ABSTRACT
Background: Neutrophil extracellular traps' (NETs') formation is a mechanism of defense that neutrophils deploy as an alternative to phagocytosis, to constrain the spread of microorganisms. Aim: The aim was to evaluate biomarkers of NETs' formation in a patient cohort admitted to intensive care unit (ICU) due to infection. Methods: Forty-six septic shock patients, 22 critical COVID-19 patients and 48 matched control subjects were recruited. Intact nucleosomes containing histone 3.1 (Nu.H3.1), or citrullinated histone H3R8 (Nu.Cit-H3R8), free citrullinated histone (Cit-H3), neutrophil elastase (NE) and myeloperoxidase (MPO) were measured. Results: Significant differences in Nu.H3.1 and NE levels were observed between septic shock and critical COVID-19 subjects as well as with controls (p-values < 0.05). The normalization of nucleosome levels according to the neutrophil count improved the discrimination between septic shock and critical COVID-19 patients. The ratio of Nu.Cit-H3R8 to Nu.H3.1 allowed the determination of nucleosome citrullination degree, presumably by PAD4. Conclusions: H3.1 and Cit-H3R8 nucleosomes appear to be interesting markers of global cell death and neutrophil activation when combined. Nu.H3.1 permits the evaluation of disease severity and differs between septic shock and critical COVID-19 patients, reflecting two distinct potential pathological processes in these conditions.
Subject(s)
COVID-19 , Extracellular Traps , Shock, Septic , Biomarkers/metabolism , Extracellular Traps/metabolism , Histones/metabolism , Humans , Neutrophils/metabolism , Nucleosomes/metabolism , Shock, Septic/metabolismABSTRACT
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with immunosuppressive properties. In cancer patients, the expression of lectin-type oxidized LDL receptor 1 (LOX-1) on granulocytic MDSC identifies a subset of MDSC that retains the most potent immunosuppressive properties. The main objective of the present work was to explore the presence of LOX-1+ MDSC in bacterial and viral sepsis. To this end, whole blood LOX-1+ cells were phenotypically, morphologically, and functionally characterized. They were monitored in 39 coronavirus disease-19 (COVID-19, viral sepsis) and 48 septic shock (bacterial sepsis) patients longitudinally sampled five times over a 3 wk period in intensive care units (ICUs). The phenotype, morphology, and immunosuppressive functions of LOX-1+ cells demonstrated that they were polymorphonuclear MDSC. In patients, we observed the significant emergence of LOX-1+ MDSC in both groups. The peak of LOX-1+ MDSC was 1 wk delayed with respect to ICU admission. In COVID-19, their elevation was more pronounced in patients with acute respiratory distress syndrome. The persistence of these cells may contribute to long lasting immunosuppression leaving the patient unable to efficiently resolve infections.
Subject(s)
COVID-19/immunology , Leukocytes, Mononuclear/immunology , Myeloid-Derived Suppressor Cells/immunology , Respiratory Distress Syndrome/physiopathology , SARS-CoV-2/immunology , Scavenger Receptors, Class E/metabolism , Shock, Septic/immunology , Aged , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Female , Humans , Male , Middle Aged , Shock, Septic/metabolism , Shock, Septic/microbiology , Shock, Septic/pathologyABSTRACT
OBJECTIVE: Disruption of intracellular Ca2+ homeostasis via excessive and pathological Ca2+ release from the endoplasmic reticulum (ER) and/or sarcoplasmic reticulum (SR) through ryanodine receptor (RyRs) Ca2+ channels play a critical role in the pathology of systemic inflammatory response syndrome (SIRS) and associated multiple organ dysfunction syndrome (MODS) in sepsis or septic shock. Dantrolene, a potent inhibitor of RyRs, is expected to ameliorate SIRS and MODS and decrease mortality in sepsis or septic shock patients. This review summarized the potential mechanisms of therapeutic effects of dantrolene in sepsis or septic shock at molecular, cell, and organ levels and provided suggestions and strategies for future clinical studies.
Subject(s)
COVID-19 Drug Treatment , Calcium Channel Blockers/therapeutic use , Dantrolene/therapeutic use , Sepsis/drug therapy , COVID-19/metabolism , Calcium/metabolism , Drug Repositioning , Endoplasmic Reticulum/metabolism , Humans , Mortality , Multiple Organ Failure , Ryanodine Receptor Calcium Release Channel/metabolism , SARS-CoV-2 , Sarcoplasmic Reticulum/metabolism , Sepsis/metabolism , Shock, Septic/drug therapy , Shock, Septic/metabolismSubject(s)
C-Reactive Protein/metabolism , COVID-19/metabolism , Pneumonia/metabolism , Sepsis/metabolism , Serum Amyloid P-Component/metabolism , Aged , Aged, 80 and over , Case-Control Studies , Female , Humans , Intensive Care Units , Interleukin-6/metabolism , Male , Middle Aged , Propensity Score , SARS-CoV-2 , Shock, Septic/metabolismSubject(s)
Betacoronavirus/metabolism , Critical Care , Pandemics , Systemic Inflammatory Response Syndrome , COVID-19 , Child , Europe/epidemiology , Humans , Mucocutaneous Lymph Node Syndrome/diagnosis , Mucocutaneous Lymph Node Syndrome/epidemiology , Mucocutaneous Lymph Node Syndrome/metabolism , Mucocutaneous Lymph Node Syndrome/therapy , SARS-CoV-2 , Shock, Septic/diagnosis , Shock, Septic/epidemiology , Shock, Septic/metabolism , Shock, Septic/therapy , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/epidemiology , Systemic Inflammatory Response Syndrome/metabolism , Systemic Inflammatory Response Syndrome/therapySubject(s)
COVID-19/metabolism , SARS-CoV-2/metabolism , Shock, Septic/metabolism , Superantigens/metabolism , Systemic Inflammatory Response Syndrome/metabolism , COVID-19/pathology , Child , Child, Preschool , Female , Humans , Male , Shock, Septic/pathology , Systemic Inflammatory Response Syndrome/pathologySubject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Immune Tolerance/physiology , Pneumonia, Viral/immunology , Shock, Septic/immunology , Aged , COVID-19 , Coronavirus Infections/metabolism , Female , Humans , Intensive Care Units/trends , Male , Middle Aged , Pandemics , Pneumonia, Viral/metabolism , Prospective Studies , SARS-CoV-2 , Shock, Septic/metabolismABSTRACT
We report the case of an 88-year-old man with coronavirus disease 2019 (COVID-19) who presented with ARDS and septic shock. The patient had exquisite BP sensitivity to low-dose angiotensin II (Ang-2), allowing for rapid liberation from high-dose vasopressors. We hypothesize that sensitivity to Ang-2 might be related to biological effect of severe acute respiratory syndrome coronavirus 2 infection. The case is suggestive of a potential role for synthetic Ang-2 for patients with COVID-19 and septic shock. Further studies are needed to confirm our observed clinical efficacy.