Ex Vivo Endotoxin Stimulation of Blood for Predicting Survival in Patients With Sepsis

BackgroundSepsis is a syndrome characterized by host immune dysfunction, with the extent of immunoparalysis differing among patients. Lipopolysaccharide (LPS) is used commonly to assess the immune function of critically ill patients with sepsis. However, the reliability of this ex vivo diagnostic test in predicting clinical outcomes remains uncertain.Research QuestionDoes LPS-induced tumor necrosis factor (TNF) production from the blood of patients with sepsis predict mortality? Secondary outcomes included ICU and hospital stay durations, nosocomial infection rate, and organ recovery rate.Study Design and MethodsHuman sepsis studies from various databases through April 2023 were evaluated. Inclusion criteria encompassed LPS-stimulated blood assays, English language, and reported clinical outcomes. Bias risk was evaluated using the Newcastle-Ottawa scale (NOS). Relationships between TNF production and mortality were analyzed at sepsis onset and during established sepsis, alongside secondary outcomes.ResultsOf 11,580 studies, 17 studies (14 adult and three pediatric) were selected for analysis. Although 15 studies were evaluated as moderate to high quality using the NOS, it is important to note that some of these studies also had identifiable biases, such as unclear methods of participant recruitment. Nine studies detailed survival outcomes associated with LPS-induced TNF production at sepsis onset, whereas five studies explored TNF production’s relationship with mortality during established sepsis. Trends suggested that lower LPS-induced TNF production correlated with higher mortality. However, heterogeneity in methodologies, especially the LPS assay protocol, hindered definitive conclusions. Publication bias was highlighted using funnel plot analysis. Concerning secondary outcomes, diminished TNF production might signify worsening organ dysfunction, although the link between cytokine production and nosocomial infection varied among studies.InterpretationFor functional immune profiling in sepsis, streamlined research methodologies are essential. This entails organizing cohorts based on microbial sources of sepsis, establishing standardized definitions of immunoparalysis, using consistent types and dosages of immune stimulants, adhering to uniform blood incubation conditions, and adopting consistent clinical outcomes. Sepsis is a syndrome characterized by host immune dysfunction, with the extent of immunoparalysis differing among patients. Lipopolysaccharide (LPS) is used commonly to assess the immune function of critically ill patients with sepsis. However, the reliability of this ex vivo diagnostic test in predicting clinical outcomes remains uncertain. Does LPS-induced tumor necrosis factor (TNF) production from the blood of patients with sepsis predict mortality? Secondary outcomes included ICU and hospital stay durations, nosocomial infection rate, and organ recovery rate. Human sepsis studies from various databases through April 2023 were evaluated. Inclusion criteria encompassed LPS-stimulated blood assays, English language, and reported clinical outcomes. Bias risk was evaluated using the Newcastle-Ottawa scale (NOS). Relationships between TNF production and mortality were analyzed at sepsis onset and during established sepsis, alongside secondary outcomes. Of 11,580 studies, 17 studies (14 adult and three pediatric) were selected for analysis. Although 15 studies were evaluated as moderate to high quality using the NOS, it is important to note that some of these studies also had identifiable biases, such as unclear methods of participant recruitment. Nine studies detailed survival outcomes associated with LPS-induced TNF production at sepsis onset, whereas five studies explored TNF production’s relationship with mortality during established sepsis. Trends suggested that lower LPS-induced TNF production correlated with higher mortality. However, heterogeneity in methodologies, especially the LPS assay protocol, hindered definitive conclusions. Publication bias was highlighted using funnel plot analysis. Concerning secondary outcomes, diminished TNF production might signify worsening organ dysfunction, although the link between cytokine production and nosocomial infection varied among studies. For functional immune profiling in sepsis, streamlined research methodologies are essential. This entails organizing cohorts based on microbial sources of sepsis, establishing standardized definitions of immunoparalysis, using consistent types and dosages of immune stimulants, adhering to uniform blood incubation conditions, and adopting consistent clinical outcomes. Take-home PointsStudy Question: Does lipopolysaccharide-induced tumor necrosis factor (TNF) production from the blood of patients with sepsis predict mortality?Results: Selected studies indicated that lower lipopolysaccharide-induced TNF production may correlate with higher mortality in sepsis, but methodologic variations and biases limited definitive conclusions.Interpretation: Streamlined research methodologies, including standardized definitions of immunoparalysis and consistent procedures for ex vivo blood stimulation, are vital for functional immune profiling in sepsis. Study Question: Does lipopolysaccharide-induced tumor necrosis factor (TNF) production from the blood of patients with sepsis predict mortality? Results: Selected studies indicated that lower lipopolysaccharide-induced TNF production may correlate with higher mortality in sepsis, but methodologic variations and biases limited definitive conclusions. Interpretation: Streamlined research methodologies, including standardized definitions of immunoparalysis and consistent procedures for ex vivo blood stimulation, are vital for functional immune profiling in sepsis. Sepsis, the leading cause of in-hospital mortality, is responsible for 11 million global deaths annually.1Buchman T.G. Simpson S.Q. Sciarretta K.L. et al.Sepsis among Medicare beneficiaries: 3. The methods, models, and forecasts of sepsis, 2012-2018.Crit Care Med. 2020; 48: 302-318Crossref PubMed Scopus (29) Google Scholar, 2Rudd K.E. Johnson S.C. 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