Affiliations: Atlanta, GA ,
Dr. Berkowitz is a senior fellow in Pulmonary and Critical Care Medicine at Emory University School of Medicine. Dr. Martin is the Director of the Medical and Cardiac Intensive Care Units at Grady Memorial Hospital and an Assistant Professor of Medicine at Emory University School of Medicine.
Correspondence to: Greg S. Martin, MD, MSc, FCCP, 49 Jesse Hill Jr Dr SE, Atlanta, GA 30303; e-mail: firstname.lastname@example.org
Although men and women may only be separated by a single chromosome, there is nothing straightforward in delineating the biological differences between sexes. Hormonal differences have often been implicated in the higher incidence of chronic autoimmune and inflammatory diseases such as multiple sclerosis, lupus, or rheumatoid arthritis in women.1Estrogen promotes adaptive immune responses,2 whereas testosterone and 5α-dihydrotestosterone suppress immune and cardiac function in several animal models.2–3 This is supported by evidence that women in their reproductive years have more vigorous cellular and hormonal immune responses including higher T-lymphocyte count and Ig concentrations than men.2–4 In a recent study by van Eijk et al,5 15 healthy men and women volunteers were injected with low-dose lipopolysaccharide (LPS). Women demonstrated a greater proinflammatory response evidenced by higher levels of tumor necrosis factor-α and interferon-γ and a greater increase in LPS-binding protein. Interestingly, although women had a greater drop in mean arterial pressure in response to LPS, vascular sensitivity to norephinephrine was most attenuated in men.
As men and women have a differential immune response to infection, it is not surprising that the incidence of sepsis (a disease of infection and inflammation) differs between sexes. This was first reported by McGowan et al,6who found a higher incidence of sepsis in men than women admitted to Boston City Hospital between 1935 and 1972. This discrepancy has been corroborated by large epidemiologic studies of sepsis7–8 and severe sepsis9that found the incidence of sepsis is 20 to 28% higher in men than women. Among septic patients, even microbes have a predilection for certain sexes. In a recent study10 of septic patients, men were more likely than women to be infected with Gram-positive organisms even after controlling for source of infection.
Despite agreement over the higher incidence of sepsis in men, there is controversy regarding whether this translates into a higher mortality. In the largest epidemiologic study8 of sepsis to date, we found that mortality rate did not differ according to sex, a finding which has been corroborated by others.7,10–13 A few single-center studies had contradictory findings: one study14observed a higher mortality rate in men, and another study15 found a higher mortality rate in women with sepsis.
In the current issue of CHEST (see page 1786), Adrie et al16 attempt to clarify the influence of sex on severe sepsis mortality using a large multicenter database (OUTCOMEREA). This database is composed of an annual random sample of patients in 12 French ICUs collected over an 8-year period; 1,692 patients (1,061 men and 631 women) were included. In agreement with prior studies,6–9 the authors found a higher incidence of severe sepsis in men; however, in contrast to others,7–13 they found a significant lower mortality rate in women compared to men. Interestingly, the mortality difference was present only in women > 50 years old. Premenopausal women (< 50 years old), who should have the greatest hormonal benefits on inflammatory mediators, did not demonstrate a difference in mortality rate from their male counterparts.
Given the robust literature7–13,17 suggesting that there is no sex-based mortality difference in patients with sepsis, why should one be convinced with the results of the current study? Prior studies suffered from small sample sizes,14–15 included predominantly surgical patients,12–15 or were biased by disparities in treatment between sexes.13 Aside from avoiding the above limitations, the novel feature of the current study is that it controlled for confounding variables and developed a propensity score to match men and women. Matching patients is a unique and important feature of the study and allowed for a better estimate of the influence of sex on outcomes. Furthermore, the authors eliminated the possibility of treatment bias by calculating nursing equivalents and found no inequalities in treatment between sexes.
How does this study compare to the literature implicating hormonal differences as the cause of disparity in sepsis between men and women? In the current study, the decreased mortality rate in postmenopausal rather than premenopausal women is in contradiction to this theory. One would infer that if sex hormones explained the disparities, then premenopausal women, not postmenopausal women, would derive a mortality rate benefit. As this was not the case, alternative hypotheses are necessary to contextualize the results.
First, there may be nonhormonal based factors influencing the differential immune response. Interleukin-6, which is released from monocytes and macrophages to stimulate B- and T-lymphocyte differentiation, has higher plasma concentrations in postmenopausal compared to premenopausal women.4,18LPS-stimulated tumor necrosis factor was found to be independent of plasma estrogen levels, oral contraceptive use, or phase of the menstrual cycle, even though it is consistently higher in women than men.19Further strengthening the argument for a nonhormonal explanation is that sex-based disparities in sepsis incidence exist in the neonatal and pediatric sepsis population despite insignificant hormonal differences.20–21
Secondly, social, environmental, economic, or personal health-related activities are impossible to quantify in any existing study population but are likely to differ among sexes. Due to routine health maintenance (including peripartum) recommendations, women are more likely to partake in chronic disease prevention.22Women, however, are less likely to receive acute health care due to cultural phenomena, differential access, and socioeconomic conditions.23 As sepsis requires acute care, lack of access leads to delays in seeking treatment for women that may contribute to a greater disease burden on presentation and subsequently worse outcomes.
Third, race has been shown to be a major source of disparities in sepsis.8,10,17 The basis for racial disparities runs the gamut of possibilities, including access to and delivery of health care, sociocultural or economic factors, the type or source of infection, and chronic comorbid medical conditions. Even race-specific genetic polymorphisms in the host response to infection may predispose certain racial groups to increased incidence or worse outcome with sepsis.24 Although their individual contributions have not been teased apart, race may contribute more to outcomes in sepsis than sex. Unfortunately, in the current study, race was not accounted for so its influence on sex-based mortality in this study population is unknown.
Fourth, hormonal manipulation, including administration of exogenous estrogens and testosterone blockade, leads to changes in cardiac function and physiology in the sepsis animal model.2,25 The current study occurred during a time when hormone-replacement therapy was considered the “standard of care” by many physicians. Although the number of patients on hormone-replacement therapy is unknown, it is likely that many postmenopausal patients were influenced by exogenous hormones, thus confounding any conclusion about hormones and mortality. Finally, as the authors note, the small sample size and low mortality rate among the premenopausal women may have led to an inconsistent reflection of the true sex-based mortality differences.
There is overwhelming evidence of a differential immune response to infection between men and women, which translates into a higher incidence of sepsis in men. The pathogenesis of this difference and the effect on mortality are less clear. Despite the long-held belief that this finding is related to sex hormones, the current study and a preponderance of other evidence suggest otherwise. When it comes to sex and sepsis, it’s time we look beyond our hormonal differences.
The authors have no conflicts of interest to disclose.
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