National Surveillance for Emerging Adenovirus Infections

描述（由研究者提供）：最近的许多报告已经证明，美国人腺病毒的流行病学发生了显著变化。自1996年以来，新发现的遗传变异，特别是血清型7菌株，与国际严重呼吸道感染流行以及孟菲斯、芝加哥、得梅因和纽约的流行有关。国际和美国的数据表明，这些新出现的毒株可能比以前流行的腺病毒毒株毒力更强。例如，骨髓移植患者中腺病毒病的发病率从3%到20%不等，由于缺乏有效的治疗，死亡率往往很高。同样，最近美国腺病毒爆发经常发生在机构儿童和医疗环境中。虽然现在已经有了快速护理点腺病毒检测等公共卫生工具，而且腺病毒疫苗也将很快再次上市，但目前的流行病学数据只是传闻，不足以支持对这些高危群体的干预决定。美国最好的腺病毒研究是在30多年前进行的，当时已知的51种血清型中不到20种。我们的中心假设是，最近发现的，可能更具毒性的腺病毒血清型菌株已成为美国各地的地方病，它们与住院和死亡风险增加有关。本申请的目的是记录这一新出现的问题，并确定严重腺病毒疾病的人类和病毒风险因素。我们的长期目标是通过在高危人群中使用腺病毒疫苗来降低腺病毒的发病率。我们建议建立一个15个站点的国家腺病毒实验室监测系统，该系统将在三个冬季期间收集临床腺病毒分离株。分离株将在3个高风险人群（<7岁的儿童;异基因干细胞或实体器官移植患者;军事学员）和“其他腺病毒疾病患者”组中进行比较。所有分离株将使用新的DNA六邻体基因测序程序进行分型，该程序与更繁琐的经典血清学分型系统高度相关。由于它们在历史上与严重疾病相关，将通过限制性酶分析进一步研究分型为3、4、7和21的分离株的亚型。利用7岁以下儿童和异基因干细胞或实体器官移植患者腺病毒感染的病历数据，我们将确定严重（住院或死亡）腺病毒疾病的环境，时间，宿主和病原体风险因素。通过病例对照方法，将对一组与严重疾病相关的50种腺病毒分离株和与之不相关的风险因子匹配的50种腺病毒分离株进行测序，以获得El、E3和E4区域中毒力的病毒预测因子。该项目在使用六邻体基因DNA序列分型和E1、E3和E4腺病毒区域的病例对照DNA测序分析以预测毒力方面具有创新性。这项研究将指导美国腺病毒疾病高危人群中快速诊断测试和类型特异性腺病毒疫苗的开发和使用。

DESCRIPTION (provided by investigator): Numerous recent reports have yielded evidence that the epidemiology of human adenoviruses in the United States has markedly changed. Since 1996, newly recognized genetic variants, particularly among serotype 7 strains, have been associated with international epidemics of severe respiratory infection, as well as epidemics in Memphis, Chicago, Des Moines, and New York. International and US data suggest that these emerging strains may be more virulent than previously endemic adenovirus strains. For instance, the incidence of adenoviral disease among bone marrow transplant patients varies from 3 percent to 20 percent and due to the lack of effective therapy, mortality is often high. Similarly, recent US adenoviral outbreaks have frequently occurred among institutionalized children and in medical settings. While public health tools such as rapid point-of-care adenoviral tests are available now and adenoviral vaccines will again be available soon, current epidemiological data are anecdotal and inadequate to support intervention decisions for such high- risk groups. The best US adenoviral studies were performed more than 30 years ago when less than 20 of the now recognized 51 serotypes were known. It is our central hypothesis that the recently identified, possibly more virulent adenovirus serotype strains have become endemic throughout the United States and that they are associated with an increased risk of hospitalization and death. Our objective in this application is to document this emerging problem, and to identify human and viral risk factors for severe adenovirus disease. Our long- term goal is to reduce adenoviral morbidity through use of adenoviral vaccines among high- risk civilian populations. We propose the establishment of a 15-site, national adenovirus laboratory surveillance system that will collect clinical adenovirus isolates over a period of three winters. Isolates will be compared across 3 high- risk populations (children <7 years of age; allogeneic stem cell or solid organ transplant patients; military trainees) and an "other patients with adenoviral disease" group. All isolates will be typed using a new DNA hexon gene sequencing procedure that highly correlates with the more tedious classical serological typing systems. As they have historically been associated with severe disease, isolates that are typed, as 3, 4, 7 and 21 will be further studied for subtype through restriction enzyme analyses. Using medical record data from adenovirus infections among children <7 years of age and allogeneic stem cell or solid organ transplant patients, we will identify environmental, temporal, host, and pathogen risk factors for severe (hospitalization or death) adenoviral disease. Through a case-control approach, a panel of 50 adenoviral isolates associated with severe disease and a risk factor-matched 50 adenoviral isolates not so associated, will be sequenced for viral predictors for virulence in the El, E3, and E4 regions. This project is innovative in its use of the hexon gene DNA sequence typing and for the case-control DNA sequencing analyses of the El, E3, and E4 adenovirus regions for predictors of virulence. This study will guide the development and use of rapid diagnostic tests and type-specific adenovirus vaccines among US populations at high risk of adenoviral disease.