The possible link between sex and infectious diseases has classically been debated, and males are often attributed as having a greater predisposition for infection and a poorer prognosis . Previously published works focused on sepsis have obtained contradictory results , making it worthwhile to deeply evaluate the actual sex and gender impact on sepsis prognosis, and validating it in each country or geographical area. This is the first study from our country regarding this topic, and we performed an exhaustive analysis to mitigate confounding factors by propensity score matching. Our study on ICU patients with sepsis revealed, after propensity score matching, that ICU and hospital mortality rates are slightly lower for males, and this result is opposite to that observed in the univariable analysis, reinforcing the need to adapt the analytical strategy for each situation. However, given this observation had not statistical significance, we can only conclude that both ICU and in-hospital mortality rates of ICU patients with sepsis or septic shock are not significantly influenced by sex. This conclusion is consistent with other previously published works [17–23]. Also, as occurs in other series [23, 24], our male patients had more comorbidities, higher septic shock incidence and both ICU and in-hospital mortality. On the contrary, women were associated with urinary primary focus of sepsis and a lower incidence of Gram-positive bacteremia, which has been widely reported .
Experimental studies have been performed to unravel the physiological mechanisms that could explain these observations and also to validate sex at a prognostic level. In animal studies, females have more advantageous immunological and cardiovascular responses against severe infections such as sepsis [24, 25] by the direct effect of their estradiol [26–28]. Moreover, genetic aspects, such as the female X chromosome mosaicism, could confer a diversification of leukocyte responses during endotoxemia . In contrast, the 5a-dihydrotestosterone present in males appears to exert a deleterious effect, weakening cardiovascular functions  and promoting the cytokine-mediated response [31–33]. Several experiments in sepsis have demonstrated the therapeutic utility of the administration of the oestrogen precursor dehydroepiandrosterone (DHEA), and the blockage of androgen-related adverse effects through the administration of androgen receptor antagonists such as flutamide .
It is generally assumed that males have a higher incidence of severe forms of sepsis [35, 36] and more organ failure [18, 19], which spurred the interest to evaluate whether females have milder symptoms and better outcomes during a septic episode. However, clinical studies attempting to evaluate the relationship between sex and sepsis prognosis have failed to achieve consistent results. All the recently published studies (in the last 15 years) that include an evaluation of the influence of sex on the outcome of ICU patients with sepsis among their primary objectives are summarized in Table 4. Several reasons could explain the disparity of results, the most evident being the geographic location of the studies, which implies socio-economic and racial differences of the enrolled population, as well as differences in diagnostic accuracy and therapeutics. Case definitions are also relevant; given some studies include a mix of surgical and medical ICU patients, or only patients with severe sepsis or septic shock. Importantly, the definitions of gender and sex were not clear in some studies, so the results could be misleading. There are also important differences in study design, outcome endpoint, statistical approach (i.e. which methodology was used to control for confounding factors) and which studies were selected. The latter point is critical, given the difficulty in identifying true confounders. For instance, there is accumulated evidence indicating that males receive both more invasive procedures and earlier antimicrobial therapy than females. A recent systematic review and meta-analysis aimed to evaluate gender-related mortality risk in ICU patients with sepsis . The authors found a slightly higher risk of mortality in women, although this result was considered inconclusive given the heterogeneity of the results obtained in each of the separately selected studies.
The strengths of our study include the fact that is the first work in which the latest sepsis criteria have been applied ; the selection of the patients was made for the first time on the basis of microbiological data, selecting only episodes caused by the most prevalent and relevant pathogens; and the use of a propensity score matching approach allowed us to obtain 2 groups carefully matched on a large set of confounding factors. Finally, this study is the first to assess the effect of sex on sepsis mortality for the Spanish population.
Our main limitations include the retrospective nature of the study, the inclusion of a single center, and the fact that we were unable to control for hormonal status and the immunological host-response. We did not perform stratification by age to separate premenopausal and postmenopausal women, contrary to what was performed in some previous studies [23, 36, 41]. Finally, we matched in the propensity score by focus and etiologic agent, due to the aforementioned differences obtained by sex. These factors could also be observed as true drivers of the pathophysiology of sepsis; thus matching by them could have biased the true sex mortality differences observed in the present work. Despite our efforts to adjust for a number of possible confounders of the association between sex and survival, we cannot disregard the possibility that residual confounding is still present due to unobserved variables.