The Obesity Paradox in Sepsis: A Theoretical Framework

Abstract

Sepsis is a life-threatening syndrome that occurs in response to a severe infection. In recent years, the understanding of the pathobiology of sepsis has been refined, with research describing an altered host response as the underlying cause. Survivors of sepsis often have long hospital stays and suffer from subsequent frailty and long-term health consequences. Predicting attributes of sepsis survivors remains challenging; however, an obesity paradox exists, wherein obese individuals survive sepsis at higher rates than their normal-weight counterparts. We present a model that describes the relationships between sepsis and obesity, focusing on inflammation as a shared pathway for dysregulation in obese and healthy-weight adults. Understanding the interaction of these complex variables is an important first step toward developing interventions and treatments to augment sepsis survival.

Approaching Inflammation Paradoxes—Proinflammatory Cytokine Blockages Induce Inflammatory Regulators

“…ii) patients experience somatic mutations (39) and inflammageing (40); iii) PCs are weakened due to single nucleotide polymorphism (41); iv) cytokine blockage therapies are used; v) genes encoded PCs and other regulators are knocked-out in mice; vi) inflammation is resurged when MHO undergoes a transition to classical metabolically unhealthy obesity (31,32) in response to the long term stimulation of metabolic disease risk factors such as hyperlipidemia, danger associated molecular patterns (DAMPs) and conditional DAMPs as we reported (42); vii) an obesity paradox exists, wherein obese individuals survive sepsis at higher rates than their normal-weight counterparts (43); viii) inflammation paradoxes are observed in the Amazon region showing that the…”

Diabetes associates with mortality in critically ill patients with SARS-CoV-2 pneumonia: No diabetes paradox in COVID-19

“…According to the diabetes paradox, obesity is also protective during critical illnesses, with reports of better outcomes in patients with obesity with ARDS [ 34 ] and sepsis [ [35] , [36] , [37] , [38] ]. The chronic low-grade inflammation status observed in patients with obesity could modulate the sepsis host response, resulting in an attenuated cytokine response, thus leading to lower mortality rates compared to individuals with normal weight [ 39 ]. In our sample, the mean BMI was 30.7 ± 7.2 kg/m 2 , which was higher in survivors than in non-survivors (p = 0.012), corroborating the protective effect of moderate obesity in critically ill patients.…”

Exploring the Obesity Paradox in A Murine Model of Sepsis: Improved Survival Despite Increased Organ Injury in Obese Mice

“…It has been postulated that the obese have a blunted inflammatory response during acute insults due to inflammatory preconditioning. That is, the heightened state of inflammation prior to the onset of sepsis provides a primed system where anti-inflammatory modulators are already upregulated to combat the chronic pro-inflammatory effects of obesity, thus suppressing the typical exaggerated pro-inflammatory response (5, 7, 8). In addition to prompting secretion of anti-inflammatory mediators, the abundance of pro-inflammatory mediators produced by adipose tissue could also confer protection in the obese due to priming of the innate immune system.…”

“…Epidemiological studies have reported that falling within an overweight or obese BMI classification appears to confer a survival advantage during sepsis (1)(2)(3)(4)(5)(6). This emerging phenomenon is referred to as the ''obesity paradox'' (5,7,8). While the association between higher BMI and increased survival is reflected in numerous clinical studies, including patients with sepsis as well as other critical illnesses, it is important to acknowledge that controversy exists.…”