IntroductionInfluenza epidemics and pandemics cause significant morbidity and mortality. An effective response to a potential pandemic requires the infrastructure to rapidly detect, characterize, and potentially contain new and emerging influenza strains at a population level. The objective of this study is to use data gathered simultaneously from community and hospital sites to develop a model of how influenza enters and spreads in a population.Methods and AnalysisStarting in the 2018-19 season, we have been enrolling individuals with acute respiratory illness from community sites throughout the Seattle metropolitan area, including clinics, childcare facilities, Seattle-Tacoma International Airport, workplaces, college campuses, and homeless shelters. At these sites, we collect clinical data and mid-nasal swabs from individuals with at least two acute respiratory symptoms. Additionally, we collect residual nasal swabs and data from individuals who seek care for respiratory symptoms at four regional hospitals. Samples are tested using a multiplex molecular assay, and influenza whole genome sequencing is performed for samples with influenza detected. Geospatial mapping and computational modeling platforms are in development to characterize the regional spread of influenza and other respiratory pathogens.Ethics and DisseminationThe study was approved by the University of Washington’s Institutional Review Board. Results will be disseminated through talks at conferences, peer-reviewed publications, and on the study website (www.seattleflu.org).Article SummaryStrengths and limitations of this study-Large-scale multiple-arm study of respiratory illness characterization with collection of samples from individuals in the community as well as in ambulatory care and hospital settings-Integration of sociodemographic, clinical, and geospatial data on a regional level-Multiplex molecular testing for multiple viral and bacterial pathogens and whole genome sequencing of influenza for detailed molecular epidemiologic characterization and transmission mapping-Geographically and socioeconomically diverse sampling of community-based acute respiratory illnesses