VIPS: Vascular Effects of Infection in Pediatric Stroke

VIPS：感染对小儿中风的血管影响

• 批准号: 8109872
• 负责人: HEATHER J FULLERTON
• 金额: $ 139.33万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-05 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109872
• 关键词: Acute; Adult; Affect; American; Arterial Disorder; Biological Assay; Biological Specimen Banks; Blood Vessels; Blood specimen; Brain; Brain imaging; Case-Control Studies; Cerebrum; Characteristics; Child; Childhood; Childhood stroke; Cohort Studies; DNA; Data; Development; Diabetes Mellitus; Disease; Dissection; Enrollment; Etiology; Event; Future; Genetic Markers; Goals; Health; Herpesviridae; Hypertension; Image; Individual; Infection; Infectious Agent; Inflammation Mediators; Inflammatory; Injury; International; Interview; Invaded; Ischemic Stroke; Laboratories; Lead; Light; Measures; Mediating; Methods; Molecular; Moyamoya Disease; Multicenter Studies; Odds Ratio; Pathway interactions; Physicians; Population; Prevalence; Principal Investigator; Recording of previous events; Recurrence; Retrospective Studies; Risk; Risk Factors; Role; Serologic tests; Site; Societies; Stenosis; Stroke; Stroke prevention; Testing; Therapeutic Intervention; Thrombosis; Time; Virus Diseases; Visit; adjudicate; age related; aged; cerebrovascular imaging; cohort; cost; cytokine; disability; hypercholesterolemia; improved; indexing; inflammatory marker; injured; prevent

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.

描述（由主要研究者提供）：成人中急性感染与动脉缺血性卒中（AIS）相关，最近的数据表明儿童中存在类似的相关性。虽然感染可能通过诱导全身性血栓前状态引起AIS，但也可能通过（1）感染因子直接侵入动脉壁或（2）局部炎性细胞因子介导的内皮损伤引起脑动脉病。儿童是研究感染对血管影响的理想受试者人群，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，动脉病变强烈预测复发。虽然这种动脉病包括确定的实体，如动脉夹层和莫亚莫亚，但大多数儿童有孤立的单侧颅内血管局灶性狭窄。其病因尚不清楚，尽管包括疱疹病毒在内的几种传染性病原体已被牵连。我们提出了一个多中心的儿童中风研究，以测试的假设，感染可以导致AIS引起血管损伤，并由此产生的动脉病变，使儿童中风复发。我们的主要目标是：（1）测量AIS儿童国际队列中近期感染和动脉病的横断面患病率和特征;（2）确定AIS儿童中近期感染是否与动脉病相关，并进一步阐明与感染部位、时间范围、感染负担和近期疱疹病毒感染的相关性;（3）前瞻性确定动脉病变和炎症标志物是否预测卒中复发，以及这些相关性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，6名加拿大人和5名非北美人），并收集（1）广泛的感染史（通过父母访谈），（2）血液样本（和CSF，如可用），和（3）临床获得但标准化的脑和脑血管成像研究。将对影像学研究进行集中审查和裁定。集中实验室检测将包括疱疹病毒的血清学和分子检测以及炎症标志物水平。将前瞻性随访受试者的复发性缺血事件。我们将储存生物标本（包括DNA），用于未来研究与血栓形成和血管损伤相关的特定感染因子和炎症介质。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卒中复发的主要预测因素，因此更好地了解血管损伤途径对于制定儿童卒中二级预防的合理策略至关重要。长期目标是确定引起动脉病的炎症介质，这些介质可能作为治疗干预的靶点。公共卫生关系：缺血性中风（大脑血管阻塞）每年影响大约4，000名美国儿童，五分之一的病例会复发，导致受影响个体终身残疾，并给社会带来巨大成本。这项拟议中的研究将通过确定感染是否会损伤血管从而使儿童易患中风来提高我们对这种疾病的理解。它还将确定复发的原因，这是制定预防儿童反复中风的方法的关键一步。