Although the Zika virus (ZIKV) typically causes mild or no symptoms in adults, during the 2015−2016 outbreak, ZIKV infection in pregnancy resulted in birth defects and neurodevelopmental disorders; however, little is known about the potential impact of ZIKV infection during infancy and early childhood. Considering the neurotropism of ZIKV and the rapidly-developing postnatal brain, it is important to understand how infection during infancy may disrupt neurodevelopment. Emerging clinical evidence supports the hypothesis that ZIKV infection during infancy can result in negative neurologic consequences. However, clinical data regarding postnatal ZIKV infection in children are limited; as such, animal models play an important role in understanding the potential complications of ZIKV infection related
to the vulnerable developing brain. Preclinical data provide insight into the potential behavioral, cognitive, and motor domains that clinical studies should examine in pediatric populations exposed to ZIKV during infancy.
Zika virus (ZIKV) is a neurotropic flavivirus that is primarily transmitted by the bite of an Aedes genus mosquito, but it has also been transmitted through sexual contact, blood transfusions, organ transplantation, and from mother to fetus during gestation [1,2]. Although vaccine clinical trials are currently under investigation , there are currently no licensed vaccines to prevent or targeted therapeutics to treat ZIKV infection. The main preventative measure is the avoidance of mosquito bites, from which it is difficult to ensure 100% protection.
Despite being first isolated in 1947, ZIKV was relatively unknown to the public for 70 years because it typically resulted in asymptomatic or mild symptoms in the majority of adults [4,5]. However, during the 2015−2016 outbreak in Brazil, it was discovered that ZIKV infection during pregnancy could result in birth defects, leading to the declaration of a global health emergency [6,7,8,9,10,11,12,13]. ZIKV spread rapidly across the Americas, and infections have now been reported in 91 countries and territories [13,14]. While ZIKV incidence no longer constitutes a current epidemic, continued infections occur, and ZIKV has adapted to persistent endemic transmission . In fact, in a recent serologic study, 9% of children aged 1–4 years were ZIKV seropositive in Indonesia, highlighting the widespread transmission in young children living in endemic areas . ZIKV is transmitted primarily by the bite of an Aedes genus mosquito, but also via sex, blood transfusions, organ transplantation, and from mother to fetus.
The passage of ZIKV into the brain, and its ability to induce pathological changes have been reported since the late 1950s [17,18,19]. During the 2015−2016 outbreak, it was discovered that ZIKV could infect neural stem cells and neural progenitor cells, causing their eventual apoptosis . Data from fetal human brain development suggests that radial glia and intermediate progenitors are particularly susceptible to ZIKV infection [21,22,23]. Recent evidence also suggests an interaction between ZIKV-infected microglia and altered neural progenitor cell differentiation and proliferation . Congenital infection with ZIKV occurs throughout gestation, with resultant microcephaly and other brain malformations [21,25,26,27] that are thought to be the consequence of the ZIKV infection of neural progenitor cells, as well as the activation of innate immune responses . Congenital ZIKV syndrome is a pattern of birth defects that includes severe microcephaly, the thinning of the cerebral cortex with subcortical calcifications, macular scarring and retinal mottling, congenital contractures, and hypertonicity . Infants with congenital ZIKV syndrome can develop seizures, hearing and vision problems, feeding difficulties, and gross motor abnormalities . While microcephaly is probably the most salient feature of congenital ZIKV syndrome, it does not occur in all cases of prenatal exposure. In fact, a prospective study of 216 toddlers with prenatal ZIKV exposure reported microcephaly in only eight (3.7%) of the cases . Although some studies report that head circumference at birth corresponds with abnormal posture and motor skills during infancy [32,33], a recent report found no correlation between head size at birth and gross motor function at 24 months of age . In fact, Nielsen-Saines and colleagues found that, despite few cases of microcephaly, one third of children with prenatal ZIKV exposure had below-average cognitive, language or motor scores on the Bayley-III evaluation . Thus, one cannot assume that infants born without microcephaly or obvious signs of congenital ZIKV syndrome will experience normal development. Language, motor, and cognitive functions gradually develop over years in early childhood, which coincides with the prolonged maturation of the brain areas that are important for these skills [35,36]. Considering this protracted development, reports of infants prenatally infected with ZIKV exhibiting the postnatal onset of microcephaly, neurologic dysfunction, and neurodevelopmental abnormalities [10,12,37,38]  further highlight the potential of ZIKV to cause ongoing damage after birth.
2. Clinical Evidence of Postnatal Zika Virus Infection
Postnatally, the brain matures exponentially, particularly in the temporal, prefrontal and parietal regions that are important for social, emotional, and executive functions, including learning, attention, and memory throughout the first two years of age in humans [35,39,40,41,42,43,44,45,46. This highly dynamic period of postnatal brain development presents a time of great vulnerability. Prolonged synaptic proliferation and neuronal maturation during postnatal development not only contribute to learning and periods of plasticity, but also allow for environmental factors to affect the maturation of both the brain and behavior [40,47,48]. Considering the neurotropism of ZIKV, can infection during infancy disrupt this crucial period of neurodevelopment?
The evidence shows that infants and children can acquire ZIKV infection postnatally, through mosquito bites and, possibly, breast milk . Children account for 10−31% of ZIKV infections in various studies [50,51,52]. However, the data on ZIKV in children are still sparse; many studies include a wide age range in their pediatric population (1 month to 18 years), and few include significant numbers of children infected with ZIKV at <1 year of age [53,54,55,56,57,58,59,60]. Acute neurologic complications of ZIKV infection in children have been described, including Guillian-Barre Syndrome, polyneuropathy, encephalitis, demyelinating disease, and inflammatory diseases of the central nervous system (CNS) [58,59,61]. A meta-analysis of pediatric ZIKV infection found that these cases are primarily mild, and most present with a fever and rash , but severe neurologic complications and death have also been reported [59,62,63,64].
Beyond the acute infection period, there have been few studies of neurodevelopment following postnatal ZIKV infection. A notable recent study of the neurologic outcomes of ZIKV included six children who were infected postnatally, one of whom was 10 months old at the time of infection and developed severe CNS involvement . Additionally, a prospective study of 60 children with postnatal ZIKV infection between 1 and 12 months of age found that 15% had adverse neurologic, hearing or eye examinations at 20−30 months of age . An additional 12.8% received an alert score in the hearing domain. For those without abnormal neurologic, eye, or hearing outcomes, there was also a positive correlation between their age at ZIKV infection and their percentile score on the Personal–Social domain, as assessed by the Escala Abreviada de Desarrollo (EAD-1), meaning that the infants who were infected later performed better. These data suggest that the neurotropism of ZIKV can lead to adverse neurodevelopmental consequences for vulnerable young brains, but the full extent of this impact is still largely unknown. There is, at present, no compelling evidence to suggest either for or against the severity of symptoms during acute infection being predictive of neurodevelopmental outcomes. As with congenital ZIKV infection in which adverse neurodevelopment has been reported in children without overt birth defects, one might speculate that mild or asymptomatic postnatal ZIKV infection in children has the potential to be associated with subsequent neurodevelopmental deficits.
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