir therapy for episodic treatment of cold sores: Results of two randomized, placebo-controlled, multicenter studies. Antimicrob Agents Chemother 47:1072-1080, 2003 74. Spruance SL, Hamill ML, Hoge WS, et al: Acyclovir prevents reactivation of herpes simplex labialis in skiers. JAMA 260:1597-1599, 1988

281 75. Gold D, Corey L: Acyclovir prophylaxis for herpes simplex virus infection. Antimicrob Agents Chemother 31:361-367, 1987 76. Spruance SL, Freeman DJ, Stewart JC, et al: The natural history of ultraviolet radiation-induced herpes simplex labialis and response to therapy with peroral and topical formulations of acyclovir. J Infect Dis 163:728-734, 1991 77. Raborn GW, Martel AY, Grace MG, et al: Herpes labialis in skiers: randomized clinical trial of acyclovir cream versus placebo. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontics 84:641-645, 1997 78. Gibson JR, Klaber MR, Harvey SG, et al: Prophylaxis against herpes labialis with acyclovir cream—a placebo-controlled study. Dermatologica 172:104-107, 1986 79. Rooney JF, Straus SE, Mannix ML, et al: Oral acyclovir to suppress frequently recurrent herpes labialis. A double-blind, placebo-controlled trial. Ann Intern Med 118:268-272, 1993 80. Baker DA, Deeter RG, Redder K, et al. Valacyclovir effective for suppression of recurrent HSV-1 herpes labialis, 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Ontario, Canada, 2000, pp 263, Abstract #464 81. Baker D, Eisen D: Valacyclovir for prevention of recurrent herpes labialis: 2 double-blind, placebo-controlled studies. Cutis 71:239-242, 2003 82. Kimberlin D, Powell D, Gruber W, et al: Administration of oral acyclovir suppressive therapy after neonatal herpes simplex virus disease limited to the skin, eyes and mouth: Results of a phase I/II trial. Pediatr Infect Dis J 15:247-254, 1996 83. Gutierrez K, Arvin AM: Long term antiviral suppression after treatment for neonatal herpes infection. Pediatr Infect Dis J 22:371-372, 2003 84. 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 285:3100-3106, 2001 85. Stone KM, Reiff-Eldridge R, White AD, et al: Pregnancy outcomes following systemic prenatal acyclovir exposure: Conclusions from the International Acyclovir Pregnancy Registry, 1984-1999. Birth Defects Res (Part A) 70:201-207, 2004 86. Braig S, Luton D, Sibony O, et al: Acyclovir prophylaxis in late pregnancy prevents recurrent genital herpes and viral shedding. Eur J Obstet Gynecol Reprod Biol 96:55-58, 2001 87. Scott LL, Sanchez PJ, Jackson GL, et al: Acyclovir suppression to prevent cesarean delivery after first-episode genital herpes. Obstet Gynecol 87:69-73, 1996 88. Scott LL, Hollier LM, McIntire D, et al: Acyclovir suppression to prevent recurrent genital herpes at delivery. Infect Dis Obstet Gynecol 10:71-77, 2002 89. Watts DH, Brown ZA, Money D, et al: A double-blind, randomized, placebo-controlled trial of acyclovir in late pregnancy for the reduction of herpes simplex virus shedding and cesarean delivery. Am J Obstet Gynecol 188:836-843, 2003 90. Kimberlin DW. Vertical transmission of HSV, 18th International Union Against Sexually Transmitted Diseases (IUSTI) Europe Congress on Sexually Transmitted Diseases. Vienna, Austria; #SAT12, Int J STD AIDS, 2002, pp 60; #SAT12 91. Sheffield JS, Hollier LM, Hill JB, et al: Acyclovir prophylaxis to prevent herpes simplex virus recurrence at delivery: A systematic review. Obstet Gynecol 102:1396-1403, 2003 92. Alexander L, Naisbett B: Patient and physician partnerships in managing genital herpes. J Infect Dis 186:S57-S65, 2002 93. Carney O, Ross E, Bunker C, et al: A prospective study of the psychological impact on patients with a first episode of genital herpes. Genitourin Med 70:40-45, 1994 94. Bergeron MG, Ke D, Menard C, et al: Rapid detection of group B streptococci in pregnant women at delivery. N Engl J Med 343:175179, 2000