Accuracy for Mortality Prediction With Additive Biomarkers Including Interleukin-6 in Critically Ill Patients: A Multicenter Prospective Observational Study

Abstract

Objectives: Several inflammation markers have been reported to be associated with unfavorable clinical outcomes in critically ill patients. We aimed to elucidate whether serum interleukin-6 concentration considered with Sequential Organ Failure Assessment score can better predict mortality in critically ill patients. Design: A prospective observational study. Setting: Five university hospitals in 2016–2018. Patients: Critically ill adult patients who met greater than or equal to two systemic inflammatory response syndrome criteria at admission were included, and those who died or were discharged within 48 hours were excluded. Interventions: Inflammatory biomarkers including interleukin (interleukin)–6, -8, and -10; tumor necrosis factor–α; C-reactive protein; and procalcitonin were blindly measured daily for 3 days. Area under the receiver operating characteristic curve for Sequential Organ Failure Assessment score at day 2 according to 28-day mortality was calculated as baseline. Combination models of Sequential Organ Failure Assessment score and additional biomarkers were developed using logistic regression, and area under the receiver operating characteristic curve calculated in each model was compared with the baseline. Measurements and Main Results: Among 161 patients included in the study, 18 (11.2%) did not survive at day 28. Univariate analysis for each biomarker identified that the interleukin-6 (days 1–3), interleukin-8 (days 0–3), and interleukin-10 (days 1–3) were higher in nonsurvivors than in survivors. Analyses of 28-day mortality prediction by a single biomarker showed interleukin-6, -8, and -10 at days 1–3 had a significant discrimination power, and the interleukin-6 at day 3 had the highest area under the receiver operating characteristic curve (0.766 [0.656–0.876]). The baseline area under the receiver operating characteristic curve for Sequential Organ Failure Assessment score predicting 28-day mortality was 0.776 (0.672–0.880). The combination model using additional interleukin-6 at day 3 had higher area under the receiver operating characteristic curve than baseline (area under the receiver operating characteristic curve = 0.844, area under the receiver operating characteristic curve improvement = 0.068 [0.002–0.133]), whereas other biomarkers did not improve accuracy in predicting 28-day mortality. Conclusions: Accuracy for 28-day mortality prediction was improved by adding serum interleukin-6 concentration to Sequential Organ Failure Assessment score.

Prognostic Value of Serum Interleukin-6 Level in Hypertensive Patients with COVID-19-Associated Pneumonia

“…Yamamoto et al found that IL-6 level on day 3 after admission had satisfactory discrimination ability for mortality in critically ill patients (AUC = 0.766; p < 0.001) [39]. IL-6 level showed somewhat lover discriminative ability in hospitalized patients (AUC = 0.74, p < 0.0001), according to a study by Laguna-Goya et al [40].…”

Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: Findings from a Mendelian randomisation study

“…2 Interleukin-6 (IL-6) is a critical cytokine involved in the innate immune response in sepsis and other severe infections and contributes in conjunction with other pathophysiological processes to adverse outcomes. [3][4][5][6] The modulation of IL-6 dynamics and its multiple different signalling pathways represents a potentially exciting therapeutic opportunity for severe infection given the key role for this cytokine and associated signalling. 3,6,7 The inflammatory role of IL-6 is mediated not by the classical or trans-presentation modes of action through a membrane bound receptor (IL6R), but through a trans-signalling mechanism where IL-6 binds a soluble form of the receptor that subsequently interacts with membrane bound signalling molecule, gp130, on cells.…”

“…[3][4][5][6] The modulation of IL-6 dynamics and its multiple different signalling pathways represents a potentially exciting therapeutic opportunity for severe infection given the key role for this cytokine and associated signalling. 3,6,7 The inflammatory role of IL-6 is mediated not by the classical or trans-presentation modes of action through a membrane bound receptor (IL6R), but through a trans-signalling mechanism where IL-6 binds a soluble form of the receptor that subsequently interacts with membrane bound signalling molecule, gp130, on cells. 7,8 Inhibition of both membrane and soluble IL6R using monoclonal antibodies such as tocilizumab or sarilumab (collectively known as IL-6 receptor antagonists, IL6RAs) have been successfully trialled in critically ill patients with COVID-19 and are now considered a standard treatment.…”

Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A Mendelian randomisation study

“…Our current best treatments remain antimicrobial therapy and organ support, with no licenced treatments outside these interventions [2]. Interleukin 6 (IL-6) is a critical cytokine involved in the innate immune response in sepsis and other severe infections and contributes in conjunction with other pathophysiological processes to adverse outcomes [3][4][5][6]. The modulation of IL-6 dynamics and its multiple different signalling pathways represents a potentially exciting therapeutic opportunity for severe infection given the key role for this cytokine and associated signalling [3,6,7].…”

“…Interleukin 6 (IL-6) is a critical cytokine involved in the innate immune response in sepsis and other severe infections and contributes in conjunction with other pathophysiological processes to adverse outcomes [3][4][5][6]. The modulation of IL-6 dynamics and its multiple different signalling pathways represents a potentially exciting therapeutic opportunity for severe infection given the key role for this cytokine and associated signalling [3,6,7]. The inflammatory role of IL-6 is mediated not by the classical or trans-presentation modes of action through a membrane bound receptor (IL6R), but through a trans-signalling mechanism where IL-6 binds a soluble form of the receptor that subsequently interacts with membrane bound signalling molecule, gp130, on cells [7,8].…”