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

项目概要/摘要 每年约有 2,000 名美国儿童遭受小儿动脉缺血性中风的折磨，其中大多数儿童永久致残，但 不太了解。小儿中风感染的血管影响 (VIPS I) 研究建立了 由 37 个站点组成的国际网络，招募了 355 名中风儿童和 354 名对照儿童。我们发现： (a) 轻微的临床感染可引发中风，而常规儿童疫苗接种则具有保护作用； (二) 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） 疮和其他常见疾病）； (c) 中风儿童复发中风的风险很高， 特别是如果他们患有动脉病。 VIPS 试点研究表明，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。全谱 导致儿童中风风险的病原体仍然未知。感染作为一种可治疗的药物是引人注目的 中风危险因素，针对病原体和下游炎症效应的可用疗法。 然而，VIPS I 的研究结果呈现出一个悖论：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； (2)“宿主反应假说”：一种不寻常的炎症反应 感染会导致中风。 全面了解特定病原体和潜在的炎症介质 儿童中风的发病机制，特别是动脉性中风，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昂， 并且需要对所涉及的病原体有先入为主的假设。下一代测序（NGS） 允许对任何已知或新型病原体进行高效、高度灵敏和公正的检测 对生物样本中的所有核酸进行测序，并将其与参考基因组进行匹配 数据库。为了研究炎症反应，多重珠阵列现在可以有效地测试大量的炎症反应。 微小血液样本上免疫介质的数量。 VIPS II 将利用这些尖端技术 解决 VIPS I 悖论并更好地了解儿童中风的原因。具体目标是 (1)识别脑卒中儿童已知和新的病原体，并确定不同病原体是否存在 与其他中风类型相比，动脉病更常见； (2)判断患儿是否患有动脉病 与其他中风类型相比，中风具有不同的炎症反应； (3) 使用数据 从目标 1 和 2 探索从感染、炎症到动脉病变的不同机制途径 中风和其他中风类型。 VIPS II 的目标是获得保护中风儿童免受额外脑损伤所需的知识 受伤。其结果将指导当前可用疗法的选择，例如抗菌药物和抗- 炎症药物——用于旨在预防复发性中风的儿科临床试验。

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.