In 2016, the World Health Organization designated the Zika virus (ZIKV) epidemic as a Public Health Emergency of International Concern because of the emerging association between microcephaly and ZIKV infection during pregnancy. Although many studies have evaluated the biochemical pathways for congenital ZIKV infection and related severe neurodevelopmental fetal and neonatal outcomes, research on health outcomes related to postnatally acquired ZIKV infection in children is lacking. The few existing epidemiological reports describe incidence rates of acquired ZIKV infection among symptomatic children only, and they predominantly include probable cases based on clinical signs and symptoms. Case reports and surveillance of acute central nervous system disease in adults and adolescents secondary to ZIKV infection suggest that ZIKV may have a broader impact on neurological health beyond that observed in congenitally exposed newborns, including neuropsychological deficits, long-term fatigue, and spinal cord lesions with unilateral paresthesia and muscle weakness. The neurotropic properties of ZIKV and its impact on developing neural cells in postnatally infected mice and nonhuman primates also raise concerns about the potential neurological sequelae of postnatal ZIKV infection, particularly in children. However, the extent to which acquired ZIKV infection can negatively affect the nervous systems and cause long-term neurological damage or cognitive effects is currently unknown. Although the existing evidence is limited, it provides the scientific premise for our hypothesis that ?ZIKV-infected children are at greater risk for developing neurological sequelae (e.g., cognitive, behavioral, sensory, motor deficits) compared to uninfected children?. Specifically, we propose to conduct a longitudinal study of 450 Nicaraguan children in the Pediatric Dengue Study Cohort (PDSC) who were ages 2? 12 during January 2016?January 2017, with and without acquired ZIKV infection, to (1) evaluate the presence and persistence of neurological symptoms among 225 children with acquired ZIKV infection by analyzing the neurological symptoms questionnaire given at the baseline visit (January 2016?January 2017) and repeated at a follow-up visit in 2019 and (2) test for associations between neurological sequelae assessed at the 2019 visit and acquired ZIKV infection in the 225 ZIKV-infected compared with the 225 ZIKV-uninfected children. We will use regression models to calculate relative risks and 95% confidence intervals for the relationship between ZIKV status, clinical indicators of neurological impairment, and neuropsychological functioning across a wide range of domains. Additionally, we will assess the role of sex as a biological variable in stratified analyses. By leveraging the existing PDSC cohort and locally tested neurodevelopmental assessment tools, our cost- effective study will provide invaluable information for determining the merit of conducting a larger and more in- depth study of the neurological impacts of acquired ZIKV infection that could be used to inform clinical practice and support the establishment of school-based educational interventions for affected children.

Public Health Relevance

Zika virus (ZIKV) infection spread throughout the Americas with devastating consequences. Recent limited evidence suggests the potential for neurological effects associated with postnatally acquired ZIKV infection in humans; however, the impact on children is unknown. We propose to conduct a longitudinal study of 450 Nicaraguan children who were ages 2?12 in 2016 to evaluate the presence and persistence of neurological symptoms associated with ZIKV infection and to test whether ZIKV-infected children are at greater risk for developing neurological outcomes compared to uninfected children.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Developmental Brain Disorders Study Section (DBD)
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Chakhtoura, Nahida Abdo
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Research Triangle Institute
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United States
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