Dataset Information

Association of plasma exosomes with severity of organ failure and mortality in patients with sepsis.

ABSTRACT: Current sepsis biomarkers may be helpful in determining organ failure and evaluating patient clinical course; however, direct molecular biomarkers to predict subsequent organ failure have not yet been discovered. Exosomes, a small population of extracellular vesicles, play an important role in the inflammatory response, coagulation process and cardiac dysfunction in sepsis. Nonetheless, the association of plasma exosome with severity and mortality of sepsis is not well known. Therefore, the overall levels of plasma exosome in sepsis patients were assessed and whether exosome levels were associated with organ failure and mortality was evaluated in the present study. Plasma level of exosomes was measured by ELISA. Among 220 patients with sepsis, 145 (66%) patients were diagnosed with septic shock. A trend of increased exosome levels in control, sepsis and septic shock groups was observed (204 µg/mL vs 525 µg/mL vs 802 µg/mL, P < 0.001). A positive linear relationship was observed between overall exosome levels and Sequential Organ Failure Assessment (SOFA) score in the study cohorts (r value = 0.47). When patients were divided into two groups according to best cut-off level, a statistical difference in 28- and 90-day mortality between patients with high and low plasma exosomes was observed. Elevated levels of plasma exosomes were associated with severity of organ failure and predictive of mortality in critically ill patients with sepsis.

SUBMITTER: Im Y

PROVIDER: S-EPMC7417686 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Association of plasma exosomes with severity of organ failure and mortality in patients with sepsis.

Im Yunjoo Y Yoo Hongseok H Lee Jin Young JY Park Junseon J Suh Gee Young GY Jeon Kyeongman K

Journal of cellular and molecular medicine 20200708 16

Current sepsis biomarkers may be helpful in determining organ failure and evaluating patient clinical course; however, direct molecular biomarkers to predict subsequent organ failure have not yet been discovered. Exosomes, a small population of extracellular vesicles, play an important role in the inflammatory response, coagulation process and cardiac dysfunction in sepsis. Nonetheless, the association of plasma exosome with severity and mortality of sepsis is not well known. Therefore, the over ...[more]

PMID: 32639098

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Project description:The Sequential Organ Failure Assessment (SOFA) was chosen in the definition of sepsis due to superior validity in predicting mortality. However, few studies have assessed the contributions of acute versus chronic organ failures to SOFA for mortality prediction.ObjectivesThe main objective in this study was to assess the relative importance of chronic and acute organ failures in mortality prediction in patients with suspected sepsis at hospital admission. We also evaluated how the presence of infection influenced the ability of SOFA to predict 30-day mortality.Design setting and participantsSingle-center prospective cohort study including 1,313 adult patients with suspected sepsis in rapid response teams in the emergency department.Main outcomes and measuresThe main outcome was 30-day mortality. We measured the maximum total SOFA score during admission (SOFATotal), whereas preexisting chronic organ failure SOFA (SOFAChronic) score was assessed by chart review, allowing calculation of the corresponding acute SOFA (SOFAAcute) score. Likelihood of infection was determined post hoc as "No infection" or "Infection."ResultsSOFAAcute and SOFAChronic were both associated with 30-day mortality, adjusted for age and sex (adjusted odds ratios [AORs], 1.3; 95% CI, 1.3-14 and 1.3; 1.2-1.7), respectively. Presence of infection was associated with lower 30-day mortality (AOR, 0.4; 95% CI, 0.2-0.6), even when corrected for SOFA. In "No infection" patients, SOFAAcute was not associated with mortality (AOR, 1.1; 95% CI, 1.0-1.2), and in this subgroup, neither SOFAAcute greater than or equal to 2 (relative risk [RR], 1.1; 95% CI, 0.6-1.8) nor SOFATotal greater than or equal to 2 (RR, 3.6; 95% CI, 0.9-14.1) was associated with higher mortality.Conclusions and relevanceChronic and acute organ failures were equally associated with 30-day mortality in suspected sepsis. A substantial part of the total SOFA score was due to chronic organ failure, calling for caution when using total SOFA in defining sepsis and as an outcome in intervention studies. SOFA's mortality prediction ability was highly dependent on actual presence of infection.

Project description:ContextSevere sepsis is typically characterized by initial cytokine-mediated hyperinflammation. Whether this hyperinflammatory phase is followed by immunosuppression is controversial. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting.ObjectivesTo determine the association of sepsis with changes in host innate and adaptive immunity and to examine potential mechanisms for putative immunosuppression.Design, setting, and participantsRapid postmortem spleen and lung tissue harvest was performed at the bedsides of 40 patients who died in intensive care units (ICUs) of academic medical centers with active severe sepsis to characterize their immune status at the time of death (2009-2011). Control spleens (n = 29) were obtained from patients who were declared brain-dead or had emergent splenectomy due to trauma; control lungs (n = 20) were obtained from transplant donors or from lung cancer resections.Main outcome measuresCytokine secretion assays and immunophenotyping of cell surface receptor-ligand expression profiles were performed to identify potential mechanisms of immune dysfunction. Immunohistochemical staining was performed to evaluate the loss of immune effector cells.ResultsThe mean ages of patients with sepsis and controls were 71.7 (SD, 15.9) and 52.7 (SD, 15.0) years, respectively. The median number of ICU days for patients with sepsis was 8 (range, 1-195 days), while control patients were in ICUs for 4 or fewer days. The median duration of sepsis was 4 days (range, 1-40 days). Compared with controls, anti-CD3/anti-CD28-stimulated splenocytes from sepsis patients had significant reductions in cytokine secretion at 5 hours: tumor necrosis factor, 5361 (95% CI, 3327-7485) pg/mL vs 418 (95% CI, 98-738) pg/mL; interferon γ, 1374 (95% CI, 550-2197) pg/mL vs 37.5 (95% CI, -5 to 80) pg/mL; interleukin 6, 3691 (95% CI, 2313-5070) vs 365 (95% CI, 87-642) pg/mL; and interleukin 10, 633 (95% CI, -269 to 1534) vs 58 (95% CI, -39 to 156) pg/mL; (P < .001 for all). There were similar reductions in 5-hour lipopolysaccharide-stimulated cytokine secretion. Cytokine secretion in sepsis patients was generally less than 10% that in controls, independent of age, duration of sepsis, corticosteroid use, and nutritional status. Although differences existed between spleen and lung, flow cytometric analysis showed increased expression of selected inhibitory receptors and ligands and expansion of suppressor cell populations in both organs. Unique differences in cellular inhibitory molecule expression existed in immune cells isolated from lungs of sepsis patients vs cancer patients and vs transplant donors. Immunohistochemical staining showed extensive depletion of splenic CD4, CD8, and HLA-DR cells and expression of ligands for inhibitory receptors on lung epithelial cells.ConclusionsPatients who die in the ICU following sepsis compared with patients who die of nonsepsis etiologies have biochemical, flow cytometric, and immunohistochemical findings consistent with immunosuppression. Targeted immune-enhancing therapy may be a valid approach in selected patients with sepsis.

Project description:Septic patients treated in the intensive care unit (ICU) often develop multiple organ failure including persistent skeletal muscle dysfunction which results in the patient’s protracted recovery process. We have demonstrated that muscle mitochondrial enzyme activities are impaired in septic ICU patients resulting in decreased cellular energy which will interfere with muscle function and metabolism. Here we use detailed phenotyping and genomics to elucidate mechanisms leading to these impairments. Methodology/Principle Findings Utilising biopsy material from seventeen patients and ten age-matched controls we demonstrate that neither mitochondrial in vivo protein synthesis nor expression of mitochondrial genes are compromised. Indeed, there was partial activation of the mitochondrial biogenesis pathway involving NRF2?/GABP and its target genes TFAM, TFB1M and TFB2M yet clearly this failed to maintain mitochondrial function. We therefore utilised transcript profiling and pathway analysis of ICU patient skeletal muscle to generate insight into the molecular defects driving loss of muscle function and metabolic homeostasis. Gene ontology analysis of Affymetrix analysis demonstrated substantial loss of muscle specific genes, a global oxidative stress response related to most probably cytokine signalling, altered insulin related signalling and a substantial overlap between patients and muscle wasting/inflammatory animal models. MicroRNA 21 processing appeared defective suggesting that post-transcriptional protein synthesis regulation is altered by disruption of tissue microRNA expression. Finally, we were able to demonstrate that the phenotype of skeletal muscle in ICU patients is not merely one of inactivity, it appears to be an actively remodelling tissue, influenced by several mediators, all of which may be open to manipulation with the aim to improve clinical outcome. Conclusions/Significance This first combined protein and transcriptome based analysis of human skeletal muscle obtained from septic patients demonstrated that losses of mitochondria and muscle mass are accompanied by sustained protein synthesis (anabolic process) while dysregulation of transcription programmes appears to fail to compensate for increased damage and proteolysis. Our analysis identified both validated and novel clinically tractable targets to manipulate these failing processes and pursuit of these could lead to new potential treatments. Keywords: Disease state analysis

Project description:Septic patients treated in the intensive care unit (ICU) often develop multiple organ failure including persistent skeletal muscle dysfunction which results in the patientâs protracted recovery process. We have demonstrated that muscle mitochondrial enzyme activities are impaired in septic ICU patients resulting in decreased cellular energy which will interfere with muscle function and metabolism. Here we use detailed phenotyping and genomics to elucidate mechanisms leading to these impairments. Methodology/Principle Findings Utilising biopsy material from seventeen patients and ten age-matched controls we demonstrate that neither mitochondrial in vivo protein synthesis nor expression of mitochondrial genes are compromised. Indeed, there was partial activation of the mitochondrial biogenesis pathway involving NRF2?/GABP and its target genes TFAM, TFB1M and TFB2M yet clearly this failed to maintain mitochondrial function. We therefore utilised transcript profiling and pathway analysis of ICU patient skeletal muscle to generate insight into the molecular defects driving loss of muscle function and metabolic homeostasis. Gene ontology analysis of Affymetrix analysis demonstrated substantial loss of muscle specific genes, a global oxidative stress response related to most probably cytokine signalling, altered insulin related signalling and a substantial overlap between patients and muscle wasting/inflammatory animal models. MicroRNA 21 processing appeared defective suggesting that post-transcriptional protein synthesis regulation is altered by disruption of tissue microRNA expression. Finally, we were able to demonstrate that the phenotype of skeletal muscle in ICU patients is not merely one of inactivity, it appears to be an actively remodelling tissue, influenced by several mediators, all of which may be open to manipulation with the aim to improve clinical outcome. Conclusions/Significance This first combined protein and transcriptome based analysis of human skeletal muscle obtained from septic patients demonstrated that losses of mitochondria and muscle mass are accompanied by sustained protein synthesis (anabolic process) while dysregulation of transcription programmes appears to fail to compensate for increased damage and proteolysis. Our analysis identified both validated and novel clinically tractable targets to manipulate these failing processes and pursuit of these could lead to new potential treatments. Experiment Overall Design: 13 septic samples, 8 controls

Dataset Information

Association of plasma exosomes with severity of organ failure and mortality in patients with sepsis.

Publications

Association of plasma exosomes with severity of organ failure and mortality in patients with sepsis.

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