Characterization of a proteomic profile associated with organ dysfunction and mortality of sepsis and septic shock

Proteomic profile; Organ dysfunction; Septic shockPerfil proteòmic; Disfunció orgànica; Xoc sèpticPerfil proteómico; Disfunción orgánica; Choque sépticoIntroduction The search for new biomarkers that allow an early diagnosis in sepsis and predict its evolution has become a necessity in medicine. The objective of this study is to identify, through omics techniques, potential protein biomarkers that are expressed in patients with sepsis and their relationship with organ dysfunction and mortality. Methods Prospective, observational and single-center study that included adult patients (≥ 18 years) who were admitted to a tertiary hospital and who met the criteria for sepsis. A mass spectrometry-based approach was used to analyze the plasma proteins in the enrolled subjects. Subsequently, using recursive feature elimination classification and cross-validation with a vector classifier, an association of these proteins with mortality and organ dysfunction was established. The protein-protein interaction network was analyzed with String software. Results 141 patients were enrolled in this study. Mass spectrometry identified 177 proteins. Of all of them, and by recursive feature elimination, nine proteins (GPX3, APOB, ORM1, SERPINF1, LYZ, C8A, CD14, APOC3 and C1QC) were associated with organ dysfunction (SOFA > 6) with an accuracy of 0.82 ± 0.06, precision of 0.85 ± 0.093, sensitivity 0.81 ± 0.10, specificity 0.84 ± 0.10 and AUC 0.82 ± 0.06. Twenty-two proteins (CLU, LUM, APOL1, SAA1, CLEBC3B, C8A, ITIH4, KNG1, AGT, C7, SAA2, APOH, HRG, AFM, APOE, APOC1, C1S, SERPINC1, IGFALS, KLKB1, CFB and BTD) were associated with mortality with an accuracy of 0.86 ± 0.05, a precision of 0.91 ± 0.05, a sensitivity of 0.91 ± 0.05, a specificity of 0.72 ± 0.17, and an area under the curve (AUC) of 0.81 ± 0.08 with a confidence interval of 95%. Conclusion In sepsis there are proteomic patterns associated with organ dysfunction and mortality.To Toni del Pino, Rosa Ras and Pol Herrero from the Proteomics and Metabolomics Area of the Center for Omic Sciences (COS), a Joint between Rovira I Virgili University and Eurecat (Reus, Spain), for their contribution to the proteomics analysis. Samples and data from patients included in this study were provided by the Vall d’Hebron University Hospital Biobank (PT20/00107), integrated in the Spanish National Biobanks Network, and they were processed following standard operating procedures with the appropriate approval of the Ethical and Scientific Committees. The authors kindly appreciate the generous donation of samples and clinical data of the donors of the Sepsis Bank of HUVH Biobank

Case report: Cytokine hemoadsorption in a case of hemophagocytic lymphohistiocytosis secondary to extranodal NK/T-cell lymphoma

Cytokine hemoadsorption; Hemophagocytic lymphohistiocytosis; Multiorgan dysfunctionHemoadsorció de citocines; Limfohistiocitosi hemofagocítica; Disfunció multiorgànicaHemoadsorción de citoquinas; Linfohistiocitosis hemofagocítica; Disfunción multiorgánicaWe discuss a single case of Hemophagocytic lymphohistiocytosis (HLH) due to NK-type non-Hodgkin lymphoma and Epstein-Barr virus reactivation with multiorgan dysfunction and distributive shock in which we performed cytokine hemoadsorption with Cytosorb ®. A full microbiological panel was carried out, including screening for imported disease, standard serologies and cultures for bacterial and fungal infection. A liver biopsy and bone marrow aspirate were performed, confirming the diagnosis. The patients fulfilled the HLH-2004 diagnostic criteria, and according to the 2018 Consensus Statements by the HLH Steering Committee of the Histiocyte Society, dexamethasone and etoposide were started. There was an associated hypercytokinemia and, due to refractory distributive shock, rescue therapy with cytokine hemoadsorption was performed during 24 h (within day 2 and 3 from ICU admission). After starting this procedure, rapid hemodynamic control was achieved with a significant reduction in vasopressor support requirements. This case report highlights that cytokine hemoadsorption can be an effective since rapid decrease in IL-10 levels and a significant hemodynamic improvement was achieved

Precision medicine in sepsis and septic shock: From omics to clinical tools

Endotype; Organ dysfunction; SepsisEndotipo; Disfunción de órganos; SepsisEndotip; Disfunció d'òrgans; SèpsiaSepsis is a heterogeneous disease with variable clinical course and several clinical phenotypes. As it is associated with an increased risk of death, patients with this condition are candidates for receipt of a very well-structured and protocolized treatment. All patients should receive the fundamental pillars of sepsis management, which are infection control, initial resuscitation, and multiorgan support. However, specific subgroups of patients may benefit from a personalized approach with interventions targeted towards specific pathophysiological mechanisms. Herein, we will review the framework for identifying subpopulations of patients with sepsis, septic shock, and multiorgan dysfunction who may benefit from specific therapies. Some of these approaches are still in the early stages of research, while others are already in routine use in clinical practice, but together will help in the effective generation and safe implementation of precision medicine in sepsis

Vitamin C deficiency in critically ill COVID-19 patients admitted to intensive care unit

COVID-19; SARS-CoV-2 pneumonia; Vitamin CCOVID-19; Neumonía por SARS-CoV-2; Vitamina CCOVID-19; Pneumònia per SARS-CoV-2; Vitamina CObjectives: To determine vitamin C plasma kinetics, through the measurement of vitamin C plasma concentrations, in critically ill Coronavirus infectious disease 2019 (COVID-19) patients, identifying eventually the onset of vitamin C deficiency. Design: Prospective, observational, single-center study. Setting: Intensive Care Unit (ICU), Vall d’Hebron University Hospital, Barcelona. Study period from November 12th, 2020, to February 24th, 2021. Patients: Patients who had a severe hypoxemic acute respiratory failure due to COVID-19 were included. Interventions: Plasma vitamin C concentrations were measured on days 1, 5, and 10 of ICU admission. There were no vitamin C enteral nor parenteral supplementation. The supportive treatment was performed following the standard of care or acute respiratory distress syndrome (ARDS) patients. Measurement: Plasma vitamin C concentrations were analyzed using an ultra-performance liquid chromatography (UPLC) system with a photodiode array detector (wavelength set to 245 nm). We categorized plasmatic levels of vitamin C as follows: undetectable: 5 mg/L). Main results: Forty-three patients were included (65% men; mean age 62 ± 10 years). The median Sequential Organ Failure Assessment (SOFA) score was 3 (1–4), and the Acute Physiology and Chronic Health disease Classification System (APACHE II) score was 13 (10–22). Five patients had shock. Bacterial coinfection was documented in 7 patients (16%). Initially all patients required high-flow oxygen therapy, and 23 (53%) further needed invasive mechanical ventilation during 21 (± 10) days. The worst PaO2/FIO2 registered was 93 (± 29). ICU and hospital survival were 77 and 74%, respectively. Low or undetectable levels remained constant throughout the study period in the vast majority of patients. Conclusion: This observational study showed vitamin C plasma levels were undetectable on ICU admission in 86% of patients with acute respiratory failure due to COVID-19 pneumonia requiring respiratory support. This finding remained consistent throughout the study period

Hemadsorption as a Treatment Option for Multisystem Inflammatory Syndrome in Children Associated With COVID-19: A Case Report

Hemoadsorció; Síndrome multisistèmica inflamatòria; Lesió del miocardi; Coronavirus SARS-CoV-2; COVID-19; 2019-nCoVHemoadsorción; Síndrome multisistémico inflamatorio; Lesión del miocardio; Coronavirus SARS-CoV-2; COVID-19; 2019-nCoVHemoadsorption; Inflammatory multisystemic syndrome; Myocardial injury; Coronavirus SARS-CoV-2; COVID-19; 2019-nCoVMultisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 is characterized by hypercytokinemia leading to overwhelming inflammation. We describe the use of a hemadsorption device as part of the supportive treatment for cytokine storm

Pulmonary Air Embolism in a Patient with COVID-19 with Extracorporeal Membrane Oxygenation Support

Embòlia aèria pulmonar; COVID-19Embolia aérea pulmonar; COVID-19Pulmonary air embolism; COVID-1

Vitamin C deficiency in critically ill COVID-19 patients admitted to intensive care unit

ObjectivesTo determine vitamin C plasma kinetics, through the measurement of vitamin C plasma concentrations, in critically ill Coronavirus infectious disease 2019 (COVID-19) patients, identifying eventually the onset of vitamin C deficiency.DesignProspective, observational, single-center study.SettingIntensive Care Unit (ICU), Vall d’Hebron University Hospital, Barcelona. Study period from November 12th, 2020, to February 24th, 2021.PatientsPatients who had a severe hypoxemic acute respiratory failure due to COVID-19 were included.InterventionsPlasma vitamin C concentrations were measured on days 1, 5, and 10 of ICU admission. There were no vitamin C enteral nor parenteral supplementation. The supportive treatment was performed following the standard of care or acute respiratory distress syndrome (ARDS) patients.MeasurementPlasma vitamin C concentrations were analyzed using an ultra-performance liquid chromatography (UPLC) system with a photodiode array detector (wavelength set to 245 nm). We categorized plasmatic levels of vitamin C as follows: undetectable: < 1,5 mg/L, deficiency: <2 mg/L. Low plasma concentrations: 2–5 mg/L; (normal plasma concentration: > 5 mg/L).Main resultsForty-three patients were included (65% men; mean age 62 ± 10 years). The median Sequential Organ Failure Assessment (SOFA) score was 3 (1–4), and the Acute Physiology and Chronic Health disease Classification System (APACHE II) score was 13 (10–22). Five patients had shock. Bacterial coinfection was documented in 7 patients (16%). Initially all patients required high-flow oxygen therapy, and 23 (53%) further needed invasive mechanical ventilation during 21 (± 10) days. The worst PaO2/FIO2 registered was 93 (± 29). ICU and hospital survival were 77 and 74%, respectively. Low or undetectable levels remained constant throughout the study period in the vast majority of patients.ConclusionThis observational study showed vitamin C plasma levels were undetectable on ICU admission in 86% of patients with acute respiratory failure due to COVID-19 pneumonia requiring respiratory support. This finding remained consistent throughout the study period

Cytokine Hemoadsorption as Rescue Therapy for Critically Ill Patients With SARS-CoV-2 Pneumonia With Severe Respiratory Failure and Hypercytokinemia

Introduction: A dysregulated inflammatory response, known as "cytokine storm", plays an important role in the pathophysiology of coronavirus 2019 disease (COVID-19). Identifying patients with a dysregulated inflammatory response and at high risk for severe respiratory failure, organ dysfunction, and death is clinically relevant, as they could benefit from the specific therapies, such as cytokine removal by hemoadsorption. This study aimed to evaluate cytokine hemoadsorption as rescue therapy in critically ill patients with SARS-CoV-2 pneumonia, severe respiratory failure refractory to prone positioning, and hypercytokinemia. Methods: In this single center, observational and retrospective study, critically ill patients with SARS-CoV-2 pneumonia, severe acute respiratory failure, and hypercytokinemia were analyzed. All the patients underwent cytokine hemoadsorption using CytoSorb ® (Cytosorbents Europe, Berlin, Germany). The indication for treatment was acute respiratory failure, inadequate clinical response to the prone position, and hypercytokinemia. Results: Among a total of 343 patients who were admitted to the intensive care unit (ICU) due to SARS-CoV-2 infection between March 3, 2020 and June 22, 2020, six patients received rescue therapy with cytokine hemoadsorption. All the patients needed invasive mechanical ventilation and prone positioning. A significant difference was found in the pre- and post-treatment D-dimer (17,868 mcg/ml [4,196-45,287] vs. 4,488 mcg/ml [3,166-17,076], p = 0.046), C-reactive protein (12.9 mg/dl [10.6] vs. 3.5 mg/dl [2.8], p = 0.028), ferritin (1,539 mcg/L [764-27,414] vs. 1,197 ng/ml [524-3,857], p = 0.04) and interleukin-6 (17,367 pg/ml [4,539-22,532] vs. 2,403 pg/ml [917-3,724], p = 0.043) levels. No significant differences in the pre- and post-treatment interleukin-10 levels (22.3 pg/ml [19.2-191] vs. 5.6 pg/ml [5.2-36.6], p = 0.068) were observed. Improvements in oxygenation (prehemoadsorption PaO/FIO ratio 103 [18.4] vs. posthemoadsorption PaO/FIO ratio 222 [20.9], p = 0.029) and in the organ dysfunction (prehemoadsorption SOFA score 9 [4.75] vs. posthemoadsorption SOFA score 7.7 [5.4], p = 0.046) were observed. ICU and in-hospital mortality was 33.7%. Conclusions: In this case series, critically ill patients with COVID-19 with severe acute respiratory failure refractory to prone positioning and hypercytokinemia who received adjuvant treatment with cytokine hemoadsorption showed a significant reduction in IL-6 plasma levels and other inflammatory biomarkers. Improvements in oxygenation and SOFA score were also observe

Proteins analyzed and their relationship with mortality /organ dysfunction.

Proteins analyzed and their relationship with mortality /organ dysfunction.</p

Shap values graphics.

A) blue = proteins expressed in patients with SOFA ≤ 6, red = proteins expressed in patients with SOFA > 6. B) blue = proteins expressed in patients survivors, red = proteins expressed in patients non-survivors.</p