Inmunoglobulina endovenosa vs. plasmaféresis para el tratamiento del Sd. Guillain-Barré relacionado a infección por Zika en población clave / Intravenous immunoglobulin vs. plasmapheresis for the treatment of Sd. Guillain-Barré related to Zika infection in the key population

INTRODUCCIÓN: Este documento técnico se realiza a solicitud de la Estrategia sanitaria nacional de prevención y control de enfermedades metaxénicas y otras transmitidas por vectores. a. Cuadro clínico: El Síndrome de Guillain-Barré (SGB) es un trastorno autoinmune poco frecuente en el que el propio sistema inmunitario de una persona ataca a los nervios periféricos. Aproximadamente dos tercios de personas con SGB presentan una infección respiratoria o entérica previa entre 2 y 4 semanas antes del inicio de los síntomas. Mientras que en el año 2016, se estableció una relación causal entre virus del Zika (ZIKV) y el desarrollo del SGB. La inmunoterapia por administración de inmunoglobulina intravenosa (IgIV) y la plasmaféresis (PE) son dos tratamientos que han sido usados para el tratamiento del SGB relacionado a infección previa por ZIKV, habiéndose extrapolado esta práctica de la experiencia al tratar el SGB no relacionado a ZIKV. b. Tecnología sanitária: Existen varios medicamentos aprobados contra el SGB como la IgIV. IgIV fue aprobada para la indicación del SGB en Europa en el 2006 por la European Medicines Agency (EMA), en los Estados Unidos en el 2008 por la United States Food and Drug Administration (FDA), y en el Perú en 2016 por la Dirección General de Medicamentos, Insumos y Drogas (DIGEMID), aunque en este último caso sólo para la inmunoglobulina humana normal 5% inyectable para la indicación del SGB agudo. El uso de la PE, por otro lado, para el tratamiento del SGB fue descrito por primera vez entre el 1978 y 1981. OBJETIVO El objetivo del presente documento es evaluar la eficacia y seguridad, así como documentos relacionados a la decisión del uso de la IgIV y PE en el tratamiento del SGB relacionado a infección por Zika en adultos, gestantes y niños. METODOLOGÍA: Se realizó una búsqueda en las principales bases de datos bibliográficas: MEDLINE, LILACS, COCHRANE, así como en buscadores genéricos de Internet incluyendo Google Scholar y TRIPDATABASE. Adicionalmente, se hizo una búsqueda dentro de la información generada por las principales instituciones internacionales de infectología, y agencias de tecnologías sanitarias que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC). RESULTADOS: Se seleccionaron una RS, una ECA, 4 evaluaciones económicas, y un estudio observacional. Se identificaron 8 guías de práctica clínica y una ETS. Lin et al. publicaron una revisión sistemática para comparar la eficacia de varios tratamientos para el SGB en octubre de 2021. Se incluyeron ECAs y ensayos clínicos no aleatorizados con adultos y niños con SGB de todos los grados de severidad (28 estudios; n=2474). El análisis indicó que la IgIV y la PE eran ambas eficaces para el tratamiento del SGB y, aunque la IgIV fue el tratamiento más efectivo, no hubo una diferencia significativa comparado con la PE (diferencia de medias [DM] = 0,073; IC95% ­ 0,26 ­ 0,41. El uso de distintas dosis de PE o IgIV, y la combinación de PE y IgIV, no demostraron tener un beneficio significativo ante el tratamiento estándar de PE (4-5 sesiones) o de IgIV (0,4-0,5g/kg/día por 4-5 días). Se encontró además otro ECA no incluido en la RS anterior (n=41, edad promedia=37.4 ± 9.2 años), publicada en 2014 que encontró que el tiempo de hospitalización era significativamente menor en los pacientes tratados con IgIV (p=0,03), además de poder ser retirados de la ventilación mecánica antes (p=0.01) y tener un tiempo hasta el inicio de la recuperación motora menor (p=0.04) comparado con pacientes tratados con PE. Un estudio observacional publicado en los Estados Unidos en 2020 coincide con el ECA anterior y encontró que los pacientes tratados con PE tenían un tiempo de hospitalización mayor (PE = 17,78 días vs. IgIV = 10,24 días), unos costos totales mayores (PE: US$149 143 vs. IgIV: US$103 223), y una tasa de mortalidad mayor (PE = 3,8% vs. IgIV = 1,4%; OR = 2,78) comparado con los pacientes tratados con IgIV. Existen varias GPC para el diagnóstico y tratamiento del SGB. La más reciente se publicó en Argentina en octubre de 2021 y indica que la IgIV (0,4g/kg/día durante 5 días) y la PE (200-250ml/kg en 5 sesiones) son tratamientos igualmente eficaces para el SGB. La guía indica que ambos tratamientos conllevan riesgos comparables a eventos adversos, aunque la PE tiene más probabilidades de interrumpirse que la IgIV. Debido a esto, y dado que la IgIV también es más fácil de administrar y, en general, tiene una mayor disponibilidad que la plasmaféresis, suele ser el tratamiento de elección. La guía también indica que aunque la evidencia en embarazadas y niños es limitada, no existen contraindicaciones de estos tratamientos en estos grupos. Sin embargo, dado que la PE requiere consideraciones y seguimiento adicionales, y como la PE solo está disponible en centros con experiencia. en su uso y parece producir mayor malestar y mayores tasas de complicaciones que la IgIV en niños, se tiende a preferir el uso de IgIV en estos grupos. Estas recomendaciones coinciden con las descritas en la guía de práctica clínica para el SGB en niños y adolescentes desarrollada por expertos en Alemania, publicada en enero de 2020. Adicionalmente, esta guía indica que en caso de contraindicaciones a la IgIV en niños y adolescentes con SGB severo, o si el tratamiento con IgIV es ineficaz, se recomienda el uso de PE, aunque no se recomienda el inicio de la PE en las 2 semanas precedentes al tratamiento con IgIV. Se encontraron otras 4 GPC internacionales: guía publicada en 2021 en Brasil por la CONITEC (por sus siglas en portugués Comissão Nacional de Incorporação de Tecnologias no SUS), guía internacional publicada en 2016 por la Organización Mundial de la Salud (OMS), guía europea publicada en 2008 por la EFNS (por sus siglas en inglés European Federation of the Neurological Societies), y guía publicada en 2003 en los Estados Unidos por la AAN (por sus siglas en inglés American Academy of Neurology). Todas estas guías coinciden con las recomendaciones descritas anteriormente. Cabe recalcar que la guía publicada por la OMS es la única en la que se encontró recomendaciones para el diagnóstico y manejo del SGB relacionado específicamente a infección previa por ZIKV. En este contexto, y después de recomendar el uso de IgIV y la PE debido a su misma eficacia, la OMS recomendó lo siguiente: 1) la selección del tratamiento debe basarse en la disponibilidad, costo y viabilidad de la administración, 2) se requiere entrenamiento en la administración apropiada de ambos tratamientos, y 3) antes de la administración de IgIV debe realizarse un muestreo de sangre para el ZIKV y otros flavivirus. También se encontraron dos GPC recientes para SGB peruanas: la primera publicada en 2018 por la oficina de calidad y el servicio de Neurocirugía del Instituto Nacional de Ciencias Neurológicas (INCN) del Ministerio de Salud (MINSA), y la segunda publicada en 2019 por el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI). Ambas guías coinciden con las recomendaciones en las guías anteriores. Se seleccionó un estudio de minimización de costos entre el uso de la IgIV vs. PE en pacientes con SGB realizado en Colombia y publicado en 2016. El estudio encontró una diferencia significativa (p=0,002) en el costo total de la atención de los pacientes tratados con IgIV (9,976 US$) comparado con PE (23,354 US$). El costo de la atención de los pacientes tratados con PE se vio afectado por el alto costo en cuanto a complicaciones y mayor estancia hospitalaria en este grupo, ya que no se encontraron diferencias significativas en el costo del procedimiento. Por otro lado, un estudio de minimización de costos en Brasil concluyó que los costos directos estimados para el tratamiento con IgIV eran significativamente mayores al tratamiento con PE. Sin embargo, este estudio solamente incluyó los costos directos del tratamiento con IgIV o PE, y excluyó costos indirectos como aquellos relacionados con complicaciones del tratamento. CONCLUSIONES: La evidencia con respeto al tratamiento del SGB con inmunoglobulina intravenosa (IgIV) o plasmaféresis (PE) en adultos es abundante y se basa en ensayos clínicos aleatorizados y noaleatorizados. No hay evidencia que el tratamiento del SGB relacionado a infección previa por Zika debe ser distinto al tratamiento estándar del SGB. Una RS analizando ECAs publicados indicó que ambos tratamientos son igual de eficaces para el tratamiento del SGB, y que el uso de distintas dosis o combinación de tratamientos no demostraron tener un beneficio significativo ante el tratamiento estándar de PE o de IgIV. Por otro lado, estudios observacionales indican que las complicaciones y el tiempo de hospitalización en pacientes tratados con PE son mayores, lo que también afecta a los costos totales del paciente, siendo mayores en pacientes tratados con PE comparado con aquellos tratados con IgIV, a pesar de que los costos directos del medicamento y sanitarios sean menores para el tratamiento con PE. Debido a esto, la mayoría de las GPC nacionales e internacionales recomiendan el tratamiento del SGB con IgIV o PE de acuerdo a la disponibilidad, costo, viabilidad de la administración y ausencia de contraindicaciones a los tratamentos. La evidencia con respeto al tratamiento del SGB con IgIV o PE en embarazadas y niños es limitada, aunque no hay evidencia actual de contraindicaciones de estos tratamientos en estos grupos. A pesar de ello, por su mayor facilidad de administración y tolerancia, tiende a haber una preferencia para el uso de IgIV en embarazadas y niños.

Pathophysiological and molecular considerations of viral and bacterial infections during maternal-fetal and -neonatal interactions of SARS-CoV-2, Zika, and Mycoplasma infectious diseases.

During pregnancy, a series of physiological changes are determined at the molecular, cellular and macroscopic level that make the mother and fetus more susceptible to certain viral and bacterial infections, especially the infections in this and the companion review. Particular situations increase susceptibility to infection in neonates. The enhanced susceptibility to certain infections increases the risk of developing particular diseases that can progress to become morbidly severe. For example, during the current pandemic caused by the SARS-CoV-2 virus, epidemiological studies have established that pregnant women with COVID-19 disease are more likely to be hospitalized. However, the risk for intensive care unit admission and mechanical ventilation is not increased compared with nonpregnant women. Although much remains unknown with this particular infection, the elevated risk of progression during pregnancy towards more severe manifestations of COVID-19 disease is not associated with an increased risk of death. In addition, the epidemiological data available in neonates suggest that their risk of acquiring COVID-19 is low compared with infants (<12 months of age). However, they might be at higher risk for progression to severe COVID-19 disease compared with older children. The data on clinical presentation and disease severity among neonates are limited and based on case reports and small case series. It is well documented the importance of the Zika virus infection as the main cause of several congenital anomalies and birth defects such as microcephaly, and also adverse pregnancy outcomes. Mycoplasma infections also increase adverse pregnancy outcomes. This review will focus on the molecular, pathophysiological and biophysical characteristics of the mother/placental-fetal/neonatal interactions and the possible mechanisms of these pathogens (SARS-CoV-2, ZIKV, and Mycoplasmas) for promoting disease at this level.

Is the ZIKV Congenital Syndrome and Microcephaly Due to Syndemism with Latent Virus Coinfection?

The emergence of the Zika virus (ZIKV) mirrors its evolutionary nature and, thus, its ability to grow in diversity or complexity (i.e., related to genome, host response, environment changes, tropism, and pathogenicity), leading to it recently joining the circle of closed congenital pathogens. The causal relation of ZIKV to microcephaly is still a much-debated issue. The identification of outbreak foci being in certain endemic urban areas characterized by a high-density population emphasizes that mixed infections might spearhead the recent appearance of a wide range of diseases that were initially attributed to ZIKV. Globally, such coinfections may have both positive and negative effects on viral replication, tropism, host response, and the viral genome. In other words, the possibility of coinfection may necessitate revisiting what is considered to be known regarding the pathogenesis and epidemiology of ZIKV diseases. ZIKV viral coinfections are already being reported with other arboviruses (e.g., chikungunya virus (CHIKV) and dengue virus (DENV)) as well as congenital pathogens (e.g., human immunodeficiency virus (HIV) and cytomegalovirus (HCMV)). However, descriptions of human latent viruses and their impacts on ZIKV disease outcomes in hosts are currently lacking. This review proposes to select some interesting human latent viruses (i.e., herpes simplex virus 2 (HSV-2), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), human parvovirus B19 (B19V), and human papillomavirus (HPV)), whose virological features and co-exposition with ZIKV may provide evidence of the syndemism process, shedding some light on the emergence of the ZIKV-induced global congenital syndrome in South America.

Zika virus protease induces caspase-independent pyroptotic cell death by directly cleaving gasdermin D.

The association of Zika virus (ZIKV) infection with a congenital malformation in fetuses, neurological, and other systemic complications in adults have brought significant global health emergency. ZIKV targets nerve cells in the brain and causes cell death, such as pyroptosis, leading to neuroinflammation. Here we described a novel mechanism of pyroptosis caused by ZIKV protease. We found that ZIKV protease directly cleaved the GSDMD into N-terminal fragment (1-249) leading to pyroptosis in a caspase-independent manner, suggesting a direct mechanism of ZIKV-induced cell death and subsequent inflammation. Our findings might shed new light to explore the pathogenesis of ZIKV infections where ZIKV protease might be a suitable target for the development of antiviral agents.

Changes in the dynamics of dengue incidence in South and Central America are possibly due to cross-population immunity after Zika virus epidemics.

OBJECTIVE: We tested the hypothesis that Zika virus (ZIKV) immunity may protect against dengue virus (DENV) infection, disease severity or human amplification, based on analysis of epidemiological data from our long-term surveillance study (2009-2016) in the city of Salvador, Brazil, that indicated a substantial reduction in the frequency of laboratory-confirmed dengue cases following the Zika outbreak. To assess whether similar patterns were observed across the Americas, we did a broader explorative investigation of historical series (2004 to 2019) of suspected cases of dengue fever, covering 20 DENV-endemic South and Central American countries. METHODS: We used segmented linear regressions of single group interrupted time series (ITS) analysis to evaluate whether the Zika epidemic had a statistical effect on the trends of annual dengue incidence. RESULTS: We observed in our 16-year historical series that in all countries, the incidence of dengue exhibited periodic oscillations over time, with a general trend of statistically significant increase during the pre-Zika period overall and for 11 of the 20 countries. Following the peak of the first population exposure to ZIKV in the Americas, in 2016, the overall rate of reported dengue cases in 2017 and 2018 in the countries under study sharply dropped (P < 0.05) and was the lowest reported since 2005. Individually in each country, a statistically significant reduction in the annual dengue incidence beginning in 2016 or in 2017-2018 occurred in 13 of the 20 studied countries. However, in 2019, reports of suspected dengue cases increased across the Americas. In Brazil, Dominican Republic, Guatemala and Honduras, dengue incidence was >5 times higher in 2019 than in 2017 and 2018, and, in 2019, they had the greater dengue incidence than in all previous years throughout the historical series. CONCLUSIONS: The widespread decline in suspected dengue cases recorded in 2017 and 2018 lends further support to our previous epidemiological hypothesis of ZIKV-induced cross-species immunity to DENV. However, the cross-protection appears to be transient (around 2 years). Long-term, prospective follow-ups of dengue reports are needed to confirm (or refute) these findings, which could have significant public health implications, in particular regarding DENV vaccine development and application.

CONTEXTE: Nous avons émis l'hypothèse que l'immunité contre le virus Zika (ZIKV) pourrait protéger contre l'infection par le virus de la dengue (DENV), la sévérité de la maladie ou l'amplification humaine, sur la base de l'analyse des données épidémiologiques de notre étude de surveillance à long terme (2009-2016) dans la ville de Salvador, au Brésil, qui a indiqué une réduction substantielle de la fréquence des cas de dengue confirmés en laboratoire à la suite de l'épidémie de Zika. MÉTHODES: Pour évaluer si des tendances similaires ont été observées dans les Amériques, nous avons mené une enquête exploratoire plus large sur des séries historiques (2004 à 2019) de cas suspects de dengue, couvrant 20 pays d'Amérique du Sud et d'Amérique centrale endémiques pour DENV. Nous avons utilisé des régressions linéaires segmentées de l'analyse des séries chronologiques interrompues pour un seul groupe pour évaluer si l'épidémie de Zika avait un effet statistique sur les tendances de l'incidence annuelle de la dengue. RÉSULTATS: Nous avons observé dans notre série historique de 16 ans que dans tous les pays, l'incidence de la dengue présentait des oscillations périodiques au fil du temps, avec une tendance générale à une augmentation statistiquement significative pendant la période pré-Zika en général et pour 11 des 20 pays. Après le pic de la première exposition de la population au ZIKV dans les Amériques en 2016, le taux global des cas de dengue rapportés en 2017 et 2018 dans les pays étudiés a fortement diminué (p <0,05) et était le plus bas depuis 2005. Individuellement dans chaque pays, une réduction statistiquement significative de l'incidence annuelle de la dengue à partir de 2016 ou en 2017-2018 s'est produite dans 13 des 20 pays étudiés. Cependant, en 2019, les reports de cas suspects de dengue ont augmenté dans les Amériques. Dans des pays comme le Brésil, la République Dominicaine, le Guatemala et le Honduras, l'incidence de la dengue était >5 fois plus élevée en 2019 qu'en 2017 et 2018, et, en 2019, l'incidence de la dengue était plus élevée qu'au cours de toutes les années précédentes de la série historique. CONCLUSIONS: Le déclin généralisé des cas suspects de dengue enregistrés en 2017 et 2018 vient étayer notre hypothèse épidémiologique précédente de l'immunité inter-espèces induite par le ZIKV contre le DENV. Cependant, la protection croisée semble être transitoire (environ 2 ans). Des suivis prospectifs à long terme des reports sur la dengue sont nécessaires pour confirmer (ou réfuter) ces résultats, qui pourraient avoir des implications importantes pour la santé publique, en particulier en ce qui concerne le développement et l'application d'un vaccin DENV.

DZC DIAG: mobile application based on expert system to aid in the diagnosis of dengue, Zika, and chikungunya.

Dengue, Zika, and chikungunya are epidemic diseases transmitted by the Aedes mosquito. These virus infections can be so severe to the point of bringing on mobility and neurological problems, or even death. Expert systems (ES) can be used as tools for the identification of patterns intended to solve problems in the same way as a professional specialist would. This work aimed to develop an ES in the form of an Android application to serve as a supportive tool in the diagnosis of these arboviruses. The goal is to associate the set of symptoms from a patient to a score related to the likelihood of them having these diseases. To make this possible, we implemented a rule-based ES which considers the presence of symptoms itself and the relation between them to associate the case under analysis to others found in the literature. We performed 96 tests (32 for each illness), and our system had a success rate of 96.88%. Resident physicians of a public hospital also analyzed these clinical cases and achieved an average success rate of 72.92%. Comparing the results of the method proposed and errors made by health professionals, we showed an improvement in the effectiveness of clinical diagnoses. Graphical abstract Figure - DZC DIAG Operating Flowchart: the physicians record patients' data and answer a series of questions related to the patient's symptoms; after all the questions, the result is generated by the expert system (score for dengue, Zika, and chikungunya); and it is saved in the same device where the test was done and uploaded online to a FTP.

Evolutionary analysis of the Musashi family: What can it tell us about Zika?

Despite worldwide research efforts since 2015, Zika virus infection and its consequences are not fully understood yet. Nowadays, it is known that microcephaly is only one of the possible outcomes of being infected by ZIKV during the early stages of life. Musashi 1 (MSI1) is an RNA-binding protein that is involved in neurodevelopmental processes. Also, ZIKV genome (a single-stranded positive-sense RNA) uses MSI1 for its replication. Here we perform an evolutionary analysis of MSI1 coding sequence and their orthologs in vertebrate species. We added original sequencing data from selected regions of interest (RNA-binding domains-RBDs of MSI1) of sixteen Platyrrhini (or New World monkeys), known to have high evolutionary rates. The Musashi family (MF) includes MSI2, TARDBP, DAZAP1, HNRNPD, HNRNPDL, and HNRNPAB, which do not interact with the virus but are critical RNA-binding proteins that act on many regulatory processes ubiquitously. We found that all sixteen primate species have the RBD1 of MSI1 conserved. While the general code sequences of MF genes are under purifying selection, the evolution of regulatory mechanisms, especially alternative splicing, seems to be a frequent phenomenon in these genes. Different isoforms differ in the N-terminal region and it affects protein size. Existing MSI1 isoforms probably diverge in their binding affinity, the kinetics of interaction, and other aspects when in the MSI1-ZIKV complex. It is a signal that some RBD-containing MSI1 isoforms can be incompatible to ZIKV binding and replication. Consequently, the chance of ZIKV successfully infecting host cells could also be associated with alternative splicing and expression of ZIKV-compatible MSI1 isoforms in both inter and intraspecific levels.

IL-27 signaling activates skin cells to induce innate antiviral proteins and protects against Zika virus infection.

In the skin, antiviral proteins and other immune molecules serve as the first line of innate antiviral defense. Here, we identify and characterize the induction of cutaneous innate antiviral proteins in response to IL-27 and its functional role during cutaneous defense against Zika virus infection. Transcriptional and phenotypic profiling of epidermal keratinocytes treated with IL-27 demonstrated activation of antiviral proteins OAS1, OAS2, OASL, and MX1 in the skin of both mice and humans. IL-27-mediated antiviral protein induction was found to occur in a STAT1- and IRF3-dependent but STAT2-independent manner. Moreover, using IL27ra mice, we demonstrate a significant role for IL-27 in inhibiting Zika virus morbidity and mortality following cutaneous, but not intravenous, inoculation. Together, our results demonstrate a critical and previously unrecognized role for IL-27 in cutaneous innate antiviral immunity against Zika virus.

Entomological Surveillance Associated with Human Zika Cases in Miri Sarawak, Malaysia.

Two confirmed human cases of Zika virus (ZIKV) were reported in the district of Miri, Sarawak, in 2016. Following that, a mosquito-based ZIKV surveillance study was conducted within 200-m radius from the case houses. Mosquito surveillance was conducted using five different methods, that is, biogents sentinel mosquito (BG) sentinel trap, modified sticky ovitrap, resting catch, larval surveillance, and conventional ovitrap. A total of 527 and 390 mosquito samples were obtained from the case houses in two localities, namely, Kampung Lopeng and Taman Shang Ri La, Miri, Sarawak, respectively. All mosquitoes collected were identified, which consisted of 11 species. Aedes albopictus, both the adult and larval stages, was the dominant species. Resting catch method obtained the highest number of adult mosquitoes (67%), whereas ovitrap showed the highest catch for larval mosquitoes (84%). Zika virus was detected in both adults and larvae of Ae. albopictus together with adults of Culex gelidus, and Culex quinquefasciatus using the real-time reverse transcriptase polymerase chain reaction (PCR) technique. It was noteworthy that Ae. albopictus positive with ZIKV were caught and obtained from four types of collection method. By contrast, Cx. gelidus and Culex quinquefasciatus adults collected from sticky ovitraps were also found positive with ZIKV. This study reveals vital information regarding the potential vectors of ZIKV and the possibility of transovarian transmission of the virus in Malaysia. These findings will be essentials for vector control program managers to devise preparedness and contingency plans of prevention and control of the arboviral disease.

Neonatal surveillance for congenital Zika infection during the 2016 microcephaly outbreak in Salvador, Brazil: Zika virus detection in asymptomatic newborns.

OBJECTIVE: To identify newborns with congenital Zika infection (CZI) at a maternity hospital in Salvador, Brazil, during the 2016 microcephaly outbreak. METHODS: A prospective study enrolled microcephalic and normocephalic newborns with suspected CZI between January and December 2016. Serology (immunoglobulins IgM and IgG) and quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) for the Zika virus were performed. Demographic and clinical characteristics of newborns with and without microcephaly were compared. RESULTS: Of the 151 newborns enrolled, 32 (21.2%) were classified as microcephalic. The majority of these cases were born between January and May 2016. IgM and IgG Zika virus antibodies were detected in 5 (23.8%) and 17 (80.9%) microcephalic newborn blood samples, respectively. Six (24%) microcephalic newborns tested positive for Zika virus by RT-qPCR in urine or placenta samples. Thirteen (11.8%) normocephalic newborns also tested positive for Zika virus by PCR in urine, plasma, or placenta samples, while IgM antibodies against Zika were detected in 4 (4.2%) others. CONCLUSIONS: Identification of 17 normocephalic CZI cases, confirmed by IgM serology or RT-qPCR for Zika virus, provides evidence that CZI can present asymptomatically at birth. This finding highlights the need for prenatal and neonatal screening for Zika virus in endemic regions.

Summit proceedings: Biomedical countermeasure development for emerging vector-borne viral diseases.

Emerging and re-emerging infectious diseases are an expanding global threat to public health, security, and economies. Increasing populations, urbanization, deforestation, climate change, anti-vaccination movements, war, and international travel are some of the contributing factors to this trend. The recent Ebola, MERS-CoV, and Zika outbreaks demonstrated we are insufficiently prepared to respond with proven safe and effective countermeasures (i.e., vaccines and therapeutics). The State University of New York Upstate Medical University and the Trudeau Institute convened a summit of key opinion and thought leaders in the life sciences and biomedical research and development enterprises to explore global biopreparedness challenges, take an inventory of existing capabilities and capacities related to preparation and response, assess current "gaps," and prospect what could be done to improve our position. Herein we describe the summit proceedings, "Translational Immunology Supporting Biomedical Countermeasure Development for Emerging Vector-borne Viral Diseases," held October 2-3, 2018, at the Trudeau Institute in Saranac Lake, NY.

Knowledge and attitude towards pregnancy-related issues of Zika virus infection among general practitioners in Indonesia.

BACKGROUND: The aim of this study was to assess the knowledge and attitudes towards pregnancy-related issues of Zika virus (ZIKV) infection among general practitioners (GPs), a frontline healthcare worker group, in Indonesia. METHODS: A cross-sectional, online survey assessing knowledge and attitudes towards ZIKV infection on multiple-item scales was sent to GPs in the Sumatra and Java islands of Indonesia. The associations between independent factors and either knowledge or attitude were assessed with logistic regressions. The correlation and association between knowledge and attitude were estimated. RESULTS: We included 457 (53.7%) out of 850 responses in the analysis. Among these, 304 (66.5%) and 111 (24.2%) respondents had a good knowledge and attitude, respectively. No demographic, workplace, professional development, or experiential characteristics related to ZIKV infection were associated with knowledge. In the multivariate analysis, only contact experience was associated with attitude. There was a significant, positive correlation between knowledge and attitude scores. CONCLUSIONS: Although knowledge of pregnancy-related complications of ZIKV infection is relatively high among GPs in Indonesia, more than 75% of them had a poor attitude towards pregnancy-related issues of Zika. Strategies for enhancing the capacity of GPs to develop positive attitudes and respond to ZIKV infection are needed.

Conocimientos y actitudes sobre el zika en gestantes del sur de Lima, Perú / Knowledge and attitudes about Zika in pregnant women from the south of Lima, Peru

RESUMEN OBJETIVOS: determinar el conocimiento y las actitudes sobre el Zika en gestantes del sur de Lima MÉTODO: Estudio transversal analítico. Se incluyeron gestantes que acudieron al establecimiento de Salud Materno Infantil de Villa María del Triunfo durante octubre del 2017. RESULTADOS: Participaron 97 gestantes, la edad promedio fue de 28,23±7,9. El mayor grupo de edad fue de 16-28 años (54,6%). Al realizar la categorización del nivel de conocimientos, apreciamos que la mayoría tuvo conocimientos buenos sobre la enfermedad (78,4%) y todas tuvieron actitudes positivas. Las gestantes con mayor nivel educativo tuvieron un mejor conocimiento de la enfermedad (p<0,001) CONCLUSIONES: El conocimiento y las actitudes de las gestantes sobre el zika, fueron por lo general buenos.

ABSTRACT OBJECTIVES: To determine knowledge and attitudes about Zika in pregnant women from southern Lima. METHOD: Cross-sectional analytical study. Pregnant women were included who attended the Maternal and Child Health center in Villa María del Triunfo during October 2017. RESULTS: 97 pregnant women participated, the average age was 28.23 ± 7.9. The largest age group was 16-28 years (54.6%). When categorizing the level of knowledge, we appreciate that most had good knowledge about the disease (78.4%) and all had positive attitudes. Pregnant women with a higher educational level had a better knowledge of the disease (p <0.001). CONCLUSIONS: The knowledge and attitudes of the pregnant women about Zika were generally good.

In silico analysis revealed Zika virus miRNAs associated with viral pathogenesis through alteration of host genes involved in immune response and neurological functions.

BACKGROUND: The concurrent Zika Virus (ZIKV) outbreaks in the United States and Northeast Brazil have evoked global surveillance. Zika infection has been correlated with severe clinical symptoms, such as microcephaly, Guillain-Barré syndrome, and other congenital brain abnormalities. Recent data suggest that ZIKV predominantly targets neural progenitor cells leading to neurological impairment. Despite the clinical evidence, detailed experimental mechanism of ZIKV neurotropic pathogenesis has not been fully understood yet. Here we hypothesized that ZIKV produces miRNAs, which target essential host genes involved in various cellular pathways facilitating their survival through immune evasion and progression of disease during brain development. METHODS: From genome sequence information using several bioinformatic tools, we predicted pri-miRNAs, pre-miRNAs, and finally the mature miRNAs produced by ZIKV. We also identified their target genes and performed functional enrichment analysis to identify the biological processes associated with these genes. Finally, we analyzed a publicly available RNA-seq data set to determine the altered expression level of the targeted genes. RESULTS: From ZIKV genome sequence, we identified and validated 47 putative novel miRNAs. Functional enrichment of the targeted genes demonstrates the involvement of various biological pathways regulating cellular signaling, neurological functions, cancer, and fetal development. The expression analysis of these genes showed that ZIKV-produced miRNAs downregulate the key genes involved in these pathways, which in turn may lead to impaired brain development. CONCLUSIONS: Our finding proposes novel ZIKV miRNAs and their targets, which upon experimental validation could help developing new therapeutics to combat ZIKV infection and minimize ZIKV-mediated pathologies.

VECTOS: An Integrated System for Monitoring Risk Factors Associated With Urban Arbovirus Transmission.

In Colombia, as in many Latin American countries, decision making and development of effective strategies for vector control of urban diseases such as dengue, Zika, and chikungunya is challenging for local health authorities. The heterogeneity of transmission in urban areas requires an efficient risk-based allocation of resources to control measures. With the objective of strengthening the capacity of local surveillance systems to identify variables that favor urban arboviral transmission, a multidisciplinary research team collaborated with the local Secretary of Health officials of 3 municipalities in Colombia (Giron, Yopal, and Buga), in the design of an integrated information system called VECTOS from 2015 to 2018. Information and communication technologies were used to develop 2 mobile applications to capture entomological and social information, as well as a web-based system for the collection, geo-referencing, and integrated information analysis using free geospatial software. This system facilitates the capture and analysis of epidemiological information from the Colombian national surveillance system (SIVIGILA), periodic entomological surveys-mosquito larvae and pupae in premises and peridomestic breeding sites-and surveys of knowledge, attitudes, and practices (KAP) in a spatial and temporal context at the neighborhood level. The data collected in VECTOS are mapped and visualized in graphical reports. The system enables real-time monitoring of weekly epidemiological indicators, entomological indices, and social surveys. Additionally, the system enables risk stratification of neighborhoods, using selected epidemiological, entomological, demographic, and environmental variables. This article describes the VECTOS system and the lessons learned during its development and use. The joint analysis of epidemiological and entomological data within a geographic information system in VECTOS gives better insight to the routinely collected data and identifies the heterogeneity of risk factors between neighborhoods. We expect the system to continue to strengthen vector control programs in evidence-based decision making and in the design and enhanced follow-up of vector control strategies.

Zika virus infection in Malaysia: an epidemiological, clinical and virological analysis.

BACKGROUND: A major outbreak of the Zika virus (ZIKV) has been reported in Brazil in 2015. Since then, it spread further to other countries in the Americas and resulted in declaration of the Public Health Emergency of International Concern (PHEIC) by World Health Organization. In 2016, Singapore reported its first minor ZIKV epidemic. Malaysia shares similar ecological environment as Brazil and Singapore which may also favor ZIKV transmission. However, no ZIKV outbreak has been reported in Malaysia to date. This study aimed to discuss all confirmed ZIKV cases captured under Malaysia ZIKV surveillance system after declaration of the PHEIC; and explore why Malaysia did not suffer a similar ZIKV outbreak as the other two countries. METHODS: This was an observational study reviewing all confirmed ZIKV cases detected in Malaysia through the ZIKV clinical surveillance and Flavivirus laboratory surveillance between June 2015 and December 2017. All basic demographic characteristics, co-morbidities, clinical, laboratory and outcome data of the confirmed ZIKV cases were collected from the source documents. RESULTS: Only eight out of 4043 cases tested positive for ZIKV infection during that period. The median age of infected patients was 48.6 years and majority was Chinese. Two of the subjects were pregnant. The median interval between the onset of disease and the first detection of ZIKV Ribonucleic Acid (RNA) in body fluid was 3 days. Six cases had ZIKV RNA detected in both serum and urine samples. Phylogenetic analysis suggests that isolates from the 7 cases of ZIKV infection came from two clusters, both of which were local circulating strains. CONCLUSION: Despite similar ecological background characteristics, Malaysia was not as affected by the recent ZIKV outbreak compared to Brazil and Singapore. This could be related to pre-existing immunity against ZIKV in this population, which developed after the first introduction of the ZIKV in Malaysia decades ago. A serosurvey to determine the seroprevalence of ZIKV in Malaysia was carried out in 2017. The differences in circulating ZIKV strains could be another reason as to why Malaysia seemed to be protected from an outbreak.

Encefalitis por virus Zika / Zika virus encephalitis

No disponible

Prior dengue virus infection and risk of Zika: A pediatric cohort in Nicaragua.

BACKGROUND: Zika virus (ZIKV) emerged in northeast Brazil in 2015 and spread rapidly across the Americas, in populations that have been largely exposed to dengue virus (DENV). The impact of prior DENV infection on ZIKV infection outcome remains unclear. To study this potential impact, we analyzed the large 2016 Zika epidemic in Managua, Nicaragua, in a pediatric cohort with well-characterized DENV infection histories. METHODS AND FINDINGS: Symptomatic ZIKV infections (Zika cases) were identified by real-time reverse transcription PCR and serology in a community-based cohort study that follows approximately 3,700 children aged 2-14 years old. Annual blood samples were used to identify clinically inapparent ZIKV infections using a novel, well-characterized serological assay. Multivariable Poisson regression was used to examine the relation between prior DENV infection and incidence of symptomatic and inapparent ZIKV infection. The generalized-growth method was used to estimate the effective reproduction number. From January 1, 2016, to February 28, 2017, 560 symptomatic ZIKV infections and 1,356 total ZIKV infections (symptomatic and inapparent) were identified, for an overall incidence of 14.0 symptomatic infections (95% CI: 12.9, 15.2) and 36.5 total infections (95% CI: 34.7, 38.6) per 100 person-years. Effective reproduction number estimates ranged from 3.3 to 3.4, depending on the ascending wave period. Incidence of symptomatic and total ZIKV infections was higher in females and older children. Analysis of the effect of prior DENV infection was performed on 3,027 participants with documented DENV infection histories, of which 743 (24.5%) had experienced at least 1 prior DENV infection during cohort follow-up. Prior DENV infection was inversely associated with risk of symptomatic ZIKV infection in the total cohort population (incidence rate ratio [IRR]: 0.63; 95% CI: 0.48, 0.81; p < 0.005) and with risk of symptomatic presentation given ZIKV infection (IRR: 0.62; 95% CI: 0.44, 0.86) when adjusted for age, sex, and recent DENV infection (1-2 years before ZIKV infection). Recent DENV infection was significantly associated with decreased risk of symptomatic ZIKV infection when adjusted for age and sex, but not when adjusted for prior DENV infection. Prior or recent DENV infection did not affect the rate of total ZIKV infections. Our findings are limited to a pediatric population and constrained by the epidemiology of the site. CONCLUSIONS: These findings support that prior DENV infection may protect individuals from symptomatic Zika. More research is needed to address the possible immunological mechanism(s) of cross-protection between ZIKV and DENV and whether DENV immunity also modulates other ZIKV infection outcomes such as neurological or congenital syndromes.

Animal Models of Zika Virus Infection during Pregnancy.

Zika virus (ZIKV) emerged suddenly in the Americas in 2015 and was associated with a widespread outbreak of microcephaly and other severe congenital abnormalities in infants born to mothers infected during pregnancy. Vertical transmission of ZIKV in humans was confirmed when viral RNA was detected in fetal and placental tissues, and this outcome has been recapitulated experimentally in animals. Unlike other flaviviruses, ZIKV is both arthropod- and sexually-transmitted, and has a broad tissue tropism in humans, including multiple tissues of the reproductive tract. The threats posed by ZIKV have prompted the development of multiple in vivo models to better understand the pathogenesis of ZIKV, particularly during pregnancy. Here, we review the progress on animal models of ZIKV infection during pregnancy. These studies have generated a foundation of insights into the biology of ZIKV, and provide a means for evaluating vaccines and therapeutics.