224 Chapter 10 Discussion In this systematic review and meta-analysis, we addressed the question of whether female sex is associated with increased mortality risk in patients with SAB. The included studies involved over 130 000 patients and identified an association between female sex and increased mortality risk in both unadjusted and adjusted analyses. Heterogeneity was observed, but substantially decreased with stratification by geographic region. This may reflect the large practice variations for SAB throughout the world, as recently described in a global survey [102]. This study sheds new light on sex differences in clinical outcomes of patients with SAB, which is an area of little clarity. Few studies have primarily focused on sex differences in outcome in SAB patients, and their results have been contradictory. Some studies reported higher mortality in female patients with SAB compared with male patient [3,5], while others did not report an overall sex-difference in mortality [6,8]. In this meta-analysis we identified a relatively large (18%) increased odds of death in female patients compared with male patients. This association was significant in both the unadjusted analysis and in an adjusted analysis that accounted for patient co-morbidities and treatment variables. Beyond patients with SAB, excess mortality has been reported in female patients with hospital-acquired bloodstream infection [103], severe sepsis [104-106], and endocarditis [107]; however, conflicting evidence has been reported as well [108]. The underlying causes of sex differences in clinical outcomes of patients with SAB were not addressed in this study. Sex-related differences in outcome may be due to a variety of social or biological factors. Firm data for a biological connection between sex differences in clinical outcomes from animal models has been elusive. Previous studies on sepsis have generally supported better outcomes in female patients relative to male [109]. This has been hypothesized to stem from the positive immunomodulatory properties of sex hormones on cell-mediated immune responses and cardiovascular functions in female patients [110,111] as well as the suppression of the anti-infective response by testosterone in male patients [112]. Even an ongoing immunological advantage in postmenopausal septic women has been reported [113]. In S aureus infections in particular, an animal study showed enhanced neutrophil bactericidal capacity in female mice [114]. However, females were more susceptible to lethal toxic shock caused by S aureus enterotoxin B in another mouse model [115]. Social factors could also be contributing to the observed differences in mortality between female and male patients with SAB. Analogous to acute myocardial infarction, where women waited longer before seeking treatment relative to men, gender-differences in health seeking behavior may exist in SAB patients [116]. Gender bias in health care delivery can potentially contribute to the difference in
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