Congenital Cytomegalovirus and Neonatal Herpes Simplex Virus Infections: to Treat Or Not to Treat?

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Congenital Cytomegalovirus and Neonatal Herpes Simplex Virus Infections: To Treat or Not to Treat?

Richard J. Whitley, MD

born to mothers who have had CMV infection before pregnancy ABSTRACT: Congenital cytomegalovirus infections are among the most (nonprimary infection).7–12 In fact, congenital CMV infection fol- common of the newborn in the developed world. These infections are the lowing a nonprimary maternal infection accounts for two-thirds to most common cause of sensorineural hearing loss. Studies utilizing ganci- three-quarters of all congenital CMV infections in highly seroim- clovir and valganciclovir demonstrate improved hearing and Bailey Devel- mune populations.5–9,13–15 This finding indicates the difficulty that opmental scores. Because of the ease of administration, valganciclovir is the will be encountered in vaccine development as congenital infection recommended treatment of choice for 6 months. Therapy should be reserved occurs in the presence of both humoral and cell-mediated immune for those babies with symptomatic disease; no data are available regarding responses. Young maternal age and non-Hispanic black race have the impact of treatment on those babies with asymptomatic disease. been associated with an increased risk of congenital CMV infec- Keywords: congenital cytomegalovirus, neonatal herpes simplex infection, tion.3,16–21 The argument that maternal immunity to CMV limits CMV, HSV, acyclovir, ganciclovir, valganciclovir, antiviral therapy intrauterine transmission is supported by the finding that the rate of intrauterine infection in women with preexisting CMV immu- (Pediatr Infect Dis J 2019;38:S60–S63) nity (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 experi- encing primary CMV infections during pregnancy is considerably ver the past 2 decades, therapies have been recommended by smaller than those with nonprimary infections, especially in highly the American Academy of Pediatrics Red Book Committee O seropositive populations, as noted above. Thus, in populations with for the management of neonatal herpes simplex virus (HSV) and near-universal seroimmunity, most infants with congenital CMV congenital cytomegalovirus (CMV) infections. Of the 2 infections, infection are born to women with nonprimary infection.5,14,25,26 neonatal HSV infection should be more amenable to treatment Transmission to the developing fetus is believed to occur because it is usually acquired by intrapartum contact with infected through hematogenous spread of infectious virus to fetal blood at maternal secretions. Thus, it is acute in nature and frequently pre- the placental interface lying between maternal and fetal blood sup- sents with the telltale sign of disease, namely, a vesicular rash, plies. Virus presumably infects the fetal liver, and after amplifica- although this may fail to develop in many infants. In contrast, con- tion in the liver, or alternatively, during primary viremia, dissemi- genital CMV infection is one which is chronic in nature and, there- nates into the fetal circulation. However, the characteristics and fore, much less likely to be amenable to successful treatment. The mechanisms of virus infection within specific fetal organs, particu- differences between these infections are summarized in Table 1. larly the fetal brain, are unknown. This review will explore the pathogenesis and treatment of Recent findings have demonstrated that multiple viral geno- both infections, emphasizing the strengths and limitations of cur- types are likely present within a single infection, suggesting that it rent knowledge and therapy. is unlikely that specific viral genotypes of CMV account for pheno- typic variations that follow fetal infection.27,28 Developing an under- CONGENITAL CYTOMEGALOVIRUS INFECTION standing of the parameters for dissemination of virus to organs in CMV infections, ubiquitous in humans, are an important the fetus, particularly the CNS, is critical for both understanding cause of congenital infection and a leading cause of sensorineu- the pathogenesis of the fetal infection, and, perhaps more impor- ral hearing loss (SNHL) worldwide.1–3 The prevalence of mater- tantly, for the rational design of prophylactic vaccines and poten- nal CMV infection is an important determinant of vertical CMV tially other interventions such as targeted biologics/therapeutics. Congenital CMV infection is a leading cause of childhood transmission. Congenital CMV infection rates are directly propor- 1,2,29 tional to maternal seroprevalence in that highly CMV-seropositive permanent hearing loss and neurodevelopmental disabilities. 4–6 Congenital CMV-associated SNHL accounts for about 25% of all populations have higher rates of congenital infection. Unlike 30 rubella and toxoplasmosis where intrauterine transmission occurs SNHL in children. The number of children with congenital CMV- related disabilities is similar to or exceeds the number of children as a result of maternal infection acquired during pregnancy (pri- with better-known conditions such as Down syndrome or spina mary infection), congenital CMV infection can occur in infants bifida.31 Approximately 85%–90% of the 20,000 to 30,000 children born with congenital CMV infection each year in the United Accepted for publication March 1, 2019. States do not exhibit any clinical abnormalities at birth (asymp- From Distinguished Professor of Pediatrics, Loeb Eminent Scholar Chair in 8,10,32 Pediatrics, Professor of Microbiology, Medicine and Neurosurgery, The Uni- tomatic congenital CMV infection). The remaining 10%–15% versity of Alabama at Birmingham, Birmingham, Alabama born with clinical abnormalities are categorized as having clini- Address for correspondence: Richard J. Whitley, MD, Distinguished Professor of cally apparent or symptomatic congenital infection. The infection Pediatrics, Loeb Eminent Scholar Chair in Pediatrics, Professor of Microbi- may involve multiple organ systems with particular predilection ology, Medicine and Neurosurgery, The University of Alabama at Birming- 33 ham, CHB 3031600 7th Avenue, SouthBirmingham, AL. E-mail: rwhitley@ for the reticuloendothelial and central nervous system (CNS). peds.uab.edu. The most commonly observed clinical findings are petechial rash, Supported by NIH NIAID Grant #N01-AI-30025. The authors have no funding jaundice, hepatomegaly, splenomegaly and microcephaly. Ophthal- or conflicts of interest to disclose. mologic examination is abnormal in approximately 10% of infants Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/19/3806-0S60 with symptomatic congenital CMV infection, with chorioretinitis DOI: 10.1097/INF.0000000000002325 and/or optic atrophy most commonly observed.34–36 Laboratory XXX S60 | www.pidj.com The Pediatric Infectious Disease Journal • Volume 38, Number 6S, June 2019

Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. The Pediatric Infectious Disease Journal • Volume 38, Number 6S, June 2019 Cytomegalovirus and Neonatal Herpes Simplex Virus

therapy, excretion virus returned in the urine to approximately 3 TABLE 1. Therapeutic Opportunities: HSV vs. CMV logs. Thus, total elimination was not achieved. Infections of the Newborn The dose of 12 mg/kg/day was selected for a controlled Phase II investigation that compared treatment with no treatment. A pla- Herpes Simplex Virus Cytomegalovirus cebo was not employed, as an indwelling catheter would be required Acquired during delivery Acquired early in gestation for 6 weeks, making it unethical. In addition to viral clearance, Usually occurs with maternal Occurs with maternal primary other endpoints included an improved brainstem-evoked response primary infection being or with non-primary infection by one gradation, or maintenance of normal hearing between base- transmitted at delivery (85%) line and 6-month follow-up. This endpoint included (1) a biologic Relatively short incubation Infection progresses over months assessment that evaluated both ears and (2) a functional assess- period in utero ment of only the best ear. Secondary endpoints included laboratory Disease of the newborn is Disease can be asymptomatic improvement abnormalities 2 weeks after the onset of therapy, and usually clinically obvious clinical improvement, particularly weight gain and improvement in Should be amenable to Should be less amenable to treatment therapy than HSV head growth. This study provided many important lessons. First, Treat For the most part, treat 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. abnormalities in children with symptomatic infection reflect the The decibel difference respectively between the 2 groups was 25 involvement of the hepatobiliary and reticuloendothelial systems and greater than 30. These changes in hearing were maintained for and include conjugated hyperbilirubinemia, thrombocytopenia and greater than 1 year.54 Importantly, the data indicated that a chronic elevations of hepatic transaminases in over half of symptomatic infection was amenable to therapy. newborns.34–36 Neuroimaging is abnormal in approximately 50%– However, these therapeutic benefits were not without evi- 70% of children with symptomatic infection at birth and intracer- dence of toxicity. Of those babies entered into this study, 48% ebral calcifications are the most common abnormality.37,38 Although required adjustment in their treatment dosage because of hemat- a number of nonspecific neuroimaging findings have been reported opoietic toxicity. Seven had medication stopped and restarted. in infants with congenital CMV, including ventricular dilatation, Four had medication permanently stopped, and 3 had the dosage cysts and lenticulostriate vasculopathy, the significance of these of medication decreased. Further, the necessity of maintaining a findings is not clear. peripheral intravenous catheter for 6 weeks was problematic in Approximately half of the infants with symptomatic infec- the treatment group because of the development of secondary line tion will develop sequelae including SNHL and cognitive and infections. motor deficits.10,32,34–36,39–43 Predictors of adverse neurologic out- As a consequence, and with the availability of oral valgan- come in children with symptomatic congenital CMV infection ciclovir, a new series of studies were instituted. Following a phar- include microcephaly, the presence of other neurologic abnor- macodynamic study,55 a controlled clinical trial of 6 weeks versus malities at birth or in early infancy, neuroimaging abnormalities 6 months of therapy was done. This study proved that 6 months of detected within the first month of life, and the presence of multi- valganciclovir therapy was superior to 6 weeks of treatment. The ple clinical findings.32,35,37,43–48 Approximately 7%–15% of asymp- change in hearing between birth and 12 months was no different tomatic children will develop SNHL. Among those with hearing between the 2 treatment groups as 57% and 73%, respectively, loss, one-half of the children with asymptomatic infection will have and had improved hearing or hearing that remained normal. How- bilateral deficits which can vary from mild high-frequency loss to ever, between birth and 24 months, there was significant evidence profound impairment.10,42,49–52 In addition, hearing loss in these chil- of improvement in the 6-month treatment group as 77% of babies dren is often progressive and/or late in onset, requiring ongoing demonstrated improved or normal hearing as compared with only monitoring.42,49,51,52 Other neurologic complications may also occur 64% of the counterpart 6-week treatment group (95% CI: 2.66 with asymptomatic congenital CMV infection, and while the data (1.02–6.91); P = 0.04). An important endpoint for these studies was are sparse, occur at a much lower frequency than in symptomatic assessment of participants using Bayley III Developmental Scales. infection.52 All of these findings indicate the chronicity of congeni- Adjusting for multiple analyses, those factors which benefitted sig- tal CMV infection. nificantly following 6 months of therapy were cognitive, language, Because of the significant morbidity associated with con- expressive and motor function. Importantly, significant hemato- genital CMV infection, it has become an important target for anti- logic toxicity was not encountered with valganciclovir treatment, viral therapy. Against this backdrop, first, ganciclovir and, then, likely attributable to the differences in peak plasma concentrations valganciclovir have been evaluated for the treatment of babies with when compared with intravenous therapy. symptomatic disease. These data have become the basis for the recommendation by the American Academy of Pediatrics Red Book for 6 months of The initial studies of ganciclovir were performed in babies 56 who had symptomatic congenital CMV infection. Intravenous gan- oral valganciclovir therapy. ciclovir was administered either at a dosage of 8 or 12 mg/kg once At present, therapy is reserved for those babies with sympto- per day for 6 weeks in a Phase IB study. The purpose of this study matic disease; however, those asymptomatically infected are at risk was to determine whether there was any impact whatsoever on for hearing loss, as noted above. Currently, a clinical trial is assess- ing the potential value of therapy in this population. Obviously, if clearance of virus from the urine and any preliminary responses to proven efficacious, a universal screening program for congenital improved hearing. By 6 weeks after the onset of therapy, the major- CMV infection would need to be instituted, as now occurs in many ity of babies who received 12 mg/kg/day had a significant decrease states in the US. 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, NEONATAL HERPES SIMPLEX VIRUS INFECTION most babies had a reduction to less than one log of virus in the urine Approximately 85% of all cases of neonatal HSV infec- but still detectable after 6 weeks. Within a month of completion of tion are acquired by intrapartum contact of the fetus with infected

maternal genital secretions. An additional 10% are acquired postna- disease, successful antiviral therapy would seem highly improba- tally as a consequence of direct contact with an infected individual, ble. Nevertheless, improvement in hearing is a remarkable accom- and 5% result from in utero transmission resulting in congenital plishment for children with this infection. Equally importantly, disease that is manifest at the time of birth. The overall incidence the availability of an oral therapeutic to improve outcome is of of neonatal HSV infection is estimated to be approximately 1 in major importance. 1500 live births in the United States.57–59 The risk of transmission Thus, all cases of neonatal HSV infection require therapy. At to the fetus is greatest for women who experience a primary infec- present time, only those children with symptomatic and congenital tion during the third trimester of gestation, resulting in an estimated CMV infection should be treated as no data exist on the potential 25%–60% incidence of transmission to newborns. Importantly, efficacy of valganciclovir in the treatment of asymptomatic disease. maternal primary infection is usually asymptomatic.60–62 Such data will be forthcoming in the next several years. Children with congenital HSV infection, albeit it rare, present with combinations of microcephaly, retinitis, microphthalmia, REFERENCES skin scarring and limb abnormalities. Babies with congenital HSV 1. Britt W. Cytomegalovirus. In: Remington J, Klein J, Wilson C, eds, et al. infection have a uniformly poor outcome with mortality in the first Infectious Diseases of the Fetus and Newborn Infant. 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