In this nationwide cohort study of a population where everyone has free access to the healthcare system and has the right to treatment without a charge, we observed that declining level of SES was associated with an increasing risk of microbiologically verified SAB. Specifically, the associated risk of SAB in individuals with basic school as highest attained educational level was more than three-fold increased compared with individuals with long higher education. Additionally, the increased relative risks of SAB were most pronounced in the youngest age group and decreased with advancing age. Lastly, the level of SES did not appear to be associated with risk of subsequent endocarditis among patients diagnosed with SAB.
It has been demonstrated that SES may influence the subsequent risk of community-acquired bacteremia, and mortality after hospitalization with bacteremia, primarily due to a larger burden of drug-abuse and chronic diseases in individuals with low SES [15, 16]. In our cohort, individuals with low SES were more exposed to medical conditions, surgical procedures, dialysis treatment and implantations of both pacemakers and prosthetic heart valves. However, although the Danish registries do not hold information on all relevant risk factors the inequality in exposure to relevant risk factors only explained part of the inverse association between decreasing SES and increasing risk of SAB.
SAB is a rare condition in young adults , but our findings suggest that the majority of individuals, who acquire the disease in a fairly young age, are individuals with the lowest SES. Noteworthy, it appeared that the impact of SES decreased with advancing age, which may reflect that with advancing age, age-related comorbidities become more important for SAB risk than educational level.
Conversely, the definition of SES is more challenging in the eldest, as well as in the youngest part of the population with no definition of SES being perfect. Since the study population was fairly young at study inclusion, we found that educational level reflected SES better than annual income and have therefore chosen this parameter. Moreover, defining SES as annual income the year prior to study inclusion did not change the pattern of the results.
As the association between SES and risk of SAB varied by age we stratified the study population in to three age groups. We included the population at the age of 30 years and above to make sure that the majority had completed their education. Additionally, we defined the eldest age-group as >70 years to increase the likelihood that the patients were in fact retired, since it is becoming increasingly common for the elderly to remain on the labor market after the age of 65 years, which is the official age of retirement in Denmark. The study population with an age younger than 70 years was stratified into young (30–50 years) and older (>50–70 years) individuals at the labor market. In an additional analysis using an age cutoff corresponding to the Danish case-control study , the increased risk of SAB was still driven by the increased risk in the youngest subjects, which supports our age-categorization.
We chose to define SES as highest attained educational level at study entry since our study population was relatively young, thus income would be a less appropriate measure of SES. First, students are given subsistence (a fairly low amount of money to live on) during secondary and university education. Second, newly educated individuals start on a lower income right after end of their studies and third, retired individuals are given pensions, and thus all will be categorized as having a low SES, if defined by income. Furthermore, education is a fairly strong predictor of an individual’s future employment and thereby income, and education is unlikely to change after early adulthood . Nonetheless, young individuals registered in the lower categories of educational attainment might in fact still be students in whom educational attainment does not accurately reflect SES, but this is probably not a substantial problem in our study, since we only included individuals’ ≥30 years of age. Additionally, defining SES according to level of income did not change the pattern of our findings.
Staphylococcus aureus is the leading cause of infective endocarditis in several countries [28, 29], but we did not find SES to be associated with subsequent risk of endocarditis among patients diagnosed with SAB, and the lack of an association did not appear to be caused by a higher mortality rate in individuals with the lowest SES. Importantly, we did not examine the overall association between SES and endocarditis, but rather if the level of SES influenced whether SAB was followed by endocarditis. The awareness of endocarditis increased noticeably during our study period, and since 2007, Danish guidelines have advocated doctors to perform both trans-thoracic echocardiography as well as trans-esophageal echocardiography in patients with SAB , and the guidelines endorsed by the European Society of Cardiology in 2009  justify routine echocardiography in these patients. Hence, our findings may suggest that after 2007 patients with SAB are examined for endocarditis in accordance with guideline recommendations irrespective of their SES. Unfortunately, we could not investigate this further since information regarding echocardiography was not digitalized before late 2006 and echocardiographic data was not accessible through the nationwide registries. However, we analyzed potential differences in the association between SES and infective endocarditis in patients with SAB prior to and after 2007 and did not find any associations.
Strengths and limitations
The present study offers several major strengths: we limited the risk of selection bias by including the entire Danish population and achieving data from nationwide registries; the completion of the Danish registers provides a minimal loss to follow-up; the coverage and validity of SES data is very high; and because SAB events were identified in the Staphylococcus aureus bacteremia Database, only microbiologically confirmed events were reported.
There are however some limitations, which merit comments. First of all, due to the register-based study design, we were not able to obtain adequate information on risk factors not systematically reported to the registries and only reported for a minor part of the population, such as information regarding intravenous drug abuse, dental procedures, smoking status or alcohol intake and comorbidities not in need of hospitalization or pharmacological treatment (e.g. diet-treated diabetes). Importantly, our main analysis of the association between SES and SAB adjusted for age, sex and calendar year and stratified by age groups was not subject to any of these limitations.
Secondly, a major limitation of this study lies in the registration of endocarditis, thus the ICD-10 codes for endocarditis in the Danish National Patient Registry, does not specify the microbiological etiology. Consequently, not all endocarditis events may be caused by Staphylococcus aureus. However, the majority of endocarditis events in these patients were diagnosed within a week after bacteremia diagnosis, and given the restrictive definition of endocarditis within a time limit of 3 months following SAB, this limitation is probably minor. We further excluded all patients with a diagnosis of endocarditis prior to SAB. The exclusion process may have omitted individuals whose SAB were in fact complicated by endocarditis, but in whom endocarditis was registered electronically prior to registration of SAB, resulting in possible underestimation of endocarditis events. Additionally, the number of endocarditis events following SAB could be underestimated due to the 3 months time period, which could explain why we observed a somewhat lower percentage of patients with subsequent endocarditis in our population compared with other studies [11, 31, 32]. It could also be explained by the fact that our study period includes 10 years where doctors did not use echocardiography routinely in patients hospitalized with SAB resulting in fewer endocarditis events. Nonetheless, the association appeared to be constant over time.
Identification of people at increased risk of SAB is an important step in preventing the disease. Our findings may contribute to increased awareness of the disease and the populations at risk, minimize doctor’s delay, and thereby improve the prognosis for these patients, for whom correct and timely treatment is crucial.