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Proteomic Profiles of Exosomes of Septic Patients Presenting to the Emergency Department Compared to Healthy Controls.

ABSTRACT: BACKGROUND:Septic Emergency Department (ED) patients provide a unique opportunity to investigate early sepsis. Recent work focuses on exosomes, nanoparticle-sized lipid vesicles (30-130 nm) that are released into the bloodstream to transfer its contents (RNA, miRNA, DNA, protein) to other cells. Little is known about how early changes related to exosomes may contribute to the dysregulated inflammatory septic response that leads to multi-organ dysfunction. We aimed to evaluate proteomic profiles of plasma derived exosomes obtained from septic ED patients and healthy controls. METHODS:This is a prospective observational pilot study evaluating a plasma proteomic exosome profile at an urban tertiary care hospital ED using a single venipuncture blood draw, collecting 40 cc Ethylenediaminetetraacetic acid (EDTA) blood. MEASUREMENTS:We recruited seven patients in the ED within 6 h of their presentation and five healthy controls. Plasma exosomes were isolated using the Invitrogen Total Exosome Isolation Kit. Exosome proteomic profiles were analyzed using fusion mass spectroscopy and Proteome Discoverer. Principal component analysis (PCA) and differential expression analysis (DEA) for sepsis versus control was performed. RESULTS:PCA of 261 proteins demonstrated septic patients and healthy controls were distributed in two groups. DEA revealed that 62 (23.8%) proteins differed between the exosomes of septic patients and healthy controls, p-value < 0.05. Adjustments using the False Discovery Rate (FDR) showed 23 proteins remained significantly different (FDR < 0.05) between sepsis and controls. Septic patients and controls were classified into two distinct groups by hierarchical clustering using the 62 nominally DE proteins. After adjustment multiple comparisons, three acute phase proteins remained significantly different between patients and controls: Serum amyloid A-1, C-reactive protein and Serum Amyloid A-2. Inflammatory response proteins immunoglobulin heavy constant ? and Fc-fragment of IgG binding protein were increased. CONCLUSION:Exosome proteomic profiles of septic ED patients differ from their healthy counterparts with regard to acute phase response and inflammation.

SUBMITTER: Morris DC

PROVIDER: S-EPMC7564089 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Proteomic Profiles of Exosomes of Septic Patients Presenting to the Emergency Department Compared to Healthy Controls.

Morris Daniel C DC Jaehne Anja K AK Chopp Michael M Zhang Zhanggang Z Poisson Laila L Chen Yalei Y Datta Indrani I Rivers Emanuel P EP

Journal of clinical medicine 20200911 9

<h4>Background</h4>Septic Emergency Department (ED) patients provide a unique opportunity to investigate early sepsis. Recent work focuses on exosomes, nanoparticle-sized lipid vesicles (30-130 nm) that are released into the bloodstream to transfer its contents (RNA, miRNA, DNA, protein) to other cells. Little is known about how early changes related to exosomes may contribute to the dysregulated inflammatory septic response that leads to multi-organ dysfunction. We aimed to evaluate proteomic p ...[more]

PMID: 32932765

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Project description:Background: Septic Emergency Department (ED) patients provide a unique opportunity to investigate early sepsis. Recent work focuses on exosomes, nanoparticle-sized lipid vesicles (30-130nm) that are released into the bloodstream to transfer its contents (RNA, miRNA, DNA, protein) to other cells. Little is known how exosomes may contribute to the dysregulated inflammatory septic response that leads to multi-organ dysfunction. We aimed to evaluate proteomic profiles of plasma derived exosomes obtained from septic ED patients and healthy controls. Methods: This is a prospective observational pilot study evaluating plasma exosome profile at an urban tertiary care hospital ED using a single venipuncture blood draw, collecting 40 cc EDTA blood. Measurements: We recruited 7 patients and 5 healthy controls. Plasma exosomes were isolated using Invitrogen Total Exosome Isolation Kit. Exosome proteomic profiles were analyzed using fusion mass spectroscopy and Proteome Discoverer. Principal component analysis (PCA) and differential expression analysis (DEA) for sepsis versus control was performed. Results: PCA of 261 proteins demonstrated septic patients and healthy controls were distributed in two groups. DEA revealed that 62 (23.8%) proteins differed between the exosomes of septic patients and healthy controls, p-value <0.05. Adjustments using False Discovery Rate (FDR) showed 23 proteins remained significantly different (FDR<0.05) between sepsis and controls. Septic patients and controls were classified into two distinct groups by hierarchical clustering using the 62 nominally DE proteins. After adjustment multiple comparisons, 3 acute phase proteins remained significantly different between patients and controls: Serum amyloid A-1, C-reactive protein and Serum Amyloid A-2. Inflammatory response proteins immunoglobulin heavy constant delta and Fc-fragment of IgG binding protein were increased. Conclusion: Exosome proteomic profiles of septic ED patients differ from their healthy counterparts in regard to acute phase response and inflammation.

Project description:OBJECTIVES:Delayed initiation of appropriate antimicrobials is linked to higher sepsis mortality. We investigated interphysician variation in septic patients' door-to-antimicrobial time. DESIGN:Retrospective cohort study. SETTING:Emergency department of an academic medical center. SUBJECTS:Adult patients treated with antimicrobials in the emergency department between 2009 and 2015 for fluid-refractory severe sepsis or septic shock. Patients who were transferred, received antimicrobials prior to emergency department arrival, or were treated by an attending physician who cared for less than five study patients were excluded. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:We employed multivariable linear regression to evaluate the association between treating attending physician and door-to-antimicrobial time after adjustment for illness severity (Acute Physiology and Chronic Health Evaluation II score), patient age, prehospital or arrival hypotension, admission from a long-term care facility, mode of arrival, weekend or nighttime admission, source of infection, and trainee involvement in care. Among 421 eligible patients, 74% received antimicrobials within 3 hours of emergency department arrival. After covariate adjustment, attending physicians' (n = 40) median door-to-antimicrobial times varied significantly, ranging from 71 to 359 minutes (p = 0.002). The percentage of each physician's patients whose antimicrobials began within 3 hours of emergency department arrival ranged from 0% to 100%. Overall, 12% of variability in antimicrobial timing was explained by the attending physician compared with 4% attributable to illness severity as measured by the Acute Physiology and Chronic Health Evaluation II score (p < 0.001). Some but not all physicians started antimicrobials later for patients who were normotensive on presentation (p = 0.017) or who had a source of infection other than pneumonia (p = 0.006). The adjusted odds of in-hospital mortality increased by 20% for each 1 hour increase in door-to-antimicrobial time (p = 0.046). CONCLUSIONS:Among patients with severe sepsis or septic shock receiving antimicrobials in the emergency department, door-to-antimicrobial times varied five-fold among treating physicians. Given the association between antimicrobial delay and mortality, interventions to reduce physician variation in antimicrobial initiation are likely indicated.

Project description:BackgroundSepsis is a life-threatening condition, causing almost one fifth of all deaths worldwide. The aim of the current study was to identify variables predictive of 7- and 30-day mortality among variables reflective of the presentation of septic patients arriving to the emergency department (ED) using machine learning.MethodsRetrospective cross-sectional design, including all patients arriving to the ED at Södersjukhuset in Sweden during 2013 and discharged with an International Classification of Diseases (ICD)-10 code corresponding to sepsis. All predictions were made using a Balanced Random Forest Classifier and 91 variables reflecting ED presentation. An exhaustive search was used to remove unnecessary variables in the final model. A 10-fold cross validation was performed and the accuracy was described using the mean value of the following: AUC, sensitivity, specificity, PPV, NPV, positive LR and negative LR.ResultsThe study population included 445 septic patients, randomised to a training (n = 356, 80%) and a validation set (n = 89, 20%). The six most important variables for predicting 7-day mortality were: "fever", "abnormal verbal response", "low saturation", "arrival by emergency medical services (EMS)", "abnormal behaviour or level of consciousness" and "chills". The model including these variables had an AUC of 0.83 (95% CI: 0.80-0.86). The final model predicting 30-day mortality used similar six variables, however, including "breathing difficulties" instead of "abnormal behaviour or level of consciousness". This model achieved an AUC = 0.80 (CI 95%, 0.78-0.82).ConclusionsThe results suggest that six specific variables were predictive of 7- and 30-day mortality with good accuracy which suggests that these symptoms, observations and mode of arrival may be important components to include along with vital signs in a future prediction tool of mortality among septic patients presenting to the ED. In addition, the Random Forests appears to be a suitable machine learning method on which to build future studies.

Dataset Information

Proteomic Profiles of Exosomes of Septic Patients Presenting to the Emergency Department Compared to Healthy Controls.

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Proteomic Profiles of Exosomes of Septic Patients Presenting to the Emergency Department Compared to Healthy Controls.

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