Abstract Rationale SARS-CoV-2 was a major cause of sepsis during the COVID-19 pandemic, but the burden and outcomes of sepsis from other respiratory viruses and during non-pandemic periods have not been well described. Methods We retrospectively analyzed electronic health record data from all adults admitted to 9 hospitals in New England, 2016-2024. Community-onset (CO) respiratory viral (RV) infections were defined as a positive RV PCR within ±48 hours of hospital arrival. RV sepsis was defined as RV infection with hypoxia (SpO294% or supplemental oxygen), plus 1 acute organ dysfunction within one day of positive viral test. We calculated overall and annual hospital incidence, in-hospital death or discharge to hospice rates (composite mortality outcome), and proportion of overall sepsis cases accounted for by 1) CO RV sepsis and 2) CO presumed-bacterial sepsis (defined using updated CDC Adult Sepsis Event criteria, excluding patients also meeting CO-RV sepsis criteria). Results Among 1,550,694 encounters from 746,752 individuals, 86,578 (5.6%) had CO presumed bacterial sepsis and 45,927 (3.0%) had CO-RV infections, of whom 11,567 (25.2%) had CO-RV sepsis. One-third of CO-RV sepsis cases (n = 3,985, 34.5%) were due to non-SARS-CoV-2 viruses, most commonly influenza A and B (n = 1,932, 16.7%), rhinovirus (n = 738, 6.4%) and RSV (n = 726, 6.3%). The composite mortality rate was 6.9% for CO-RV infections, 18.5% for RV sepsis, and 20.4% for CO presumed bacterial sepsis. While SARS-CoV-2-associated sepsis had the highest mortality (20.9%), non-SARS-CoV-2 viral sepsis also carried substantial risk, with mortality rates ranging from 11.9% for influenza to 21.1% for respiratory adenovirus (13.8% overall). CO-RV sepsis incidence and proportion of overall sepsis cases peaked in 2020 (17.8% of all sepsis cases) and 2022 (20.3% of sepsis cases) but remained above pre-pandemic levels through 2024 (13.8% of sepsis cases, compared to 1.8-5.3% from 2016-2019). Non-SARS-CoV-2 CO-RV sepsis counts have increased since 2021 and now account for as many sepsis cases as SARS-CoV-2 (Figure, panel A). Composite mortality for RV sepsis peaked in 2020 (25.4%) and 2021 (22.2%) then stabilized between 14.7-16.8% in 2022-2024 (Figure, panels B-D). Conclusions Respiratory viruses are a major and persistent cause of sepsis in hospitalized patients, with mortality rates comparable to presumed bacterial sepsis. Although SARS-CoV-2 drove an initial surge in RV sepsis during the COVID-19 pandemic, non-SARS-CoV-2 viruses account for a substantial and increasing portion of sepsis cases, likely reflecting increased testing and recognition of RV infections and underscoring the need for continued RV sepsis testing, surveillance, and prevention beyond COVID-19. This abstract is funded by: AHRQ
Shappell et al. (2026) studied this question.