Global, regional, and national sepsis incidence and mortality, 1990–2021: a systematic analysis

Background The global burden of sepsis, a life-threatening dysregulated host response to infection leading to organ dysfunction, remains challenging to quantify. We aimed to comprehensively estimate the global, regional, and national burden of sepsis, including the impact of the COVID-19 pandemic and underlying causes of sepsis-related deaths with co-occurring infectious syndromes.Methods We used multiple cause-of-death, hospital, minimally invasive tissue sampling, and linked death certificate and hospital record data representing 149 million deaths, covering 4290 location-years with mortality estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 to capture explicit and implicit sepsis cases and deaths. We estimated age-location-sex-specific fractions of sepsis-related deaths from 195 underlying causes of death and 22 infectious syndromes from 1990 to 2021 using binomial logistic regression models, and estimated sepsis-related deaths using GBD cause-specific mortality estimates. Using 250 million hospital admissions and 7 center dot 82 million deaths from hospital data, representing 1310 location-years, we modelled case fatality rates by use of binomial logistic regression, applied to sepsis death estimates to estimate sepsis incidence by age, location, and year.Findings In 2021, we estimated 166 million (95% uncertainty interval 135-201) sepsis cases and 21 center dot 4 million (20 center dot 3-22 center dot 5) all-cause sepsis-related deaths globally, representing 31 center dot 5% of total global deaths. Sepsis-related deaths decreased between 1990 and 2019, followed by a surge in 2020 and 2021. As of 2021, individuals aged 15 years and older experienced increases across incidence (230%) and mortality (26 center dot 3%) since 1990. Those aged 70 years and older had the highest sepsis-related mortality in 2021 (9 center dot 28 million [8 center dot 74-9 center dot 86] deaths). Sepsis-related deaths from infectious underlying causes decreased from 11 center dot 8 million (11 center dot 1-12 center dot 5) in 1990 to 8 center dot 34 million (7 center dot 72-9 center dot 01) in 2019, then increased by 86 center dot 4% to 15 center dot 5 million (14 center dot 7-16 center dot 4) in 2021. Sepsis-related mortality due to non-infectious underlying causes of death increased from 4 center dot 69 million (4 center dot 35-5 center dot 05) in 1990 to 5 center dot 81 million (5 center dot 40-6 center dot 25) in 2021; the leading non-infectious underlying causes of death with sepsis were stroke, chronic obstructive pulmonary disease, and cirrhosis. In 2021, bloodstream infections inclusive of HIV and malaria (3 center dot 08 million [2 center dot 83-3 center dot 35]) and lower respiratory infections inclusive of COVID-19 (11 center dot 33 million [1 center dot 20-1 center dot 47]) were the most prominent infectious syndromes complicating sepsis-related deaths from non-infectious underlying causes, representing a consistent trend since 1990.Interpretation The global burden of sepsis increased in 2020 and 2021, reversing progress from 1990. Sepsis incidence and mortality increased in people aged 15 years and older, especially those aged 70 years and older, and as a complication of non-infectious underlying causes of death such as stroke, primarily through bloodstream infections and lower respiratory infections. The global burden of sepsis is substantial, and sepsis is increasingly a complication of non-infectious causes of death. Copyright (c) 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.