Persistent and Recurring Viral Infections: The Human Herpesviruses

Persistent and Recurring Viral Infections: The Human Herpesviruses Mark R. Schleiss, MD

n the course of evolution, the herpesvirinae have likely existed from the beginning of humankind. These viruses share a number of biological features, including the largest genomes of any human pathogens, the presence of “immune evasion” genes that have been pirated from the host during evolution, and the ability to cause ubiquitous infection in the human population. There is considerable variation in the clinical disease manifestations associated with these pathogens, however, including such diverse syndromes as viral encephalitis, mononucleosis, and cancer. A common feature of all of members of the human herpesvirus family is the propensity of these viruses to establish latent, lifelong infections. Recently there have been a number of important advances in our understanding of herpesvirus pathogenesis, including better definition of the correlates of protective immunity, development of effective antiviral therapies, and progress in testing and implementing effective vaccines against some of these agents. This review summarizes the biology of these viruses, the diseases associated with infection by these pathogens, and the new advances in disease control for herpesviruses, with a particular emphasis on how these viruses impact the health of infants and children.

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Herpesvirus Classification and Disease Syndromes The herpesviruses share many common structural and biological features. These are enveloped viruses, with genomes consisting of double-stranded DNA. There are currently eight recognized herpesviruses From the University of Minnesota Medical School, Department of Pediatrics, Minneapolis, Minnesota. Curr Probl Pediatr Adolesc Health Care 2009;39:7-23 1538-5442/$ - see front matter © 2008 Mosby, Inc. All rights reserved. doi:10.1016/j.cppeds.2008.10.003

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associated with disease in humans (Table 1). Based on some key biological and clinical differences, the herpesviruses are subdivided into three groups: the alphaherpesviruses, including herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) and varicella-zoster virus (VZV); the betaherpesviruses, including human cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), and human herpesvirus 7 (HHV-7); and the gammaherpesviruses, a group consisting of Epstein–Barr virus (EBV) and Kaposi sarcoma herpesvirus (KSHV; also known as human herpesvirus 8 or HHV-8). The basic biology and clinical features associated with each of these viruses are reviewed below.

Alphaherpesviruses: HSV-1, HSV-2, and VZV HSV-1 and HSV-2 Infection. HSV-1 and HSV-2 demonstrate a high degree of similarity, both at the molecular level and in their clinical manifestations. The degree of genetic relatedness is approximately 45%, and the genome structures and morphological appearance of the viruses are virtually identical.1 HSV-1 and HSV-2 are both acquired predominately at mucosal surfaces and require intimate contact for transmission. Following primary infection in epithelial cells, virus rapidly traffics via the axon to the dorsal route ganglia,2 where latency is established. HSV latency is incompletely understood. The latent state is characterized by cessation of virtually all gene transcription, except for the “latency-associated transcript”, which is expressed in the dorsal route ganglia even as the rest of the viral genome maintains a quiescent state.3 The function of the latency-associated transcript is unknown but may involve a novel RNA-mediated mechanism, since there does not appear to be a protein product associated with the transcript.4 Following a number of triggers, including ultraviolet radiation, stress, and immunosuppression, the virus reactivates at the level of the dorsal route ganglia and initiates a cascade of viral gene transcription that leads to production of infectious virus,

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TABLE 1. The human herpesviruses

Viruses

Shared features

Alphaherpesviruses Herpes simplex virus 1 (HSV-1) Vesicular skin lesions Herpes simplex virus 2 (HSV-2) Infection of neuronal cells Varicella-zoster virus (VZV) Latency in ganglia Disease in fetus and newborn Betaherpesviruses Cytomegalovirus (CMV) Latent infection of leukocytes Human herpevirus 6 (HHV-6) Potential to infect multiple Human herpesvirus 7 (HHV-7) cells types including CNS Vertical transmission (congenital infection) Gammaherpesviruses Epstein–Barr virus (EBV) Malignant transformation of Kaposi sarcoma herpes virus/ cells human herpesvirus 8 (KSHV/ Development of human canHHV-8) cers

TABLE 2. Disease manifestations of infection with the human herpesviruses

HSV-1, HSV-2

VZV

CMV

HHV-6, HHV-7

which can traffic via the axon to the cutaneous surface or ocular surface, producing disease.5 The recrudescence of HSV lesions, usually manifest as vesicular and/or ulcerative lesions at the site of primary infection, can in turn lead to person-to-person transmission. However, frank lesions need not be present for patients to spread infection to susceptible individuals, since asymptomatic/subclinical shedding is well documented in the setting of genital herpes and is known to be associated with transmission of HSV (see below). A wide variety of disease syndromes are associated with primary as well as recurrent HSV infection. Classically, HSV-1 has been described as causing disease “above the belt,” whereas HSV-2 is associated with disease “below the belt”: hence, the finding of HSV-2 antibodies in seroprevalence studies is generally viewed as indicative of genital herpes (see below). However, these distinctions are imprecise, and either HSV-1 or HSV-2 can be associated with any of the following syndromes. The diverse clinical manifestations associated with HSV infection are summarized in Table 2. The most common disease associated with HSV infection is herpetic gingivostomatitis, characterized typically by peri- and intraoral lesions involving the pharyngeal mucosa. This entity can be confused with the oropharyngeal lesions associated with Stevens– Johnson syndrome, enterovirus infection, and other infectious syndromes. The disease is self-limited, although occasionally very young children with primary gingivostomatitis may require short hospitalization for hydration purposes (since the discomfort associated with the lesions may preclude the child from consum-

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EBV

KSHV (HHV-8)

Encephalitis Aseptic meningitis Herpetic keratitis Gingivostomatitis/pharyngitis Herpetic whitlow Herpes gladiatorum Eczema herpeticum Genital herpes Neonatal herpes Varicella (chickenpox) Herpes zoster Encephalitis Fetal varicella syndrome Mononucleosis Infections in immunocompromised Pneumonia Retinitis Viremia Congenital CMV infection Roseola infantum (exanthem subitum) Febrile seizures Encephalitis Congenital transmission Infectious mononucleosis EBV-associated malignancies Burkitt’s lymphoma Nasopharngeal carcinoma Non-Burkitt’s lymphomas EBV associated posttransplant lymphoproliferative syndrome (PTLD) Kaposi sarcoma Castleman’s disease

ing adequate fluid intake).6 HSV infection of the oropharynx may present in adolescence as herpetic pharyngitis7; it may be indistinguishable from other causes of pharyngitis and should be considered in cases of culture-negative pharyngitis unresponsive to antibiotic therapies. Another common manifestation of HSV infection in adolescent patients is the primary cutaneous infection associated with the close, skin-toskin contact that occurs during athletic competition, particularly wrestling. This syndrome is referred to as herpes gladiatorum.8 If a primary HSV lesion involves the fingers or hand, it is referred to as a herpetic whitlow; in the era before universal precautions, these lesions were once considered occupational hazards for dentists, dental hygienists, and other health care providers who commonly handled oropharyngeal secretions.9 In children with atopic dermatitis, cutaneous HSV infection can be associated with eczema herpeticum, a serious illness that can be associated with systemic symptoms.10 The new finding of multiple itchy, watery vesicles that occur on skin previously affected by atopic dermatitis should

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suggest this diagnosis, particularly if fever or other systemic symptoms are present. Although other disease syndromes caused by HSV are less common, they are potentially very serious. One such syndrome is herpetic keratitis, characterized by infection of the corneal epithelium. It is generally believed that this syndrome occurs in the context of reactivation of latent HSV in the trigeminal ganglion; interestingly, it appears that the lesion is largely due to an immunopathologic inflammatory response to infection. This syndrome is the leading cause of cornea blindness in the developed world and classically produces a “dendritic” branching pattern of keratitis, demonstrable with fluorescein staining, and representing the virus branching out to envelop the corneal surface; in children, the disease tends to be bilateral and recurs frequently.11 HSV encephalitis is the most common sporadic cause of viral encephalitis in North America and may be associated with either primary infection or reactivation of latent infection.12 A prodrome of malaise, fever, headache, and nausea is followed by acute or subacute onset of an encephalopathy whose symptoms include lethargy, confusion, and delirium. Seizures, aphasia, and other focal deficits also may be present, and the possibility of HSV encephalitis must be considered in any febrile patient with a focal seizure. The infection has a predilection for involving the temporal lobes. If untreated, mortality rates can exceed 70%.13 Infection with HSV-1 or HSV-2 can result in genital herpes. This infection is the most common cause of genital ulcerative disease in the developed world, and the prevalence of genital HSV, as defined by seropositivity for HSV-2 antibodies, has increased steadily in recent years.14 Genital herpes is characterized by blisters, ulcers, or crusts on the genital area, buttocks, or both; typically, symptomatic disease presents with a mixture of vesicles, ruptured vesicles with resulting ulcers, and crusted lesions. Systemic flu-like symptoms such as headache, fever, and swollen glands can accompany an outbreak of genital herpes. Other symptoms include dysuria, urinary retention, vaginal or penile discharge, genital itching, burning or tingling, and groin sensitivity. Genital lesions vary in number, are painful in nature, and, if untreated, persist for up to 21 days.15 Interestingly, it has been recognized in recent years that many individuals with genital herpes are asymptomatic and unaware of their status.16 Patients with symptomatic recurrences of genital HSV are advised to avoid sexual contact

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until lesions have crusted over and cleared; however, it has been shown using very sensitive techniques such as polymerase chain reaction (PCR) detection of viral nucleic acids that such individuals continue to shed virus in between symptomatic episodes.17 Since individuals with asymptomatic genital herpes shed virus frequently in the absence of lesions, all HSV-2-seropositive individuals are probably at risk for transmitting infection unknowingly. For the pediatrician, a particularly important category of HSV-associated disease is that of neonatal herpes. In the USA, neonatal herpes occurs in approximately 1 in 2500 births.18,19 The majority of cases occur in infants born to women who were recently infected, rather than to women with longstanding histories of recurrent genital herpes. As noted, many primary genital HSV infections are minimally symptomatic, and therefore can escape clinical detection in the mother but nonetheless pose a major risk to the baby. Neonatal infection with HSV is thought to be due to the presence of virus in the maternal genital tract. Accordingly, intrapartum interventions that have the risk of penetrating fetal skin, such as scalp electrode monitoring, increase the risk of transmission to the infant.20 Rarely, cases of intrauterine infection have been described, often associated with overwhelming maternal infection and usually resulting in fetal demise.21 Primary infection late in pregnancy poses a higher risk of transmission to the infant than do primary infections occurring before or early in pregnancy, suggesting that the evolution of a maternal antibody response may confer some measure of protection for the infant.22 Neonatal herpes can have devastating long-term consequences. Infection may present in newborns in one of three forms: disease limited to the skin, eye, or mucous membranes (SEM disease); disease involving the central nervous system (CNS disease); or disseminated HSV infection, frequently presenting as a sepsis-like syndrome, with pneumonia, hepatitis, and viremia commonly encountered.18,19 There can be overlap in these syndromes; importantly, pediatricians should recognize that in approximately one-third of cases of neonatal HSV presenting as CNS disease, skin lesions are never observed during the course of the illness. Even with prompt recognition and therapy, the risk of long-term morbidity, particularly neurodevelopmental morbidity, is significant. Recent developments in the approach to HSV infections among women of childbearing age include consideration of

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maternal screening programs, and the use of antiviral agents in women at risk for transmission of infection. The availability of reliable kits that allow specific serodiagnosis of HSV-1 and HSV-2 infections has enabled the identification of women with genital HSV during pregnancy.22 Although routine seroscreening of pregnant women is not currently considered a standard of care, screening in some instances, including situations where maternal anxiety exists, seems justified. There is no evidence that routine administration of suppressive antivirals during pregnancy can improve outcomes or reduce disease in newborns,23,24 although such practice is currently commonplace in obstetrics. Careful monitoring for the presence of active HSV lesions near term has been recommended, as cesarean delivery can reduce the risk of transmission to the newborn; one benefit of suppressive antiviral therapy during pregnancy for women with histories of genital herpes is the reduction in cesarean sections that results from prevention of reactivation at term.25 A history-based strategy misses many “at-risk” deliveries, however, as many HSV-2-seropositive women are asymptomatic, do not know that they have genital herpes, and may unknowingly shed virus at the time of delivery. Management of neonates potentially exposed to HSV in the birth canal is controversial. This situation arises when, following vaginal delivery, a lesion not noticed during labor and delivery is discovered. Some authorities recommend neonatal surface cultures and administration of prophylactic antivirals, but there is little evidence to support this approach. The most important element is maternal history. Term infants exposed to HSV in the birth canal, but born to women with longstanding histories of recurrent genital herpes, are at very low risk (⬍1%) of infection, and careful observation is likely all that is needed.26 If the maternal HSV history is unclear, the infant is premature, or other obstetric complications are present, antiviral therapy is warranted. VZV Infection. The other prototypical alphaherpesvirus is varicella-zoster virus (VZV). Like HSV, this virus is associated with vesicular lesions, infection of neuronal tissue, and latent infection of ganglia. Like HSV, primary infection occurs at mucosal surfaces; however, in contrast to HSV, VZV transmission does not require intimate, skin-to-skin contact, and in fact, is more commonly transmitted by respiratory secretions via an aerosol route.27 The most common clinical manifestation of VZV infection is chickenpox. The pathogenesis of VZV has been well-described and

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FIG 1. Invasive soft-tissue infection due to S. pyogenes complicating chickenpox. This child developed fever and soft-tissue swelling on the fifth day of varicella-zoster infection. Leading edge aspirate of cellulitis grew S. pyogenes (group A streptotococcus; GAS). Although patient responded to intravenous penicillin and clindamycin, operative debridement was necessary because of clinical suspicion of early necrotizing fasciitis. Vaccination against varicella has significantly reduced the incidence of life-threatening soft-tissue infections with GAS in children (see text). (Color version of figure is available online.)

differs in several aspects from HSV infection.28 When a susceptible individual is exposed to VZV, the virus initially undergoes primary replication, beginning 3 to 4 days after exposure, occurring in the oropharynx and regional lymph nodes. This is followed by a primary viremia; a secondary viremia, during which the reticuloendothelial system is seeded, occurs 10 to 21 days after exposure. Late in this secondary viremia phase, cutaneous lesions become evident and may continue to develop for the next 3 to 7 days. Viremic seeding of the respiratory mucosa also occurs toward the end of the incubation period and is associated with a high degree of communicability 1 to 2 days before onset of rash. The rash of varicella often is preceded by a 24to 48-hour period of fever, malaise, and systemic symptoms. The exanthem begins as erythematous, pruritic macules that develop into papules and fluidfilled vesicles, followed by eventual crusting of the vesicles, typically within 4 to 5 days of the onset of the initial lesion. The average number of lesions is approximately 300 to 400; however, lesions may occasionally be absent in the setting of primary infection. In contrast, there may be over 1000 lesions in immunocompromised children or in the setting of severe infection. In immunocompromised children, a malig-

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nant form of the disease, known as hemorrhagic varicella, is associated with thrombocytopenia, a disseminated intravascular coagulation (DIC)-like picture, and high mortality rates.29 In recent years, suprainfection with Streptococcus pyogenes (group A streptococcus) has emerged as a major cause of morbidity and occasional mortality (Fig 1). In the postvaricella vaccine era, the incidence of such suprainfections appears to be decreasing.30 The other common clinical manifestation of VZV infection is herpes zoster (shingles). Like HSV, VZV becomes latent in dorsal root ganglia cells. It remains there until reactivation, at which time the virus travels back to the skin along the sensory nerve. Reactivation likely is due to declining cell-mediated immunity, which explains the increased incidence in the elderly and in immunocompromised patients. This age-related decline in immunity is the basis for vaccination against zoster in individuals over the age of 60 (see below). Other less common complications of VZV infection include encephalitis and cerebellitis (postviral cerebellar ataxia).31 Varicella is also associated with Reye syndrome, almost exclusively in children who receive aspirin therapy; thus, salicylates should be avoided in all children afflicted with chickenpox. VZV infection during pregnancy can be associated with congenital varicella syndrome (CVS).32 Maternal VZV infection during the first 6 months of pregnancy is associated with CVS, with the highest risk occurring between 13 and 20 weeks of pregnancy; in this setting, the incidence of CVS following exposure is estimated to be approximately 2%. Characteristic symptoms of CVS include skin lesions, typically in a dermatomal distribution, neurological defects, ophthalmologic complications, and skeletal anomalies. Approximately 30% of infants with CVS die in the first months of life. CVS appears to be a complication of primary VZV infection only and has not been described following maternal herpes zoster (shingles) during pregnancy. Management of such pregnancies is complex. Pregnant women who are susceptible to varicella should receive varicella zoster immune globulin (VariZIG, see below) in any setting where CVS is a concern. The pathogenesis of CVS is presumed to be a consequence of viremic seeding of the placenta, with subsequent infection of the fetus. Placental abnormalities described in pregnancies complicated by CVS include basal chronic villitis with lymphohistiocytic infiltrate, and occasional multinucleated giant cells. A study of infants born to women exposed to VZV between 8 and

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21 weeks of pregnancy detected VZV DNA in multiple tissues including lung, liver, skin, and adrenal gland. Primary maternal VZV infection in late pregnancy can be associated with neonatal varicella, occurring in infants born to mothers developing chickenpox less than 5 days before, and up to 2 days after, delivery.

Betaherpesviruses: CMV, HHV-6, and HHV-7 Cytomegalovirus (CMV) Infection. Of all the human herpesviruses described to date, infection with CMV is arguably the most important cause of morbidity and mortality in the developed world. Although primary infection with this agent is generally asymptomatic in healthy adults, several high-risk groups, including immunocompromised organ-transplant recipients and human immunodeficiency virus (HIV)infected individuals, are at risk of developing life- and sight-threatening CMV disease. Of particular interest to pediatricians is the observation that CMV has emerged in recent years as the most important congenital viral infection and as the most important infectious disease associated with mental retardation, hearing loss, and developmental disabilities in children. Human cytomegalovirus was first isolated in tissue culture in 1956, and the propensity of this organism to infect salivary glands led to its initial designation as salivary gland virus. In 1960, the virus was renamed “cytomegalovirus” by Weller, and during the 1970s and 1980s, knowledge of the role of CMV as an important pathogen with diverse clinical manifestations grew steadily.33 Taxonomically a betaherpesvirus, it is the largest member of the herpesvirus family, with a double-stranded DNA genome of ⬎240 kbp, capable of encoding over 200 potential protein products. The pathogenesis of CMV infection has recently been the subject of a comprehensive review.34 An understanding of the function of viral proteins provides insights into potential therapeutic interventions. As with the other herpesviruses, the structure of the viral particle is that of an icosahedral capsid, surrounded by a lipid bilayer outer envelope. The lipid bilayer outer envelope contains the virally encoded glycoproteins that are the major targets of host neutralizing antibody responses. These glycoproteins are candidates for human vaccine design (see below). The proteinaceous layer between the envelope and the inner capsid, the viral tegument, contains proteins that are also major targets of host cell-mediated immune

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responses, and potential subunit vaccine candidates. Another clinically important gene product, the UL97 gene product, is a phosphotransferase required for activation of the antiviral agent, ganciclovir, to its active form. Every mammal appears to be infected with its own, species-specific cytomegalovirus, and there is no evidence for infections across species in nature. Hence, humans are the only natural host for human CMV infection. Although most adults eventually become infected with CMV, the epidemiology of this infection is complex, and the age at which an individual acquires CMV depends greatly on geographic location, socioeconomic status, cultural factors, and childrearing practices.35-37 In developing countries, most children acquire CMV infection early in life, with adult seroprevalence approaching 100% by early adulthood. In contrast, in developed countries, the seroprevalence of CMV may be well below 50% in young adults of middle upper socioeconomic status. This observation has important implications for congenital CMV epidemiology, since CMV-seronegative women of childbearing age are at major risk of giving birth to infants with symptomatic congenital infection if primary infection is acquired during pregnancy. Transmission of CMV infection may occur throughout life, chiefly via contact with infected secretions. CMV infections in newborn infants are common and most are subclinical. Approximately 1% (range, 0.52.5%) of all newborns are congenitally infected with CMV. The majority of these infections occur in infants born to mothers with preexisting immunity, and although clinically silent at birth, infection can lead to long-term sequelae, most notably sensorineural hearing loss.38 The route of acquisition of CMV infection acquired in utero is believed to be transplacental.39 CMV may also be transmitted perinatally, both by aspiration of cervicovaginal secretions in the birth canal and, more commonly, by breastfeeding.40 Indeed, over 50% of infants fed with breast milk that contains infectious virus will become CMV-infected. Infants who are not congenitally or perinatally infected with CMV are at high risk to acquire infection in daycare centers. The prevalence of CMV infection in daycare center attendants, particularly children under 2 years of age, approximates 80% in some studies. Virus may be readily transmitted to susceptible children via saliva, urine, and fomites, and these children in turn may transmit infection to their parents.41 Such horizontal transmission of infection in daycare centers

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appears to play a major role in the epidemiology of many CMV infections in young parents. In adulthood, sexual activity is probably the most important route of acquisition of CMV, particularly in women,42 although the observation that virus is present in saliva, cervicovaginal secretions, and semen makes it unclear which route(s) of transmission is primarily responsible for establishment of infection. Saliva alone appears to be sufficient for transmission of CMV, and this route of transmission may be responsible for those cases of heterophile-negative mononucleosis that are attributable to CMV.43 The hallmark symptoms of CMV mononucleosis are fever and severe malaise. An atypical lymphocytosis is present, as is mild elevation of liver enzymes. It may be difficult to clinically differentiate CMV mononucleosis from EBV-induced mononucleosis (see below). CMV mononucleosis is typically associated with less pharyngitis and less splenomegaly. As with EBV mononucleosis, the use of ß-lactam antibiotics in association with CMV mononucleosis may precipitate a generalized morbilliform rash. Kissing as well as contact with infectious body fluids, such as saliva and urine, appear to be ways in which CMV is transmitted from toddlers to seronegative parents, and educating women of childbearing age about these potential risks may be a valuable strategy for prevention of primary maternal infections during subsequent pregnancies.44,45 Other important routes of transmission include blood transfusion and solid organ transplantation. Before screening of blood products for CMV antibodies prior to transfusion became commonplace, transfusion-associated CMV was an important cause of morbidity and mortality in premature infants, although the routine use in most blood banks of leukofiltration has largely eliminated the problem of posttransfusion CMV.46 Current estimates suggest that 30,000 to 40,000 infants in the United States are born annually with congenital CMV infection, making CMV by far the most common and important of all congenital infections. Both the likelihood of congenital infection as well as the extent of disease in the newborn depend on maternal immune status. Approximately 10% of congenitally infected infants have clinical evidence of disease at birth. This, the most severe form of congenital CMV infection, is referred to as “cytomegalic inclusion disease,” (CID) characterized by intrauterine growth retardation, hepatosplenomegaly, hematological abnormalities (particularly thrombocytopenia), and

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a variety of cutaneous manifestations, including petechiae and purpura (so-called “blueberry muffin” baby).47,48 The most significant manifestations of CID are those involving the CNS.49 Microcephaly, ventriculomegaly, cerebral atrophy, chorioretinitis, and sensorineural hearing loss are the most common neurological consequences of CID. Intracerebral calcifications classically demonstrate a periventricular distribution and are commonly encountered by computed tomography scan. The finding of intracranial calcifications is predictive of cognitive and audiologic deficits in later life and predicts a poor neurodevelopmental prognosis. Indeed, it has been estimated that congenital CMV may be second only to Down syndrome as an identifiable cause of mental retardation in children. Infants with asymptomatic congenital CMV infection are also at risk for neurodevelopmental sequelae. The major consequence of inapparent congenital CMV infection is sensorineural hearing loss.38 Between 15 and 20% of these infants will have unilateral or bilateral deafness. Routine newborn audiologic screening may miss cases of CMV-associated hearing loss, since this may be a lesion that becomes evident months or even years after delivery.50,51 Thus, a case can be made for universal screening of newborns for congenital CMV infection, and this is an area of active research, focusing in particular on the use of newborn blood spots for PCR-based amplification of CMV DNA sequences.52-54 CMV also causes several diverse clinical syndromes in immunocompromised patients.55,56 Disease manifestations vary in severity depending on the degree of host immunosuppression. Infection may occur due to reactivation of latent virus or may be newly acquired via organ or bone marrow transplant from a seropositive donor. Infections may also be mixed in nature, with both donor and recipient isolates present. Viral dissemination leads to multiple organ system involvement, with the most important clinical manifestations consisting of pneumonitis, gastrointestinal disease, and retinitis. A variety of other syndromes have been attributed to CMV infection, although cause and effect relationships are often difficult to establish. Menetrier’s disease is a rare disorder characterized by hyperplasia and hypertrophy of the gastric mucous glands that result in massive enlargement of the gastric folds. The majority of cases appear to be CMV-associated, although the pathogenesis is unknown.57 In children with congen-

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ital HIV infection, coinfection with CMV appears to accelerate the HIV disease progression and HIVassociated neurological disease. Evidence is accumulating that suggests that CMV infection may be a cofactor in the pathogenesis of atherosclerosis, posttransplant vascular sclerosis, postangioplasty restenosis, immunosenescence, and malignancies.58 Such observations provide support for the concept of universal childhood vaccination against CMV (see below). Human Herpesvirus 6 (HHV-6) and 7 (HHV-7) Infection. HHV-6 was isolated in tissue culture in 1986 from peripheral blood leukocytes of patients with both lymphoproliferative disorders and HIV infection. The virus was eventually shown to have a tropism for T-cells, and molecular studies revealed homology with human cytomegalovirus. These findings suggested that the virus belonged to the family Herpesviridae. For several years after discovery it remained a “virus in search of a disease,” but it is now known to be the major etiologic agent of roseola infantum (exanthem subitum), and has been implicated in other clinical syndromes. HHV-6 is a prototypical betaherpesvirus, with a double-stranded DNA genome contained within an icosahedral capsid, surrounded by an outer envelope. HHV-6 is subclassified as either variant A or B, based on differences in nucleotide sequence, restriction enzyme profile, and reactivity with monoclonal antibodies. HHV-6B is the subtype typically associated with exanthem subitum.59 Infection with HHV-6 is ubiquitous, and virtually all children are infected by 2 to 3 years of age. Infection is seldom seen before 6 months of age, presumably due to the protective effect of transplacental antibody, and peaks between 6 and 12 months of age. HHV-6 can be found in the salivary gland and is shed in saliva of seropositive individuals, suggesting that saliva is the probable route of acquisition of infection. Primary infection in children most likely occurs via contact with HHV-6 shed in the secretions of older children or caregivers. HHV-6 can also be associated with congenital infections, although the clinical significance of such infections is not fully characterized.60 The spectrum of disease associated with primary HHV-6 infection is broad, ranging from asymptomatic infection to fatal disseminated disease. Most commonly, however, primary infection occurs early in life and is manifest either as exanthem subitum or as an undifferentiated febrile illness. Exanthem subitum is a common acute febrile illness of infants and young

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children characterized by 3 to 5 days of fever followed by rapid defervescence and the appearance of an erythematous macular or maculopapular rash. This entity was first described by Zahorsky in 1910 and was at one time classified as “sixth disease” among the classic exanthematous illnesses of childhood.61 The infection is characterized by viremia before the onset of the rash. Fever can be quite significant. Before development of the characteristic rash, there are few other clinical clues to reliably indicate that the febrile illness is due to HHV-6, although posterior auricular adenopathy is commonly noted on physical examination. Because of the high fever and lack of differentiating clinical findings, many young infants will be subjected to extensive laboratory evaluation and empiric antibiotic therapy before the onset of the characteristic exanthem. In those children treated empirically with antimicrobials, the onset of the characteristic rash may often be misinterpreted as an antibiotic “allergy.” The rash is either papular, macular, or maculopapular and appears mainly on the trunk. The pathogenesis of the rash is unknown but is presumed to be immune mediated. The rash usually fades within 3 to 4 days following onset. HHV-6 infection can also be a common cause of undifferentiated febrile illness without rash in infants. In one study, evidence for acute HHV-6 infection was identified in approximately 10% of children presenting to an emergency department for evaluation of high fever. A peak fever higher than 40°C was found in 65% of the acutely HHV-6-infected children in this study.62 Inflammation of tympanic membranes and a modest depression in total leukocyte count were the only other features that differentiated these children from those without HHV-6 infection. Since very young infants with high fever due to HHV-6 infection are difficult to discriminate from those with occult bacteremia, many young infants with acute HHV-6 infection are treated with antibiotic therapy. HHV-6 infection can also be associated with CNS complications in children both with and without rash. Febrile convulsions appear to be the most common complication associated with HHV-6 infection. In a large study of emergency room visits, HHV-6 accounted for one-third of all febrile seizures in children younger than 2 years of age. In some children, seizures may be prolonged or recurrent in nature.63 However, in another, prospective population-based study of 81 children with a well-defined time of acquisition of HHV-6, although 93% had symptoms, none had sei-

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zures.64 The role of primary HHV-6 infection as a cause of neurological disease in children requires further study. Other neurologic complications reported in acute HHV-6 infection have included encephalitis, meningoencephalitis, and aseptic meningitis. Provocative reports have hypothesized that latent CNS infection with HHV-6 may play a causative role in temporal lobe epilepsy, and controversial reports in adult patients have proposed a link to HHV-6 infection in the CNS and multiple sclerosis.65 Immunocompromised patients appear to be at increased risk for disease associated with HHV-6. It is presumed that the majority of such syndromes reflect reactivation of latent injection under conditions of immunosuppression. There are reports linking reactivation of HHV-6 with allograft rejection. HHV-6 reactivation has also been considered to contribute to an immunomodulatory and immunosuppressive milieu in the transplant patient that may, in turn, facilitate infection with other opportunistic pathogens, such as CMV and fungal infections, thereby contributing to an increased overall mortality.66 In hematopoietic stem cell transplant patients, HHV-6 has been implicated as a cause of encephalitis.67 HHV-7 is highly related to HHV-6, and, like HHV-6, is responsible for the common childhood illness, exanthem subitum.68 HHV-7 is a betaherpesvirus, structurally and molecularly similar to cytomegalovirus and HHV-6. It was first isolated from CD4⫹ T-cells of a healthy individual. The high degree of homology with HHV-6 creates difficulty in interpretation of serologic assays (which are largely investigational in nature and not generally useful for clinical practice), because there is considerably cross-reactivity of antibodies between HHV-6 and HHV-7 proteins. As with HHV-6, infection with HHV-7 appears to be ubiquitous, although infection appears to be acquired somewhat later in life than is HHV-6.69,70 By 2 years of age, approximately 40 to 45% of children have antibodies to HHV-7, and by 6 years of age, 70% of children are seropositive. Like other betaherpesviruses, HHV-7 can be found in the saliva, suggesting a route for person-to-person transmission. Primary infection is clearly associated with exanthem subitum, and the rash is clinically indistinguishable from that caused by HHV-6. It has been estimated that HHV-7 may be responsible for up to 10% of episodes of exanthem subitum. Other reported clinical manifestations of primary HHV-7 infection include fever of unknown origin, simple

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febrile seizures, lymphadenopathy, hepatitis, and heterophile-negative mononucleosis.71 Viremia can occur either as a consequence of primary infection, or from reactivation of latent infection.70,72 As with HHV-6, congenital infections with HHV-7 have been reported.60

Gammaherpesviruses: Epstein–Barr Virus (EBV) and HHV-8 (KSHV) EBV Infection. EBV was originally discovered by electron microscopy of cells cultured from a patient with Burkitt’s lymphoma,73 underscoring the key differentiating feature of the gammaherpesviruses: their ability to effect malignant transformation, leading to human cancers. Shortly after the discovery of EBV, the virus was shown to be the etiologic agent of heterophile-positive infectious mononucleosis (described below).74 As with other herpesviruses, the EBV viral genome is encased within a nucleocapsid, surrounded by the viral envelope. Before the virus enters the B-cell, the major envelope glycoprotein, gp350, binds to the viral receptor, the CD21 molecule (the C3d complement receptor). This receptor–ligand interaction has implications for the tropism of disease in the human host, since the major sites where the CD21 receptor is expressed are on the oropharyngeal epithelium and on the surface of the B-cell. Infection of epithelial cells by EBV in vitro results in active replication, with production of virus and lysis of the cell. In contrast, infection of B-cells by EBV in vitro results in a latent infection, with immortalization of the cells. After infecting B-cells, the linear EBV genome becomes circular, forming an episome, and the genome usually remains latent in these B-cells. Viral replication is spontaneously activated in only a small percentage of latently infected B-cells. Infection of humans with EBV usually occurs by contact with oral secretions. The virus replicates in cells in the oropharynx, and nearly all seropositive persons actively shed virus in the saliva. The disease syndrome most often produced by the EBV virus is infectious mononucleosis (IM).74 Whether or not EBV produces signs and symptoms of disease depends on the age of the individual at the time of primary infection. Most EBV infections of infants and children are minimally symptomatic, whereas infections of adolescents and adults frequently result in the mononucleosis syndrome, most commonly characterized by fever, lymphadenopathy, and pharyngitis.

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Other prominent signs of IM include splenomegaly, palatal petechiae, and hepatomegaly. Rare complications include thrombocytopenia, aplastic anemia, myocarditis, hepatitis, genital ulcers, splenic rupture, encephalitis, aseptic meningitis, and rash. Because of the risk of splenic rupture, children and adolescents with acute IM who have splenomegaly should refrain from contact sports until their illness resolves. The rash associated with EBV infection is precipitated by the intercurrent use of beta-lactam antibiotics, in particular, ampicillin and amoxicillin, and these antibiotics are relatively contraindicated in the patient with IM. For the patient with IM who has an intercurrent group A streptococcal pharyngitis, penicillin VK is preferable to semisynthetic penicillins. One of the characteristic laboratory abnormalities of IM is the presence of an atypical lymphocytosis. The atypical lymphocytes are made up of T-cells, mounting a response to EBV-infected B-cells. Most of the symptoms of IM are due to the activation of these T-cells in response to infection. Activation of B-cells by EBV, with resultant production of polyclonal antibodies, causes elevated titers of heterophile antibodies and occasionally causes increases in cold agglutinins, cryoglobulins, antinuclear antibodies, or rheumatoid factor. Another important feature of EBV infection is its ability to induce human cancers. These include Burkitt’s lymphoma, nasopharyngeal carcinoma, and other lymphomas, such as Hodgkin’s and nonHodgkin’s lymphomas.75,76 There is a relationship between EBV-associated Burkitt’s lymphoma and endemic malaria infection; it is believed that chronic B-cell stimulation associated with malaria infection contributes to the pathogenesis of lymphoma, and recently a malaria protein, CIDR1alpha, has been identified that is able to drive EBV replication in latently infected B-cells.77 EBV is also a cause of posttransplant lymphoproliferative disease (PTLD), a major complication following solid organ and hematopoietic stem cell transplantation.78 The highest risk of PTLD is in individuals who are EBV-seronegative pretransplant; hence, children are disproportionately represented in PTLD cases. Kaposi Sarcoma Herpesvirus (KSHV) Infection. The history of the identification of KSHV was unique among the Herpesviridae insofar as the virus was initially “discovered” through identification of novel DNA sequences, using powerful molecular detection techniques.79 KSHV is also known as human herpes-

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virus 8 (HHV-8). Working with tissue from HIVinfected individuals with Kaposi’s sarcoma (KS), Chang and colleagues used a technique referred to as “representational difference analysis” to identify disease-specific DNA sequences in KS tissue. On DNA sequence analysis, the deduced amino acid sequences were found to have strong homology to proteins from the gammaherpesvirus subfamily, which, as noted, includes the EBV. This observation was striking in view of the known ability of EBV to persist in lymphocytes, immortalize cells, and produce human malignancies (Burkitt’s lymphoma and nasopharyngeal carcinoma). Hence the novel gammaherpesvirus, HHV-8 (also referred to as KS herpesvirus, or KSHV), appeared to be a new herpesvirus with the potential to be associated with human malignancy. Eventually the KSHV/HHV-8 virus was cultivated in tissue culture, proving that these DNA sequences corresponded to a morphologically identifiable viral particle.80 Structurally, HHV-8 consists of a prototypical enveloped particle, similar to other herpesviruses. HHV-8 appears to be B-cell tropic, particularly for the CD19 subset of B-lymphocytes. The virus also appears to infect endothelial cells in vivo, the cells that are the precursors to KS. The virus presumably establishes latent infection following primary infection, although the site(s) of latency is unknown. Evolutionarily, HHV-8 appears to have undergone considerable recombination with host genes, and the viral genome contains a variety of transduced cellular oncogenes and chemokine homologs that are probably important in the pathogenesis of KS.81 It is estimated that 10% of the genes encoded by HHV-8 promote KS development due to either mitogenic, antiapoptotic, chemoattractive, angiogenic, or transforming activities. The precise contribution of these viral gene products to the pathogenesis of KS is under intense investigation in many laboratories. The epidemiology of primary HHV-8 infection appears to vary considerably worldwide. Indeed, the routes of acquisition of infection and mechanisms responsible for person-to-person transmission remain uncertain. After the virus was initially discovered, the unique role it seemed to play in inducing malignant disease in HIV-infected patients suggested that the primary route of transmission of HHV-8 was through sexual contact, particularly among gay men. However, more recent evidence suggests that other routes of infection exist, including transmission by saliva.82 A recent cross-sectional study of the seroprevalence of

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HHV-8 in children and adolescents in the USA indicated a prevalence of approximately 1%.83 There appears to be considerable regional variation in prevalence in the USA. In a population of children in south Texas, the seroprevalence was 26%, strongly suggesting that nonsexual modes of transmission predominate.84 In sub-Saharan Africa, prevalence in children is even higher, approaching 60% in some studies.85 There are reports of infections in infants that suggest the possible of vertical transmission, but congenital infection has not been demonstrable by PCR techniques.86 HHV-8 can also be transmitted by blood transfusion.87 As serological and nucleic acid based diagnostic tests become more widely available, a better assessment of the worldwide seroepidemiology of HHV-8 infection will become feasible. Most primary infections with HHV-8 are probably asymptomatic, although the clinical course of primary symptomatic HHV-8 infection in immunocompetent children recently has been described.88 In this study, fever and rash were noted with primary infection. The rash first appeared on the face and gradually spread to the trunk, arms, and legs. It initially consisted of discrete red macules that blanched with pressure and eventually became papular. The median duration of the rash was 6 days, and fever persisted for a median of 10 days: some children had high fever (temperature, 39°C). An upper respiratory tract infection appeared as a secondary symptom in most, and a lower respiratory tract infection appeared as a secondary symptom in one-third of symptomatic children, although major respiratory complications did not occur during the course of primary HHV-8 infection. Prior HHV-8 infection appears to be usually necessary, but not sufficient, for the development of the malignancy, KS. KS is a multifocal vascular neoplasm involving skin, visceral organs, and lymph nodes. Lesions histopathologically contain distinctive proliferating cells, so-called “spindle” cells, as well as activated endothelial cells, fibroblasts, smooth muscle cells, and infiltrating inflammatory cells. Three variants of KS are described89: “classical” KS, which is chiefly an indolent, slowly progressive form of KS seen in elderly, HIV-negative Mediterranean men, “endemic” KS, a variant seen in Africa (including a “lymphadenopathic” form seen predominantly in young children), and “epidemic” KS, seen in HIVinfected patients. All variants are associated with HHV-8. The factors responsible for malignant trans-

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TABLE 3. Antiviral interventions for herpesvirus infections

Antiviral agents

Mechanism of action

Clinical uses

Acyclovir (ACV) Valacyclovir (VAL) Famciclovir (FAM) Penciclovir (PCV)

Inhibition of HSV DNA polymerase DNA synthesis chain terminator Drug requires phosphorylation by viral gene product (thymidine kinase) Penciclovir only available as topical formulation

Ganciclovir (GCV) Valganciclovir (Valgan)

Inhibition of CMV DNA polymerase Drug requires phosphorylation by virus-specific kinase (UL97 protein) Valganciclovir is prodrug of GCV Inhibition of CMV DNA polymerase Does not require phosphorylation for activity

All primary HSV diseases Neonatal HSV Suppressive of latent HSV infection (genital HSV suppression) Primary VZV infection Herpes zoster (postherpetic neuralgia) CMV end-organ disease in immune compromised CMV retinitis in AIDS Symptomatic congenital CMV infections (ameliorates CMV-induced hearing loss) CMV end-organ disease in immune compromised CMV retinitis in AIDS GCV resistance Prophylaxis against CMV disease in transplant setting Possible value for prevention of congenital CMV infection/disease Postexposure prophylaxis in high-risk individuals (pregnancy, immune compromised) following exposure to VZV

Foscarnet (FOS) Cidofovir (CDV) CMV immune globulin (CMV-Ig)

Uncertain; presumed to be due to direct neutralization of viral infectivity?

Varicella-zoster immune globulin (VariZig)

Uncertain; presumed to be due to direct neutralization of viral infectivity? Replaces VZig

formation of HHV-8-infected endothelial cells into tumor are unknown. Other malignant diseases have been associated with HHV-8, including multicentric Castleman’s disease, a lymphoproliferative syndrome associated with HIV infection, and another acquired immunodeficiency syndrome (AIDS)-associated malignancy, primary effusion lymphomas. HHV-8 is causally related to these tumors in HIV-negative patients as well. Other malignancies, including skin cancer and multiple myeloma, have been associated with HHV-8 in the literature, but these reports are controversial and the causal link remains unproven (Table 2). Links between HHV-8 and pemphigus, sarcoidosis, and Kikuchi’s disease have been postulated,90 and recently, there have been associations reported between HHV-8 and hemophagocytic syndromes.91 In the absence of standardized serologic assays, serodiagnosis of HHV-8 infection is problematic. Tissue from any case of KS, primary effusion lymphomas, or multicentric Castleman’s disease that is encountered in a child should probably be investigated for the presence of HHV-8 DNA sequences, in collaboration with a reference laboratory. HIV serology should also be performed in such patients. AIDSassociated KS has been reported to regress following administration of highly active antiretroviral therapy, suggesting that reversal of immunosuppression may promote resolution of the tumor.

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Therapeutic Interventions for Herpesviruses Antiviral Therapy The advent of modern antiviral therapy came with the development of the prototypical nucleoside analog, acyclovir, in the mid-1980s. Acyclovir was first developed for topical administration for genital herpes, but parenteral and oral formulations rapidly became available, and these are now preferred for virtually all therapeutic settings. Acyclovir and the related antivirals, valacyclovir and famciclovir, are indicated in the therapy of HSV and VZV infection.92,93 Currently licensed antiviral agents for herpesvirus infections are indicated in Table 3. Acyclovir is an analog of guanosine, a nucleoside integral in DNA synthesis, and this feature is integral to its mechanism of action. One critical feature is the selectivity of acyclovir for HSV- or VZV-infected cells. In the HSV-infected human cell, acyclovir enters the cell and is converted to acyclovir monophosphate by a HSV-specific enzyme known as thymidine kinase. Intracellular enzymes add two more phosphates to eventually form the active drug, acyclovir triphosphate. Acyclovir triphosphate competes with 2-deoxyguanosine triphosphate as a substrate for viral DNA polymerase and has a second mechanism of antiviral activity, functioning as a chain terminator in the newly synthesized HSV DNA molecules formed during viral DNA replication.

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The fact that acyclovir has marked selectivity for virally infected cells contributes substantially to its very favorable safety profile. Acyclovir triphosphate’s minimal production in noninfected cells and its reduced affinity for cellular DNA polymerase limits its potential for side effects. However, acyclovir has relatively poor oral bioavailability and requires either higher dosing or intravenous administration for the more severe manifestations of herpes simplex infections (ie, neonatal herpes, herpes encephalitis). To improve the bioavailability of oral dosing, valacyclovir was developed in the mid-1990s. Valacyclovir provides a high bioavailability of acyclovir, three- to fivefold higher than that obtained with oral acyclovir, and it is equivalent to plasma levels achieved with doses of intravenous acyclovir. An L-valine ester of acyclovir, valacyclovir is rapidly metabolized into valine and acyclovir by the enzyme valacyclovir hydrolase in the gastrointestinal tract and liver. As a prodrug, valacyclovir does not have any intrinsic antiviral activity until it is biotransformed into acyclovir. In contrast to oral acyclovir, which must be dosed up to five times daily, valacyclovir is efficacious when dosed much less frequently (either once daily, or twice daily, depending on the indication; Table 3). Another relatively recently developed nucleoside analog, famciclovir, is also useful in the management of HSV and VZV infections. Like valacyclovir, famciclovir is a pro-drug, converted following oral administration to penciclovir. As with acyclovir, penciclovir is phosphorylated in virus-infected cells to its active form, first by thymidine kinase, and then cellular enzymes. Penciclovir triphosphate has a very long intracellular half-life compared with acyclovir triphosphate, a feature that contributes to its more convenient dosage regimens than acyclovir (either twice daily, or three times daily, depending on the indication). Clinical indications for the use of antiviral therapy for HSV and VZV infections are summarized in Table 3. A unique clinical application of nucleoside antivirals has been the recently adopted approach of treating pregnant patients with oral anti-HSV drugs in the setting of perceived risk of transmission to the newborn infant. Randomized, placebo-controlled trials of oral acyclovir in late pregnancy suggest that therapy reduces viral shedding in women with primary and recurrent genital HSV infection and decreases the likelihood of clinical recurrences. In such pregnancies a clinical benefit is inferred, since reduced recurrences may reduce the need for cesarean sections, an inter-

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vention normally recommended if genital lesions are noted at term. Such therapy appears to be safe for both mother and infant, and well tolerated, but additional studies will be required to definitively show that such a strategy reduces the likelihood of neonatal herpes. For the infected neonate, intravenous acyclovir should be used as the first-line therapy. Infants with neonatal herpes have a significant risk of long-term neurodevelopmental morbidity, even if skin lesions are the only disease manifestations noted; moreover, a correlation exists between the development of neurologic deficits and the frequency of cutaneous HSV recurrences over the first few months of life.94 Therefore, some experts advocate long-term oral acyclovir suppressive therapy be administered for the first 6 months of life, to prevent both clinical and subclinical reactivation events, and, presumably, to improve neurologic outcomes.95 Nucleoside analogs and other types of viral polymerase inhibitors are also available for the treatment of CMV infection.96 Currently four antiviral therapies are U.S. Food and Drug Administration approved for the prophylaxis and/or therapy of systemic CMV infection. Experience with these agents is limited in pediatrics; however, anti-CMV therapy in general should be administered only after consultation with an expert familiar with dosage and side effects. Ganciclovir was the first compound licensed for treatment of CMV infections. It is a synthetic acyclic nucleotide structurally similar to guanine. Its structure is similar to that of acyclovir, and, like acyclovir, it requires phosphorylation for antiviral activity, by the viral UL97 gene, a protein kinase. Ganciclovir is indicated in immunocompromised children (HIV infection, transplant recipients, other immunocompromised states) when there is clinical and virologic evidence of specific end-organ disease (pneumonitis, enteritis, etc). In contrast to the relatively nontoxic acyclovir, ganciclovir is myelosuppressive, often a dose-limiting toxicity in immunocompromised patients. Ganciclovir is also commonly used as preemptive therapy in transplant patients at high risk of developing disease (for example, a CMV-seronegative recipient of an organ from a CMV-seropositive donor). There is relatively little information concerning the use of ganciclovir in the setting of congenital CMV infection. A trial sponsored by the Collaborative Antiviral Study Group demonstrated that ganciclovir therapy begun in the neonatal period in symptomatically infected infants with congenital CMV infection involving the CNS prevented hearing deterioration at 6

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months and that the benefits appeared to persist at or beyond 1 year of age.97 Almost two-thirds of treated infants have significant neutropenia noted during therapy. Based on this study, ganciclovir therapy should probably be offered to any infant with congenital CMV infection with any evidence of CNS involvement, including sensorineural hearing loss. Additional studies will be required to examine whether ganciclovir improves outcomes, in particular, long-term hearing outcomes, in asymptomatic congenitally infected infants. Recently, the valine ester of ganciclovir, valganciclovir, has been licensed. In contrast to oral ganciclovir, oral valganciclovir has a substantially improved bioavailability. There is clinical experience with valganciclovir in treatment and prophylaxis against CMV infection and disease in oncology patients, but little pediatric experience. Ideally, the use of oral valganciclovir would obviate the need for prolonged central venous access for 6 weeks of parenteral ganciclovir in symptomatic congenitally infected infants. This strategy is currently under study by the Collaborative Antiviral Study Group. Alternatives to ganciclovir include forcarnet (trisodium phosphonoformate) and cidofovir (S)-1-(3-Hydroxy2-Phosphonylmethoxypropyl) Cytosine (HPMPC). Pediatric experience with these agents is limited. Although potentially useful in the setting of ganciclovir resistance, the toxicities of these antivirals are significant, and these agents should be used only in exceptional circumstances. Immunoglobulins have also been useful in the control of CMV disease. A CMV hyperimmunoglobulin (Cytogam®) has been shown to decrease the incidence of CMV disease when administered posttransplant to high-risk transplant recipients when administered alone or in combination with nucleoside antivirals. Immunoglobulin may also be administered therapeutically for CMV disease, in combination with ganciclovir. A recent uncontrolled study was conducted using high-titer CMV immune globulin therapy of pregnant women with primary CMV infections, and evidence by amniocentesis of fetal infection. Hightiter CMV immune globulin was safe and was associated with a statistically significantly reduced likelihood of CMV disease compared with a no-treatment group.98 These results, as well as results of follow-up studies of placental and fetal health, suggest that immune globulin therapy may be effective at limiting or even reversing CMV-induced injury in utero.

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Information is limited regarding therapy of other herpesvirus infections. HHV-6 infections in hematopoeitic stem cell transplantation (HSCT) patients appear to respond to foscarnet and/or cidofovir therapy, but antiviral treatment of HHV-6 is probably not warranted outside of this circumstance. The use of antiviral drugs for EBV IM in immunocompetent adolescents has not been recommended, although a recent study of valacyclovir in college students presenting in the first 7 days of illness suggested a therapeutic benefit. In this study, there were significant reductions in viral shedding conferred by valacyclovir compared with untreated controls, and at the end of the treatment period, the number of reported symptoms (P ⫽ 0.03) and the severity of illness (P ⫽ 0.049) were reduced among valacyclovir recipients as compared with controls. If these observations can be confirmed in placebo-controlled studies, nucleoside treatment may be an option for IM.99 There is very little information about the clinical utility of therapy for HHV-8 (KSHV) infection. No controlled trials of specific antiviral therapy have been conducted for KS, although treatment with either oral or intravenous ganciclovir was associated with a strongly reduced risk of KS in AIDS patients before the advent of highly active antiretroviral therapy, suggesting an antiviral effect of ganciclovir against HHV-8.100 This was further corroborated by a recent study that demonstrated that valganciclovir therapy was associated with significant reductions in KSHV/HHV8 shedding as measured by PCR.101 Although these are intriguing data, chemotherapy and radiation therapy remain the mainstays of therapy for most cases of KS, as well as other HHV-8-associated tumors.

Vaccines Despite decades of research, the only vaccine-preventable herpesvirus infection at this time is VZV. In 1995, a live, attenuated varicella vaccine was licensed in the USA for use among healthy children aged ⱖ12 months, adolescents, and adults.102 The varicella vaccine is derived from the Oka strain, a Japanese clinical isolate, which was attenuated by passage in semipermissive guinea pig embryo fibroblasts. At the time of initial licensure, the Advisory Committee on Immunization Practices (ACIP) recommended routine varicella vaccination of children aged 12 to 18 months, catch-up vaccination of susceptible children aged 19 months to 12 years, and vaccination of susceptible persons who have close contact with persons at high

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risk for serious complications. Although varicella vaccination significantly decreased the burden of VZV disease in the USA, it did not eliminate transmission in communities.103 Therefore, a two-dose vaccination strategy was recently adopted. The most recent updated ACIP recommendations, as of 2007, are as follows: (1) implementation of a routine two-dose varicella vaccination program for children, with the first dose administered at age 12 to 15 months and the second dose at age 4 to 6 years; (2) a second dose catch-up varicella vaccination for children, adolescents, and adults who previously had received one dose; (3) routine vaccination of all healthy persons aged ⬎13 years without evidence of immunity; (4) prenatal assessment and postpartum vaccination; (5) expanding the use of the varicella vaccine for HIV-infected children with age-specific CD4⫹ T-lymphocyte percentages of 15 to 24% and adolescents and adults with CD4⫹ T-lymphocyte counts ⬎200 cells/␮L; and (6) establishing middle school, high school, and college entry vaccination requirements.104 In addition to varicella vaccination, the live, attenuated Oka strain of VZV has also been employed in the generation of a recently licensed live virus vaccine against herpes zoster. This vaccine has been shown to reduce the incidence of herpes zoster by approximately 50% in a pivotal phase III study of 38,000 adults aged 60 and older who received the vaccine.105 The vaccine also reduced by 66.5% the number of cases of postherpetic neuralgia and reduced the severity and duration of pain and discomfort associated with shingles by 61.1%. This vaccine was approved for licensure in early 2006. It is recommended by ACIP that the vaccine be given to all adults age 60 and over, including those who have had a previous episode of shingles. Of note, the zoster vaccine has significantly increased potency compared with varicella vaccine. Each 0.65 mL dose of zoster vaccine contains a minimum of 19,400 PFU (4.29 log10) of Oka/Merck strain of VZV; its minimum potency is at least 14 times the potency of VARIVAX®, which contains a minimum of 1350 (approximately 3.13 log10) PFU. Zoster vaccine, because of its increased potency, cannot be considered to be a substitute for varicella vaccine. Vaccines for other members of the herpesvirus family have lagged behind those for VZV infection. A doubleblind, randomized trial of a herpes simplex virus type 2 (HSV-2) glycoprotein-D-subunit vaccine, adjuvanted with alum and 3-O-deacylated-monophosphoryl lipid A, was conducted in a cadre of individuals whose regular sexual partners had a history of genital herpes.106 The

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primary endpoint was the occurrence of genital herpes disease. The vaccine was found to be efficacious in women who were seronegative for both HSV-1 and HSV-2 antibodies; however, it was not efficacious in women who were seropositive for HSV-1 and seronegative for HSV-2 at baseline. The vaccine had no efficacy in men irrespective of serostatus. If these results are replicated in subsequent studies, licensure of a genital HSV-2 vaccine therefore might be limited to women. Similarly, EBV vaccines are still in the investigational stage. Most attention has been focused on subunit vaccination against the major gp350/220 glycoprotein complex on the EBV envelope. In one study of 181 EBVseronegative healthy adult volunteers using a subunit vaccine based on this protein, immunization had demonstrable efficacy in preventing the development of IM induced by EBV infection, but no efficacy in preventing asymptomatic EBV infection.107 Given the significant impact of IM on the health and functioning of adolescents, further studies of this vaccine seem warranted. EBV vaccination is also being studied to help prevent PTLD in susceptible transplant recipients. The potential impact of the 350/220 vaccine on EBV-associated malignancies such as Burkitt lymphoma and nasopharyngeal carcinoma (NPC) is highly speculative at this time, but intriguing to contemplate. Of all the vaccines for herpesviruses, the most sorely needed is a vaccine against CMV infection. The Institute of Medicine characterized a vaccine capable of preventing the sequelae of congenital CMV as the single highest priority vaccine for clinical development.108 A number of vaccine strategies have been developed and are currently in clinical trials. The successful prevention of congenital CMV infection and disease in animal models of congenital CMV infection provides support for the continued testing of vaccines for this important public health issue. Although several vaccine candidates are in clinical trials, none are close to licensure at this time. No vaccines for HHV-6 or HHV-7 have yet been designed; given the ubiquitous and generally benign nature of these infections, it is unclear how enthusiastically such vaccines might be incorporated into clinical practice. Similarly, no KSHV/HHV8 vaccines have been designed or known to be in research and development; additional fundamental knowledge will be required about the biology of this virus, the epidemiology and spectrum of disease observed in immunocompetent individuals, and the factors that led to the development

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of malignancy, before a rational vaccination-based approach to disease prevention could be considered.

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