Sepsis with liver dysfunction and coagulopathy predicts an inflammatory pattern of macrophage activation

Abstract

Background Interleukin-1 receptor antagonists can reduce mortality in septic shock patients with hepatobiliary dysfunction and disseminated intravascular coagulation (HBD + DIC), an organ failure pattern with inflammatory features consistent with macrophage activation. Identification of clinical phenotypes in sepsis may allow for improved care. We aim to describe the occurrence of HBD + DIC in a contemporary cohort of patients with sepsis and determine the association of this phenotype with known macrophage activation syndrome (MAS) biomarkers and mortality. We performed a retrospective nested case–control study in adult septic shock patients with concurrent HBD + DIC and an equal number of age-matched controls, with comparative analyses of all-cause mortality and circulating biomarkers between the groups. Multiple logistic regression explored the effect of HBD + DIC on mortality and the discriminatory power of the measured biomarkers for HBD + DIC and mortality. Results Six percent of septic shock patients (n = 82/1341) had HBD + DIC, which was an independent risk factor for 90-day mortality (OR = 3.1, 95% CI 1.4–7.5, p = 0.008). Relative to sepsis controls, the HBD + DIC cohort had increased levels of 21 of the 26 biomarkers related to macrophage activation (p < 0.05). This panel was predictive of both HBD + DIC (sensitivity = 82%, specificity = 84%) and mortality (sensitivity = 92%, specificity = 90%). Conclusion The HBD + DIC phenotype identified patients with high mortality and a molecular signature resembling that of MAS. These observations suggest trials of MAS-directed therapies are warranted.

Disseminated Intravascular Coagulation in Sepsis and Associated Factors

“…In a previous case–control study on the incidence of liver disease on DIC in septic patients conducted by Anderko et al (2022), it was found that 6% (82 of a total sample of 1341) of patients with septic shock had hepatobiliary dysfunction and DIC [ 21 ]. It was also shown that the condition was an independent risk factor for patient mortality at 90 days (OR 3.1, 95% CI: 1.4–7.5, p: 0.008) [ 21 ]. However, there are currently no prospective studies assessing the association between liver function in septic patients and risk of DIC.…”

Advances in Immune Monitoring Approaches for Sepsis-Induced Immunosuppression

“…Notably, macrophages carry out a reprogramming toward an immunosuppressive phenotype in the development of sepsis, which potentiate sepsis-induced immune depression ( 4 , 34 ). Nevertheless, excessive activation of macrophages can lead to a hyperinflammatory state in sepsis, namely, macrophage activation syndrome (MAS), in association with organ dysfunctions and early death ( 35 , 36 ). Given that, the selection of molecules targeting macrophage polarization and functions is of great clinical significance in seeking novel measures for diagnosis and the treatment of septic complications.…”

“…Strikingly, a group of septic shock patients were complicated with MAS, a clinical phenotype characterized by fever, hepatosplenomegaly, hepatobiliary dysfunction, and disseminated intravascular coagulation ( 148 , 149 ). Those patients often have a rapidly progressing organ failure, with a significantly higher risk of early death ( 35 ). The pathogenesis involves overactivation of macrophages, for which a positive feedback loop of various proinflammatory mediators eventually leads to fulminant cytokine storm ( 36 ).…”

“…Among them, elevated ferritin concentration has been well accepted as a diagnostic hallmark of MAS, which is also associated with unfavorable clinical outcomes in septic patients ( 150 ). Other than ferritin, the plasma levels of IL-1β, IL-6, IL-18, and sCD163 might serve as potential biomarkers in recognizing sepsis complicated with MAS ( 35 , 149 ).…”

Developing an ensemble machine learning model for early prediction of sepsis-associated acute kidney injury

“…Epidemiologically, sepsis of varying degrees is thought to affect more than 30 million patients worldwide each year, with more than 60% of them dying ( Fleischmann et al., 2016 ). Organ dysfunction, one of the most important features of sepsis, not only increases ICU stay length, hospitalization time, and cost burden for patients but also leads to further deterioration of patient condition and is closely related to poor prognosis ( Anderko et al., 2022 ; Kakihana et al., 2016 ). A prospective multicenter clinical study from Japan demonstrated that organ dysfunction due to sepsis produces higher mortality and re-hospitalization rates ( Fujishima et al., 2014 ).…”