Evaluation of Medical Conditions Associated With Zika Virus Infection in Managua, Nicaragua
Evaluation of Medical Conditions Associated With Zika Virus Infection in Managua, Nicaragua
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.
 The researchers will conduct a longitudinal study of approximately 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.
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 the hypothesis that ZIKV-infected children are at greater
 risk for developing neurological sequelae (e.g., cognitive, behavioral, sensory, motor
 deficits) compared to uninfected children. The researchers will conduct a longitudinal study
 of approximately 450 Nicaraguan children in the Pediatric Dengue Cohort Study (PDCS) who were
 ages 2- 12 during January 2016-January 2017, with and without acquired ZIKV infection, to
 accomplish the following aims:

 Aim 1: Evaluate the presence and persistence of neurological symptoms among children with
 acquired ZIKV infection. Children from the PDCS who presented to a local clinic with
 ZIKV-like symptoms from January 2016 through January 2017 were tested for ZIKV and given a
 baseline symptoms questionnaire that included neurological symptoms (e.g., seizures,
 headaches, muscle weakness, fatigue). The researchers will enroll 225 symptomatic
 ZIKV-infected children who were ages 2-12 during that time period and give them the same
 symptoms questionnaire at a follow-up visit in 2019. The researchers will analyze the
 baseline and follow-up symptoms data to evaluate ZIKV-associated neurological symptom
 severity and persistence.

 Aim 2: Test for associations between neurological sequelae and acquired ZIKV infection.

 Hypothesis: ZIKV-infected children are at greater risk for developing neurological sequelae
 (e.g., cognitive, behavioral, sensory, and motor deficits) compared to uninfected children.
 The researchers will enroll an equal number of ZIKV-uninfected PDCS children matched by age
 and sex to the ZIKV-infected children described in Aim 1 to provide a comparison group. For
 both ZIKV-infected and uninfected children, at the 2019/2020 study visit, the researchers
 will assess (1) clinical indicators of neurological impairment (e.g., vision, hearing, motor,
 and sensory functioning) by direct observation; (2) functioning across a wide range of
 domains (e.g., executive function, visual-spatial thinking, processing speed, attention,
 adaptive behavior) by administering a comprehensive neuropsychological assessment battery;
 and (3) factors related to neurological functioning (e.g., mood and sleep disorders).

 The researchers 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 the researchers will assess the role of sex as a biological variable in stratified
 analyses. By leveraging the existing PDCS cohort and locally tested neurodevelopmental
 assessment tools, our cost-effective the 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.
Inclusion Criteria:

 -  5-15 years of age at the time of enrollment;

 -  Active in the PDCS

 -  Complete data on age, sex, and ZIKV status;

 -  Willingness to participate in the study visit;

 -  Written parental permission and assent to participate, as appropriate by age.

 Exclusion Criteria:

 -  Children with evidence in their medical charts of a diagnosis of a neurological (e.g.,
 traumatic brain injuries, seizure disorder, stroke) or neurodevelopmental disorder
 (e.g., ADHD, Autism, Intellectual Disability) before January 2016.