Consistent with Martin's findings (2
), we found significant racial variation in the incidence and outcome of severe sepsis. Blacks do indeed have a higher rate of severe sepsis—almost double that of whites. The difference in incidence was evident by age 20 and continued throughout the adult lifespan. After accounting for differences in poverty and geography, black race remained independently associated with higher severe sepsis incidence. In contrast, Hispanic ethnicity appeared protective, conditional on similar regional urbanicity and poverty.
We were intrigued by these differences and considered several possible explanations. We considered whether blacks had a higher incidence due to susceptibility to particular infections or particular organ system dysfunctions. However, the severe sepsis syndrome characteristics were not markedly different between the groups with regard to site of infection, microbiologic etiology, and both the number and type of organ dysfunction. Another possibility was a difference in baseline population health. Although we could not evaluate the health status of the entire population, the burden of chronic conditions among severe sepsis cases did not differ substantially across racial groups. Furthermore, because differences in severe sepsis incidence occurred by age 20, differences in chronic disease are unlikely to explain differences in incidence, especially considering that patients with HIV/AIDS were excluded from the analysis. Blacks and Hispanics generally receive fewer elective procedures than whites, and the proportion of severe sepsis cases associated with operative procedures was much lower in these minorities than among whites ().
PROPORTION OF SEVERE SEPSIS CASES WITH THE MOST COMMON SURGICAL DIAGNOSIS RELATED GROUPS IN SIX U.S. STATES, BY RACE/ETHNICITY
We noted that people living in areas with higher rates of poverty had higher severe sepsis incidence. This finding was consistent across all six states and is consistent with the class effect postulated by Isaacs and Schroeder, in which people in lower socioeconomic classes are hypothesized to engage in less healthy lifestyles (14
), or the effect hypothesized by Marmot, in which those in lower classes experience higher stress due to lower social control (15
). Nevertheless, the black disparity in incidence was independent of the disproportionate representation of blacks in ZIP codes from poorer areas. On the other hand, Hispanics had a lower adjusted incidence of severe sepsis than would have been predicted by their residence in poorer areas. This could occur if the exposure variable—proportion of whites below poverty line—overestimated Hispanic privation (i.e., that Hispanics in any given ZIP code were better off than whites), which is unlikely. Or it could indicate that the socioeconomic health gradient among Hispanics is less steep than among whites or blacks, a phenomenon observed among recent Mexican immigrants in particular (16
Overall mortality for blacks is higher than for whites, due both to greater incidence and higher case fatality. We found that the higher ICU case fatality rates among blacks disappeared after accounting for differences in clinical characteristics and the specific treating hospital. This suggests that higher crude ICU case fatality among black patients is attributable in part to differences in measured illness severity, and also in part to the unmeasured illness severity among patients treated at hospitals to which blacks are disproportionately admitted or differences in the quality of these hospitals. Blacks were more likely to be admitted to urban teaching hospitals with slightly higher (white) case fatality. This phenomenon—blacks being treated at large, urban teaching hospitals and hospitals with poorer quality processes and outcomes of care—has been previously reported in the literature on acute myocardial infarction outcomes and is a significant contributor to populationwide disparities in treatment and outcome of acute myocardial infarction among blacks (5
Of course, residual unmeasured differences in behavior (e.g., tobacco use), case mix (e.g., neutropenia) (18
), pharmaceutical use (e.g., statins [19
]), health care resources, social factors such as poverty, and within-hospital variations in treatment by race (e.g., intensity [21
]) could still persist, despite our statistical analyses. Nevertheless, it also is possible that the greater adjusted incidence among blacks and the lower incidence among Hispanics could be due to differences in the underlying biologic response to infection and injury. Severe sepsis is often characterized as a syndrome of overly exuberant inflammation, and other inflammatory diseases, such as systemic lupus erythematosis, have also been reported to be more common and more severe in blacks (23
). One possible explanation is different genetic susceptibility to sepsis between blacks and whites. Individuals of European and African ancestry likely faced different environmental selection pressures from infectious agents. For example, sickle cell disorders, which inhibit the malarial life cycle, are inherited predominantly among peoples originating from areas where malaria is endemic. Unlike sickle cell disorders, sepsis does not follow Mendelian inheritance, but a large number of studies have suggested both the incidence and outcome of severe sepsis are influenced by functional polymorphisms in many innate immunity genes (24
). Recently, Ness and colleagues examined the allele frequency of several polymorphisms previously implicated in sepsis and other inflammatory disorders, reporting considerable racial differences in their distributions (25
A biologic basis for racial disparities in susceptibility and outcome of sepsis has potentially important implications for future therapeutic interventions. Understanding why these differences exist, including careful evaluation of genetic variance, could provide insight into the pathophysiology of sepsis. Furthermore, it is possible that different strategies will have different clinical efficacy in different racial groups, akin to recent findings in heart failure, with implications for future trial design in sepsis (26
). Hypotheses regarding potential race-associated differences in innate susceptibility do not belie the reality that differences in incidence and outcomes among blacks in particular could be narrowed with the eradication of disparities in primary care access and in income, education, and social stressors that underlie differences in healthy lifestyles.
There are important limitations to our study. Statewide hospital discharge datasets are good but imperfect data sources for generating rates of diseases within hospitalized patients. The identification of severe sepsis using ICD-9 codes to identify infection and acute organ dysfunction may be insensitive (27
), and misclassification of infections may affect case fatality estimates (28
). However, we would not expect coding error to differ by race within the same hospital in our ICU admission and case fatality models. Also, because we are using hospital discharge data, we can explore inpatient case fatality only, and not longer term postdischarge outcomes.
The source of race data for the numerator (severe sepsis cases in hospital administrative data) and the denominator (census-based population studies) may not be strictly comparable since self-reporting of racial/ethnic group may be limited among critically ill patients. When we compare the distribution of whites, blacks, Hispanics, and “other” race/ethnic groups in our six-state database with the Medicare Provider Analysis and Review (MedPAR) files from the same six states (the race data for MedPAR comes from Social Security enrollment data files, which have 95% sensitivity for black race, but <60% sensitivity for Hispanic ethnicity [positive predictive value for black race and Hispanic ethnicity are both >96%] [29
]), we find that black race may be slightly underreported in our data (8.6 vs. 9.2%) and Hispanic ethnicity is more frequently reported (7.3 vs. 3.2%). Thus, it appears that blacks in our discharge data may sometimes be misclassified as white, Hispanic, or other, or to have missing race data, which would bias our findings toward the null.
We estimated our incidence model at the ZIP code level, the smallest unit of geography for which we had both hospital discharge data and census data. Smaller units of geography, such as the block group or census track, are more sensitive to identification of the socioeconomic gradients (30
). It is possible that our ZIP code–level analyses failed to detect gradients that would be found at smaller units of aggregation. It is less likely, but possible, that our ZIP code–level findings would be contrary to those that would be found using smaller units of aggregation.
The generalizability of our findings to patients with HIV/AIDS or patients of VA/military hospitals is unknown. Both these groups have a high percentage of minorities. Thus, their exclusion from the numerator counts in our analysis likely leads to an underestimate of the discrepancy in severe sepsis incidence rates. Our data were limited to six states in the northeast, southeast, and south. Generalizability to other areas may be limited, although our states do comprise a large proportion of the U.S. population and our results were generally consistent across states.
In summary, in this large-scale population-based study, we found that black race is associated with higher incidence and case fatality from severe sepsis, whereas Hispanic ethnicity is associated with lower incidence. Blacks' residence in regions with greater economic privation contributes to greater severe sepsis incidence. The remaining adjusted incidence differences may reflect residual confounding or could signal biologic differences in susceptibility. Blacks' clinical characteristics and differences in the hospitals to which they are admitted explained their greater ICU case fatality rate. The explanatory power of the particular treating hospitals may represent unmeasured illness severity among all patients in those hospitals and/or lower quality of care. Thus, it is possible that the overall mortality disparity among blacks could be partially ameliorated by focused interventions to improve processes and outcomes of care at the hospitals that disproportionately treat blacks.