Spatiotemporal overlapping of dengue, chikungunya, and malaria infections in children in Kenya.

Malaria, chikungunya virus (CHIKV), and dengue virus (DENV) are endemic causes of fever among children in Kenya. The risks of infection are multifactorial and may be influenced by built and social environments. The high resolution overlapping of these diseases and factors affecting their spatial heterogeneity has not been investigated in Kenya. From 2014-2018, we prospectively followed a cohort of children from four communities in both coastal and western Kenya. Overall, 9.8% were CHIKV seropositive, 5.5% were DENV seropositive, and 39.1% were malaria positive (3521 children tested). The spatial analysis identified hot-spots for all three diseases in each site and in multiple years. The results of the model showed that the risk of exposure was linked to demographics with common factors for the three diseases including the presence of litter, crowded households, and higher wealth in these communities. These insights are of high importance to improve surveillance and targeted control of mosquito-borne diseases in Kenya.

A Retrospective Study of the Seroprevalence of Dengue Virus and Chikungunya Virus Exposures in Nigeria, 2010-2018.

Arboviruses are important public health threats in many regions of the world. Nigeria has experienced outbreaks of arboviruses over the past decades, leading to concerns of widespread endemicity, which are frequently misdiagnosed. This study aimed to determine the seroprevalence of dengue virus (DENV) (a flavivirus) and chikungunya virus (CHIKV) (an alphavirus) infections in three major population centers of Nigeria. A convenience sample of 701 sera was collected from both healthy and febrile participants between August 2010 and March 2018. Sera were tested for prior exposure to CHIKV virus and DENV using indirect IgG ELISA. Results showed that 54.1% (379/701) of participants were seropositive for anti-DENV antibodies, 41.3% (290/701) were seropositive for anti-CHIKV antibodies, and 20.1% (141/701) had previous exposure to both. The seropositivity for prior CHIKV exposure and prior exposure to DENV and CHIKV was significantly associated with age (CHIKV: OR = 2.7 (95% CI: 1.7-4.3); DENV and CHIKV: OR = 2.2 (95% CI: 1.2-4.0) for adults compared to participants under 18 years old). Overall, the high seropositivity across all age groups suggests that arboviral infections are prevalent in Nigeria and indicates that surveillance and further epidemiological studies are required to determine the true burden of these infections and the spectrum of diseases associated with these exposures.

Neurodevelopment in normocephalic children with and without prenatal Zika virus exposure.

OBJECTIVE: Zika virus (ZIKV) targets neural stem cells in the developing brain. However, the majority of ZIKV-exposed children are born without apparent neurological manifestations. It remains unclear if these children were protected from ZIKV neurotropism or if they harbour subtle pathology that is disruptive to brain development. We assess this by comparing neurodevelopmental outcomes in normocephalic ZIKV-exposed children relative to a parallel control group of unexposed controls. DESIGN: Cohort study. SETTING: Public health centres in Grenada, West Indies. PATIENTS: 384 mother-child pairs were enrolled during a period of active ZIKV transmission (April 2016-March 2017) and prospectively followed up to 30 months. Child exposure status was based on laboratory assessment of prenatal and postnatal maternal serum. MAIN OUTCOME MEASURES: The INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) package and Cardiff Vision Tests, administered and scored by research staff masked to child's exposure status. RESULTS: A total of 131 normocephalic ZIKV exposed (n=68) and unexposed (n=63) children were assessed between 22 and 30 months of age. Approximately half of these children completed vision testing. There were no group differences in sociodemographics. Deficits in visual acuity (31%) and contrast sensitivity (23%) were apparent in the ZIKV-exposed infants in the absence of cognitive, motor, language or behavioural delays. CONCLUSIONS: Overall neurodevelopment is likely to be unaffected in ZIKV-exposed children with normal head circumference at birth and normal head growth in the first 2 years of life. However, the visual system may be selectively vulnerable, which indicates the need for vision testing by 3 years of age.

Climate predicts geographic and temporal variation in mosquito-borne disease dynamics on two continents.

Climate drives population dynamics through multiple mechanisms, which can lead to seemingly context-dependent effects of climate on natural populations. For climate-sensitive diseases, such as dengue, chikungunya, and Zika, climate appears to have opposing effects in different contexts. Here we show that a model, parameterized with laboratory measured climate-driven mosquito physiology, captures three key epidemic characteristics across ecologically and culturally distinct settings in Ecuador and Kenya: the number, timing, and duration of outbreaks. The model generates a range of disease dynamics consistent with observed Aedes aegypti abundances and laboratory-confirmed arboviral incidence with variable accuracy (28-85% for vectors, 44-88% for incidence). The model predicted vector dynamics better in sites with a smaller proportion of young children in the population, lower mean temperature, and homes with piped water and made of cement. Models with limited calibration that robustly capture climate-virus relationships can help guide intervention efforts and climate change disease projections.

Focal epilepsy features in a child with Congenital Zika Syndrome.

Zika virus (ZIKV) is a mosquito-borne, single-stranded DNA flavivirus that is teratogenic and neurotropic. Similar to the teratogenic effects of other TORCH infections, ZIKV infection during pregnancy can have an adverse impact on fetal and neonatal development. Epilepsy is detected in 48-96% of children with Congenital Zika Syndrome (CZS) and microcephaly. Early epilepsy surveillance is needed in children with prenatal ZIKV exposure; yet, most ZIKV-endemic regions do not have specialist epilepsy care. Here, we describe the demographic, clinical, imaging, and EEG characteristics of a 2-year-old child with CZS and microcephaly who presented with focal epileptiform activity, suboptimal growth, and severe neurodevelopmental delays. Administration of a brief seizure questionnaire by allied health professionals to the patient's caregiver helped to characterize the child's seizure semiology and differentiate focal from generalized seizure features. A telemedicine EEG interpretation platform provided valuable diagnostic information for the patient's local pediatrician to integrate into her treatment plan. This case illustrates that CZS can present with focal epilepsy features and that a telemedicine approach can be used to bridge the gap between epilepsy specialists and local care providers in resource limited ZIKV-endemic regions to achieve better seizure control in children with CZS.

Epilepsy surveillance in normocephalic children with and without prenatal Zika virus exposure.

Children with Congenital Zika Syndrome and microcephaly are at high risk for epilepsy; however, the risk is unclear in normocephalic children with prenatal Zika virus (ZIKV) exposure [Exposed Children (EC)]. In this prospective cohort study, we performed epilepsy screening in normocephalic EC alongside a parallel group of normocephalic unexposed children [Unexposed Children (UC)]. We compared the incidence rate of epilepsy among EC and UC at one year of life to global incidence rates. Pregnant women were recruited from public health centers during the ZIKV outbreak in Grenada, West Indies and assessed for prior ZIKV infection using a plasmonic-gold platform that measures IgG antibodies in serum. Normocephalic children born to mothers with positive ZIKV results during pregnancy were classified as EC and those born to mothers with negative ZIKV results during and after pregnancy were classified as UC. Epilepsy screening procedures included a pediatric epilepsy screening questionnaire and video electroencephalography (vEEG). vEEG was collected using a multi-channel microEEG® system for a minimum of 20 minutes along with video recording of participant behavior time-locked to the EEG. vEEGs were interpreted independently by two pediatric epileptologists, who were blinded to ZIKV status, via telemedicine platform. Positive screening cases were referred to a local pediatrician for an epilepsy diagnostic evaluation. Epilepsy screens were positive in 2/71 EC (IR: 0.028; 95% CI: 0.003-0.098) and 0/71 UC. In both epilepsy-positive cases, questionnaire responses and interictal vEEGs were consistent with focal, rather than generalized, seizures. Both children met criteria for a clinical diagnosis of epilepsy and good seizure control was achieved with carbamazepine. Our results indicate that epilepsy rates are modestly elevated in EC. Given our small sample size, results should be considered preliminary. They support the use of epilepsy screening procedures in larger epidemiological studies of children with congenital ZIKV exposure, even in the absence of microcephaly, and provide guidance for conducting epilepsy surveillance in resource limited settings.

High Dengue Burden and Circulation of 4 Virus Serotypes among Children with Undifferentiated Fever, Kenya, 2014-2017.

Little is known about the extent and serotypes of dengue viruses circulating in Africa. We evaluated the presence of dengue viremia during 4 years of surveillance (2014-2017) among children with febrile illness in Kenya. Acutely ill febrile children were recruited from 4 clinical sites in western and coastal Kenya, and 1,022 participant samples were tested by using a highly sensitive real-time reverse transcription PCR. A complete case analysis with genomic sequencing and phylogenetic analyses was conducted to characterize the presence of dengue viremia among participants during 2014-2017. Dengue viremia was detected in 41.9% (361/862) of outpatient children who had undifferentiated febrile illness in Kenya. Of children with confirmed dengue viremia, 51.5% (150/291) had malaria parasitemia. All 4 dengue virus serotypes were detected, and phylogenetic analyses showed several viruses from novel lineages. Our results suggests high levels of dengue virus infection among children with undifferentiated febrile illness in Kenya.

Evidence of transovarial transmission of Chikungunya and Dengue viruses in field-caught mosquitoes in Kenya.

Arboviruses are among the most important emerging pathogens due to their increasing public health impact. In Kenya, continued population growth and associated urbanization are conducive to vector spread in both urban and rural environments, yet mechanisms of viral amplification in vector populations is often overlooked when assessing risks for outbreaks. Thus, the characterization of local arbovirus circulation in mosquito populations is imperative to better inform risk assessments and vector control practices. Aedes species mosquitoes were captured at varying stages of their life cycle during different seasons between January 2014 and May 2016 at four distinct sites in Kenya, and tested for chikungunya (CHIKV), dengue (DENV) and Zika (ZIKV) viruses by RT-PCR. CHIKV was detected in 45 (5.9%) and DENV in 3 (0.4%) mosquito pools. No ZIKV was detected. Significant regional variation in prevalence was observed, with greater frequency of CHIKV on the coast. DENV was detected exclusively on the coast. Both viruses were detected in immature mosquitoes of both sexes, providing evidence of transovarial transmission of these arboviruses in local mosquitoes. This phenomenon may be driving underlying viral maintenance that may largely contribute to periodic re-emergence among humans in Kenya.

Rift Valley Fever: Important Considerations for Risk Mitigation and Future Outbreaks.

Rift Valley fever virus (RVFV) is a zoonotic phlebovirus of the Phenuiviridae family with great opportunity for emergence in previously unaffected regions, despite its current geographical limits. Outbreaks of RVFV often infect humans or domesticated animals, such as livestock, concurrently and occur sporadically, ranging from localized outbreaks in villages to multi-country events that spread rapidly. The true burden of Rift Valley fever (RVF) is not well defined due to underreporting, misdiagnosis caused by the broad spectrum of disease presentation, and minimal access for rapid and accurate laboratory confirmation. Severe symptoms may include hemorrhagic fever, loss of vision, psychological impairment or disturbances, and organ failure. Those living in endemic areas and travelers should be aware of the potential for exposure to ongoing outbreaks or interepidemic transmission, and engage in behaviors to minimize exposure risks, as vaccinations in humans are currently unavailable and animal vaccinations are not used routinely or ubiquitously. The lack of vaccines approved for use in humans is concerning, as RVFV has proven to be highly pathogenic in naïve populations, causing severe disease in a large percent of confirmed cases, which could have considerable impact on human health.

The influence of raw milk exposures on Rift Valley fever virus transmission.

Rift Valley fever virus (RVFV) is a zoonotic phlebovirus that can be transmitted to humans or livestock by mosquitoes or through direct contact with contaminated bodily fluids and tissues. Exposure to bodily fluids and tissues varies by types of behaviors engaged for occupational tasks, homestead responsibilities, or use in dietary or therapeutic capacities. While previous studies have included milk exposures in their analyses, their primary focus on livestock exposures has been on animal handling, breeding, and slaughter. We analyzed data from multiple field surveys in Kenya with the aim of associating RVFV infection to raw milk exposures from common animal species. Of those with evidence of prior RVFV infection by serology (n = 267), 77.2% engaged in milking livestock compared to 32.0% for 3,956 co-local seronegative individuals (p < 0.001), and 86.5% of seropositive individuals consumed raw milk compared to 33.4% seronegative individuals (p < 0.001). Individuals who milked and also consumed raw milk had greater odds of RVFV exposure than individuals whose only contact to raw milk was through milking. Increased risks were associated with exposure to milk sourced from cows (p < 0.001), sheep (p < 0.001), and goats (p < 0.001), but not camels (p = 0.98 for consuming, p = 0.21 for milking). Our data suggest that exposure to raw milk may contribute to a significant number of cases of RVFV, especially during outbreaks and in endemic areas, and that some animal species may be associated with a higher risk for RVFV exposure. Livestock trade is regulated to limit RVFV spread from endemic areas, yet further interventions designed to fully understand the risk of RVFV exposure from raw milk are imperative.

Acute Flavivirus and Alphavirus Infections among Children in Two Different Areas of Kenya, 2015.

Alphaviruses and flaviviruses are known to be endemic in Eastern Africa, but few data are available to evaluate the prevalence of these infections. This leads to missed opportunities for prevention against future outbreaks. This cohort study investigated the frequency of alphavirus and flavivirus incident infections in two regions of Kenya and identified potential risk factors. Seroconversions for alphavirus and flavivirus infections were identified by immunoglobulin G enzyme-linked immunosorbent assay (IgG-ELISA) in a cohort of 1,604 acutely ill children over the year 2015. The annual incidence was 0.5% (0.2-1.2%) for alphaviruses and 1.2% (0.7-2.2%) for flaviviruses. Overall, seroprevalence was significantly higher for alphaviruses in western Kenya than on the coast (P = 0.014), whereas flavivirus seroprevalence was higher on the coast (P = 0.044). Poverty indicators did not emerge as risk factors, but reliance on household water storage was associated with increased exposure to both alphaviruses and flaviviruses (odds ratio = 2.3).

Serological and spatial analysis of alphavirus and flavivirus prevalence and risk factors in a rural community in western Kenya.

Alphaviruses, such as chikungunya virus, and flaviviruses, such as dengue virus, are (re)-emerging arboviruses that are endemic in tropical environments. In Africa, arbovirus infections are often undiagnosed and unreported, with febrile illnesses often assumed to be malaria. This cross-sectional study aimed to characterize the seroprevalence of alphaviruses and flaviviruses among children (ages 5-14, n = 250) and adults (ages 15 ≥ 75, n = 250) in western Kenya. Risk factors for seropositivity were explored using Lasso regression. Overall, 67% of participants showed alphavirus seropositivity (CI95 63%-70%), and 1.6% of participants showed flavivirus seropositivity (CI95 0.7%-3%). Children aged 10-14 were more likely to be seropositive to an alphavirus than adults (p < 0.001), suggesting a recent transmission period. Alphavirus and flavivirus seropositivity was detected in the youngest participants (age 5-9), providing evidence of inter-epidemic transmission. Demographic variables that were significantly different amongst those with previous infection versus those without infection included age, education level, and occupation. Behavioral and environmental variables significantly different amongst those in with previous infection to those without infection included taking animals for grazing, fishing, and recent village flooding. Experience of recent fever was also found to be a significant indicator of infection (p = 0.027). These results confirm alphavirus and flavivirus exposure in western Kenya, while illustrating significantly higher alphavirus transmission compared to previous studies.

Rift Valley Fever Seroprevalence in Coastal Kenya.

Rift Valley fever virus (RVFV) causes severe disease in both animals and humans, resulting in significant economic and public health damages. The objective of this study was to measure RVFV seroprevalence in six coastal Kenyan villages between 2009 and 2011, and characterize individual-, household-, and community-level risk factors for prior RVFV exposure. Sera were tested for anti-RVFV IgG via enzyme-linked immunosorbent assay. Overall, 51 (1.8%; confidence interval [CI95] 1.3-2.3) of 2,871 samples were seropositive for RVFV. Seroprevalence differed significantly among villages, and was highest in Jego Village (18/300; 6.0%; CI95 3.6-9.3) and lowest in Magodzoni (0/248). Adults were more likely to be seropositive than children (P < 0.001). Seropositive subjects were less likely to own land or a motor vehicle (P < 0.01), suggesting exposure is associated with lower socioeconomic standing (P = 0.03). RVFV exposure appears to be low in coastal Kenya, although with some variability among villages.

Clinical aspects of Zika virus.

PURPOSE OF REVIEW: Zika virus (ZIKV) is a mosquito-borne flavivirus that has caused a sudden and explosive outbreak in South America and the Caribbean in the last year, and has been declared a public health emergency by the WHO. As ZIKV afflicts previously naive populations, more severe clinical presentations and sequelae have been observed. A specific emphasis has been placed on the neurological effects in infants resulting from viral exposure in utero. RECENT FINDINGS: Acute onset of ZIKV disease is seen in approximately 20% of cases, whereas most individuals (80%) exposed are asymptomatic. Presentation of illness is typically mild, with disease spectrum ranging from arthralgia and rash to encephalitis, myelitis, and Guillain-Barré syndrome. Infants have been uniquely impacted by the current outbreak with significant congenital exposure resulting in permanent neurological defects and developmental complications. SUMMARY: The current ZIKV outbreak has illustrated the emergent capabilities of mosquito-borne viruses and the teratogenic nature of ZIKV. Causality and risk factors associated with severe manifestations, as well as chronic sequelae, have yet to be determined. Extensive research is required to understand the molecular mechanisms of infection, develop improved assays for differential diagnosis, and improve overall knowledge of the spectrum of ZIKV disease in order to develop modes of prevention and treatment.