VIPS: Vascular Effects of Infection in Pediatric Stroke

描述(由主要研究人员提供)：成人的急性感染与动脉缺血性中风(AIS)有关，最近的数据表明儿童中也有类似的相关性。虽然感染可以通过诱导全身血栓前状态而导致AIS，但它也可能通过(1)感染性物质直接侵入动脉壁或(2)局部炎症细胞因子介导的内皮损伤而导致脑动脉病变。儿童是研究感染对血管影响的理想研究对象，因为缺乏与年龄相关的动脉粥样硬化危险因素。此外，最近的数据表明，在患有AIS的儿童中，动脉病变强烈预示着复发。虽然这种动脉病变包括已建立的实体，如动脉夹层和烟雾，但大多数儿童都有孤立的单侧局限性颅内血管狭窄。尽管包括疱疹病毒在内的几种感染性因素已被牵连，但其病因尚不清楚。我们建议对儿童卒中进行一项多中心研究，以验证以下假设：感染可通过导致血管损伤而导致AIS，从而导致动脉病变使儿童容易复发卒中。我们的主要目标是：(1)测量AIS儿童中近期感染和动脉病变的横断面患病率和特征；(2)确定近期感染是否与AIS儿童中的动脉病变相关，并进一步阐明与感染地点、时间框架、感染负担和最近的疱疹病毒感染的关联；(3)前瞻性地确定动脉病变和炎症标志物是否预测中风复发，以及这些关联是否因动脉病变类型而异。方法：在3年的时间里，我们将在25个中心(14个美国中心，6个加拿大中心，5个非北美中心)前瞻性地招募480名患有AIS的儿童(1个月到18岁)，收集(1)广泛的感染史(通过父母访谈)，(2)血液样本(如果有的话，还有脑脊液)，(3)临床获得但标准化的脑血管成像检查。影像研究将集中审查和裁决。集中化的实验室分析将包括疱疹病毒的血清学和分子分析，以及炎症标志物的水平。受试者将被前瞻性地跟踪观察是否有复发的缺血事件。我们将保存生物标本(包括DNA)，以供将来研究与血栓形成和血管损伤相关的特定感染性病原体和炎症介质。意义/未来方向：从这项研究中获得的数据将阐明感染在儿童中风中的作用。由于动脉病变可能是儿童复发卒中的主要预测因素，因此更好地了解血管损伤途径对于制定合理的儿童卒中二级预防策略至关重要。长期目标是确定引起动脉病变的炎性介质，作为治疗干预的靶点。公共卫生相关性：缺血性中风(脑血管阻塞)每年影响大约4,000名美国儿童，每5例中就有1例复发，导致受影响个人终身残疾，给社会带来巨大代价。这项拟议的研究将通过确定感染是否会损伤血管，从而使儿童容易中风，从而提高我们对这种疾病的理解。它还将确定复发的原因，这是朝着制定防止儿童反复中风的方法迈出的关键一步。

DESCRIPTION (provided by principal investigator): Acute infections have been associated with arterial ischemic stroke (AIS) in adults, and recent data suggest a similar association in children. Although infection may cause AIS by inducing a systemic pro-thrombotic state, it may also cause a cerebral arteriopathy through either (1) direct invasion by infectious agents into arterial walls, or (2) endothelial injury mediated by local inflammatory cytokines. Children are the ideal subject population to study the vascular effects of infection because of the absence of age-related atherosclerotic risk factors. Furthermore, recent data suggest that, in children with AIS, arteriopathy strongly predicts recurrence. While this arteriopathy includes established entities, such as arterial dissection and moya moya, most children have an isolated unilateral focal stenosis of intracranial vessels. The etiology of this remains unclear, although several infectious agents, including herpes viruses, have been implicated. We propose a multicenter study of childhood stroke to test the hypotheses that infection can lead to AIS by causing vascular injury, and the resultant arteriopathy predisposes children to recurrent stroke. Our primary aims are: (1) to measure the cross-sectional prevalence and characteristics of both recent infections and arteriopathy in an international cohort of children with AIS; (2) to determine whether recent infection is associated with arteriopathy among children with AIS, and to further elucidate associations with infection site, time frame, infectious burden, and recent herpes virus infections; (3) to prospectively determine if arteriopathy and inflammatory markers predict stroke recurrence, and whether these associations vary by type arteriopathy. Methods: Over 3 years, we will prospectively enroll 480 children (aged 1 month to through18 years) with AIS at 25 centers (14 U.S., 6 Canadian, and 5 non-North American) and collect (1) extensive infectious histories (through parental interview), (2) blood samples (and CSF, when available), and (3) clinically obtained but standardized brain and cerebrovascular imaging studies. Imaging studies will be centrally reviewed and adjudicated. Centralized laboratory assays will include serologies and molecular assays for herpes viruses, and levels of inflammatory markers. Subjects will be followed prospectively for recurrent ischemic events. We will bank biological specimens (including DNA) for future studies of specific infectious agents and mediators of inflammation relevant to thrombosis and vascular injury. Significance/Future Directions: The data obtained from this study will shed light on the role of infection in childhood stroke. Because arteriopathy is likely the major predictor of recurrent stroke in children, a better understanding of the vascular injury pathway is critical for the development of rational strategies for secondary stroke prevention in children. The long-term goal is to identify inflammatory mediators causing arteriopathy that may serve as targets for therapeutic intervention. PUBLIC HEALTH RELEVANCE: Ischemic stroke (blockage of blood vessels to the brain) affects approximately 4,000 U.S. children per year, and recurs in 1 out of 5 cases, causing lifelong disabilities in affected individuals and great costs to society. The proposed study will improve our understanding of this disease by determining whether infections injure blood vessels and thereby predispose children to stroke. It will also determine causes of recurrence, a crucial step towards developing ways to prevent repeated strokes in children.