Relative adrenal insufficiency is a risk factor and endotype of sepsis - A proof-of-concept study to support a precision medicine approach to guide glucocorticoid therapy for sepsis

Abstract

Introduction25-60% of septic patients experience relative adrenal insufficiency (RAI) and glucocorticoid (GC) is frequently used in septic patients. However, the efficacy of GC therapy and whether GC therapy should be based on the status of RAI are highly controversial. Our poor understanding about the pathogenesis of RAI and a lack of RAI animal model present significant barriers to address these critical issues.MethodsScavenger receptor BI (SR-BI) regulates stress-induced GC (iGC) production in response to stress. We generated SF1CreSR-BIfl/fl mice and utilized the mice as a RAI model to elucidate the pathogenesis of RAI and GC therapy in sepsis. SF1CreSR-BIfl/fl mice did not express SR-BI in adrenal gland and lacked iGC production upon ACTH stimulation, thus, they are RAI.Results and DiscussionRAI mice were susceptible to cecal ligation and puncture (CLP)-induced sepsis (6.7% survival in SF1CreSR-BIfl/fl mice versus 86.4% in SR-BIfl/fl mice; p = 0.0001). Compared to a well-controlled systemic inflammatory response in SR-BIfl/fl mice, SF1CreSR-BIfl/fl mice featured a persistent hyperinflammatory response. Supplementation of a low stress dose of GC to SF1CreSR-BIfl/fl mice kept the inflammatory response under control and rescued the mice. However, SR-BIfl/fl mice receiving GC treatment exhibited significantly less survival compared to SR-BIfl/fl mice without GC treatment. In conclusions, we demonstrated that RAI is a risk factor for death in this mouse model of sepsis. We further demonstrated that RAI is an endotype of sepsis, which features persistent hyperinflammatory response. We found that GC treatment benefits mice with RAI but harms mice without RAI. Our study provides a proof of concept to support a precision medicine approach for sepsis therapy – selectively applying GC therapy for a subgroup of patients with RAI.

The adrenal stress response is an essential host response against therapy-induced lethal immune activation

“…SR-BI is a physiological HDL receptor and is well known for protecting against cardiovascular disease in both rodents and humans by mediating reverse cholesterol transportation in the liver (15). Our laboratory and others previously reported that SR-BI protects against polymicrobial sepsis (16)(17)(18) through multiple mechanisms, including mediating iGC production in the adrenal gland (17,(19)(20)(21). Thus, we hypothesized that SR-BI promotes iGC production in response to T cell activation in this noninfectious context by mediating the uptake of cholesteryl ester from HDL (Fig.…”

Immune dysregulation in sepsis: experiences, lessons and perspectives

“…25-60% of patients with sepsis experience relative adrenal insufficiency (RAI). Glucocorticoid treatment of mice with CLP-induced sepsis was found to be beneficial in RAI mice but detrimental in mice without RAI [ 47 ]. In the first phase 3 trial by Annane et al, low doses of hydrocortisone significantly reduced mortality in patients with septic shock and RAI [ 48 ].…”