Higher mortality following SARS-CoV-2 infection in rural versus urban dwellers persists for two years post-infection

A. Jerrod Anzalone (), Michael T. Vest, Makayla E. Schissel, Bradley Price, William B. Hillegass, Ronald Horswell, San Chu, Clifford J. Rosen, Lucio Miele, Susan L. Santangelo, Gordon S. Smith and Sally L. Hodder
Additional contact information
A. Jerrod Anzalone: University of Nebraska Medical Center
Michael T. Vest: Christiana Care Health System
Makayla E. Schissel: University of Nebraska Medical Center
Bradley Price: West Virginia University
William B. Hillegass: University of Mississippi Medical Center
Ronald Horswell: Pennington Biomedical Research Center
San Chu: Pennington Biomedical Research Center
Clifford J. Rosen: MaineHealth Institute for Research
Lucio Miele: Louisiana State University Health Sciences Center
Susan L. Santangelo: MaineHealth Institute for Research
Gordon S. Smith: West Virginia University
Sally L. Hodder: West Virginia University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Previous studies demonstrated higher short-term mortality among rural compared with urban residents infected with SARS-CoV-2. However, whether this difference persists remains uncertain. This retrospective cohort study analyzed two-year post-COVID-19 mortality by rurality using the National Clinical Cohort Collaborative COVID-19 Enclave, a United States-based longitudinal electronic health record repository. We analyzed mortality among patients infected with SARS-CoV-2 between April 2020 and December 2022, with follow-up until December 2024. Patients were categorized into urban, urban-adjacent rural (UAR), and nonurban-adjacent rural (NAR) groups based on residential ZIP Code. Mortality differences were assessed using Kaplan-Meier analysis and weighted multivariable Cox regression, with weights derived from demographic factors and models adjusted for background clinical risk and social vulnerability. Among 3,082,978 SARS-CoV-2-infected patients, we found a significant association between rurality and increased two-year all-cause mortality post-infection. Adjusted hazards for two-year mortality for UAR and NAR were 1.19 (95% CI 1.18-1.21) and 1.26 (1.22-1.29). A reference cohort of 4,153,216 COVID-19-negative patients showed a modest yet consistent rural mortality penalty, with a similar relative hazard across cohorts, an observed rurality-COVID-19 interaction, and a greater absolute number of deaths following SARS-CoV-2 infection. Our findings emphasize ongoing rural mortality disparities and the importance of public health efforts in rural communities.

Date: 2025
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DOI: 10.1038/s41467-025-63944-8

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