Parenteral therapy of viral infections of the newborn and infant became a reality with the introduction of vidarabine (adenine arabinoside) for the treatment of neonatal herpes simplex virus (HSV) infections in the early 1980s. Since then, acyclovir has become the treatment of choice for neonatal HSV infections, as well as a number of other herpesvirus infections. Similarly, ganciclovir has been established as beneficial for the treatment of congenital cytomegalovirus (CMV) infections that involve the central nervous system (CNS). Although other viruses can infect the newborn, including rubella and parvovirus, this chapter will review the lessons learned from treating neonatal and congenital infections and will consider therapies for respiratory virus infections of infants. Although the natural history of these diseases is reviewed elsewhere in this textbook, a brief summary will precede a detailed discussion of established and alternative therapeutics. The reader is referred to more extensive reviews of antiviral therapy in children and adults (1).

Neonatal HSV infections occur in approximately 1 in 3,200 deliveries in the USA (2) and of these, approximately two-thirds develop some form of CNS disease (3). The majority of cases are caused by HSV-2 (4). The risk of transmission is increased with primary maternal infection during the third trimester and can be decreased by cesarean delivery if HSV has been isolated from the cervix or external genitalia near the time of delivery (2). As reviewed by Kimberlin, 85% of neonatal HSV cases occur due to peripartum transmission, 10% occur via postnatal transmission, and only 5% are due to transmission in utero (5).

Infants with intrauterine HSV infection are characterized by the triad of cutaneous (active lesions, scarring), neurologic (microcephaly, hydranencephaly), and eye findings (chorioretinitis, microphthalmia) present at birth. Intrauterine HSV infection has been found to occur with both primary and recurrent maternal HSV infections (6), although the risk from a recurrent infection is less.

HSV infection acquired in the peripartum or postpartum period can be categorized as skin, eye, and/or mouth (SEM) disease, CNS disease, or disseminated disease. By definition, SEM disease does not involve the CNS. Disseminated disease may involve the CNS along with multiple other organ systems including the liver, adrenals, gastrointestinal tract, and the skin, eyes, or mouth. CNS disease may have skin involvement but does not involve other visceral systems. Of all infants with neonatal HSV infections, approximately 33% have CNS disease, while about 25% have disseminated disease (7). Of infants with disseminated disease, approximately 60% to 75% will have CNS involvement (8). Therefore, by combining these statistics, it can be approximated that 50% of infants with neonatal HSV infection will have CNS involvement.

The pathogenesis of CNS involvement in neonatal HSV infections differs depending on whether or not the infection is disseminated. Encephalitis associated with dissemination is due to hematogenous spread, whereas isolated encephalitis or encephalitis associated with only skin involvement likely occurs because of retrograde intraneuronal transport of HSV (3). This corresponds to the clinical presentations of disseminated versus CNS disease in that the blood-borne spread of disseminated disease presents earlier (9 to 11 days of life on average) and causes more diffuse brain involvement with multiple areas of hemorrhagic necrosis, while CNS disease occurring via slower axonal transport presents later (around 16 to 17 days of life) and typically causes more focal CNS involvement (9).

In the pre-antiviral era, infants with neonatal HSV
infections had significant morbidity and mortality. Infants with disseminated disease had an 85% mortality by 1 year of age, and only 50% of survivors had normal neurodevelopmental outcomes; likewise, infants with CNS disease had a mortality rate of 50% by 1 year of age with only 33% of survivors having normal neurodevelopmental outcomes (10). The early era of antiviral therapy for neonatal HSV infection was marked by improved mortality with intravenous vidarabine as well as with standard dose (SD) intravenous acyclovir (30 mg per kg per day in three divided doses). The 1 year mortality for disseminated disease improved to 50% with vidarabine and 61% with SD acyclovir, whereas the 1 year mortality for CNS disease dropped to 14% for both vidarabine and SD acyclovir (11). More recently, high-dose (HD) acyclovir has been shown to further improve upon these mortality figures. Using HD intravenous acyclovir (60 mg per kg per day in three divided doses for 21 days), Kimberlin demonstrated 1 year mortality rates of 29% and 4% for disseminated and CNS diseases, respectively (12). This study also showed that HD acyclovir improves morbidity for infants with disseminated disease (83% of survivors had normal neurodevelopmental outcomes) but not for infants with CNS disease (31% of survivors had normal neurodevelopmental outcomes).

Babies with SEM involvement have the best prognosis and, as noted below, require only 14 days of HD intravenous acyclovir therapy. Importantly, health care providers must exclude an asymptomatic or subclinical CNS infection at presentation by determining whether the cerebrospinal fluid (CSF) is negative for HSV DNA by polymerase chain reaction. With skin recurrences, the management (intravenous vs. oral therapy) of these children must be individualized according to the nature of their illness at the time of recurrence.

Infants can also experience primary gingivostomatitis secondary to HSV-1. Limited controlled clinical trial data are available to define efficacy of therapy, but most experts would recommend treatment, either intravenous or oral, depending upon the severity of illness.

Women who experience primary varicella zoster virus (VZV) infections within 48 hours of delivery have children at risk for the development of chickenpox within the first 3 weeks of life. Newborns delivered to these women traditionally receive zoster immune globulin (ZIG) to prevent disease. However, with sporadic shortages of ZIG, some newborns may experience neonatal disease. Although no controlled clinical trials have evaluated acyclovir therapy of this disease, experts would recommend this drug for the treatment of neonatal VZV disease.

CMV commonly infects humans worldwide, with a seroprevalence of approximately 40% in adolescents and approaching 90% in adults with poor socioeconomic status (28,29). Congenital CMV infection is the most common congenital infection in the developed world and occurs in about 1% of liveborn infants in the United States (30). Congenital CMV infections most commonly occur via intrauterine transmission, but since the virus is shed in body fluids, transmission can also be acquired perinatally during delivery or postnatally through breast milk.

Of all infants born with congenital CMV infection, approximately 7% to 10% have clinically evident disease at birth (31). Clinical characteristics of intrauterine infection include intrauterine growth restriction, hepatosplenomegaly, jaundice, thrombocytopenia, microcephaly, periventricular calcifications, and chorioretinitis. As reviewed by Dollard, true mortality rates are difficult to obtain and have been reported to be as high as 30% for symptomatic infants (32), but more likely average about 5% to 10% (33). Death usually is due to non-CNS manifestations of the infection, such as hepatic dysfunction or bleeding. An estimated 40% to 58% of infants with symptomatic congenital CMV infection have permanent sequelae, whereas infants who are asymptomatic at birth suffer permanent sequelae nearly 14% of the time (32). Sensorineural hearing loss (SNHL), mental retardation, seizures, psychomotor and speech delays, learning disabilities, chorioretinitis, optic nerve atrophy, and defects in dentition are the most common long-term consequences (34). As opposed to intrauterine infections, perinatally acquired CMV infections are not typically associated with long-term sequelae, though acute illness has been reported in premature very low-birth-weight infants (35). In full-term infants, perinatal infections are commonly asymptomatic, but may present with pneumonitis within the first few months of life (36).

Congenital CMV infection is the consequence of maternal-fetal infection, with most symptomatic congenital cases occurring because of asymptomatic maternal infection. The pathogenesis of CNS involvement in congenital CMV infection begins with disseminated viremic spread, including the endothelial cells of the brain and epithelial cells of the choroid plexus. From the endothelial cells of the brain, the virus spreads to contiguous astrocytes. From the choroid plexus, the virus spreads to the ependymal surfaces via the CSF. Once these cells are infected, the virus undergoes continuous replication, which leads to characteristic intranuclear inclusion bodies and cell death. As antibodies are produced in the face of continuous viral replication, immune complexes form as well, leading to further immune-mediated damage (34). Although the specific pathogenesis of CMV-mediated SNHL has not been elucidated, histology has shown evidence of infection in the cells of both the cochlear and vestibular endolabyrinth (37). CMV has also been isolated from the cochlear perilymph upon autopsy of infants with congenital CMV infection (38).

Recent studies of ganciclovir treatment of congenital CMV infections involving the CNS have been promising. Using ganciclovir at doses of 12 mg per kg per day divided every 12 hours for a duration of 6 weeks, improved hearing outcomes were demonstrated in neonates with symptomatic congenital CMV infections involving the CNS (as evidenced by microcephaly, intracranial calcifications, abnormal CSF for age, chorioretinitis, and/or hearing deficits) (39). The primary endpoint was improved brainstem-evoked response (BSER) between baseline and 6-month follow-up (or no deterioration at the 6-month follow-up if the baseline BSER was normal). For total evaluable ears, 69% of patients who received ganciclovir met the primary endpoint as opposed to 39% of the control group. No patients receiving ganciclovir had worsening of their hearing between baseline and 6 months. Ganciclovir recipients also had more rapid resolution of alanine aminotransferase (ALT) abnormalities than did the control group, though they were significantly more likely to become neutropenic. Additional analyses of this randomized controlled trail suggest that ganciclovir may also reduce neurodevelopment delays (40). Improvement of mortality has not yet been shown with ganciclovir therapy.