Over the past 2 decades, therapies have been recommended by the American Academy of Pediatrics Red Book Committee for the management of neonatal herpes simplex virus (HSV) and congenital cytomegalovirus (CMV) infections. Of the 2 infections, neonatal HSV infection should be more amenable to treatment because it is usually acquired by intrapartum contact with infected maternal secretions. Thus, it is acute in nature and frequently presents with the telltale sign of disease, namely, a vesicular rash, although this may fail to develop in many infants. In contrast, congenital CMV infection is one which is chronic in nature and, therefore, much less likely to be amenable to successful treatment. The differences between these infections are summarized in Table 1.
This review will explore the pathogenesis and treatment of both infections, emphasizing the strengths and limitations of current knowledge and therapy.
CONGENITAL CYTOMEGALOVIRUS INFECTION
CMV infections, ubiquitous in humans, are an important cause of congenital infection and a leading cause of sensorineural hearing loss (SNHL) worldwide.1–3 The prevalence of maternal CMV infection is an important determinant of vertical CMV transmission. Congenital CMV infection rates are directly proportional to maternal seroprevalence in that highly CMV-seropositive populations have higher rates of congenital infection.4–6 Unlike rubella and toxoplasmosis where intrauterine transmission occurs as a result of maternal infection acquired during pregnancy (primary infection), congenital CMV infection can occur in infants born to mothers who have had CMV infection before pregnancy (nonprimary infection).7–12 In fact, congenital CMV infection following a nonprimary maternal infection accounts for two-thirds to three-quarters of all congenital CMV infections in highly seroimmune populations.5–9,13–15 This finding indicates the difficulty that will be encountered in vaccine development as congenital infection occurs in the presence of both humoral and cell-mediated immune responses. Young maternal age and non-Hispanic black race have been associated with an increased risk of congenital CMV infection.3,16–21 The argument that maternal immunity to CMV limits intrauterine transmission is supported by the finding that the rate of intrauterine infection in women with preexisting CMV immunity (nonprimary maternal infection) is about 1%–1.5%, which is about 20–30-fold less than in women with primary CMV infection during pregnancy.1,5,22–24 However, the number of women experiencing primary CMV infections during pregnancy is considerably smaller than those with nonprimary infections, especially in highly seropositive populations, as noted above. Thus, in populations with near-universal seroimmunity, most infants with congenital CMV infection are born to women with nonprimary infection.5,14,25,26
Transmission to the developing fetus is believed to occur through hematogenous spread of infectious virus to fetal blood at the placental interface lying between maternal and fetal blood supplies. Virus presumably infects the fetal liver, and after amplification in the liver, or alternatively, during primary viremia, disseminates into the fetal circulation. However, the characteristics and mechanisms of virus infection within specific fetal organs, particularly the fetal brain, are unknown.
Recent findings have demonstrated that multiple viral genotypes are likely present within a single infection, suggesting that it is unlikely that specific viral genotypes of CMV account for phenotypic variations that follow fetal infection.27,28 Developing an understanding of the parameters for dissemination of virus to organs in the fetus, particularly the CNS, is critical for both understanding the pathogenesis of the fetal infection, and, perhaps more importantly, for the rational design of prophylactic vaccines and potentially other interventions such as targeted biologics/therapeutics.
Congenital CMV infection is a leading cause of childhood permanent hearing loss and neurodevelopmental disabilities.1,2,29 Congenital CMV-associated SNHL accounts for about 25% of all SNHL in children.30 The number of children with congenital CMV-related disabilities is similar to or exceeds the number of children with better-known conditions such as Down syndrome or spina bifida.31 Approximately 85%–90% of the 20,000 to 30,000 children born with congenital CMV infection each year in the United States do not exhibit any clinical abnormalities at birth (asymptomatic congenital CMV infection).8,10,32 The remaining 10%–15% born with clinical abnormalities are categorized as having clinically apparent or symptomatic congenital infection. The infection may involve multiple organ systems with particular predilection for the reticuloendothelial and central nervous system (CNS).33 The most commonly observed clinical findings are petechial rash, jaundice, hepatomegaly, splenomegaly and microcephaly. Ophthalmologic examination is abnormal in approximately 10% of infants with symptomatic congenital CMV infection, with chorioretinitis and/or optic atrophy most commonly observed.34–36 Laboratory abnormalities in children with symptomatic infection reflect the involvement of the hepatobiliary and reticuloendothelial systems and include conjugated hyperbilirubinemia, thrombocytopenia and elevations of hepatic transaminases in over half of symptomatic newborns.34–36 Neuroimaging is abnormal in approximately 50%–70% of children with symptomatic infection at birth and intracerebral calcifications are the most common abnormality.37,38 Although a number of nonspecific neuroimaging findings have been reported in infants with congenital CMV, including ventricular dilatation, cysts and lenticulostriate vasculopathy, the significance of these findings is not clear.
Approximately half of the infants with symptomatic infection will develop sequelae including SNHL and cognitive and motor deficits.10,32,34–36,39–43 Predictors of adverse neurologic outcome in children with symptomatic congenital CMV infection include microcephaly, the presence of other neurologic abnormalities at birth or in early infancy, neuroimaging abnormalities detected within the first month of life, and the presence of multiple clinical findings.32,35,37,43–48 Approximately 7%–15% of asymptomatic children will develop SNHL. Among those with hearing loss, one-half of the children with asymptomatic infection will have bilateral deficits which can vary from mild high-frequency loss to profound impairment.10,42,49–52 In addition, hearing loss in these children is often progressive and/or late in onset, requiring ongoing monitoring.42,49,51,52 Other neurologic complications may also occur with asymptomatic congenital CMV infection, and while the data are sparse, occur at a much lower frequency than in symptomatic infection.52 All of these findings indicate the chronicity of congenital CMV infection.
Because of the significant morbidity associated with congenital CMV infection, it has become an important target for antiviral therapy. Against this backdrop, first, ganciclovir and, then, valganciclovir have been evaluated for the treatment of babies with symptomatic disease.
The initial studies of ganciclovir were performed in babies who had symptomatic congenital CMV infection. Intravenous ganciclovir was administered either at a dosage of 8 or 12 mg/kg once per day for 6 weeks in a Phase IB study. The purpose of this study was to determine whether there was any impact whatsoever on clearance of virus from the urine and any preliminary responses to improved hearing. By 6 weeks after the onset of therapy, the majority of babies who received 12 mg/kg/day had a significant decrease in viral load in urine and a statistically greater reduction than that observed in those who received 8 mg/kg/day.53 At the initiation of therapy, virus load was approximately 5 logs. At the high dose, most babies had a reduction to less than one log of virus in the urine but still detectable after 6 weeks. Within a month of completion of therapy, excretion virus returned in the urine to approximately 3 logs. Thus, total elimination was not achieved.
The dose of 12 mg/kg/day was selected for a controlled Phase II investigation that compared treatment with no treatment. A placebo was not employed, as an indwelling catheter would be required for 6 weeks, making it unethical. In addition to viral clearance, other endpoints included an improved brainstem-evoked response by one gradation, or maintenance of normal hearing between baseline and 6-month follow-up. This endpoint included (1) a biologic assessment that evaluated both ears and (2) a functional assessment of only the best ear. Secondary endpoints included laboratory improvement abnormalities 2 weeks after the onset of therapy, and clinical improvement, particularly weight gain and improvement in head growth. This study provided many important lessons. First, regarding the primary endpoint, ganciclovir recipients had a 79% stabilization in hearing, or ultimately, improvement. In the counterpart no-treatment group, only 32% achieved this same endpoint. The decibel difference respectively between the 2 groups was 25 and greater than 30. These changes in hearing were maintained for greater than 1 year.54 Importantly, the data indicated that a chronic infection was amenable to therapy.
However, these therapeutic benefits were not without evidence of toxicity. Of those babies entered into this study, 48% required adjustment in their treatment dosage because of hematopoietic toxicity. Seven had medication stopped and restarted. Four had medication permanently stopped, and 3 had the dosage of medication decreased. Further, the necessity of maintaining a peripheral intravenous catheter for 6 weeks was problematic in the treatment group because of the development of secondary line infections.
As a consequence, and with the availability of oral valganciclovir, a new series of studies were instituted. Following a pharmacodynamic study,55 a controlled clinical trial of 6 weeks versus 6 months of therapy was done. This study proved that 6 months of valganciclovir therapy was superior to 6 weeks of treatment. The change in hearing between birth and 12 months was no different between the 2 treatment groups as 57% and 73%, respectively, and had improved hearing or hearing that remained normal. However, between birth and 24 months, there was significant evidence of improvement in the 6-month treatment group as 77% of babies demonstrated improved or normal hearing as compared with only 64% of the counterpart 6-week treatment group (95% CI: 2.66 (1.02–6.91); P = 0.04). An important endpoint for these studies was assessment of participants using Bayley III Developmental Scales. Adjusting for multiple analyses, those factors which benefitted significantly following 6 months of therapy were cognitive, language, expressive and motor function. Importantly, significant hematologic toxicity was not encountered with valganciclovir treatment, likely attributable to the differences in peak plasma concentrations when compared with intravenous therapy.
These data have become the basis for the recommendation by the American Academy of Pediatrics Red Book for 6 months of oral valganciclovir therapy.56
At present, therapy is reserved for those babies with symptomatic disease; however, those asymptomatically infected are at risk for hearing loss, as noted above. Currently, a clinical trial is assessing the potential value of therapy in this population. Obviously, if proven efficacious, a universal screening program for congenital CMV infection would need to be instituted, as now occurs in many states in the US.
NEONATAL HERPES SIMPLEX VIRUS INFECTION
Approximately 85% of all cases of neonatal HSV infection are acquired by intrapartum contact of the fetus with infected maternal genital secretions. An additional 10% are acquired postnatally as a consequence of direct contact with an infected individual, and 5% result from in utero transmission resulting in congenital disease that is manifest at the time of birth. The overall incidence of neonatal HSV infection is estimated to be approximately 1 in 1500 live births in the United States.57–59 The risk of transmission to the fetus is greatest for women who experience a primary infection during the third trimester of gestation, resulting in an estimated 25%–60% incidence of transmission to newborns. Importantly, maternal primary infection is usually asymptomatic.60–62
Children with congenital HSV infection, albeit it rare, present with combinations of microcephaly, retinitis, microphthalmia, skin scarring and limb abnormalities. Babies with congenital HSV infection have a uniformly poor outcome with mortality in the first month of life in excess of 60%.63
With the exception of congenital HSV infection, children who acquire neonatal herpes present between day 7 and 21 days of life, depending upon clinical manifestations. Children with disease caused by HSV infection present in 1 of the 3 fashions. Disease can be localized to the skin, eye and mouth, occurring in approximately 45% of newborns. These babies present at 7–11 days of life on average. Children with encephalitis, accounting for approximately 35% of newborns, present on average at 2 weeks of life. These children may or may not have skin, eye or mouth involvement as well. Finally, children with multiorgan disseminated disease account for 25% of cases, presenting at approximately 7–11 days of life.63,64
Prognosis with therapy varies according to disease classification. For those children with multiorgan disseminated disease, the mortality is approximately 30%. Approximately, 3 of the 4 of these children will have CNS disease as well, with attendant complications. Those children with encephalitis, but without multiorgan involvement, have a lower mortality of 3%–5%, but the risk for significant neurologic impairment is high. These children can have impaired intellectual potential, seizure disorders, spasticity and not infrequently, microcephaly. Notably, children with CNS disease caused by HSV-2 have a poorer outcome than those babies with HSV-1 infection for unknown reasons.65 Finally, children with disease localized to the skin, eye and mouth have the best prognosis. In the absence of asymptomatic CNS involvement, these children virtually all develop normally but will have recurrent lesions.66,67
Because of the recurrences of CNS disease, the effect of long-term administration of acyclovir was evaluated in a placebo-controlled study. Suppressive acyclovir therapy, when administered for 6 months in babies who had encephalitis, resulted in an improved neurologic outcome, implying that HSV can replicate subclinically in CNS. Findings from a placebo-controlled study indicate that the Bayley Developmental assessment was significantly better in the treated group as compared with placebo recipients.68 Acyclovir recipients had a median Bailey Score of 90.5 versus the placebo recipients of 66.5 (P = 0.46). This parallels normal development in 69% and 33% of babies, respectively. Six months of suppressive therapy following intravenous treatment is the latest American Academy of Pediatrics recommendation56 and is currently the standard of care globally.
There are significant differences in the pathogenesis of congenital CMV and HSV infections of the newborn. While it would seem logical that neonatal HSV infections would be both more amenable to therapy and associated with a better outcome, severe disease, including both morbidity and mortality, are still significant, in spite of efficacious antiviral therapy. Similarly, with congenital CMV infection, because of the chronicity of the disease, successful antiviral therapy would seem highly improbable. Nevertheless, improvement in hearing is a remarkable accomplishment for children with this infection. Equally importantly, the availability of an oral therapeutic to improve outcome is of major importance.
Thus, all cases of neonatal HSV infection require therapy. At present time, only those children with symptomatic and congenital CMV infection should be treated as no data exist on the potential efficacy of valganciclovir in the treatment of asymptomatic disease. Such data will be forthcoming in the next several years.
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