Yellow fever in Brazil: new insights on an old disease

摘要 黄热病病毒(YFV)广泛分布于南美洲和非洲的热带地区， 近年来，大规模黄热病暴发导致数千人死亡。YF 通常发生在非洲和美洲的偏远地区，那里的患者很少或根本无法接触到 先进的医疗保健和实验室测试；因此，我们对YF在人类身上的大部分了解是非常 有限，包括对流行病学、发病机制、治疗方法和 感染不同阶段疾病的宿主/病毒学决定因素。2016年12月，一场大规模的 巴西东南部发生了黑热病暴发(2155例人间病例)，占总病例的46%(n=1002) 37%的死亡(n=340)发生在米纳斯吉拉斯州。2016-2018年，共有299人确认YF 这些病例被收治在米纳斯吉拉斯贝洛奥里藏特的爱德华多·德梅内塞斯医院。我们的团队已经 维护一个包含流行病学和临床数据的数据库，并对这些数据进行长期跟踪 患者，以及可以探测的临床样本的生物库，以重新定义临床病程和 这种重要病原体的发病机制。我们独特的特征良好的队列包括：(I) 演变为死亡的患者；(Ii)康复的患者；(Iii)恢复并发展出新的临床 以黄热病命名的晚发性肝炎样综合征(LHEP-YF)；及(Iv)接受 使用索莫布韦的非标签治疗。在这里，我们建议(I)重新定义YF的临床病程并确定 严重疾病表现的社会、人口和共病风险因素，包括 LHEP-YF的研制，(II)研究YF的病毒和免疫学致病机理 通过确定病毒学和免疫学生物标志物来预测YF的预后 与严重疾病相关，并评估潜在治疗方法的效果。我们经验丰富的 研究团队将采取跨学科的方法，将基础病毒学和应用病毒学结合起来， 免疫学、流行病学和临床传染病填补流行病学、临床的重要空白 YFV的疾病、病理生理学和生物学。巴西东南部最近爆发的YFV疫情造成了 前所未有的机会来分析我们独特的数据库和保存完好的数百个样本 在住院的YF患者中。这一信息将对建立议定书和更多 预防这种重要病原体致病和死亡的应用研究。

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.