Trends in Pneumonia and Sepsis-Related Mortality Across the United States, 1999– 2024: A CDC WONDER-Based Population Study

Trends in Pneumonia and Sepsis-Related Mortality Across the United States, 1999– 2024: A CDC WONDER-Based Population Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Trends in Pneumonia and Sepsis-Related Mortality Across the United States, 1999– 2024: A CDC WONDER-Based Population Study Ammad Uddin, Muhammad Salik Uddin, Hassan Abdul Aziz Dhedhi, Muhammad Tahir, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9005126/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose This research investigated the national patterns and inequalities in mortality associated with pneumonia-related sepsis in the United States from 1999 to 2024. The study explored the variations in mortality rates over time as well as among different demographic and geographic groups, with the objective of pinpointing high-risk populations to inform prevention and early intervention approaches. Methods Retrospective population evaluation was performed utilizing the CDC WONDER Multiple Cause-of-Death database from 2000–2023. Adults aged ≥ 25 years with sepsis (ICD-10 A40–A41) and pneumonia (ICD-10 J12–J18) on death certificates were analyzed. Age-adjusted mortality rates (AAMRs) were estimated per 100,000 population based on the 2000 U.S. standard population. Temporal patterns were examined through Joinpoint regression to determine the annual percent change (APC) and mean annual percent change (AAPC), stratified for sex, race, region, urbanization, and age. Results 1,039,577 pneumonia-sepsis fatalities were recorded from 1999 to 2024. AAMR increased from 16.6 in 1999 to 18.2 in 2024, peaking acutely in 2018–2021 and then decreasing. Mortality was higher in men (21.9) compared to women (14.4), and highest in non-Hispanic Blacks (27.5). The South had the highest burden (19.7), with significant differences throughout the different states. Adults 65 and above had the highest mortality (69.3), and rural and urban areas had parallel curves. Conclusion Sepsis related to pneumonia continues to have a significant U.S. mortality burden, with striking variation by sex, race, geography and age. The 2018–2021 surge highlights the burden of public health emergencies and the need for concentrated, equitable prevention and care interventions. Pneumonia sepsis mortality sex race disparities Figures Figure 1 1.INTRODUCTION Sepsis, which is a potentially lethal organ dysfunction resulting from a host response to infection that is improperly regulated, remains among the most serious medical emergency situations within modern-day healthcare ( 1 ). This complex syndrome arises once the body's immune response overreacts to an infection, causing widespread inflammation capable of causing organ systems harm and inducing organ failure ( 2 ). Pneumonia, as a type of acute infection localized in the lung parenchyma ( 3 ), remains among the most common initiators responsible for the development of sepsis, especially in instances concerning inpatients within hospitals alongside susceptible populations including the elderly and individuals suffering from immune comptonization. The relationship between sepsis and pneumonia often remains quite alarming considering that sepsis within the context of pneumonia often presents with a quick clinical deterioration and poses significant challenges concerning expedient detection and response ( 4 ). Sepsis is mentioned as a leading cause of mortality in the United States, responsible for a minimum of 350,000 deaths in a year and as the leading cause of in-hospital deaths in the country ( 5 ). The occurrence of sepsis has exhibited alarming rising patterns, and hospitalizations were up by 40% in the 2016–2021 period ( 6 ). Pneumonia is responsible for more than 53,000 deaths in a year and induces around 2.6 million emergency room visits, thereby being a forceful contributor in the sepsis burden as a whole ( 7 ). The mortality percentages among sepsis vary substantially by severity groups, from 5.6% among sepsis without organ dysfunction up to 34.2% in septic shock, and with pneumonia-related sepsis typically manifesting in the higher severity groups by virtue of respiratory failure ( 8 ). The economic costs of sepsis and pneumonia cause significant strains on healthcare systems. Hospital care costs for sepsis have jumped from $ 31.2 billion in 2016 to $ 52.1 billion in 2021 and account for over 14% of all hospital costs ( 9 ). The average expense exceeds $ 32,000 per sepsis patient, and many associated with pneumonia require long-term respiratory support and lengthy critical care stays ( 10 ). These costs do not include meaningful indirect costs associated with long-term disabilities and reduced function among survivors with post-sepsis syndrome. In spite of improvement in sepsis recognition processes, there are still gaps in the knowledge of particular patterns in mortality linked with sepsis resulting from pneumonia in various populations. Hence, the present study adopts the CDC WONDER database in undertaking a thorough mortality pattern analysis among sepsis patients triggered by pneumonia. The study purports to assess mortality rate disparities by age, race, sex, and locality among patients aged 25 and older, in a bid to differentiate populations under particular risks and locality disparities as a guide in formulating targeted intervention plans. 2.METHODS 2.1 Population and study design The CDC Wonder (Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research) database was employed to retrieve death certificates on Sepsis and Pneumonia-related mortality from 1999 to 2024 ( 11 ). The CDC Database was used to retrieve data of individuals aged 25 years and older, identified from death certificates listing Sepsis (ICD-10 code A40-A41) ( 12 ) and Pneumonia (ICD-10 code J12-J18) as causes of death from 1999 to 2024 ( 13 ). The Multiple Cause-of-Death Public Use records were utilized to ensure the inclusion of all instances where Sepsis and Pneumonia were recorded as either a direct or underlying cause of death. Given that the data were extracted from a publicly accessible database, institutional review board approval was not required. This study was conducted in accordance with the reporting guidelines established by the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) standards ( 14 ). 2.2 Data Abstraction The data extracted for analysis specifically included variables such as gender, race, age groups, urbanization level, state, and census region. Gender categories included male and female. Racial groups were classified as NH White, NH Black or African American, NH others, and Hispanic or Latino (check racial groups). This classification follows the categories established by the CDC WONDER database and has been used in prior studies. The dataset incorporates cause-of-mortality information from all 50 states and the District of Columbia, primarily focusing on adults aged 25 years and older. Age groups were characterized as 25–44 years (younger adults), 45–64 years (middle-aged adults), and 65 + years (older adults). Based on the 2013 U.S. Census classification, the population was categorized by urbanization level into urban (large metropolitan, medium/small metropolitan) and rural (population < 50,000) counties. Census regions were split into Northeast, Midwest, South, and West, under the regional definitions provided by the U.S. Census Bureau. 2.3 Statistical Analysis To analyze national trajectories in sepsis and pneumonia-associated mortality, we computed the crude and age-adjusted mortality rate (AAMR) per 100,000 population from 1999 to 2024, disaggregated by year, gender, race, and urban–rural status, employing a 95% confidence interval (CI). The U.S. population from the year 1999 was used as the baseline population for calculating age-adjusted mortality rates (AAMR) ( 15 ). Furthermore, to assess changes in mortality related to sepsis and pneumonia the Joinpoint Regression Program (version 5.3.0 National Cancer Institute) was employed throughout the study period ( 16 ). Annual percent change (APC) and its corresponding 95% CI in the AAMRs were computed using this software. Substantial shifts in annual mortality trends were identified by fitting linear segments at points where evident changes over time were observed. The Monte Carlo permutation method was utilized to determine the annual percentage change (APC) in AAMRs, along with 95% confidence intervals (CIs). A two-tailed t-test (test for parallelism) was performed to determine whether the APC and AAPC values indicated an increase or decrease in deaths during the study period. A p-value of < 0.05 was regarded as statistically significant. 3.RESULTS Between 1999 and 2024, there were a total 1,039,577 deaths related to pneumonia and sepsis-related mortality. (Supplementary Table 1) . Most of these deaths (88.6%) occurred in medical facilities, followed by deaths at the nursing homes or long-term care facilities (5.2%), hospice facilities (3.1%) and decedent's home (2.2%). A small number of cases (0.9%) had other places of death. (Supplementary Table 2). 3.1 Annual trends Throughout the study period from 1999 to 2024, AAMR increased from 16.6 (95% CI: 16.4 to 16.8) in 1999 to 18.2 in 2024. The AAMR remained relatively stable from 1999 to 2018 (APC = 0.6, 95% CI: -0.6 to 1.4; p = 0.226, non-significant ). From 2018 onwards till 2021 AAMR increased steeply (APC = 16.8, 9 % CI: 6.7 to 21.7; p < 0.001), followed by a sharp fall in AAMR till 2024 (APC = -15.3, 9 % CI: -23.0 to -9.9; p < 0.001). ( Fig. 1 , Supplementary Table 3) 3.2 Sex Throughout the study period from 1999 to 2024, the AAMR was consistently higher for men than for women. Specifically, the overall AAMRs were 21.9 (95% CI: 21.6 to 22.2) for men and 14.4 (95% CI: 14.2 to 14.6) for women. (Supplementary Table 4) In men, the AAMR demonstrated a stabilized trajectory, between 1999 and 2018 (APC = 0.3, 95% CI: -0.8 to 1.5; p = 0.529, non-significant ). This was followed by a sharp increase in AAMR (APC = 18.9, 95% CI: 8.5 to 23.9; p < 0.001) till 2021. Finally, there was a significant decline till 2024 (APC = -16.7, 95% CI: -24.5 to -11.9; p < 0.001). Females displayed analogous trajectories, with stable AAMR until 2018, followed by an increase and subsequent decline. (Supplementary Table 3, Supplementary Fig. 1) 3.3 Age Group Throughout the study period from 1999 to 2024, the overall AAMR was highest in the 65–85 + age group at 69.3 (95% CI: 68.5 to 70.1), followed by 45–64 age group 9.3 (95% CI: 9.1 to 9.5), while the 25–44 age group had the lowest overall AAMR 1.6 (95% CI: 1.6 to 1.7). For the 65–85 age group, there was a notable rise in AAMR with a declining period afterwards. A slight increase occurred from 1999 to 2018 (APC = 0.4, 95% CI: -0.8 to 1.1; p = 0.384, non-significant ), followed by a substantial rise until 2021 (APC = 11.9, 95 CI: 3.9 to 15.9; p = 0.002). Finally, AAMR declined till 2024 (APC = -11.7, 95% CI: -19.8 to -6.3; p = 0.004). 45–64 and 25–44 age groups demonstrated similar trends: a slight increase, followed by a rise and later decline. (Supplementary Fig. 2, Supplementary Table 5). 3.4 Race NH Black or African Americans had the highest overall AAMR among all the ethnicities throughout the study period, with an AAMR of 27.5 (95% CI: 26.8 to 28.3). Meanwhile, the Hispanic or Latino, NH others, NH White populations had AAMRs of 20.1 (95% CI: 19.4 to 20.9), 16.6 (95% CI: 15.8 to 17.5), and 16.1 (95% CI: 15.9 to 16.3), respectively. (Supplementary Table 6) The trends for NH Black or African Americans, NH others, NH Whites, and Hispanic or Latinos can be divided into three segments. For NH Black or African Americans, the AAMR demonstrated a declined trajectory, between 1999 and 2018 (APC = -0.9, 95% CI: -1.8 to -0.2; p = 0.008). This was followed by a sharp increase in AAMR (APC = 20.4, 95% CI: 11.0 to 25.5; p < 0.001) till 2021. Finally, there was a significant decline till 2024 (APC = -17.3, 95% CI: -23.7 to -12.3; p < 0.001). NH others and Hispanic or Latinos showed analogous trajectories: a slight decline, followed by an increase and later decline. For NH Whites, the initial phase from 1999 to 2018 showed an increase in AAMR (APC = 0.94, 95% CI: -0.5 to 1.7; p = 0.111, non-significant ). This was followed by a sharper rise extending to 2021 (APC of 13.9, 95% CI: 4.8 to 18.2; p < 0.001). Finally, there was a significant decline till 2024 (APC = -12.4, 95% CI: -21.3 to -7.0; p = 0.005). (Supplementary Fig. 3) 3.5 Geographic regions States exhibited significant differences in AAMR, with values ranging from 27.0 in District of Columbia to 8.5 in Vermont. States in the upper 90th percentile of AAMRs for pneumonia and sepsis-related patients included District of Columbia, Kentucky, Nevada, West Virginia, and Mississippi. These states had AAMRs that were nearly three times higher than those in the lower 10th percentile, which included Vermont, Minnesota, Oregon, Montana, and Wisconsin. (Supplementary Table 7). During the period from 1999 to 2024, the south region exhibited the highest overall AAMR at 19.7 (95% CI: 19.4 to 20.0), followed by the West with an overall AAMR of 17.3 (95% CI: 17.0 to 17.7), the Northeast at 16.4 (95% CI: 16.0 to 16.7), and the Midwest at 14.9 (95% CI: 14.6 to 15.3). (Supplementary Table 8). The South saw a slight increase in AAMR between 1999 and 2018 (APC = 0.8, 95% CI: -0.5 to 1.8; p = 0.201, non-significant ). This was followed by a sharp increase in AAMR (APC = 20.7, 95% CI: 9.0 to 26.5; p < 0.001) till 2021. Finally, there was a significant decline till 2024 (APC = -17.6, 95% CI: -26.4 to -11.9; p < 0.001). The West and Midwest regions showed analogous trajectories, with a slight rise, followed by an increase and subsequent decline. The Northeast region experienced an initial decline from 1999 to 2011 (APC = -1.3, 95% CI: -3.5 to -0.2; p = 0.022), followed by a moderate increase until 2021 (APC of 3.0, 95% CI: 1.7 to 9.0; p = 0.006). Finally, a steep decline in AAMR was observed until 2024 (APC = -7.4, 95% CI: -16.2 to -1.8; p = 0.012). (Supplementary Fig. 4). Throughout the period from 1999 to 2020, the overall AAMRs were 17.1 (95% CI: 16.8 to 17.6) for rural areas and 16.7 (95% CI: 16.5 to 16.9) for urban areas. The trends for rural areas can be divided into two segments. The initial phase from 1999 to 2010 exhibited a slight increase in AAMR (APC = 0.4 95% CI: -2.9 to 1.8; p = 0.733, non-significant ). This was followed by a steeper rise until 2020 (APC of 5.0, 95% CI: 3.7 to 8.3; p < 0.001). Similarly, urban areas showed parallel trends in AAMR, with a slight increase from 1999 to 2018 (APC = 0.4, 95% CI: -0.6 to 1.0; p = 0.357, non-significant ). Subsequently, a sharper rise was observed until 2020 (APC = 17.2, 95% CI: 4.3 to 23.4; p < 0.001). (Supplementary Fig. 5, Supplementary Table 9). 4.DISCUSSION This study provides a comprehensive analysis of pneumonia and sepsis-related mortality in the United States from 1999 to 2024, elucidating critical temporal trends and demographic disparities. Our findings reveal a substantial and concerning shift in what had been a stable two-decade mortality trend, characterized by a sharp escalation in the age-adjusted mortality rate that peaked in 2021 before subsequently declining. A vast majority of these deaths occurred in a medical facility, highlighting the acute severity of this disease combination. The analysis further underscores profound and persistent disparities: men consistently experienced higher mortality rates than women, and Non-Hispanic Black individuals bore the highest mortality burden overall, a finding made more troubling as the recent mortality surge sharply reversed a pre-existing trend of improvement for this group. Geographically, the mortality burden was disproportionately concentrated in the Southern states, with significant variation observed at the state level. While older adults consistently faced the highest absolute mortality risk, this recent period of escalation represents a critical public health event that intensely magnified long-standing vulnerabilities across the population. The pathophysiological link between pneumonia and sepsis is a destructive feedback loop, where a localized infection triggers a systemic response that ultimately becomes more lethal than the original pathogen. Inside the lungs, the immune system first mounts a controlled and necessary defense against the invading microbes ( 17 ). The critical failure point occurs when this local battle is lost, allowing the infection and its inflammatory byproducts to breach the pulmonary barrier and flood the circulation ( 18 ). This event initiates a dysregulated, system-wide immune activation, a cytokine storm that loses all proportion and precision ( 19 ). Consequently, the body's own signaling molecules induce widespread vasodilation, capillary leakage, and a disordered coagulation state, which collectively sabotage organ perfusion and lead to septic shock ( 20 ). Pneumonia thus acts as a dual threat; it establishes the primary infection while simultaneously compromising the body's oxygen supply, a combination that dramatically accelerates the spiral into multi-organ failure. The 26-year mortality narrative for pneumonia and sepsis unfolds in three distinct acts: a long period of fragile stability, a sudden and catastrophic disruption, and a subsequent period of rapid recovery. The relative stasis observed from 1999 to 2018 likely reflects a stalemate between competing public health forces. On one hand, advances such as widespread pneumococcal vaccination and improved sepsis care protocols worked to suppress mortality ( 21 )( 22 ). On the other hand, a growing population of older adults and a rising prevalence of comorbidities like diabetes and COPD created a larger pool of vulnerable individuals, effectively neutralizing those gains ( 23 ). This delicate balance was completely shattered by the arrival of the COVID-19 pandemic, which explains the sharp mortality escalation peaking in 2021. The SARS-CoV-2 virus acted as an unprecedented driver of viral pneumonia and sepsis, overwhelming hospital systems and directly causing a surge in deaths ( 24 ). Just as abruptly, the sharp decline after 2021 points to the impact of mass vaccination campaigns, the emergence of less virulent viral variants, and a healthcare system that had adapted its treatment strategies, collectively mitigating the pandemic's deadliest effects ( 25 ). The disparity in pneumonia and sepsis mortality between sexes presents as a dynamic process of risk amplification rather than a static vulnerability. The consistently elevated mortality in men, which escalated more sharply than in women during the 2018 to 2021 surge, suggests a powerful interaction between a foundational susceptibility and an acute viral trigger. The established male predisposition for more severe infectious disease outcomes is likely rooted in a convergence of factors: a hormonal and genetic context that can foster a dysregulated inflammatory response, a higher burden of cardiovascular comorbidities at earlier ages, and a greater prevalence of behaviors that compromise pulmonary health ( 26 )( 27 )( 28 )( 29 ). This underlying risk profile, while significant on its own, does not fully account for the widening mortality gap during the pandemic. The more potent explanation is that the SARS-CoV-2 virus acted as a specific and severe stressor on this already fragile male substrate. The data now strongly indicate that men mount a less effective antiviral immune response to this particular pathogen ( 30 )( 31 ). Therefore, the pattern observed suggests a synergistic effect; the pandemic virus appears to have selectively exploited the multi-layered biological and clinical vulnerabilities of men, turning a chronic disadvantage into an acute and disproportionate catastrophe. The stark mortality gap in pneumonia and sepsis deaths across racial and ethnic groups is not a reflection of the pathogens involved, but a direct indictment of structural inequalities that cultivate vulnerability to respiratory infections. Long before the pandemic, a higher prevalence of conditions like asthma, diabetes, and hypertension in Black and Hispanic communities created a population with diminished physiological reserve to fight and survive severe pneumonia ( 32 )( 33 )( 34 ). The modest but steady pre-2018 decline in mortality for these groups shows these disparities are not inevitable. However, the arrival of COVID-19 acted as a seismic shock, introducing a novel virus known to cause severe viral pneumonia and frequently progress to sepsis ( 35 )( 36 ). This crisis transformed the higher baseline risk into a catastrophic mortality event. The data therefore reveal how structural forces create a fertile ground for respiratory pathogens, ensuring that when a widespread virus emerges, the lethal progression from pneumonia to fatal sepsis follows the predictable and unjust lines of race and ethnicity in America. Mortality patterns by age revealed two distinct narratives: the expected high burden in older adults and, more alarmingly, a sharp proportional surge in death rates among younger and middle-aged cohorts. The profound mortality risk in the 65 + population aligns with the classic understanding of immunosenescence, where an aging immune system is less capable of preventing a localized pneumonia from progressing to systemic sepsis ( 37 )( 38 ). The more concerning trend is the dramatic surge in mortality among younger adults, which points to an erosion of the traditional health advantages of youth. This suggests a premature accumulation of risk factors, particularly the rising prevalence of obesity and metabolic syndrome, which creates a state of chronic inflammation that primes even a younger person for a catastrophic response to a severe respiratory infection ( 39 )( 40 ). The COVID-19 pandemic did not create this vulnerability but rather exploited it with lethal efficiency, acting as the acute trigger on a population that was already becoming less resilient. Collectively, these findings signal a dangerous convergence: the timeless threat of infection in old age is now meeting a modern epidemic of chronic disease in the young, expanding the clinical profile of who is most at risk for fatal pneumonia and sepsis. The geography of mortality from pneumonia and sepsis in the U.S. is not random but follows predictable contours of social and economic disadvantage, revealing how 'place' can determine resilience to infection. The heavy concentration of deaths in the South, a pattern that mirrors the nation's "Stroke Belt" and "Sepsis Belt," points to a shared etiology of foundational risk factors ( 41 )( 42 ). This regional pattern is largely a story of nonmetropolitan America. Rural communities often face a dual burden: a population with a higher prevalence of chronic illnesses that predispose individuals to severe pneumonia, confronting a healthcare system with limited capacity for the specialized critical care needed to manage sepsis ( 43 )( 44 ). The COVID-19 pandemic, however, introduced a counterintuitive dynamic. While rural areas had a poor baseline, the pandemic's unique transmission characteristics made dense urban centers acutely vulnerable, overwhelming even well-resourced hospital systems through the sheer volume of cases ( 45 ). This complex interplay of risks is rendered in sharp relief at the state level and these geographic risks are not organic; they are shaped by policy and environment. State-level decisions on Medicaid expansion, for instance, directly impact access to care in many of these high-burden regions ( 46 ), while disparities in environmental factors like regional air quality can heighten the underlying risk of developing severe pneumonia in the first place ( 47 ). These complex forces are rendered in sharp relief at the state level. A state like West Virginia becomes an archetype of the rural risk profile, where poor population health and limited infrastructure converge. In contrast, the high mortality in the District of Columbia illustrates an urban archetype, where concentrated socioeconomic and racial inequity creates a similar level of vulnerability, proving that the drivers of risk are multifaceted ( 48 ). Therefore, the map of pneumonia and sepsis mortality is ultimately a map of systemic vulnerabilities, where geography serves as a proxy for a deep interplay of policy, environment, and the enduring legacy of social inequity. The overwhelming predominance of in-hospital deaths confirms the condition's status as an acute crisis, where mortality often represents a failure of even the most aggressive intervention ( 49 ). The smaller fraction of deaths in nursing homes signifies a different trajectory: a frail population succumbing to an infection deemed insurmountable, where hospitalization may be forgone to honor goals of care ( 50 ). More troubling are the deaths at home; though few, they point to critical breakdowns in outpatient services, where a rapidly fulminant infection either evaded recognition or where barriers prevented timely access to a hospital ( 51 ). The near-absence of hospice as a place of death is also revealing, suggesting sepsis is treated with curative intent until the very end, potentially highlighting a systemic underutilization of palliative care for this devastating condition ( 52 ). The findings of this study are not merely observational; they constitute an urgent call to action for clinicians, policymakers, and researchers to address the profound vulnerabilities unmasked by pneumonia and sepsis. For clinicians, this requires a heightened index of suspicion for sepsis, especially in high-risk demographic groups, and a renewed focus on the aggressive outpatient management of the chronic diseases that create this vulnerability ( 53 ). Our data also suggest a critical need to better integrate palliative care conversations for patients with overwhelming infection, where the focus on curative intent may come at the cost of patient comfort ( 54 ). Policymakers, in turn, must address the structural drivers of these disparities. This includes implementing policies that expand health insurance coverage, investing in the public health infrastructure of underserved regions, and tackling the social and environmental determinants that increasthe baseline risk of severe respiratory infection ( 55 )( 56 ). Finally, the research agenda must now evolve beyond describing these trends. The priority should be on prospective, individual-level studies to confirm these ecological findings and, most importantly, on implementation science to test targeted interventions designed to eliminate the stark inequities identified here ( 57 )( 58 ). LIMITATIONS Our interpretation is constrained by the known limitations of death certificate data, where the complexity of sepsis can lead to diagnostic misclassification, potentially misestimating its true mortality burden ( 59 ). The observed trends are also susceptible to a surveillance artifact; evolving clinical definitions and heightened awareness of sepsis over the past two decades have likely produced a "coding drift" that can mimic a true rise in mortality ( 60 ). As an ecological study, our findings demonstrate population-level associations, not individual causation, a limitation magnified by the absence of granular clinical data like pathogen type or patient vaccination status, which are key unmeasured confounders. Despite these constraints, the study's strength lies in its large, population-based scale, offering a powerful view of broad epidemiological patterns that demand further investigation. 5.CONCLUSION In conclusion, this 26-year analysis reveals that a long period of fragile stability in pneumonia and sepsis mortality, representing a stalemate between medical progress and worsening population health, was decisively shattered by the COVID-19 pandemic. The mortality burden falls disproportionately on men, older adults, and Non-Hispanic Black individuals, and is geographically concentrated in the South, reflecting a convergence of biological susceptibility, immunosenescence, and profound structural inequities. Ultimately, these findings should serve as a clear directive to move beyond documenting these disparities and toward implementing robust, equitable public health strategies that strengthen our collective resilience against future infectious threats. Abbreviations Age-Adjusted Mortality Rates (AAMR) Average Annual Percentage Changes (AAPC) Annual Percent Change (APC) Non-Hispanic (NH) Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research (CDC-WONDER) Declarations Author Contribution Author Contributions:Conceptualization: Shaheer Bin Shafiq, Ammad UddinStudy Design and Methodology: Asim Sajjad, Hassan Abdul Aziz Dhedhi Data Acquisition and Curation: Ammad Uddin, Muhammad Tahir, Muhammad Salik UddinStatistical Analysis and Interpretation: Ammad Uddin, Ahmed Anwaar Uddin Manuscript Drafting: Ammad Uddin Muhammad Salik UddinCritical Revision of the Manuscript: Hassan Abdul Aziz Dhedhi, Shaheer Bin Shafiq, Muhammad Tahir, Ammad Uddin, Asim Sajjad Supervision: Rida Shakeel Validation & Final Approval: All authors Data Availability The data supporting the findings of this study are publicly available from the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database References Laboratory Evaluation of Sepsis |. Treatment & Management | Point of Care. Accessed: Sep. 11, 2025. [Online]. Available: https://www.statpearls.com/point-of-care/145900 Avni T, Lador A, Lev S, Leibovici L, Paul M, Grossman A. Sepsis: Diagnosis and Management, Am Fam Physician , vol. 101, no. 7, pp. 409–418, Apr. 2020, 10.1371/JOURNAL.PONE.0129305 Torres A et al. Dec., Pneumonia, Nat Rev Dis Primers , vol. 7, no. 1, 2021, 10.1038/S41572-021-00259-0 Darkwah S, Kotey FCN, Ahenkorah J, Adutwum-Ofosu KK, Donkor ES. Sepsis-Related Lung Injury and the Complication of Extrapulmonary Pneumococcal Pneumonia. Diseases. Apr. 2024;12(4):72. 10.3390/DISEASES12040072 . Dantes RB, United States. Sepsis Program Activities in Acute Care Hospitals — National Healthcare Safety Network, 2022, MMWR Morb Mortal Wkly Rep , vol. 72, no. 34, pp. 907–911, Aug. 2025. 10.15585/MMWR.MM7234A2 AHRQ’s Portrait of Sepsis Reveals Its Alarming Human Toll | Agency for Healthcare Research and Quality. Accessed: Sep. 11, 2025. [Online]. Available: https://www.ahrq.gov/news/blog/ahrqviews/portrait-of-sepsis.html Holland E, et al. Demographic and regional trends of pneumonia mortality in the United States, 1999 to 2022. Sci Rep. Dec. 2025;15(1):1–11. 10.1038/S41598-025-94715-6;SUBJMETA . Paoli CJ, Reynolds MA, Sinha M, Gitlin M, Crouser E. Epidemiology and costs of sepsis in the United States-an analysis based on timing of diagnosis and severity level. Crit Care Med. 2018;46(12):1889–97. 10.1097/CCM.0000000000003342 . New Federal Report Shows Dire State of Sepsis Care in the US - End Sepsis. Accessed: Sep. 11, 2025. [Online]. Available: https://www.endsepsis.org/2024/10/09/congressional-report-on-sepsis-released/ Arefian H, et al. Hospital-related cost of sepsis: A systematic review. J Infect. Feb. 2017;74(2):107–17. 10.1016/J.JINF.2016.11.006 . Multiple Cause of Death Data on CDC WONDER. Accessed: Sep. 11, 2025. [Online]. Available: https://wonder.cdc.gov/mcd.html Morrissey R, et al. Demographic and regional trends of sepsis mortality in the United States, 1999–2022. BMC Infect Dis. Dec. 2025;25(1):504. 10.1186/S12879-025-10921-7 . Obianyo CM, et al. Trends and Disparities in Pneumonia-Related Mortality in the U.S. Population: A Nationwide Analysis Using the CDC WONDER Data. Cureus. May 2025;17(5):e83371. 10.7759/CUREUS.83371 . von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. Strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies, BMJ , vol. 335, no. 7624, pp. 806–808, Oct. 2007, 10.1136/BMJ.39335.541782.AD Age standardization. of death rates: implementation of the year 2000 standard - PubMed. Accessed: Sep. 11, 2025. [Online]. Available: https://pubmed.ncbi.nlm.nih.gov/9796247/ Joinpoint Regression Program. Accessed: Sep. 11, 2025. [Online]. Available: https://surveillance.cancer.gov/joinpoint/ Mizgerd JP. Acute Lower Respiratory Tract Infection. N Engl J Med. Feb. 2008;358(7):716. 10.1056/NEJMRA074111 . Singer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. Feb. 2016;315(8):801–10. 10.1001/JAMA.2016.0287 . Fajgenbaum DC, June CH. Cytokine Storm, New England Journal of Medicine , vol. 383, no. 23, pp. 2255–2273, Dec. 2020, 10.1056/NEJMRA2026131 Gotts JE, Matthay MA. Sepsis: pathophysiology and clinical management. BMJ. May 2016;353. 10.1136/BMJ.I1585 . Vadlamudi NK, Chen A, Marra F. Impact of the 13-Valent Pneumococcal Conjugate Vaccine Among Adults: A Systematic Review and Meta-analysis, Clinical Infectious Diseases , vol. 69, no. 1, pp. 34–49, Jun. 2019, 10.1093/CID/CIY872 Levy MM et al. Feb., The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis, Intensive Care Med , vol. 36, no. 2, p. 222, 2010, 10.1007/S00134-009-1738-3 Boersma P, Black LI, Ward BW. Prevalence of Multiple Chronic Conditions Among US Adults, 2018. Prev Chronic Dis. Sep. 2020;17. 10.5888/PCD17.200130 . Vincent JL. Covid-19: It’s All About Sepsis. Future Microbiol. Feb. 2021;16(3):131–3. 10.2217/FMB-2020-0312 . Marziano V et al. Jul., The decline of COVID-19 severity and lethality over two years of pandemic, medRxiv , p. 2022.07.01.22277137, 2022, 10.1101/2022.07.01.22277137 Angele MK, Pratschke S, Hubbard WJ, Chaudry IH. Gender differences in sepsis. Virulence. 2014;5(1):12–9. 10.4161/VIRU.26982 . Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. Oct. 2016;16(10):626–38. 10.1038/NRI.2016.90;SUBJMETA . Mauvais-Jarvis F, et al. Sex and gender: modifiers of health, disease, and medicine. Lancet. Aug. 2020;396(10250):565–82. 10.1016/S0140-6736(20)31561-0 . Kritsotakis G, Psarrou M, Vassilaki M, Androulaki Z, Philalithis AE. Gender differences in the prevalence and clustering of multiple health risk behaviours in young adults. J Adv Nurs. Sep. 2016;72(9):2098–113. 10.1111/JAN.12981 . Peckham H, et al. Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission. Nat Commun. Dec. 2020;11(1):6317. 10.1038/S41467-020-19741-6 . Takahashi T, et al. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature. Dec. 2020;588(7837):315–20. 10.1038/S41586-020-2700-3;TECHMETA . Daniel H, Bornstein SS, Kane GC, for the H. Apr. and P. P. C. of the A. C. of Physicians*, Addressing Social Determinants to Improve Patient Care and Promote Health Equity: An American College of Physicians Position Paper, https : //doi.org/10.7326/M17-2441 , vol. 168, no. 8, pp. 577–578, 2018, 10.7326/M17-2441 Churchwell K et al. Dec., Call to Action: Structural Racism as a Fundamental Driver of Health Disparities: A Presidential Advisory From the American Heart Association, Circulation , vol. 142, no. 24, pp. E454–E468, 2020, 10.1161/CIR.0000000000000936 Burton DC, et al. Socioeconomic and racial/ethnic disparities in the incidence of bacteremic pneumonia among US adults. Am J Public Health. Oct. 2010;100(10):1904–11. 10.2105/AJPH.2009.181313 . Color of Coronavirus. COVID-19 deaths analyzed by race and ethnicity — APM Research Lab. Accessed: Sep. 11, 2025. [Online]. Available: https://www.apmresearchlab.org/covid/deaths-by-race Andrasfay T, Goldman N. Reductions in 2020 US life expectancy due to COVID-19 and the disproportionate impact on the Black and Latino populations, Proceedings of the National Academy of Sciences , vol. 118, no. 5, p. e2014746118, Feb. 2021, 10.1073/PNAS.2014746118 Meyer KC. The role of immunity and inflammation in lung senescence and susceptibility to infection in the elderly. Semin Respir Crit Care Med. 2010;31(5):561–74. 10.1055/S-0030-1265897/ID/24/BIB . Starr ME, Saito H. Sepsis in Old Age: Review of Human and Animal Studies. Aging Dis. Apr. 2014;5(2):126–36. 10.14336/AD.2014.0500126 . Wall HK, Ritchey MD, Gillespie C, Omura JD, Jamal A, George MG. Vital Signs: Prevalence of Key Cardiovascular Disease Risk Factors for Million Hearts 2022 — United States, 2011–2016, MMWR Morb Mortal Wkly Rep , vol. 67, no. 35, pp. 983–991, Sep. 2019, 10.15585/MMWR.MM6735A4 Popkin BM, et al. Individuals with obesity and COVID-19: A global perspective on the epidemiology and biological relationships. Obes Rev. Nov. 2020;21(11):e13128. 10.1111/OBR.13128 . Hu JR, et al. Risk-standardized sepsis mortality map of the United States. Digit Health. Jan. 2022;8:20552076211072400. 10.1177/20552076211072400 . Howard G, Howard VJ. Twenty Years of Progress Toward Understanding the Stroke Belt, Stroke , vol. 51, no. 3, pp. 742–750, Mar. 2020, 10.1161/STROKEAHA.119.024155 Isaacs B. Save rural health care: Time for a significant paradigm shift. J Am Osteopath Assoc. Sep. 2019;119(9):551–5. 10.7556/JAOA2019.098/MACHINEREADABLECITATION/RIS . Peake SL, Judd N. Supporting rural community-based critical care. Curr Opin Crit Care. Dec. 2007;13(6):720–4. 10.1097/MCC.0B013E3282F1BB21 . Whittle RS, Diaz-Artiles A. An ecological study of socioeconomic predictors in detection of COVID-19 cases across neighborhoods in New York City. BMC Med. Sep. 2020;18(1):271. 10.1186/S12916-020-01731-6 . Lee BP, Dodge JL, Terrault NA. Medicaid expansion and variability in mortality in the USA: a national, observational cohort study. Lancet Public Health. Jan. 2021;7(1):e48. 10.1016/S2468-2667(21)00252-8 . Neupane B, Jerrett M, Burnett RT, Marrie T, Arain A, Loeb M. Long-term exposure to ambient air pollution and risk of hospitalization with community-acquired pneumonia in older adults, Am J Respir Crit Care Med , vol. 181, no. 1, pp. 47–53, Jan. 2010, 10.1164/RCCM.200901-0160OC King CJ, Buckley BO, Maheshwari R, Griffith DM. Feb., Race, Place, And Structural Racism: A Review Of Health And History In Washington, D.C., https://doi.org/10.1377/hlthaff.2021 . 01805 , vol. 41, no. 2, pp. 273–280, 2022, 10.1377/HLTHAFF.2021.01805 Rhee C, et al. Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009–2014. JAMA. Oct. 2017;318:1241. 10.1001/JAMA.2017.13836 . Yoshikawa TT, Reyes BJ, Ouslander JG. Sepsis in Older Adults in Long-Term Care Facilities: Challenges in Diagnosis and Management, J Am Geriatr Soc , vol. 67, no. 11, pp. 2234–2239, Nov. 2019, 10.1111/JGS.16194 Sterling SA, Puskarich MA, Jones AE. Prehospital treatment of sepsis: What really makes the ‘golden hour’ golden? Crit Care. Dec. 2014;18(1):1–2. 10.1186/S13054-014-0697-4/METRICS . Kleinpell R. New guidelines for sepsis care integrating palliative care and end of life care concepts, BMJ Support Palliat Care , vol. 2, no. 2, pp. 194–194, Jun. 2012, 10.1136/BMJSPCARE-2012-000250.90 Evans L, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. Nov. 2021;47(11):1181. 10.1007/S00134-021-06506-Y . Manfredi RA, et al. Early palliative intervention in septic patients reduces healthcare utilization. Am J Emerg Med. Dec. 2021;50:773–7. 10.1016/J.AJEM.2021.09.075 . Weinstein JN, Geller A, Negussie Y, Baciu A. Communities in Action: Pathways to Health Equity, Communities in Action: Pathways to Health Equity , pp. 1–558, Apr. 2017, 10.17226/24624 Cole MB, Galárraga O, Wilson IB, Wright B, Trivedi AN. At Federally Funded Health Centers, Medicaid Expansion Was Associated With Improved Quality Of Care. https://doi.org/10.1377/hlthaff. 2016. 0804 , vol. 36, no. 1, pp. 40–48, Aug. 2017, 10.1377/HLTHAFF.2016.0804 Shelton RC, Brownson RC. Enhancing Impact: A Call to Action for Equitable Implementation Science. Prev Sci. Apr. 2023;25:174. 10.1007/S11121-023-01589-Z . no. Suppl 1. Benson RT, Koroshetz WJ. Health Disparities: Research That Matters, Stroke , vol. 29, no. 2, pp. 663–669, Mar. 2022, 10.1161/STROKEAHA.121.035087 Jolley RJ, Sawka KJ, Yergens DW, Quan H, Jetté N, Doig CJ. Validity of administrative data in recording sepsis: A systematic review. Crit Care. Apr. 2015;19(1):1–12. 10.1186/S13054-015-0847-3/TABLES/3 . Rhee C, Murphy MV, Li L, Platt R, Klompas M. Comparison of Trends in Sepsis Incidence and Coding Using Administrative Claims Versus Objective Clinical Data. Clin Infect Dis. Jan. 2015;60(1):88–95. 10.1093/CID/CIU750 . Additional Declarations No competing interests reported. Supplementary Files TABLES.docx GRAPHSCOMPLETE.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9005126","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":598973998,"identity":"ac7910f9-7025-4467-8c7a-644525e683b8","order_by":0,"name":"Ammad Uddin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3UlEQVRIiWNgGAWjYLACHoMaOfvjDUCWgQWxWgqOGTOcOQDSIkGslg/MiQ03EkBMIrTwTzud+OGNARtj48znVzf8KJBg4G/vTsCrReJ27mbJOQYyzMzSOWU3e4AOkzhzdgN+a27nbpDmMWBjY5POSbvBA9RiIJGLX4s80JbfPAbMPDySZ9Ju/iFGi8Ht3G1AW5glJCTYj90myhZDoBbLOQbHDAx4cthuyxhI8BD0ixzQYTfe/Kmp38B+/NnNN39s5Pjbewl4HwF4DMAkscpBgP0BKapHwSgYBaNgBAEAAERG8MJZvwwAAAAASUVORK5CYII=","orcid":"","institution":"Dow University of Health Sciences","correspondingAuthor":true,"prefix":"","firstName":"Ammad","middleName":"","lastName":"Uddin","suffix":""},{"id":598973999,"identity":"8b270b92-a3f0-401d-b397-4e8174227721","order_by":1,"name":"Muhammad Salik Uddin","email":"","orcid":"","institution":"Dow University of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Muhammad","middleName":"Salik","lastName":"Uddin","suffix":""},{"id":598974000,"identity":"fc92ad28-50ea-4c29-8074-7e30a3f66d4f","order_by":2,"name":"Hassan Abdul Aziz Dhedhi","email":"","orcid":"","institution":"Dow University of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Hassan","middleName":"Abdul Aziz","lastName":"Dhedhi","suffix":""},{"id":598974001,"identity":"ebf9d3b8-96e8-49ac-8293-3eb44de5dce6","order_by":3,"name":"Muhammad Tahir","email":"","orcid":"","institution":"Dow University of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Muhammad","middleName":"","lastName":"Tahir","suffix":""},{"id":598974002,"identity":"671281fb-b78d-4946-a2a4-b9731d00cf10","order_by":4,"name":"Asim Sajjad","email":"","orcid":"","institution":"Dow University of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Asim","middleName":"","lastName":"Sajjad","suffix":""},{"id":598974003,"identity":"5863f3ee-d496-4984-81ca-69311db75627","order_by":5,"name":"Shaheer Bin Shafiq","email":"","orcid":"","institution":"Dow University of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Shaheer","middleName":"Bin","lastName":"Shafiq","suffix":""},{"id":598974004,"identity":"94080620-0cfe-4965-80de-18bf072d7a76","order_by":6,"name":"Rida Shakeel","email":"","orcid":"","institution":"Dow University of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Rida","middleName":"","lastName":"Shakeel","suffix":""},{"id":598974005,"identity":"b608211a-7719-40bb-82e4-c0d58ad5451e","order_by":7,"name":"Ahmed Anwaar Uddin","email":"","orcid":"","institution":"Dow International Medical College, Dow University of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ahmed","middleName":"Anwaar","lastName":"Uddin","suffix":""}],"badges":[],"createdAt":"2026-03-02 03:23:44","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9005126/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9005126/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103797114,"identity":"226a59cb-cc49-4f2c-83c5-c6e7dc5ab2b6","added_by":"auto","created_at":"2026-03-03 04:25:11","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":241804,"visible":true,"origin":"","legend":"\u003cp\u003eCentral illustration depicting trends in demographics and disparities in Pneumonia-related Mortality among adults with Sepsis patients in the United States from 1999 to 2024.\u003c/p\u003e","description":"","filename":"Picture1.png","url":"https://assets-eu.researchsquare.com/files/rs-9005126/v1/ce9daf98f4f3b22f4caf936c.png"},{"id":104886668,"identity":"6a7863e9-e5e8-403b-98f0-d408371ceab6","added_by":"auto","created_at":"2026-03-18 10:09:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1002455,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9005126/v1/6173287a-e793-4f8d-9264-432380a7df77.pdf"},{"id":103797089,"identity":"e00d3a84-c998-400a-9d15-472861210aae","added_by":"auto","created_at":"2026-03-03 04:25:04","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":54836,"visible":true,"origin":"","legend":"","description":"","filename":"TABLES.docx","url":"https://assets-eu.researchsquare.com/files/rs-9005126/v1/a1d41a60ed58fc7df5c6c5a7.docx"},{"id":103797120,"identity":"160d255c-8171-40fc-95f6-4ad6d4c887bc","added_by":"auto","created_at":"2026-03-03 04:25:20","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":280563,"visible":true,"origin":"","legend":"","description":"","filename":"GRAPHSCOMPLETE.docx","url":"https://assets-eu.researchsquare.com/files/rs-9005126/v1/80b395c1e21312ef0ea0b9de.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Trends in Pneumonia and Sepsis-Related Mortality Across the United States, 1999– 2024: A CDC WONDER-Based Population Study","fulltext":[{"header":"1.INTRODUCTION","content":"\u003cp\u003eSepsis, which is a potentially lethal organ dysfunction resulting from a host response to infection that is improperly regulated, remains among the most serious medical emergency situations within modern-day healthcare (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). This complex syndrome arises once the body's immune response overreacts to an infection, causing widespread inflammation capable of causing organ systems harm and inducing organ failure (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Pneumonia, as a type of acute infection localized in the lung parenchyma (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), remains among the most common initiators responsible for the development of sepsis, especially in instances concerning inpatients within hospitals alongside susceptible populations including the elderly and individuals suffering from immune comptonization. The relationship between sepsis and pneumonia often remains quite alarming considering that sepsis within the context of pneumonia often presents with a quick clinical deterioration and poses significant challenges concerning expedient detection and response (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSepsis is mentioned as a leading cause of mortality in the United States, responsible for a minimum of 350,000 deaths in a year and as the leading cause of in-hospital deaths in the country (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The occurrence of sepsis has exhibited alarming rising patterns, and hospitalizations were up by 40% in the 2016\u0026ndash;2021 period (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Pneumonia is responsible for more than 53,000 deaths in a year and induces around 2.6\u0026nbsp;million emergency room visits, thereby being a forceful contributor in the sepsis burden as a whole (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). The mortality percentages among sepsis vary substantially by severity groups, from 5.6% among sepsis without organ dysfunction up to 34.2% in septic shock, and with pneumonia-related sepsis typically manifesting in the higher severity groups by virtue of respiratory failure (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe economic costs of sepsis and pneumonia cause significant strains on healthcare systems. Hospital care costs for sepsis have jumped from \u003cspan\u003e$\u003c/span\u003e31.2\u0026nbsp;billion in 2016 to \u003cspan\u003e$\u003c/span\u003e52.1\u0026nbsp;billion in 2021 and account for over 14% of all hospital costs (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The average expense exceeds \u003cspan\u003e$\u003c/span\u003e32,000 per sepsis patient, and many associated with pneumonia require long-term respiratory support and lengthy critical care stays (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). These costs do not include meaningful indirect costs associated with long-term disabilities and reduced function among survivors with post-sepsis syndrome.\u003c/p\u003e \u003cp\u003eIn spite of improvement in sepsis recognition processes, there are still gaps in the knowledge of particular patterns in mortality linked with sepsis resulting from pneumonia in various populations. Hence, the present study adopts the CDC WONDER database in undertaking a thorough mortality pattern analysis among sepsis patients triggered by pneumonia. The study purports to assess mortality rate disparities by age, race, sex, and locality among patients aged 25 and older, in a bid to differentiate populations under particular risks and locality disparities as a guide in formulating targeted intervention plans.\u003c/p\u003e"},{"header":"2.METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Population and study design\u003c/h2\u003e \u003cp\u003eThe CDC Wonder (Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research) database was employed to retrieve death certificates on Sepsis and Pneumonia-related mortality from 1999 to 2024 (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). The CDC Database was used to retrieve data of individuals aged 25 years and older, identified from death certificates listing Sepsis (ICD-10 code A40-A41) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) and Pneumonia (ICD-10 code J12-J18) as causes of death from 1999 to 2024 (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). The Multiple Cause-of-Death Public Use records were utilized to ensure the inclusion of all instances where Sepsis and Pneumonia were recorded as either a direct or underlying cause of death. Given that the data were extracted from a publicly accessible database, institutional review board approval was not required. This study was conducted in accordance with the reporting guidelines established by the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) standards (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Data Abstraction\u003c/h2\u003e \u003cp\u003eThe data extracted for analysis specifically included variables such as gender, race, age groups, urbanization level, state, and census region. Gender categories included male and female. Racial groups were classified as NH White, NH Black or African American, NH others, and Hispanic or Latino (check racial groups). This classification follows the categories established by the CDC WONDER database and has been used in prior studies. The dataset incorporates cause-of-mortality information from all 50 states and the District of Columbia, primarily focusing on adults aged 25 years and older. Age groups were characterized as 25\u0026ndash;44 years (younger adults), 45\u0026ndash;64 years (middle-aged adults), and 65\u0026thinsp;+\u0026thinsp;years (older adults). Based on the 2013 U.S. Census classification, the population was categorized by urbanization level into urban (large metropolitan, medium/small metropolitan) and rural (population\u0026thinsp;\u0026lt;\u0026thinsp;50,000) counties. Census regions were split into Northeast, Midwest, South, and West, under the regional definitions provided by the U.S. Census Bureau.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistical Analysis\u003c/h2\u003e \u003cp\u003eTo analyze national trajectories in sepsis and pneumonia-associated mortality, we computed the crude and age-adjusted mortality rate (AAMR) per 100,000 population from 1999 to 2024, disaggregated by year, gender, race, and urban\u0026ndash;rural status, \u003cb\u003eemploying\u003c/b\u003e a 95% confidence interval (CI). The U.S. population from the year 1999 was used as the baseline population for calculating age-adjusted mortality rates (AAMR) (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Furthermore, to assess changes in mortality related to sepsis and pneumonia the Joinpoint Regression Program (version 5.3.0 National Cancer Institute) was employed throughout the study period (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Annual percent change (APC) and its corresponding 95% CI in the AAMRs were computed using this software. Substantial shifts in annual mortality trends were identified by fitting linear segments at points where evident changes over time were observed. The Monte Carlo permutation method was utilized to determine the annual percentage change (APC) in AAMRs, along with 95% confidence intervals (CIs). A two-tailed t-test (test for parallelism) was performed to determine whether the APC and AAPC values indicated an increase or decrease in deaths during the study period. A p-value of \u0026lt;\u0026thinsp;0.05 was regarded as statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3.RESULTS","content":"\u003cp\u003eBetween 1999 and 2024, there were a total 1,039,577 deaths related to pneumonia and sepsis-related mortality. \u003cb\u003e(Supplementary Table\u0026nbsp;1)\u003c/b\u003e. Most of these deaths (88.6%) occurred in medical facilities, followed by deaths at the nursing homes or long-term care facilities (5.2%), hospice facilities (3.1%) and decedent's home (2.2%). A small number of cases (0.9%) had other places of death. \u003cb\u003e(Supplementary Table\u0026nbsp;2).\u003c/b\u003e\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Annual trends\u003c/h2\u003e \u003cp\u003eThroughout the study period from 1999 to 2024, AAMR increased from 16.6 (95% CI: 16.4 to 16.8) in 1999 to 18.2 in 2024.\u003c/p\u003e \u003cp\u003eThe AAMR remained relatively stable from 1999 to 2018 (APC\u0026thinsp;=\u0026thinsp;0.6, 95% CI: -0.6 to 1.4; p\u0026thinsp;=\u0026thinsp;0.226, \u003cb\u003enon-significant\u003c/b\u003e). From 2018 onwards till 2021 AAMR increased steeply (APC\u0026thinsp;=\u0026thinsp;16.8, 9 % CI: 6.7 to 21.7; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), followed by a sharp fall in AAMR till 2024 (APC = -15.3, 9 % CI: -23.0 to -9.9; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eSupplementary Table\u0026nbsp;3)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Sex\u003c/h2\u003e \u003cp\u003eThroughout the study period from 1999 to 2024, the AAMR was consistently higher for men than for women. Specifically, the overall AAMRs were 21.9 (95% CI: 21.6 to 22.2) for men and 14.4 (95% CI: 14.2 to 14.6) for women. \u003cb\u003e(Supplementary Table\u0026nbsp;4)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIn men, the AAMR demonstrated a stabilized trajectory, between 1999 and 2018 (APC\u0026thinsp;=\u0026thinsp;0.3, 95% CI: -0.8 to 1.5; p\u0026thinsp;=\u0026thinsp;0.529, \u003cb\u003enon-significant\u003c/b\u003e). This was followed by a sharp increase in AAMR (APC\u0026thinsp;=\u0026thinsp;18.9, 95% CI: 8.5 to 23.9; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) till 2021. Finally, there was a significant decline till 2024 (APC = -16.7, 95% CI: -24.5 to -11.9; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Females displayed analogous trajectories, with stable AAMR until 2018, followed by an increase and subsequent decline. \u003cb\u003e(Supplementary Table\u0026nbsp;3, Supplementary Fig.\u0026nbsp;1)\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Age Group\u003c/h2\u003e \u003cp\u003eThroughout the study period from 1999 to 2024, the overall AAMR was highest in the 65\u0026ndash;85\u0026thinsp;+\u0026thinsp;age group at 69.3 (95% CI: 68.5 to 70.1), followed by 45\u0026ndash;64 age group 9.3 (95% CI: 9.1 to 9.5), while the 25\u0026ndash;44 age group had the lowest overall AAMR 1.6 (95% CI: 1.6 to 1.7).\u003c/p\u003e \u003cp\u003eFor the 65\u0026ndash;85 age group, there was a notable rise in AAMR with a declining period afterwards. A slight increase occurred from 1999 to 2018 (APC\u0026thinsp;=\u0026thinsp;0.4, 95% CI: -0.8 to 1.1; p\u0026thinsp;=\u0026thinsp;0.384, \u003cb\u003enon-significant\u003c/b\u003e), followed by a substantial rise until 2021 (APC\u0026thinsp;=\u0026thinsp;11.9, 95 CI: 3.9 to 15.9; p\u0026thinsp;=\u0026thinsp;0.002). Finally, AAMR declined till 2024 (APC = -11.7, 95% CI: -19.8 to -6.3; p\u0026thinsp;=\u0026thinsp;0.004). 45\u0026ndash;64 and 25\u0026ndash;44 age groups demonstrated similar trends: a slight increase, followed by a rise and later decline. \u003cb\u003e(Supplementary Fig.\u0026nbsp;2, Supplementary Table\u0026nbsp;5).\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Race\u003c/h2\u003e \u003cp\u003eNH Black or African Americans had the highest overall AAMR among all the ethnicities throughout the study period, with an AAMR of 27.5 (95% CI: 26.8 to 28.3). Meanwhile, the Hispanic or Latino, NH others, NH White populations had AAMRs of 20.1 (95% CI: 19.4 to 20.9), 16.6 (95% CI: 15.8 to 17.5), and 16.1 (95% CI: 15.9 to 16.3), respectively. \u003cb\u003e(Supplementary Table\u0026nbsp;6)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe trends for NH Black or African Americans, NH others, NH Whites, and Hispanic or Latinos can be divided into three segments. For NH Black or African Americans, the AAMR demonstrated a declined trajectory, between 1999 and 2018 (APC = -0.9, 95% CI: -1.8 to -0.2; p\u0026thinsp;=\u0026thinsp;0.008). This was followed by a sharp increase in AAMR (APC\u0026thinsp;=\u0026thinsp;20.4, 95% CI: 11.0 to 25.5; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) till 2021. Finally, there was a significant decline till 2024 (APC = -17.3, 95% CI: -23.7 to -12.3; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). NH others and Hispanic or Latinos showed analogous trajectories: a slight decline, followed by an increase and later decline. For NH Whites, the initial phase from 1999 to 2018 showed an increase in AAMR (APC\u0026thinsp;=\u0026thinsp;0.94, 95% CI: -0.5 to 1.7; p\u0026thinsp;=\u0026thinsp;0.111, \u003cb\u003enon-significant\u003c/b\u003e). This was followed by a sharper rise extending to 2021 (APC of 13.9, 95% CI: 4.8 to 18.2; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Finally, there was a significant decline till 2024 (APC = -12.4, 95% CI: -21.3 to -7.0; p\u0026thinsp;=\u0026thinsp;0.005). \u003cb\u003e(Supplementary Fig.\u0026nbsp;3)\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Geographic regions\u003c/h2\u003e \u003cp\u003eStates exhibited significant differences in AAMR, with values ranging from 27.0 in District of Columbia to 8.5 in Vermont. States in the upper 90th percentile of AAMRs for pneumonia and sepsis-related patients included District of Columbia, Kentucky, Nevada, West Virginia, and Mississippi. These states had AAMRs that were nearly three times higher than those in the lower 10th percentile, which included Vermont, Minnesota, Oregon, Montana, and Wisconsin. \u003cb\u003e(Supplementary Table\u0026nbsp;7).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eDuring the period from 1999 to 2024, the south region exhibited the highest overall AAMR at 19.7 (95% CI: 19.4 to 20.0), followed by the West with an overall AAMR of 17.3 (95% CI: 17.0 to 17.7), the Northeast at 16.4 (95% CI: 16.0 to 16.7), and the Midwest at 14.9 (95% CI: 14.6 to 15.3). \u003cb\u003e(Supplementary Table\u0026nbsp;8).\u003c/b\u003e The South saw a slight increase in AAMR between 1999 and 2018 (APC\u0026thinsp;=\u0026thinsp;0.8, 95% CI: -0.5 to 1.8; p\u0026thinsp;=\u0026thinsp;0.201, \u003cb\u003enon-significant\u003c/b\u003e). This was followed by a sharp increase in AAMR (APC\u0026thinsp;=\u0026thinsp;20.7, 95% CI: 9.0 to 26.5; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) till 2021. Finally, there was a significant decline till 2024 (APC = -17.6, 95% CI: -26.4 to -11.9; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The West and Midwest regions showed analogous trajectories, with a slight rise, followed by an increase and subsequent decline. The Northeast region experienced an initial decline from 1999 to 2011 (APC = -1.3, 95% CI: -3.5 to -0.2; p\u0026thinsp;=\u0026thinsp;0.022), followed by a moderate increase until 2021 (APC of 3.0, 95% CI: 1.7 to 9.0; p\u0026thinsp;=\u0026thinsp;0.006). Finally, a steep decline in AAMR was observed until 2024 (APC = -7.4, 95% CI: -16.2 to -1.8; p\u0026thinsp;=\u0026thinsp;0.012). \u003cb\u003e(Supplementary Fig.\u0026nbsp;4).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThroughout the period from 1999 to 2020, the overall AAMRs were 17.1 (95% CI: 16.8 to 17.6) for rural areas and 16.7 (95% CI: 16.5 to 16.9) for urban areas. The trends for rural areas can be divided into two segments. The initial phase from 1999 to 2010 exhibited a slight increase in AAMR (APC\u0026thinsp;=\u0026thinsp;0.4 95% CI: -2.9 to 1.8; p\u0026thinsp;=\u0026thinsp;0.733, \u003cb\u003enon-significant\u003c/b\u003e). This was followed by a steeper rise until 2020 (APC of 5.0, 95% CI: 3.7 to 8.3; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Similarly, urban areas showed parallel trends in AAMR, with a slight increase from 1999 to 2018 (APC\u0026thinsp;=\u0026thinsp;0.4, 95% CI: -0.6 to 1.0; p\u0026thinsp;=\u0026thinsp;0.357, \u003cb\u003enon-significant\u003c/b\u003e). Subsequently, a sharper rise was observed until 2020 (APC\u0026thinsp;=\u0026thinsp;17.2, 95% CI: 4.3 to 23.4; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). \u003cb\u003e(Supplementary Fig.\u0026nbsp;5, Supplementary Table\u0026nbsp;9).\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"4.DISCUSSION","content":"\u003cp\u003eThis study provides a comprehensive analysis of pneumonia and sepsis-related mortality in the United States from 1999 to 2024, elucidating critical temporal trends and demographic disparities. Our findings reveal a substantial and concerning shift in what had been a stable two-decade mortality trend, characterized by a sharp escalation in the age-adjusted mortality rate that peaked in 2021 before subsequently declining. A vast majority of these deaths occurred in a medical facility, highlighting the acute severity of this disease combination. The analysis further underscores profound and persistent disparities: men consistently experienced higher mortality rates than women, and Non-Hispanic Black individuals bore the highest mortality burden overall, a finding made more troubling as the recent mortality surge sharply reversed a pre-existing trend of improvement for this group. Geographically, the mortality burden was disproportionately concentrated in the Southern states, with significant variation observed at the state level. While older adults consistently faced the highest absolute mortality risk, this recent period of escalation represents a critical public health event that intensely magnified long-standing vulnerabilities across the population.\u003c/p\u003e \u003cp\u003eThe pathophysiological link between pneumonia and sepsis is a destructive feedback loop, where a localized infection triggers a systemic response that ultimately becomes more lethal than the original pathogen. Inside the lungs, the immune system first mounts a controlled and necessary defense against the invading microbes (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). The critical failure point occurs when this local battle is lost, allowing the infection and its inflammatory byproducts to breach the pulmonary barrier and flood the circulation (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). This event initiates a dysregulated, system-wide immune activation, a cytokine storm that loses all proportion and precision (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Consequently, the body's own signaling molecules induce widespread vasodilation, capillary leakage, and a disordered coagulation state, which collectively sabotage organ perfusion and lead to septic shock (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Pneumonia thus acts as a dual threat; it establishes the primary infection while simultaneously compromising the body's oxygen supply, a combination that dramatically accelerates the spiral into multi-organ failure.\u003c/p\u003e \u003cp\u003eThe 26-year mortality narrative for pneumonia and sepsis unfolds in three distinct acts: a long period of fragile stability, a sudden and catastrophic disruption, and a subsequent period of rapid recovery. The relative stasis observed from 1999 to 2018 likely reflects a stalemate between competing public health forces. On one hand, advances such as widespread pneumococcal vaccination and improved sepsis care protocols worked to suppress mortality (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). On the other hand, a growing population of older adults and a rising prevalence of comorbidities like diabetes and COPD created a larger pool of vulnerable individuals, effectively neutralizing those gains (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). This delicate balance was completely shattered by the arrival of the COVID-19 pandemic, which explains the sharp mortality escalation peaking in 2021. The SARS-CoV-2 virus acted as an unprecedented driver of viral pneumonia and sepsis, overwhelming hospital systems and directly causing a surge in deaths (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Just as abruptly, the sharp decline after 2021 points to the impact of mass vaccination campaigns, the emergence of less virulent viral variants, and a healthcare system that had adapted its treatment strategies, collectively mitigating the pandemic's deadliest effects (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe disparity in pneumonia and sepsis mortality between sexes presents as a dynamic process of risk amplification rather than a static vulnerability. The consistently elevated mortality in men, which escalated more sharply than in women during the 2018 to 2021 surge, suggests a powerful interaction between a foundational susceptibility and an acute viral trigger. The established male predisposition for more severe infectious disease outcomes is likely rooted in a convergence of factors: a hormonal and genetic context that can foster a dysregulated inflammatory response, a higher burden of cardiovascular comorbidities at earlier ages, and a greater prevalence of behaviors that compromise pulmonary health (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e)(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e)(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). This underlying risk profile, while significant on its own, does not fully account for the widening mortality gap during the pandemic. The more potent explanation is that the SARS-CoV-2 virus acted as a specific and severe stressor on this already fragile male substrate. The data now strongly indicate that men mount a less effective antiviral immune response to this particular pathogen (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e)(\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Therefore, the pattern observed suggests a synergistic effect; the pandemic virus appears to have selectively exploited the multi-layered biological and clinical vulnerabilities of men, turning a chronic disadvantage into an acute and disproportionate catastrophe.\u003c/p\u003e \u003cp\u003eThe stark mortality gap in pneumonia and sepsis deaths across racial and ethnic groups is not a reflection of the pathogens involved, but a direct indictment of structural inequalities that cultivate vulnerability to respiratory infections. Long before the pandemic, a higher prevalence of conditions like asthma, diabetes, and hypertension in Black and Hispanic communities created a population with diminished physiological reserve to fight and survive severe pneumonia (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e)(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e)(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). The modest but steady pre-2018 decline in mortality for these groups shows these disparities are not inevitable. However, the arrival of COVID-19 acted as a seismic shock, introducing a novel virus known to cause severe viral pneumonia and frequently progress to sepsis (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e)(\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). This crisis transformed the higher baseline risk into a catastrophic mortality event. The data therefore reveal how structural forces create a fertile ground for respiratory pathogens, ensuring that when a widespread virus emerges, the lethal progression from pneumonia to fatal sepsis follows the predictable and unjust lines of race and ethnicity in America.\u003c/p\u003e \u003cp\u003eMortality patterns by age revealed two distinct narratives: the expected high burden in older adults and, more alarmingly, a sharp proportional surge in death rates among younger and middle-aged cohorts. The profound mortality risk in the 65\u0026thinsp;+\u0026thinsp;population aligns with the classic understanding of immunosenescence, where an aging immune system is less capable of preventing a localized pneumonia from progressing to systemic sepsis (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e)(\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). The more concerning trend is the dramatic surge in mortality among younger adults, which points to an erosion of the traditional health advantages of youth. This suggests a premature accumulation of risk factors, particularly the rising prevalence of obesity and metabolic syndrome, which creates a state of chronic inflammation that primes even a younger person for a catastrophic response to a severe respiratory infection (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e)(\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). The COVID-19 pandemic did not create this vulnerability but rather exploited it with lethal efficiency, acting as the acute trigger on a population that was already becoming less resilient. Collectively, these findings signal a dangerous convergence: the timeless threat of infection in old age is now meeting a modern epidemic of chronic disease in the young, expanding the clinical profile of who is most at risk for fatal pneumonia and sepsis.\u003c/p\u003e \u003cp\u003eThe geography of mortality from pneumonia and sepsis in the U.S. is not random but follows predictable contours of social and economic disadvantage, revealing how 'place' can determine resilience to infection. The heavy concentration of deaths in the South, a pattern that mirrors the nation's \"Stroke Belt\" and \"Sepsis Belt,\" points to a shared etiology of foundational risk factors (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e)(\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). This regional pattern is largely a story of nonmetropolitan America. Rural communities often face a dual burden: a population with a higher prevalence of chronic illnesses that predispose individuals to severe pneumonia, confronting a healthcare system with limited capacity for the specialized critical care needed to manage sepsis (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e)(\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). The COVID-19 pandemic, however, introduced a counterintuitive dynamic. While rural areas had a poor baseline, the pandemic's unique transmission characteristics made dense urban centers acutely vulnerable, overwhelming even well-resourced hospital systems through the sheer volume of cases (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis complex interplay of risks is rendered in sharp relief at the state level and these geographic risks are not organic; they are shaped by policy and environment. State-level decisions on Medicaid expansion, for instance, directly impact access to care in many of these high-burden regions (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e), while disparities in environmental factors like regional air quality can heighten the underlying risk of developing severe pneumonia in the first place (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e). These complex forces are rendered in sharp relief at the state level. A state like West Virginia becomes an archetype of the rural risk profile, where poor population health and limited infrastructure converge. In contrast, the high mortality in the District of Columbia illustrates an urban archetype, where concentrated socioeconomic and racial inequity creates a similar level of vulnerability, proving that the drivers of risk are multifaceted (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e). Therefore, the map of pneumonia and sepsis mortality is ultimately a map of systemic vulnerabilities, where geography serves as a proxy for a deep interplay of policy, environment, and the enduring legacy of social inequity.\u003c/p\u003e \u003cp\u003eThe overwhelming predominance of in-hospital deaths confirms the condition's status as an acute crisis, where mortality often represents a failure of even the most aggressive intervention (\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e). The smaller fraction of deaths in nursing homes signifies a different trajectory: a frail population succumbing to an infection deemed insurmountable, where hospitalization may be forgone to honor goals of care (\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e). More troubling are the deaths at home; though few, they point to critical breakdowns in outpatient services, where a rapidly fulminant infection either evaded recognition or where barriers prevented timely access to a hospital (\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e). The near-absence of hospice as a place of death is also revealing, suggesting sepsis is treated with curative intent until the very end, potentially highlighting a systemic underutilization of palliative care for this devastating condition (\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe findings of this study are not merely observational; they constitute an urgent call to action for clinicians, policymakers, and researchers to address the profound vulnerabilities unmasked by pneumonia and sepsis. For clinicians, this requires a heightened index of suspicion for sepsis, especially in high-risk demographic groups, and a renewed focus on the aggressive outpatient management of the chronic diseases that create this vulnerability (\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e). Our data also suggest a critical need to better integrate palliative care conversations for patients with overwhelming infection, where the focus on curative intent may come at the cost of patient comfort (\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e). Policymakers, in turn, must address the structural drivers of these disparities. This includes implementing policies that expand health insurance coverage, investing in the public health infrastructure of underserved regions, and tackling the social and environmental determinants that increasthe baseline risk of severe respiratory infection (\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e)(\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e). Finally, the research agenda must now evolve beyond describing these trends. The priority should be on prospective, individual-level studies to confirm these ecological findings and, most importantly, on implementation science to test targeted interventions designed to eliminate the stark inequities identified here (\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e)(\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003eLIMITATIONS\u003c/b\u003e \u003c/p\u003e \u003cp\u003eOur interpretation is constrained by the known limitations of death certificate data, where the complexity of sepsis can lead to diagnostic misclassification, potentially misestimating its true mortality burden (\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e). The observed trends are also susceptible to a surveillance artifact; evolving clinical definitions and heightened awareness of sepsis over the past two decades have likely produced a \"coding drift\" that can mimic a true rise in mortality (\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e). As an ecological study, our findings demonstrate population-level associations, not individual causation, a limitation magnified by the absence of granular clinical data like pathogen type or patient vaccination status, which are key unmeasured confounders. Despite these constraints, the study's strength lies in its large, population-based scale, offering a powerful view of broad epidemiological patterns that demand further investigation.\u003c/p\u003e"},{"header":"5.CONCLUSION","content":"\u003cp\u003eIn conclusion, this 26-year analysis reveals that a long period of fragile stability in pneumonia and sepsis mortality, representing a stalemate between medical progress and worsening population health, was decisively shattered by the COVID-19 pandemic. The mortality burden falls disproportionately on men, older adults, and Non-Hispanic Black individuals, and is geographically concentrated in the South, reflecting a convergence of biological susceptibility, immunosenescence, and profound structural inequities. Ultimately, these findings should serve as a clear directive to move beyond documenting these disparities and toward implementing robust, equitable public health strategies that strengthen our collective resilience against future infectious threats.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAge-Adjusted Mortality Rates (AAMR)\u003c/p\u003e\n\u003cp\u003eAverage Annual Percentage Changes (AAPC)\u003c/p\u003e\n\u003cp\u003eAnnual Percent Change (APC)\u003c/p\u003e\n\u003cp\u003eNon-Hispanic (NH)\u003c/p\u003e\n\u003cp\u003eCenters for Disease Control and Prevention\u0026apos;s Wide-ranging Online Data for Epidemiologic Research (CDC-WONDER)\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eAuthor Contributions:Conceptualization: Shaheer Bin Shafiq, Ammad UddinStudy Design and Methodology: Asim Sajjad, Hassan Abdul Aziz Dhedhi Data Acquisition and Curation: Ammad Uddin, Muhammad Tahir, Muhammad Salik UddinStatistical Analysis and Interpretation: Ammad Uddin, Ahmed Anwaar Uddin Manuscript Drafting: Ammad Uddin Muhammad Salik UddinCritical Revision of the Manuscript: Hassan Abdul Aziz Dhedhi, Shaheer Bin Shafiq, Muhammad Tahir, Ammad Uddin, Asim Sajjad Supervision: Rida Shakeel Validation \u0026amp; Final Approval: All authors\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe data supporting the findings of this study are publicly available from the Centers for Disease Control and Prevention\u0026apos;s Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLaboratory Evaluation of Sepsis |. Treatment \u0026amp; Management | Point of Care. Accessed: Sep. 11, 2025. [Online]. Available: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.statpearls.com/point-of-care/145900\u003c/span\u003e\u003cspan address=\"https://www.statpearls.com/point-of-care/145900\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAvni T, Lador A, Lev S, Leibovici L, Paul M, Grossman A. Sepsis: Diagnosis and Management, \u003cem\u003eAm Fam Physician\u003c/em\u003e, vol. 101, no. 7, pp. 409\u0026ndash;418, Apr. 2020, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1371/JOURNAL.PONE.0129305\u003c/span\u003e\u003cspan address=\"10.1371/JOURNAL.PONE.0129305\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTorres A et al. Dec., Pneumonia, \u003cem\u003eNat Rev Dis Primers\u003c/em\u003e, vol. 7, no. 1, 2021, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/S41572-021-00259-0\u003c/span\u003e\u003cspan address=\"10.1038/S41572-021-00259-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDarkwah S, Kotey FCN, Ahenkorah J, Adutwum-Ofosu KK, Donkor ES. Sepsis-Related Lung Injury and the Complication of Extrapulmonary Pneumococcal Pneumonia. Diseases. Apr. 2024;12(4):72. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/DISEASES12040072\u003c/span\u003e\u003cspan address=\"10.3390/DISEASES12040072\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDantes RB, United States. Sepsis Program Activities in Acute Care Hospitals \u0026mdash; National Healthcare Safety Network, 2022, \u003cem\u003eMMWR Morb Mortal Wkly Rep\u003c/em\u003e, vol. 72, no. 34, pp. 907\u0026ndash;911, Aug. 2025. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.15585/MMWR.MM7234A2\u003c/span\u003e\u003cspan address=\"10.15585/MMWR.MM7234A2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAHRQ\u0026rsquo;s Portrait of Sepsis Reveals Its Alarming Human Toll | Agency for Healthcare Research and Quality. Accessed: Sep. 11, 2025. [Online]. Available: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ahrq.gov/news/blog/ahrqviews/portrait-of-sepsis.html\u003c/span\u003e\u003cspan address=\"https://www.ahrq.gov/news/blog/ahrqviews/portrait-of-sepsis.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolland E, et al. Demographic and regional trends of pneumonia mortality in the United States, 1999 to 2022. Sci Rep. Dec. 2025;15(1):1\u0026ndash;11. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/S41598-025-94715-6;SUBJMETA\u003c/span\u003e\u003cspan address=\"10.1038/S41598-025-94715-6;SUBJMETA\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaoli CJ, Reynolds MA, Sinha M, Gitlin M, Crouser E. Epidemiology and costs of sepsis in the United States-an analysis based on timing of diagnosis and severity level. Crit Care Med. 2018;46(12):1889\u0026ndash;97. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/CCM.0000000000003342\u003c/span\u003e\u003cspan address=\"10.1097/CCM.0000000000003342\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNew Federal Report Shows Dire State of Sepsis Care in the US - End Sepsis. Accessed: Sep. 11, 2025. [Online]. Available: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.endsepsis.org/2024/10/09/congressional-report-on-sepsis-released/\u003c/span\u003e\u003cspan address=\"https://www.endsepsis.org/2024/10/09/congressional-report-on-sepsis-released/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArefian H, et al. Hospital-related cost of sepsis: A systematic review. J Infect. Feb. 2017;74(2):107\u0026ndash;17. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/J.JINF.2016.11.006\u003c/span\u003e\u003cspan address=\"10.1016/J.JINF.2016.11.006\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMultiple Cause of Death Data on CDC WONDER. Accessed: Sep. 11, 2025. [Online]. Available: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://wonder.cdc.gov/mcd.html\u003c/span\u003e\u003cspan address=\"https://wonder.cdc.gov/mcd.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorrissey R, et al. Demographic and regional trends of sepsis mortality in the United States, 1999\u0026ndash;2022. BMC Infect Dis. Dec. 2025;25(1):504. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/S12879-025-10921-7\u003c/span\u003e\u003cspan address=\"10.1186/S12879-025-10921-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eObianyo CM, et al. Trends and Disparities in Pneumonia-Related Mortality in the U.S. Population: A Nationwide Analysis Using the CDC WONDER Data. Cureus. May 2025;17(5):e83371. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7759/CUREUS.83371\u003c/span\u003e\u003cspan address=\"10.7759/CUREUS.83371\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evon Elm E, Altman DG, Egger M, Pocock SJ, G\u0026oslash;tzsche PC, Vandenbroucke JP. Strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies, \u003cem\u003eBMJ\u003c/em\u003e, vol. 335, no. 7624, pp. 806\u0026ndash;808, Oct. 2007, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/BMJ.39335.541782.AD\u003c/span\u003e\u003cspan address=\"10.1136/BMJ.39335.541782.AD\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAge standardization. of death rates: implementation of the year 2000 standard - PubMed. Accessed: Sep. 11, 2025. [Online]. Available: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/9796247/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/9796247/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJoinpoint Regression Program. Accessed: Sep. 11, 2025. [Online]. Available: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://surveillance.cancer.gov/joinpoint/\u003c/span\u003e\u003cspan address=\"https://surveillance.cancer.gov/joinpoint/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMizgerd JP. Acute Lower Respiratory Tract Infection. N Engl J Med. Feb. 2008;358(7):716. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMRA074111\u003c/span\u003e\u003cspan address=\"10.1056/NEJMRA074111\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSinger M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. Feb. 2016;315(8):801\u0026ndash;10. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/JAMA.2016.0287\u003c/span\u003e\u003cspan address=\"10.1001/JAMA.2016.0287\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFajgenbaum DC, June CH. Cytokine Storm, \u003cem\u003eNew England Journal of Medicine\u003c/em\u003e, vol. 383, no. 23, pp. 2255\u0026ndash;2273, Dec. 2020, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMRA2026131\u003c/span\u003e\u003cspan address=\"10.1056/NEJMRA2026131\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGotts JE, Matthay MA. Sepsis: pathophysiology and clinical management. BMJ. May 2016;353. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/BMJ.I1585\u003c/span\u003e\u003cspan address=\"10.1136/BMJ.I1585\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVadlamudi NK, Chen A, Marra F. Impact of the 13-Valent Pneumococcal Conjugate Vaccine Among Adults: A Systematic Review and Meta-analysis, \u003cem\u003eClinical Infectious Diseases\u003c/em\u003e, vol. 69, no. 1, pp. 34\u0026ndash;49, Jun. 2019, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/CID/CIY872\u003c/span\u003e\u003cspan address=\"10.1093/CID/CIY872\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevy MM et al. Feb., The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis, \u003cem\u003eIntensive Care Med\u003c/em\u003e, vol. 36, no. 2, p. 222, 2010, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/S00134-009-1738-3\u003c/span\u003e\u003cspan address=\"10.1007/S00134-009-1738-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoersma P, Black LI, Ward BW. Prevalence of Multiple Chronic Conditions Among US Adults, 2018. Prev Chronic Dis. Sep. 2020;17. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5888/PCD17.200130\u003c/span\u003e\u003cspan address=\"10.5888/PCD17.200130\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVincent JL. Covid-19: It\u0026rsquo;s All About Sepsis. Future Microbiol. Feb. 2021;16(3):131\u0026ndash;3. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2217/FMB-2020-0312\u003c/span\u003e\u003cspan address=\"10.2217/FMB-2020-0312\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarziano V et al. Jul., The decline of COVID-19 severity and lethality over two years of pandemic, \u003cem\u003emedRxiv\u003c/em\u003e, p. 2022.07.01.22277137, 2022, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1101/2022.07.01.22277137\u003c/span\u003e\u003cspan address=\"10.1101/2022.07.01.22277137\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAngele MK, Pratschke S, Hubbard WJ, Chaudry IH. Gender differences in sepsis. Virulence. 2014;5(1):12\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4161/VIRU.26982\u003c/span\u003e\u003cspan address=\"10.4161/VIRU.26982\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKlein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. Oct. 2016;16(10):626\u0026ndash;38. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/NRI.2016.90;SUBJMETA\u003c/span\u003e\u003cspan address=\"10.1038/NRI.2016.90;SUBJMETA\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMauvais-Jarvis F, et al. Sex and gender: modifiers of health, disease, and medicine. Lancet. Aug. 2020;396(10250):565\u0026ndash;82. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S0140-6736(20)31561-0\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(20)31561-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKritsotakis G, Psarrou M, Vassilaki M, Androulaki Z, Philalithis AE. Gender differences in the prevalence and clustering of multiple health risk behaviours in young adults. J Adv Nurs. Sep. 2016;72(9):2098\u0026ndash;113. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/JAN.12981\u003c/span\u003e\u003cspan address=\"10.1111/JAN.12981\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeckham H, et al. Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission. Nat Commun. Dec. 2020;11(1):6317. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/S41467-020-19741-6\u003c/span\u003e\u003cspan address=\"10.1038/S41467-020-19741-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakahashi T, et al. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature. Dec. 2020;588(7837):315\u0026ndash;20. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/S41586-020-2700-3;TECHMETA\u003c/span\u003e\u003cspan address=\"10.1038/S41586-020-2700-3;TECHMETA\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDaniel H, Bornstein SS, Kane GC, for the H. Apr. and P. P. C. of the A. C. of Physicians*, Addressing Social Determinants to Improve Patient Care and Promote Health Equity: An American College of Physicians Position Paper, \u003cem\u003ehttps\u003c/em\u003e:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e//doi.org/10.7326/M17-2441\u003c/span\u003e\u003cspan address=\"http:////doi.org/10.7326/M17-2441\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, vol. 168, no. 8, pp. 577\u0026ndash;578, 2018, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7326/M17-2441\u003c/span\u003e\u003cspan address=\"10.7326/M17-2441\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChurchwell K et al. Dec., Call to Action: Structural Racism as a Fundamental Driver of Health Disparities: A Presidential Advisory From the American Heart Association, \u003cem\u003eCirculation\u003c/em\u003e, vol. 142, no. 24, pp. E454\u0026ndash;E468, 2020, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/CIR.0000000000000936\u003c/span\u003e\u003cspan address=\"10.1161/CIR.0000000000000936\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurton DC, et al. Socioeconomic and racial/ethnic disparities in the incidence of bacteremic pneumonia among US adults. Am J Public Health. Oct. 2010;100(10):1904\u0026ndash;11. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2105/AJPH.2009.181313\u003c/span\u003e\u003cspan address=\"10.2105/AJPH.2009.181313\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColor of Coronavirus. COVID-19 deaths analyzed by race and ethnicity \u0026mdash; APM Research Lab. Accessed: Sep. 11, 2025. [Online]. Available: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.apmresearchlab.org/covid/deaths-by-race\u003c/span\u003e\u003cspan address=\"https://www.apmresearchlab.org/covid/deaths-by-race\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndrasfay T, Goldman N. Reductions in 2020 US life expectancy due to COVID-19 and the disproportionate impact on the Black and Latino populations, \u003cem\u003eProceedings of the National Academy of Sciences\u003c/em\u003e, vol. 118, no. 5, p. e2014746118, Feb. 2021, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1073/PNAS.2014746118\u003c/span\u003e\u003cspan address=\"10.1073/PNAS.2014746118\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeyer KC. The role of immunity and inflammation in lung senescence and susceptibility to infection in the elderly. Semin Respir Crit Care Med. 2010;31(5):561\u0026ndash;74. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1055/S-0030-1265897/ID/24/BIB\u003c/span\u003e\u003cspan address=\"10.1055/S-0030-1265897/ID/24/BIB\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStarr ME, Saito H. Sepsis in Old Age: Review of Human and Animal Studies. Aging Dis. Apr. 2014;5(2):126\u0026ndash;36. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.14336/AD.2014.0500126\u003c/span\u003e\u003cspan address=\"10.14336/AD.2014.0500126\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWall HK, Ritchey MD, Gillespie C, Omura JD, Jamal A, George MG. Vital Signs: Prevalence of Key Cardiovascular Disease Risk Factors for Million Hearts 2022 \u0026mdash; United States, 2011\u0026ndash;2016, \u003cem\u003eMMWR Morb Mortal Wkly Rep\u003c/em\u003e, vol. 67, no. 35, pp. 983\u0026ndash;991, Sep. 2019, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.15585/MMWR.MM6735A4\u003c/span\u003e\u003cspan address=\"10.15585/MMWR.MM6735A4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePopkin BM, et al. Individuals with obesity and COVID-19: A global perspective on the epidemiology and biological relationships. Obes Rev. Nov. 2020;21(11):e13128. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/OBR.13128\u003c/span\u003e\u003cspan address=\"10.1111/OBR.13128\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu JR, et al. Risk-standardized sepsis mortality map of the United States. Digit Health. Jan. 2022;8:20552076211072400. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/20552076211072400\u003c/span\u003e\u003cspan address=\"10.1177/20552076211072400\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoward G, Howard VJ. Twenty Years of Progress Toward Understanding the Stroke Belt, \u003cem\u003eStroke\u003c/em\u003e, vol. 51, no. 3, pp. 742\u0026ndash;750, Mar. 2020, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/STROKEAHA.119.024155\u003c/span\u003e\u003cspan address=\"10.1161/STROKEAHA.119.024155\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIsaacs B. Save rural health care: Time for a significant paradigm shift. J Am Osteopath Assoc. Sep. 2019;119(9):551\u0026ndash;5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7556/JAOA2019.098/MACHINEREADABLECITATION/RIS\u003c/span\u003e\u003cspan address=\"10.7556/JAOA2019.098/MACHINEREADABLECITATION/RIS\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeake SL, Judd N. Supporting rural community-based critical care. Curr Opin Crit Care. Dec. 2007;13(6):720\u0026ndash;4. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/MCC.0B013E3282F1BB21\u003c/span\u003e\u003cspan address=\"10.1097/MCC.0B013E3282F1BB21\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWhittle RS, Diaz-Artiles A. An ecological study of socioeconomic predictors in detection of COVID-19 cases across neighborhoods in New York City. BMC Med. Sep. 2020;18(1):271. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/S12916-020-01731-6\u003c/span\u003e\u003cspan address=\"10.1186/S12916-020-01731-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee BP, Dodge JL, Terrault NA. Medicaid expansion and variability in mortality in the USA: a national, observational cohort study. Lancet Public Health. Jan. 2021;7(1):e48. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S2468-2667(21)00252-8\u003c/span\u003e\u003cspan address=\"10.1016/S2468-2667(21)00252-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeupane B, Jerrett M, Burnett RT, Marrie T, Arain A, Loeb M. Long-term exposure to ambient air pollution and risk of hospitalization with community-acquired pneumonia in older adults, \u003cem\u003eAm J Respir Crit Care Med\u003c/em\u003e, vol. 181, no. 1, pp. 47\u0026ndash;53, Jan. 2010, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1164/RCCM.200901-0160OC\u003c/span\u003e\u003cspan address=\"10.1164/RCCM.200901-0160OC\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKing CJ, Buckley BO, Maheshwari R, Griffith DM. Feb., Race, Place, And Structural Racism: A Review Of Health And History In Washington, D.C., \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1377/hlthaff.2021\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1377/hlthaff.2021\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003cem\u003e01805\u003c/em\u003e, vol. 41, no. 2, pp. 273\u0026ndash;280, 2022, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1377/HLTHAFF.2021.01805\u003c/span\u003e\u003cspan address=\"10.1377/HLTHAFF.2021.01805\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRhee C, et al. Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009\u0026ndash;2014. JAMA. Oct. 2017;318:1241. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/JAMA.2017.13836\u003c/span\u003e\u003cspan address=\"10.1001/JAMA.2017.13836\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshikawa TT, Reyes BJ, Ouslander JG. Sepsis in Older Adults in Long-Term Care Facilities: Challenges in Diagnosis and Management, \u003cem\u003eJ Am Geriatr Soc\u003c/em\u003e, vol. 67, no. 11, pp. 2234\u0026ndash;2239, Nov. 2019, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/JGS.16194\u003c/span\u003e\u003cspan address=\"10.1111/JGS.16194\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSterling SA, Puskarich MA, Jones AE. Prehospital treatment of sepsis: What really makes the \u0026lsquo;golden hour\u0026rsquo; golden? Crit Care. Dec. 2014;18(1):1\u0026ndash;2. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/S13054-014-0697-4/METRICS\u003c/span\u003e\u003cspan address=\"10.1186/S13054-014-0697-4/METRICS\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKleinpell R. New guidelines for sepsis care integrating palliative care and end of life care concepts, \u003cem\u003eBMJ Support Palliat Care\u003c/em\u003e, vol. 2, no. 2, pp. 194\u0026ndash;194, Jun. 2012, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/BMJSPCARE-2012-000250.90\u003c/span\u003e\u003cspan address=\"10.1136/BMJSPCARE-2012-000250.90\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEvans L, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. Nov. 2021;47(11):1181. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/S00134-021-06506-Y\u003c/span\u003e\u003cspan address=\"10.1007/S00134-021-06506-Y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eManfredi RA, et al. Early palliative intervention in septic patients reduces healthcare utilization. Am J Emerg Med. Dec. 2021;50:773\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/J.AJEM.2021.09.075\u003c/span\u003e\u003cspan address=\"10.1016/J.AJEM.2021.09.075\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeinstein JN, Geller A, Negussie Y, Baciu A. Communities in Action: Pathways to Health Equity, \u003cem\u003eCommunities in Action: Pathways to Health Equity\u003c/em\u003e, pp. 1\u0026ndash;558, Apr. 2017, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.17226/24624\u003c/span\u003e\u003cspan address=\"10.17226/24624\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCole MB, Gal\u0026aacute;rraga O, Wilson IB, Wright B, Trivedi AN. At Federally Funded Health Centers, Medicaid Expansion Was Associated With Improved Quality Of Care. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1377/hlthaff.\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1377/hlthaff.\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e2016.\u003cem\u003e0804\u003c/em\u003e, vol. 36, no. 1, pp. 40\u0026ndash;48, Aug. 2017, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1377/HLTHAFF.2016.0804\u003c/span\u003e\u003cspan address=\"10.1377/HLTHAFF.2016.0804\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShelton RC, Brownson RC. Enhancing Impact: A Call to Action for Equitable Implementation Science. Prev Sci. Apr. 2023;25:174. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/S11121-023-01589-Z\u003c/span\u003e\u003cspan address=\"10.1007/S11121-023-01589-Z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. no. Suppl 1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBenson RT, Koroshetz WJ. Health Disparities: Research That Matters, \u003cem\u003eStroke\u003c/em\u003e, vol. 29, no. 2, pp. 663\u0026ndash;669, Mar. 2022, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/STROKEAHA.121.035087\u003c/span\u003e\u003cspan address=\"10.1161/STROKEAHA.121.035087\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJolley RJ, Sawka KJ, Yergens DW, Quan H, Jett\u0026eacute; N, Doig CJ. Validity of administrative data in recording sepsis: A systematic review. Crit Care. Apr. 2015;19(1):1\u0026ndash;12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/S13054-015-0847-3/TABLES/3\u003c/span\u003e\u003cspan address=\"10.1186/S13054-015-0847-3/TABLES/3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRhee C, Murphy MV, Li L, Platt R, Klompas M. Comparison of Trends in Sepsis Incidence and Coding Using Administrative Claims Versus Objective Clinical Data. Clin Infect Dis. Jan. 2015;60(1):88\u0026ndash;95. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/CID/CIU750\u003c/span\u003e\u003cspan address=\"10.1093/CID/CIU750\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pneumonia, sepsis, mortality, sex, race, disparities","lastPublishedDoi":"10.21203/rs.3.rs-9005126/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9005126/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eThis research investigated the national patterns and inequalities in mortality associated with pneumonia-related sepsis in the United States from 1999 to 2024. The study explored the variations in mortality rates over time as well as among different demographic and geographic groups, with the objective of pinpointing high-risk populations to inform prevention and early intervention approaches.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eRetrospective population evaluation was performed utilizing the CDC WONDER Multiple Cause-of-Death database from 2000\u0026ndash;2023. Adults aged\u0026thinsp;\u0026ge;\u0026thinsp;25 years with sepsis (ICD-10 A40\u0026ndash;A41) and pneumonia (ICD-10 J12\u0026ndash;J18) on death certificates were analyzed. Age-adjusted mortality rates (AAMRs) were estimated per 100,000 population based on the 2000 U.S. standard population. Temporal patterns were examined through Joinpoint regression to determine the annual percent change (APC) and mean annual percent change (AAPC), stratified for sex, race, region, urbanization, and age.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e1,039,577 pneumonia-sepsis fatalities were recorded from 1999 to 2024. AAMR increased from 16.6 in 1999 to 18.2 in 2024, peaking acutely in 2018\u0026ndash;2021 and then decreasing. Mortality was higher in men (21.9) compared to women (14.4), and highest in non-Hispanic Blacks (27.5). The South had the highest burden (19.7), with significant differences throughout the different states. Adults 65 and above had the highest mortality (69.3), and rural and urban areas had parallel curves.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eSepsis related to pneumonia continues to have a significant U.S. mortality burden, with striking variation by sex, race, geography and age. The 2018\u0026ndash;2021 surge highlights the burden of public health emergencies and the need for concentrated, equitable prevention and care interventions.\u003c/p\u003e","manuscriptTitle":"Trends in Pneumonia and Sepsis-Related Mortality Across the United States, 1999– 2024: A CDC WONDER-Based Population Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-03 04:24:19","doi":"10.21203/rs.3.rs-9005126/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"99aace00-41f1-4401-8eb0-56d2c069cd22","owner":[],"postedDate":"March 3rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-08T00:53:26+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-03 04:24:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9005126","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9005126","identity":"rs-9005126","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}