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. Agesa K.M. et al.Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study.Lancet. 2020; 395: 200-211Abstract Full Text Full Text PDF PubMed Google Scholar, 3Rhee C. Jones T.M. Hamad Y. et al.Prevalence, underlying causes, and preventability of sepsis-associated mortality in US acute care hospitals.JAMA Netw Open. 2019; 2e187571Crossref Scopus (260) Google Scholar In the United States alone, the management of sepsis incurs a conservative estimate of $62 billion in health care costs, surpassing all other disease states in terms of financial impact.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. Agesa K.M. et al.Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study.Lancet. 2020; 395: 200-211Abstract Full Text Full Text PDF PubMed Google Scholar,4Eguia E. Bunn C. Kulshrestha S. et al.Trends, Cost, and Mortality From Sepsis After Trauma in the United States: an evaluation of the National Inpatient Sample of Hospitalizations, 2012-2016.Crit Care Med. 2020; 48: 1296-1303Crossref PubMed Scopus (15) Google Scholar Immune dysfunction (persistent inflammation, immunosuppression, or both) during sepsis contributes to most of the disease’s morbidity and mortality, because patients become increasingly susceptible to pathogens that usually are eliminated rapidly in healthy patients.5Hotchkiss R.S. Monneret G. Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy.Nat Rev Immunol. 2013; 13: 862-874Crossref PubMed Scopus (1623) Google Scholar,6Skrupky L.P. Kerby P.W. Hotchkiss R.S. Advances in the management of sepsis and the understanding of key immunologic defects.Anesthesiology. 2011; 115: 1349-1362Crossref PubMed Scopus (86) Google Scholar At the time of death, approximately 80% of patients have evidence of an unresolved septic focus,7Torgersen C. Moser P. Luckner G. et al.Macroscopic postmortem findings in 235 surgical intensive care patients with sepsis.Anesth Analg. 2009; 108: 1841-1847Crossref PubMed Scopus (180) Google Scholar and secondary infections complicate the clinical course of approximately 13.5% of patients with sepsis and 39% of patients with septic shock.8van Vught L.A. Klein Klouwenberg P.M. Spitoni C. et al.Incidence, risk factors, and attributable mortality of secondary infections in the intensive care unit after admission for sepsis.JAMA. 2016; 315: 1469-1479Crossref PubMed Google Scholar,9Zhao G.J. Li D. Zhao Q. et al.Incidence, risk factors and impact on outcomes of secondary infection in patients with septic shock: an 8-year retrospective study.Sci Rep. 2016; 638361Crossref Scopus (41) Google Scholar The cause of secondary infection is believed to be a phenomenon called immunoparalysis.10Volk H.D. Reinke P. Docke W.D. Clinical aspects: from systemic inflammation to ‘immunoparalysis.’.Chem Immunol. 2000; 74: PubMed Google K.M. Sepsis immunosuppression: for secondary infections and Care Med. 2013; PubMed Scopus Google Scholar This the to an immune after to and Sepsis-induced immune immune 2016; PubMed Scopus Google S. et al.Sepsis in that impact mortality to secondary Immunol. 2011; PubMed Scopus Google Scholar may from the of tumor necrosis factor of and of and other immune H.D. Reinke P. Docke W.D. Clinical aspects: from systemic inflammation to ‘immunoparalysis.’.Chem Immunol. 2000; 74: PubMed Google K.M. 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