Abstract Rationale Influenza remains a critical public health threat with substantial inter-seasonal variation. Following COVID-19's unprecedented disruption of respiratory virus circulation patterns, understanding post-pandemic influenza mortality trends has become essential for healthcare preparedness and resource allocation. We theorized that, the return of normal respiratory virus circulation would reveal significant changes in influenza mortality burden compared to pandemic-suppressed seasons. Methods We conducted longitudinal analysis of weekly influenza mortality surveillance data from the National Vital Statistics System spanning five consecutive seasons (2020-21 through 2024-25). Data included weekly counts of influenza deaths, total deaths, and percentage of deaths attributed to influenza. Statistical analyses employed descriptive statistics, independent samples t-tests, one-way ANOVA, and Pearson correlation using Python. Temporal patterns were visualized to identify seasonal peaks and trends. The 2024-25 season was 95% complete at time of analysis. Results Total seasonal influenza deaths demonstrated dramatic escalation from 931 deaths in 2020-21 to 18,488 deaths in 2024-25, representing a nearly 20-fold increase (19.9x). Mean weekly deaths surged from 17.6 (SD 10.0) to 362.5 (SD 549.7), a 20.6-fold increase. Peak mortality rates increased 56-fold, from 0.05% in 2020-21 to 2.79% in 2024-25. The highest single-week death toll (1,866 deaths) occurred in week 7 of the 2024-25 season. One-way ANOVA confirmed highly significant inter-seasonal variation (F = 11.657, p 0.0001). Progressive increases were observed across intermediate seasons: 3,056 deaths (2021-22), 9,868 deaths (2022-23), and 10,505 deaths (2023-24). The 2024-25 season exhibits the highest mortality burden despite being 95% complete at analysis, representing the most severe influenza season in this five-year period. This abstract is funded by: None
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