Neurological and neuropsychological sequelae of Zika virus infection in children in León, Nicaragua.

Objectives: To describe the presence and persistence of neurological and neuropsychological sequelae among children with acquired Zika virus infection and assess whether those sequelae were more common in children infected with Zika virus compared to uninfected children. Methods: We conducted a prospective cohort study of children with and without Zika virus infection in León, Nicaragua, using a standard clinical assessment tool and questionnaire to collect data on symptoms at three visits, about 6 months apart, and a battery of standardized instruments to evaluate neurocognitive function, behavior, depression, and anxiety at the last two visits. Results: Sixty-two children were enrolled, with no significant differences in demographics by infection group. Children infected with Zika virus had a range of neurological symptoms, some of which persisted for 6 to 12 months; however, no consistent pattern of symptoms was observed. At baseline a small percentage of children infected with Zika virus had an abnormal finger-to-nose test (13%), cold touch response (13%), and vibration response (15%) versus 0% in the uninfected group. Neurocognitive deficits and behavioral problems were common in both groups, with no significant differences between the groups. Children infected with Zika virus had lower cognitive efficiency scores at the 6-month visit. Anxiety and depression were infrequent in both groups. Conclusions: Larger studies are needed to definitively investigate the relationship between Zika virus infection and neurological symptoms and neurocognitive problems, with adjustment for factors affecting cognition and behavior, including mood and sleep disorders, home learning environment, history of neuroinvasive infections, and detailed family history of neuropsychological problems.

Neurological and neuropsychological sequelae of Zika virus infection in children in León, Nicaragua

[ABSTRACT]. Objectives. To describe the presence and persistence of neurological and neuropsychological sequelae among children with acquired Zika virus infection and assess whether those sequelae were more common in children infected with Zika virus compared to uninfected children. Methods. We conducted a prospective cohort study of children with and without Zika virus infection in León, Nicaragua, using a standard clinical assessment tool and questionnaire to collect data on symptoms at three visits, about 6 months apart, and a battery of standardized instruments to evaluate neurocognitive function, behavior, depression, and anxiety at the last two visits. Results. Sixty-two children were enrolled, with no significant differences in demographics by infection group. Children infected with Zika virus had a range of neurological symptoms, some of which persisted for 6 to 12 months; however, no consistent pattern of symptoms was observed. At baseline a small percentage of children infected with Zika virus had an abnormal finger-to-nose test (13%), cold touch response (13%), and vibration response (15%) versus 0% in the uninfected group. Neurocognitive deficits and behavioral problems were common in both groups, with no significant differences between the groups. Children infected with Zika virus had lower cognitive efficiency scores at the 6-month visit. Anxiety and depression were infrequent in both groups. Conclusions. Larger studies are needed to definitively investigate the relationship between Zika virus infec- tion and neurological symptoms and neurocognitive problems, with adjustment for factors affecting cognition and behavior, including mood and sleep disorders, home learning environment, history of neuroinvasive infec- tions, and detailed family history of neuropsychological problems.

[RESUMEN]. Objetivos. Describir la presencia y persistencia de secuelas neurológicas y neuropsicológicas en pacientes pediátricos que contrajeron la infección por el virus del Zika y evaluar si dichas secuelas fueron más comunes en los infectados con el virus del Zika en comparación con los no infectados. Métodos. Se realizó un estudio de cohorte prospectivo en pacientes pediátricos con y sin infección por el virus del Zika en León (Nicaragua), con una herramienta de evaluación clínica estándar y un cuestionario para recopilar datos sobre los síntomas en tres visitas, con aproximadamente seis meses de diferencia, y un con- junto de instrumentos estandarizados para evaluar la función neurocognitiva, el comportamiento, la depresión y la ansiedad en las últimas dos visitas. Resultados. Participaron 62 niños y niñas sin diferencias significativas en la demografía por grupo de infección. Los participantes infectados con el virus del Zika mostraron una variedad de síntomas neurológi- cos, algunos de los cuales persistieron entre 6 y 12 meses; no obstante, no se observó un patrón sistemático en los síntomas. Al inicio del estudio, un pequeño porcentaje de participantes infectados con el virus del Zika mostró resultados anormales a las pruebas dedo-nariz (13%), respuesta al tacto (frío) (13%) y respuesta a la vibración (15%), frente a un 0% en el grupo no infectado. Los déficits neurocognitivos y los problemas de comportamiento fueron comunes en ambos grupos, sin diferencias significativas entre los grupos. Los partic- ipantes infectados con el virus del Zika mostraron puntuaciones de eficiencia cognitiva más bajas en la visita a los 6 meses. La ansiedad y la depresión fueron poco frecuentes en ambos grupos. Conclusiones. Son necesarios estudios más amplios para investigar definitivamente la relación entre la infec- ción por el virus del Zika y los síntomas neurológicos y los problemas neurocognitivos, haciendo ajustes para los factores relacionados con la cognición y el comportamiento, incluidos los trastornos del estado de ánimo y el sueño, el entorno de aprendizaje en el hogar, los antecedentes de infecciones neuroinvasivas y los antecedentes familiares detallados de problemas neuropsicológicos.

[RESUMO]. Objetivos. Descrever a presença e a persistência de sequelas neurológicas e neuropsicológicas em crianças com infecção pelo vírus zika e avaliar se essas sequelas foram mais comuns em crianças infectadas pelo vírus zika em comparação com crianças não infectadas. Métodos. Realizamos um estudo de coorte prospectivo em crianças com e sem infecção pelo vírus zika em León, Nicarágua, usando uma ferramenta de avaliação clínica padrão e um questionário para coletar dados de sintomas em três consultas, com cerca de 6 meses de intervalo, além de um conjunto de ferramentas padronizadas para avaliar função neurocognitiva, comportamento, depressão e ansiedade nas duas últimas consultas. Resultados. Foram incluídas 62 crianças, sem diferenças significativas nas características demográficas por grupo de infecção. As crianças infectadas pelo vírus zika tinham uma gama de sintomas neurológicos, alguns dos quais persistiram por 6 a 12 meses. Entretanto, não se observou nenhum padrão consistente de sintomas. No início do estudo, uma pequena porcentagem de crianças infectadas com o vírus zika apresen- tou resultado anormal na prova índex-nariz (13%), resposta ao toque frio (13%) e sensibilidade vibratória (15%), em comparação a 0% no grupo não infectado. Déficits neurocognitivos e problemas comportamentais foram frequentes em ambos os grupos, mas sem diferenças significativas entre eles. As crianças infectadas com o vírus zika tiveram resultados mais baixos de eficiência cognitiva na consulta de 6 meses. Ansiedade e depressão não foram observadas com frequência em ambos os grupos. Conclusões. São necessários estudos mais amplos para investigar a relação exata entre a infecção pelo vírus zika e sintomas neurológicos e problemas neurocognitivos, com ajuste para fatores que afetam a cog- nição e o comportamento, incluindo distúrbios do humor e do sono, ambiente de aprendizagem em casa, história de infecções neuroinvasivas e história familiar detalhada de problemas neuropsicológicos.

Neurological and neuropsychological sequelae of Zika virus infection in children in León, Nicaragua / Secuelas neurológicas y neuropsicológicas de la infección por el virus del Zika en niños y niñas en León, Nicaragua / Sequelas neurológicas e neuropsicológicas da infecção pelo vírus zika em crianças em León, Nicarágua

ABSTRACT Objectives. To describe the presence and persistence of neurological and neuropsychological sequelae among children with acquired Zika virus infection and assess whether those sequelae were more common in children infected with Zika virus compared to uninfected children. Methods. We conducted a prospective cohort study of children with and without Zika virus infection in León, Nicaragua, using a standard clinical assessment tool and questionnaire to collect data on symptoms at three visits, about 6 months apart, and a battery of standardized instruments to evaluate neurocognitive function, behavior, depression, and anxiety at the last two visits. Results. Sixty-two children were enrolled, with no significant differences in demographics by infection group. Children infected with Zika virus had a range of neurological symptoms, some of which persisted for 6 to 12 months; however, no consistent pattern of symptoms was observed. At baseline a small percentage of children infected with Zika virus had an abnormal finger-to-nose test (13%), cold touch response (13%), and vibration response (15%) versus 0% in the uninfected group. Neurocognitive deficits and behavioral problems were common in both groups, with no significant differences between the groups. Children infected with Zika virus had lower cognitive efficiency scores at the 6-month visit. Anxiety and depression were infrequent in both groups. Conclusions. Larger studies are needed to definitively investigate the relationship between Zika virus infection and neurological symptoms and neurocognitive problems, with adjustment for factors affecting cognition and behavior, including mood and sleep disorders, home learning environment, history of neuroinvasive infections, and detailed family history of neuropsychological problems.

RESUMEN Objetivos. Describir la presencia y persistencia de secuelas neurológicas y neuropsicológicas en pacientes pediátricos que contrajeron la infección por el virus del Zika y evaluar si dichas secuelas fueron más comunes en los infectados con el virus del Zika en comparación con los no infectados. Métodos. Se realizó un estudio de cohorte prospectivo en pacientes pediátricos con y sin infección por el virus del Zika en León (Nicaragua), con una herramienta de evaluación clínica estándar y un cuestionario para recopilar datos sobre los síntomas en tres visitas, con aproximadamente seis meses de diferencia, y un conjunto de instrumentos estandarizados para evaluar la función neurocognitiva, el comportamiento, la depresión y la ansiedad en las últimas dos visitas. Resultados. Participaron 62 niños y niñas sin diferencias significativas en la demografía por grupo de infección. Los participantes infectados con el virus del Zika mostraron una variedad de síntomas neurológicos, algunos de los cuales persistieron entre 6 y 12 meses; no obstante, no se observó un patrón sistemático en los síntomas. Al inicio del estudio, un pequeño porcentaje de participantes infectados con el virus del Zika mostró resultados anormales a las pruebas dedo-nariz (13%), respuesta al tacto (frío) (13%) y respuesta a la vibración (15%), frente a un 0% en el grupo no infectado. Los déficits neurocognitivos y los problemas de comportamiento fueron comunes en ambos grupos, sin diferencias significativas entre los grupos. Los participantes infectados con el virus del Zika mostraron puntuaciones de eficiencia cognitiva más bajas en la visita a los 6 meses. La ansiedad y la depresión fueron poco frecuentes en ambos grupos. Conclusiones. Son necesarios estudios más amplios para investigar definitivamente la relación entre la infección por el virus del Zika y los síntomas neurológicos y los problemas neurocognitivos, haciendo ajustes para los factores relacionados con la cognición y el comportamiento, incluidos los trastornos del estado de ánimo y el sueño, el entorno de aprendizaje en el hogar, los antecedentes de infecciones neuroinvasivas y los antecedentes familiares detallados de problemas neuropsicológicos.

RESUMO Objetivos. Descrever a presença e a persistência de sequelas neurológicas e neuropsicológicas em crianças com infecção pelo vírus zika e avaliar se essas sequelas foram mais comuns em crianças infectadas pelo vírus zika em comparação com crianças não infectadas. Métodos. Realizamos um estudo de coorte prospectivo em crianças com e sem infecção pelo vírus zika em León, Nicarágua, usando uma ferramenta de avaliação clínica padrão e um questionário para coletar dados de sintomas em três consultas, com cerca de 6 meses de intervalo, além de um conjunto de ferramentas padronizadas para avaliar função neurocognitiva, comportamento, depressão e ansiedade nas duas últimas consultas. Resultados. Foram incluídas 62 crianças, sem diferenças significativas nas características demográficas por grupo de infecção. As crianças infectadas pelo vírus zika tinham uma gama de sintomas neurológicos, alguns dos quais persistiram por 6 a 12 meses. Entretanto, não se observou nenhum padrão consistente de sintomas. No início do estudo, uma pequena porcentagem de crianças infectadas com o vírus zika apresentou resultado anormal na prova índex-nariz (13%), resposta ao toque frio (13%) e sensibilidade vibratória (15%), em comparação a 0% no grupo não infectado. Déficits neurocognitivos e problemas comportamentais foram frequentes em ambos os grupos, mas sem diferenças significativas entre eles. As crianças infectadas com o vírus zika tiveram resultados mais baixos de eficiência cognitiva na consulta de 6 meses. Ansiedade e depressão não foram observadas com frequência em ambos os grupos. Conclusões. São necessários estudos mais amplos para investigar a relação exata entre a infecção pelo vírus zika e sintomas neurológicos e problemas neurocognitivos, com ajuste para fatores que afetam a cognição e o comportamento, incluindo distúrbios do humor e do sono, ambiente de aprendizagem em casa, história de infecções neuroinvasivas e história familiar detalhada de problemas neuropsicológicos.

Correction to: International prospective observational cohort study of Zika in infants and pregnancy (ZIP study): study protocol.

Following publication of the original article [1], the author mentioned that two additional NIH staff were involved in the development of the protocol who did not receive recognition in the Acknowledgments section in their published article.

International prospective observational cohort study of Zika in infants and pregnancy (ZIP study): study protocol.

BACKGROUND: Until recently, Zika virus (ZIKV) infections were considered mild and self-limiting. Since 2015, they have been associated with an increase in microcephaly and other birth defects in newborns. While this association has been observed in case reports and epidemiological studies, the nature and extent of the relationship between ZIKV and adverse pregnancy and pediatric health outcomes is not well understood. With the unique opportunity to prospectively explore the full spectrum of issues related to ZIKV exposure during pregnancy, we undertook a multi-country, prospective cohort study to evaluate the association between ZIKV and pregnancy, neonatal, and infant outcomes. METHODS: At research sites in ZIKV endemic regions of Brazil (4 sites), Colombia, Guatemala, Nicaragua, Puerto Rico (2 sites), and Peru, up to 10,000 pregnant women will be recruited and consented in the first and early second trimesters of pregnancy and then followed through delivery up to 6 weeks post-partum; their infants will be followed until at least 1 year of age. Pregnant women with symptomatic ZIKV infection confirmed by presence of ZIKV RNA and/or IgM for ZIKV will also be enrolled, regardless of gestational age. Participants will be tested monthly for ZIKV infection; additional demographic, physical, laboratory and environmental data will be collected to assess the potential interaction of these variables with ZIKV infection. Delivery outcomes and detailed infant assessments, including physical and neurological outcomes, will be obtained. DISCUSSION: With the emergence of ZIKV in the Americas and its association with adverse pregnancy outcomes in this region, a much better understanding of the spectrum of clinical outcomes associated with exposure to ZIKV during pregnancy is needed. This cohort study will provide information about maternal, fetal, and infant outcomes related to ZIKV infection, including congenital ZIKV syndrome, and manifestations that are not detectable at birth but may appear during the first year of life. In addition, the flexibility of the study design has provided an opportunity to modify study parameters in real time to provide rigorous research data to answer the most critical questions about the impact of congenital ZIKV exposure. TRIAL REGISTRATION: NCT02856984 . Registered August 5, 2016. Retrospectively registered.

Review: Evidence of Neurological Sequelae in Children With Acquired Zika Virus Infection.

Limited information is available on health outcomes related to Zika virus infection acquired during childhood. Zika virus can cause severe central nervous system malformations in congenitally exposed fetuses and neonates. In vitro studies show the capacity of Zika virus to infect neural progenitor cells, induce central and peripheral neuronal cell deaths, and target different brain cells over the course of brain development. Studies of postnatally infected mice and nonhuman primates have detected degradation of neural cells and morphologic brain cell changes consistent with a broad neuroinflammatory response. In addition, case reports of central nervous system disease in adults and in adolescents secondary to Zika virus infection suggest that Zika virus may have a broader impact on neurological health beyond that observed in congenitally exposed newborns. Long-term neurological complications have been observed with other acquired flaviviral infections, with clinical symptoms manifesting for years after primary infection. The extent to which postnatal Zika virus infection in humans negatively affects the central and peripheral nervous systems and causes long-term neurological damage or cognitive effects is currently unknown. To better understand the potential for neurological sequelae associated with acquired Zika virus infection in children, we reviewed the biological, clinical, and epidemiologic literature and summarized the evidence for this link. First, we review biological mechanisms for neurological manifestations of Zika virus infection in experimental studies. Second, we review observational studies of congenital Zika virus infection and case studies and surveillance reports of neurological sequelae of Zika virus infection in adults and in children. Lastly, we discuss the challenges of conducting Zika virus-neurological sequela studies and future directions for pediatric Zika virus research.

Pesticide use and risk of end-stage renal disease among licensed pesticide applicators in the Agricultural Health Study.

OBJECTIVES: Experimental studies suggest a relationship between pesticide exposure and renal impairment, but epidemiological evidence is limited. We evaluated the association between exposure to 39 specific pesticides and end-stage renal disease (ESRD) incidence in the Agricultural Health Study, a prospective cohort study of licensed pesticide applicators in Iowa and North Carolina. METHODS: Via linkage to the US Renal Data System, we identified 320 ESRD cases diagnosed between enrolment (1993-1997) and December 2011 among 55 580 male licensed pesticide applicators. Participants provided information on use of pesticides via self-administered questionnaires. Lifetime pesticide use was defined as the product of duration and frequency of use and then modified by an intensity factor to account for differences in pesticide application practices. Cox proportional hazards models, adjusted for age and state, were used to estimate associations between ESRD and: (1) ordinal categories of intensity-weighted lifetime use of 39 pesticides, (2) poisoning and high-level pesticide exposures and (3) pesticide exposure resulting in a medical visit or hospitalisation. RESULTS: Positive exposure-response trends were observed for the herbicides alachlor, atrazine, metolachlor, paraquat, and pendimethalin, and the insecticide permethrin. More than one medical visit due to pesticide use (HR=2.13; 95% CI 1.17 to 3.89) and hospitalisation due to pesticide use (HR=3.05; 95% CI 1.67 to 5.58) were significantly associated with ESRD. CONCLUSIONS: Our findings support an association between ESRD and chronic exposure to specific pesticides, and suggest pesticide exposures resulting in medical visits may increase the risk of ESRD. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT00352924.

Pesticide exposure and end-stage renal disease risk among wives of pesticide applicators in the Agricultural Health Study.

BACKGROUND: Pesticide exposure has been found to cause renal damage and dysfunction in experimental studies, but epidemiological research on the renal effects of chronic low-level pesticide exposure is limited. We investigated the relationships between end-stage renal disease (ESRD) among wives of licensed pesticide applicators (N=31,142) in the Agricultural Health Study (AHS) and (1) personal pesticide use, (2) exposure to the husband's pesticide use, and (3) other pesticide-associated farming and household activities. METHODS: AHS participants reported pesticide exposure via self-administered questionnaires at enrollment (1993-1997). ESRD cases were identified via linkage to the United States Renal Data System. Associations between ESRD and pesticide exposures were estimated with Cox proportional hazard regression models controlling for age at enrollment. Models of associations with farming and household factors were additionally adjusted for personal use of pesticides. RESULTS: We identified 98 ESRD cases diagnosed between enrollment and 31 December 2011. Although women who ever applied pesticides (56% of cohort) were less likely than those who did not apply to develop ESRD (Hazard Ratio (HR): 0.42; 95% CI: 0.28, 0.64), among women who did apply pesticides, the rate of ESRD was significantly elevated among those who reported the highest (vs. lowest) cumulative general pesticide use (HR: 4.22; 95% CI: 1.26, 14.20). Among wives who never applied pesticides, ESRD was associated with husbands' ever use of paraquat (HR=1.99; 95% CI: 1.14, 3.47) and butylate (HR=1.71; 95% CI: 1.00, 2.95), with a positive exposure-response pattern for husband's cumulative use of these pesticides. CONCLUSIONS: ESRD may be associated with direct and/or indirect exposure to pesticides among farm women. Future studies should evaluate indirect exposure risk among other rural populations.

The TALKS study to improve communication, logistical, and financial barriers to live donor kidney transplantation in African Americans: protocol of a randomized clinical trial.

BACKGROUND: Live donor kidney transplantation (LDKT), an optimal therapy for many patients with end-stage kidney disease, is underutilized, particularly by African Americans. Potential recipient difficulties initiating and sustaining conversations about LDKT, identifying willing and medically eligible donors, and potential donors' logistical and financial hurdles have been cited as potential contributors to race disparities in LDKT. Few interventions specifically targeting these factors have been tested. METHODS/DESIGN: We report the protocol of the Talking about Living Kidney Donation Support (TALKS) study, a study designed to evaluate the effectiveness of behavioral, educational and financial assistance interventions to improve access to LDKT among African Americans on the deceased donor kidney transplant recipient waiting list. We adapted a previously tested educational and social worker intervention shown to improve consideration and pursuit of LDKT among patients and their family members for its use among patients on the kidney transplant waiting list. We also developed a financial assistance intervention to help potential donors overcome logistical and financial challenges they might face during the pursuit of live kidney donation. We will evaluate the effectiveness of these interventions by conducting a randomized controlled trial in which patients on the deceased donor waiting list receive 1) usual care while on the transplant waiting list, 2) the educational and social worker intervention, or 3) the educational and social worker intervention plus the option of participating in the financial assistance program. The primary outcome of the randomized controlled trial will measure potential recipients' live kidney donor activation (a composite rate of live donor inquiries, completed new live donor evaluations, or live kidney donation) at 1 year. DISCUSSION: The TALKS study will rigorously assess the effectiveness of promising interventions to reduce race disparities in LDKT. TRIAL REGISTRATION: NCT02369354.

A population-based study of prevalence and risk factors of chronic kidney disease in León, Nicaragua.

BACKGROUND: Recent studies have shown an excess of chronic kidney disease (CKD) among younger adult males in the Pacific coastal region of Nicaragua and suggest a non-conventional CKD etiology in this region. These studies have been conducted in small, non-representative populations. OBJECTIVES: We conducted a large population-based cross-sectional study to estimate CKD prevalence in León, Nicaragua, and to evaluate the association between previously investigated risk factors and CKD. METHODS: Estimated glomerular filtration rate, derived using the MDRD equation, was assessed to determine CKD status of 2275 León residents. Multivariable logistic regression was used to estimate adjusted prevalence odds ratios. León CKD prevalence was also standardized to the demographic distributions of the León Health and Demographic Surveillance System and the León 2005 Census. RESULTS: CKD prevalence was 9.1%; twice as high for males (13.8%) than females (5.8%). In addition to gender, older age, rural zone, lower education level, and self-reported high blood pressure, more years of agricultural work, lija (unregulated alcohol) consumption, and higher levels of daily water consumption were significantly associated with CKD. Notably, self-reported diabetes was associated with CKD in adjusted models for females but not males. CONCLUSIONS: Our findings are comparable to those found in regional studies and further support the hypothesis of a Mesoamerican Nephropathy.

CONTEXTE: Selon de récentes études, il existerait une prévalence d'insuffisance rénale chronique (IRC) excessive chez les jeunes adultes de sexe masculin de la côte du Pacifique du Nicaragua. Ces études, qui ont été conduites sur des échantillons non représentatifs de la population, suggèrent une étiologie non classique de l'IRC dans cette région. OBJECTIFS DE L'ÉTUDE: Nous avons effectué une étude transversale portant sur un vaste échantillon de population, afin de pouvoir estimer la prévalence d'IRC dans la ville nicaraguéenne de León, d'une part, et évaluer la présence de liens entre l'IRC et certains facteurs de risque ayant été étudiés, d'autre part. MÉTHODE: Pour déterminer le statut d'IRC de 2275 résidents de la ville de León, nous avons utilisé le débit de filtration glomérulaire estimé, selon l'équation du MDRD. Une régression logistique multivariée a été utilisée pour estimer les ratios de probabilité corrigés de prévalence. La prévalence d'IRC de León a également été normalisée sur la base de la distribution démographique du Health and Demographic Surveillance System de León et avec son recensement de 2005. RÉSULTATS: La prévalence d'IRC était de 9,1%; elle était deux fois plus élevée chez les hommes (13,8%) que chez les femmes (5,8%). D'autres facteurs ont été liés de façon significative à l'IRC: la vieillesse, la vie rurale, un niveau d'éducation faible, une hypertension autodéclarée, plusieurs années de travail en agriculture, et la consommation de lija (alcool non contrôlé) et de grandes quantités d'eau. Le diabète autodéclaré était également lié à l'IRC dans les modèles ajustés chez les femmes, mais non chez les homm es. CONCLUSIONS: Nos résultats sont comparables à ceux des études locales et supportent l'hypothèse de l'existence d'une néphropathie méso-américaine.