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.
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