DETECTION AND DISCOVERY OF VIRUSES IN PEDIATRIC ACUTE LIVER FAILURE

 描述(由申请人提供)：儿童急性肝功能衰竭(PALF)是一种危及生命的疾病，在这种疾病中，先前健康的儿童继发于肝功能迅速丧失而病情危重。由美国国立卫生研究院资助的正在进行的多中心PALF研究小组成立于1999年，目的是研究儿童急性肝衰竭的病因、发病机制、诊断、预后和治疗。值得注意的是，大约40%的PALF患者对他们的肝功能衰竭没有明确的病因诊断(“不确定”)。至少在这些受试者中，未被识别的病毒感染可能在肝功能衰竭的病因中起到关键作用。在这项提案中，将使用最先进的病原体发现方法来评估PALF患者的肝脏和血清样本中是否存在病毒。这一患者队列是独一无二的，代表了世界上最大的PALF患者标本储存库。具体地说，超高吞吐量下一代测序将与定制的生物信息学分析管道结合使用，以确定在不确定情况下存在的已知和新病毒的谱。检测到的任何此类病毒都可能是PALF的潜在候选病原体。作为与PALF建立联系的第一步，将进行病例对照分析，以确定原因不明的PALF病例与非感染性病因的PALF病例以及健康对照的血清中每种药物的流行率。

 DESCRIPTION (provided by applicant): Pediatric acute liver failure (PALF) is a life threatening disorder in which previously healthy children become critically ill secondary to rapid loss of hepatic function. The ongoing, multi-center, NIH-funded PALF Study Group was started in 1999 with the goal of studying the etiology, pathogenesis, diagnosis, prognosis and treatment of acute liver failure in children. Strikingly, approximately 40% of the subjects in the PALF cohor have no final specific etiologic diagnosis ("indeterminate") for their hepatic failure. It is likel that unrecognized viral infection may play a critical role in the etiology of liver failure in at least ome of these subjects. In this proposal, state-of-the-art methods for pathogen discovery will be used to evaluate liver and serum specimens from PALF patients for the presence of viruses. This patient cohort is unique, and represents the largest repository of specimens from PALF patients in the world. Specifically, ultra-high throughput Next Generation sequencing will be used in conjunction with a customized bioinformatics analysis pipeline to define the spectrum of viruses, both known and novel, present in the indeterminate cases. Any such viruses detected would be potential candidate etiologic agents of PALF. As a first step towards establishing an association with PALF, case-control analyses will be performed to define prevalence of each of these agents in serum of unexplained PALF cases as compared to PALF cases with non-infectious etiologies as well as to healthy controls.