The Vascular effects of Infection in Pediatric Stroke (VIPS II) Study

项目摘要/摘要 儿童动脉缺血性中风每年困扰≈2,000名美国儿童，其中大多数永久残疾，但仍是 人们对此知之甚少。感染对儿童卒中的血管影响(VIPS I)研究建立了一个 由37个地点组成的国际网络招募了355名中风儿童和354名对照儿童。我们发现： (A)轻微临床感染是中风的诱因，而儿童常规疫苗接种具有保护性；(B) 几乎一半的中风儿童患有急性疱疹病毒感染(水痘、感冒的原因 (C)中风儿童中风复发的风险很高， 尤其是如果他们有动脉病的话。VIPS的一项初步研究表明，其他常见的童年 病原体也可能发挥作用，可能与疱疹病毒结合在一起。全光谱的 导致儿童中风风险的病原体仍不清楚。感染是一种令人信服的可治疗方法 中风风险因素，有针对病原体和下游炎症影响的现有治疗方法。 然而，VIPS I的发现提出了一个悖论：感染很常见，而儿童中风并不常见。 可能的解释是：(1)“感染假说”：不寻常的病原体菌株，或组合 病原体，导致中风；和(2)“宿主反应假说”：一种不寻常的炎症反应 感染会导致中风。 对特定病原体和潜在的炎症介质都有透彻的了解 儿童卒中的发病机制，特别是动脉病理性卒中，需要制定策略来减少 儿童复发性中风。通过传统方法进行广泛的感染检测成本高得令人望而却步， 并且需要对所涉及的病原体进行先入为主的假设。下一代测序(NGS) 允许通过以下方式高效、高度敏感和无偏见地检测任何已知或新的病原体 对生物样本中的所有核酸进行测序，并将它们与参考基因组进行匹配 数据库。为了研究炎症反应，多重珠子阵列现在可以有效地测试一个大的 微量血液样本上的免疫介体数量。VIPS II将使用这些尖端技术来 解决VIPs I悖论，更好地理解儿童中风的原因。具体目标是 (1)在中风儿童中识别已知和新的病原体，并确定不同的病原体 动脉病变与其他中风类型的对比；(2)确定患有动脉病变的儿童 与其他类型的中风相比，中风有不同的炎症反应；以及(3)使用数据 从目标1和目标2探索从感染到炎症再到动脉病变的不同机制 笔划和其他笔划类型。 VIPS II的目标是获得保护中风儿童免受额外大脑伤害所需的知识 受伤。它的结果将指导目前可用的治疗方法的选择--如抗微生物药物和抗肿瘤药物。 炎症性药物--一项旨在预防中风复发的儿科临床试验。

PROJECT SUMMARY/ABSTRACT Pediatric arterial ischemic stroke afflicts ≈2,000 U.S. children every year, permanently disabling most, yet is poorly understood. The Vascular effects of Infection in Pediatric Stroke (VIPS I) study established an international network of 37 sites that enrolled 355 children with stroke and 354 controls. We discovered: (a) minor clinical infections act as a stroke trigger, while routine childhood vaccinations are protective; (b) almost half of children with stroke have an acute herpesvirus infection (the cause of chicken pox, cold sores, and other common illnesses); and (c) children with stroke have a high risk of recurrent stroke, particularly if they have an arteriopathy. A VIPS pilot study suggests that other common childhood pathogens may also play a role, possibly in combination with herpesviruses. The full spectrum of pathogens that contribute to childhood stroke risk remains unknown. Infection is compelling as a treatable stroke risk factor, with available therapies for both pathogens and downstream inflammatory effects. However, VIPS I findings present a paradox: infection is common, while childhood stroke is uncommon. Possible explanations are (1) the “infection hypothesis”: unusual pathogen strains, or combinations of pathogens, lead to stroke; and (2) the “host response hypothesis”: an unusual inflammatory response to infection leads to stroke. A thorough understanding of both the specific pathogens and inflammatory mediators underlying childhood stroke pathogenesis, particularly arteriopathic stroke, is needed to develop strategies to reduce recurrent stroke in children. Broad testing for infections through traditional methods is prohibitively costly, and requires preconceived assumptions about the pathogens involved. Next generation sequencing (NGS) allows for the efficient, highly sensitive and unbiased detection of any pathogen, known or novel, by sequencing all nucleic acids in a biological sample and matching them with genomes in a reference database. To study the inflammatory response, multiplex bead arrays can now efficiently test for a large number of immune mediators on tiny blood samples. VIPS II will use these cutting-edge techniques to address the VIPS I paradox and better understand the causes of childhood stroke. The specific aims are to (1) identify known and novel pathogens in children with stroke, and determine whether different pathogens are seen with arteriopathic versus other stroke types; (2) determine whether children with arteriopathic stroke have a different inflammatory response compared to those with other stroke types; and (3) use data from Aims 1 and 2 to explore different mechanistic pathways from infection, to inflammation, to arteriopathic stroke, and other stroke types. The goal of VIPS II is to gain the knowledge needed to protect children with stroke from additional brain injury. Its results will guide the selection of currently available therapies—such as antimicrobials and anti- inflammatory medications—for a pediatric clinical trial aimed at preventing recurrent stroke.