Geographically persistent clusters of La Crosse virus disease in the Appalachian region of the United States from 2003 to 2021.

La Crosse virus (LACV) is a mosquito-borne pathogen that causes more pediatric neuroinvasive disease than any other arbovirus in the United States. The geographic focus of reported LACV neuroinvasive disease (LACV-ND) expanded from the Midwest into Appalachia in the 1990s, and most cases have been reported from a few high-risk foci since then. Here, we used publicly available human disease data to investigate changes in the distribution of geographic LACV-ND clusters between 2003 and 2021 and to investigate socioeconomic and demographic predictors of county-level disease risk in states with persistent clusters. We used spatial scan statistics to identify high-risk clusters from 2003-2021 and a generalized linear mixed model to identify socioeconomic and demographic predictors of disease risk. The distribution of LACV-ND clusters was consistent during the study period, with an intermittent cluster in the upper Midwest and three persistent clusters in Appalachia that included counties in east Tennessee / western North Carolina, West Virginia, and Ohio. In those states, county-level cumulative incidence was higher when more of the population was white and when median household income was lower. Public health officials should target efforts to reduce LACV-ND incidence in areas with consistent high risks.