This study confirms the association of baseline chronic medical conditions with the risk of future sepsis events. While prior studies have linked medical comorbidities with severity of sepsis or degree of organ dysfunction, there have been no efforts connecting these conditions at stable baseline with risk of future sepsis events. 
The findings of this study may prove useful in sepsis care, pointing to risk detection, stratification and reduction as potential sepsis management strategies. Risk prevention and reduction strategies have proven effective for common medical conditions such as cardiovascular disease and stroke. 
We emphasize that this study identifies associations between baseline chronic medical conditions and sepsis but does not indicate a causal relationship. However, there are possible pathophysiologic connections between chronic medical conditions and the future risk of sepsis. Numerous common conditions have been associated with chronic inflammation, including obesity, diabetes, heart disease and smoking, among others. 
Inflammation plays a central role in sepsis pathophysiology, and chronic inflammation could raise the risk of progression to sepsis when subjected to a bacterial pathogen. 
Chronic inflammation may also indicate individuals prone to developing a dysfunctional or exaggerated response to microbial infection. Associations between vascular disease and sepsis have not been previously described but are plausible given the role of endothelial dysfunction in sepsis pathophysiology. 
The notion of sepsis prevention is also plausible given the mutable nature of many of the risk factors identified in this study. For example, hypertension and dyslipidemia control are possible through pharmacotherapy and have resulted in large reductions in cardiovascular and cerebrovascular disease. 
Glycemic control may limit sequelae of diabetes as well as the risk of pneumonia hospitalization. 
Smoking cessation is an important strategy for reducing cardiovascular risk and could yield similar benefits for sepsis risk reduction. 
Outside of these conditions, aggressive vaccination strategies may provide another approach for curtailing disease. While seeming to overlap with risk factors already identified for other diseases, the identification of new relationships with sepsis is important because health behavior changes may be motivated differently by different medical conditions. Most importantly, our study confirms that an individual’s risk of sepsis is associated with the number of chronic medical conditions present. Therefore, if causal relationships were confirmed, mitigation of a combination of risk factors might reduce lifetime sepsis risk.
Our study offers additional perspectives of sepsis epidemiology and its risk factors. For example, half of the sepsis in this series involved infection types other than pneumonia. 
Diabetes and chronic kidney disease have been associated with increased sepsis mortality; our study suggests that increased sepsis attack rates may partially explain the increased sepsis mortality in these subgroups. 
While recent studies highlight the increased risk of acute atrial fibrillation and stroke following a sepsis event, our study indicates that baseline atrial fibrillation and stroke are also precursors for sepsis. 
In contrast to studies suggesting a protective role from dyslipidemia, our study indicates that baseline dyslipidemia is clearly associated with an increased risk of sepsis. 
We also observed some unexpected findings. In contrast to prior studies, we did not detect a gender disparity in incident sepsis. 
Although alcoholism has been implicated in immune system compromise, moderate alcohol use in this cohort appeared to be protective against sepsis, a finding consistent with studies suggesting similar protective effects against cardiovascular disease. 
Most importantly, in this study whites were at increased risk of sepsis compared with blacks, a finding that differs from published reports. 
One potential explanation is that compared with whites, blacks in the REGARDS cohort may have underreported hospitalizations for serious infection. Also, prior studies of gender and sepsis were limited to hospitalized sepsis patients and did not evaluate the risk of sepsis among community dwelling individuals. We emphasize the preliminary nature of this observation and the need for more in-depth analysis to confirm this association and its possible explanations.
An important strength of our study was the use of a national population-based REGARDS cohort, which enabled us to connect baseline characteristics with the incidence of sepsis in individuals from across the US. Prior studies of sepsis epidemiology have been limited to single centers, patients admitted to intensive care units, or larger efforts based upon regional or national hospital discharge data. 
Analyses based upon discharge data are limited by the accuracy of assigned diagnoses and have only limited ability to identify baseline patient characteristics or risk factors. In contrast, our study prospectively identified sepsis through the review of Emergency Department or hospital admission records, allowing for more certain identification of sepsis as a reason for (vs. sequelae of) hospitalization. While population-based sepsis studies have occurred in Denmark and other countries, in a prior study we identified two-fold regional variations in US sepsis mortality, underscoring the need for observations specific to the US. 
Due to time lags in event reports and record retrieval, we could not review medical records for 1,157 individuals with reported serious infection hospitalizations, a figure expected to yield an additional 300 sepsis events. In the primary analysis we treated these observations as censored non-sepsis events. When repeating the analysis without these individuals, we identified largely similar results. Furthermore, compared with individuals included in the analysis, excluded subjects were older and exhibited a greater number of chronic medical conditions. Therefore, if we were to include these participants, we would likely observe even stronger associations with sepsis. The similar gender and race distribution between included and excluded cases provides assurance that medical record retrieval differences were not due to reporting or detection bias.
We did not examine severity variants of sepsis such as severe sepsis and septic shock because these conditions often develop later in the hospital course. Our study is relevant to the care of more advanced stages of sepsis because it identifies individuals at the earliest stages of disease, setting the stage for preventing subsequent severe sepsis and septic shock. We also did not study repeat sepsis events.
Participants reported hospitalizations for infection, potentially leading to under-identification of sepsis events due to recall or reporting biases. Our approach utilized prospective, systematic, dual review of hospital records using consensus definitions. While we were able to retrieve a large number of hospital records, the inability to retrieve select medical records may have biased the estimates.
Factors outside the scope of this analysis may potentially be associated with sepsis incidence; for example, biomarkers or genetic polymorphisms. Community level factors such as quality of care or antimicrobial resistance may also potentially influence sepsis risk. By design, the REGARDS cohort contains only African Americans and whites, and thus we could not examine associations with other racial groups or Hispanic ethnicity. While we examined income and education, other sociodemographic factors such as marital status may have altered sepsis risk. History of cancer was not ascertained by REGARDS. Our study indicates the presence of chronic medical conditions but not their quality of control. We could not detect potentially relevant comorbidities such as chronic liver disease. Because of the focus of this analysis on chronic medical conditions, we opted to limit examination of these and other confounders.