National Surveillance for Emerging Adenovirus Infections

描述(由研究人员提供)：许多最近的报告表明，美国的人腺病毒流行病学已经发生了显着变化。自1996年以来，新发现的基因变异，特别是在血清7型菌株中，与严重呼吸道感染的国际流行以及孟菲斯、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，美国最近的腺病毒暴发经常发生在收容机构的儿童和医疗环境中。虽然公共卫生工具，如快速护理点腺病毒检测现在已经可用，腺病毒疫苗很快也将再次可用，但目前的流行病学数据是坊间传闻，不足以支持对此类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种血清型中只有不到20种。我们的中心假设是，最近发现的可能更具毒力的腺病毒血清型毒株已经成为美国的地方性流行病，它们与住院和死亡风险的增加有关。我们在这项应用中的目标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平民人群中使用腺病毒疫苗来减少腺病毒发病率。我们建议建立一个15个地点的国家腺病毒实验室监测系统，该系统将在三个冬季收集临床腺病毒分离株。分离株将在3个高危人群(7岁儿童；异基因干细胞或实体器官移植患者；军事实习生)和“其他腺病毒病患者”组中进行比较。所有分离株都将使用一种新的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。由于历史上它们与严重疾病有关，被分型为3、4、7和21的分离株将通过限制性内切酶分析进一步研究亚型。使用7岁儿童和异基因干细胞或实体器官移植患者中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、宿主和病原体危险因素。通过病例对照方法，将对与严重疾病相关的50株腺病毒分离株和与风险因素匹配的50株未如此相关的腺病毒分离株进行测序，以确定E1、E3和E4区域的病毒毒力预测因子。该项目在使用六邻体基因DNA序列分型以及用于预测毒力的E1、E3和E4腺病毒区域的病例对照DNA测序分析方面具有创新性。这项研究将指导在美国腺病毒疾病高危人群中开发和使用快速诊断测试和特定类型的腺病毒疫苗。

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.