Yellow fever in Brazil: new insights on an old disease

巴西黄热病：对一种古老疾病的新见解

• 批准号: 9890124
• 负责人: OLINDO ASSIS MARTINS FILHO
• 金额: $ 15.74万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-18 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890124
• 关键词: Acute; Adult; Africa; Americas; Angola; Antibody Response; Antiviral Agents; Area; Bilirubin; Biological; Biology; Brazil; Caring; Cause of Death; Cellular Immunity; Cessation of life; Clinical; Clinical Data; Communicable Diseases; Convalescence; Data; Data Set; Databases; Democratic Republic of the Congo; Development; Disease; Disease Outbreaks; Disease Outcome; Epidemic; Epidemiology; Fever; Flaviviridae; Flavivirus; Functional disorder; Future; Hepatic; Hepatitis; Hospitals; Human; IL8 gene; Immune response; Immunologic Markers; Immunologics; Immunology; In Vitro; Infection; Inflammation Mediators; Inflammatory; Interleukin-10; Investigation; Knowledge; Label; Laboratories; Life; Longterm Follow-up; MEKs; Measures; Mediator of activation protein; Medical; Morbidity - disease rate; Names; Outcome; Oxidative Stress; Pathogenesis; Patient-Focused Outcomes; Patients; Pattern; Peripheral Blood Mononuclear Cell; Pharmacology; Phase; Predictive Factor; Preventative vaccination; Prevention; Preventive vaccine; Protocols documentation; Public Health; RANTES; Reporting; Research; Risk Factors; Sampling; South Africa; South America; Syndrome; TNF gene; Testing; Therapeutic; Time; Transaminases; Viral; Yellow Fever; Yellow Fever Virus Infection; Yellow fever virus; biobank; clinical care; clinically significant; cohort; comorbidity; data warehouse; epidemiologic data; experience; follow-up; holistic approach; in vivo; inhibitor/antagonist; insight; interdisciplinary approach; longitudinal database; molecular marker; mortality; mouse model; neutralizing antibody; novel; off-label use; outcome forecast; pathogen; predictive marker; preservation; prevent; social; virology

ABSTRACT Yellow fever virus (YFV) is widely distributed in the tropics of South America and Africa, being responsible for massive yellow fever outbreaks causing deaths of thousands of people in recent years. YF usually occurs in remote areas of Africa and the Americas where patients have little or no access to advanced medical care and laboratory tests; therefore, much of what we know about YF in humans is very limited including poorly understood epidemiology, pathogenesis, therapeutic approaches, and host/virological determinants of disease during different phases of infection. In December 2016, a massive sylvatic YF outbreak (2,155 human cases) took place in Southeast Brazil, with 46% of total cases (n=1,002) and 37% of deaths (n=340) occuring in Minas Gerais state. From 2016 to 2018, a total of 299 confirmed YF cases were admitted at Eduardo de Menezes Hospital, in Belo Horizonte, Minas Gerais. Our group has maintained a database containing epidemiological and clinical data with long-term follow up from those patients, as well a biological bank of clinical samples that can be probed to redefine the clinical course and pathogenesis of this important pathogen. Our unique well-characterized cohorts include: (i) patients who evolved to death; (ii) patients who recovered; (iii) patients who recovered and developed a novel clinical syndrome named late hepatitis-like syndrome after yellow fever (LHep-YF); and (iv) patients who received off-label treatment with sofosbuvir. Here we propose to (i) redefine the clinical course of YF and determine the social, demographic, and co-morbid risk factors for severe presentations of disease, including development of LHep-YF, (ii) investigate the viral and immunologic pathogenesis of YF throughout the continuum of disease and (iii) predict YF prognosis by identifying virological and immunological biomarkers associated with severe disease and assessing the effects of potential treatments. Our experienced research team will take an interdisciplinary approach that integrates basic and applied virology, immunology, epidemiology, and clinical infectious disease to fill important gaps on epidemiology, clinical disease, pathophysiology, and biology of YFV. The recent YFV outbreaks in Southeast Brazil create an unprecedented opportunity to analyze our unique bank of data and well-preserved samples from hundreds of hospitalized YF patients. This information will be crucial for the establishment of protocols and more applied studies to prevent morbidity and mortality from this important pathogen.

抽象的 黄热病病毒（YFV）广泛分布在南美和非洲的热带地区 近年来导致数千人死亡的大规模黄热病暴发。是的 通常发生在非洲和美洲的偏远地区 先进的医疗和实验室测试；因此，我们对人类中YF的了解大部分是非常 限制包括知识的流行病学，发病机理，治疗方法和 在不同阶段的感染阶段，宿主/病毒学决定因素。 2016年12月，一个大规模 Sylvatic YF爆发（2,155例人类案件）在巴西东南部发生，其中46％的总案例（n = 1,002） 在Minas Gerais州发生的37％的死亡（n = 340）。从2016年到2018年，共有299个确认的YF 病例在Minas Gerais的Belo Horizo​​nte的Eduardo de Menezes医院被录用。我们的小组有 维护一个包含流行病学和临床数据的数据库，并从中进行了长期跟进 患者以及一个可以探测以重新定义临床过程的临床样本的生物库 这种重要病原体的发病机理。我们独特的特征良好的队列包括：（i）患者 演变为死亡； （ii）康复的患者； （iii）恢复并开发新临床的患者 黄热病（LHEP-YF）以黄热病（LHEP-YF）称为晚期乙型肝炎综合征； （iv）接受的患者 Sofosbuvir的标签外处理。在这里，我们建议（i）重新定义YF的临床过程并确定 严重表现疾病的社会，人口和合并风险因素，包括 LHEP-YF的发展，（ii）研究YF的病毒和免疫发病机理 疾病的连续性和（iii）通过鉴定病毒学和免疫生物标志物来预测YF预后 与严重疾病有关并评估潜在治疗的影响。我们经验丰富的 研究团队将采用跨学科的方法，以整合基本和应用的病毒学， 免疫学，流行病学和临床传染病，以填补有关流行病学的重要空白 YFV的疾病，病理生理学和生物学。巴西东南部最近发生的YFV爆发创造了 前所未有的机会，可以分析我们独特的数据银行和数百个保存完好的样本 住院的YF患者。这些信息对于建立协议以及更多信息至关重要 应用研究以防止这种重要病原体的发病率和死亡率。