Elevated hsCRP levels detected using high-sensitivity assay techniques have been associated with risk of cardiovascular disease, stroke and all-cause mortality.
In this study of individuals in the REGARDS cohort, we found that elevated baseline hsCRP was associated with increased risk of future sepsis events. This finding suggests that knowledge of hsCRP level could help to identify individuals at increased risk for sepsis.
There are plausible pathophysiologic connections between elevated baseline hsCRP and future sepsis events. CRP is believed to activate complement, interact with cell surface receptors, induce a prothrombotic state, increase expression of inflammatory mediators, and upregulate endothelial cell adhesion molecules, among other actions. 
Many of the same inflammatory processes also play key roles in sepsis. 
For example, we previously identified associations between inflammatory and endothelial activation biomarkers and future sepsis events. 
Collectively, these observations suggest that elevated hsCRP may signal individuals with a chronic low-grade proinflammatory state and prone to the hyperinflammatory state characteristic of sepsis. An important question requiring additional study is whether hsCRP exerts a direct effect upon sepsis susceptibility or represents a marker of the inflammatory process that is causal in increasing sepsis risk.
Prior studies have associated acute CRP increases (on the order of 10–200 mg/dL) as a marker of sepsis illness severity as well as predicted of sepsis outcomes.
For example, in a series of 50 critically ill sepsis patients, Schmit, et al. observed that CRP on hospital admission was 16.7±10.6 mg/dL and that the magnitude of CPR decrease was associated with response to antimicrobial therapy. 
Povoa, et al. studied 891 intensive care unit patients with community-acquired sepsis, observing a mean hospital admission CRP level of 20.1±13.9 mg/dL and finding association between rates of CRP decline and hospital survival. 
In contrast, our findings are based upon levels determined at a stable phase of health using a high-sensitivity
CRP assay, which detects levels as low as 0.04 mg/L. In addition, we focused upon the association between baseline
hsCRP levels and risk of future
sepsis events – not the acute course of illness.
Prior studies have examined the association between CRP levels and infection risk. For example, in a case-control study of 144 patients with HIV infection, Bjerk, et al. found that higher hsCRP was associated with a two-fold increased odds ratio for pneumonia. 
In a study of 3,075 elderly (>70 years old) participants in the Health ABC cohort, Yende, et al. found that higher baseline CRP levels were not independently associated with pneumonia risk. 
However, Yende’s effort did not utilize the newer high sensitivity CRP assay, as we used in the current study. We note that in the current study we did identify an independent association between baseline hsCRP and non-sepsis infection risk. While we did not separately examine pneumonia cases, over half of the sepsis cases in this series were due to lung infections.
We emphasize that we did not set out to develop a sepsis risk prediction rule using hsCRP. Our study merely indicates the presence of an association between hsCRP and future sepsis risk. However, given the results of this study, hsCRP may potentially play a role in a formal derivation of a risk prediction model. If the risk predictive abilities of hsCRP were validated, there could be plausible strategies to reduce the risk or impact of sepsis. For example, individuals at high risk of sepsis may merit more proactive treatment at the earliest stages of microbial infection, with earlier initiation of antibiotics, reduced thresholds for hospital admission, more aggressive early resuscitation, or more vigilant laboratory and physiologic monitoring during hospitalization. Statin therapy reduces cardiovascular events in individuals with elevated baseline hsCRP. 
Gupta, et al. showed that statin use was associated with a reduced risk of hospitalization for sepsis among individuals with chronic kidney disease. 
Other studies of hospitalized sepsis patients have suggested mitigated disease severity and organ dysfunction among those with pre-existing statin use. 
Limitations of this study should be noted. To maintain consistency with prior cardiovascular studies, in this study we defined elevated baseline hsCRP as >3.0 mg/L. 
However, other hsCRP cutpoints are potentially possible for different age, sex or racial groups and merit additional study. Due to time lags in event reports and record retrieval, we have not yet reviewed medical records for a portion of individuals with reported serious infection hospitalizations. Furthermore, compared with individuals included in the analysis, excluded individuals were more likely to be black and to exhibit higher hsCRP levels. Therefore, our reported HRs may represent underestimates. Because REGARDS is not a surveillance study, we may not have detected all sepsis events. 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; however, it is possible that associations between hsCRP and various forms of sepsis may differ than those reported here. We also did not examine associations between hsCRP and repeat sepsis events.
By design, the REGARDS cohort includes only African Americans and whites, and thus we could not examine associations among other racial groups or Hispanic ethnicity. History of cancer was not ascertained by REGARDS, and this may represent an important risk factor for subsequent sepsis. Also, our study was able to detect the presence of chronic medical conditions but not their level of severity. Because the study did not collect information on pulmonary conditions, we used pulmonary medications as a surrogate for chronic lung disease. Our analysis utilized baseline hsCRP measurements; we could not assess the effect of changes of hsCRP over time. While we observed an association between elevated hsCRP and sepsis risk, elevated hsCRP may reflect risk for a host of inflammatory conditions not limited to sepsis; for example, cardiovascular disease and stroke. 
In this study elevated hsCRP at a stable phase of health was associated with increased risk of future sepsis events. hsCRP may identify individuals at increased risk for sepsis.