Sepsis—Pathophysiology and Therapeutic Concepts

Frontiers in Medicine, Journal Year: 2021, Volume and Issue: 8

Published: May 14, 2021

Sepsis is a life-threatening condition and global disease burden. Today, the heterogeneous syndrome defined as severe organ dysfunction caused by dysregulated host response to infection, with renewed emphasis on immune pathophysiology. Despite all efforts of experimental clinical research during last three decades, ability positively influence course outcome remains limited. Evidence-based therapy still consists basic causal supportive measures, while adjuvant interventions such blood purification or targeted immunotherapy largely remain without proof effectiveness so far. With this review, we aim provide an overview sepsis pathophysiology, update choice therapeutic approaches targeting different immunological mechanisms in septic shock, call for paradigm shift from pathogen potentially more promising angle.

Language: Английский

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

World Journal of Critical Care Medicine, Journal Year: 2022, Volume and Issue: 11(1), P. 1 - 21

Published: Jan. 4, 2022

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

Language: Английский

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A new hope? Possibilities of therapeutic IgA antibodies in the treatment of inflammatory lung diseases

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: March 27, 2023

Inflammatory lung diseases represent a persistent burden for patients and the global healthcare system. The combination of high morbidity, (partially) mortality limited innovations in last decades, have resulted great demand new therapeutics. Are therapeutic IgA antibodies possibly hope treatment inflammatory diseases? Current research increasingly unravels elementary functions as protector against infections modulator overwhelming inflammation. With focus on IgA, this review describes pathological alterations mucosal immunity how they contribute to chronic inflammation most common diseases. current knowledge circulation, particularly respiratory mucosa, are summarized. interplay between neutrophils seems be key control In addition, hurdles benefits antibodies, well currently known clinically used preparations described. data highlighted here, together with upcoming strategies aiming at circumventing pitfalls may pave way promising antibody class application

Language: Английский

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Destabilisation of T cell-dependent humoral immunity in sepsis

Clinical Science, Journal Year: 2024, Volume and Issue: 138(1), P. 65 - 85

Published: Jan. 1, 2024

Abstract Sepsis is a heterogeneous condition defined as life-threatening organ dysfunction caused by dysregulated host response to infection. For some, sepsis presents predominantly suppressive disorder, whilst others experience pro-inflammatory which can culminate in ‘cytokine storm’. Frequently, patients signs of concurrent hyper-inflammation and immunosuppression, underpinning the difficulty directing effective treatment. Although intensive care unit mortality rates have improved recent years, one-third discharged die within following year. Half post-sepsis deaths are due exacerbation pre-existing conditions, half complications arising from deteriorated immune system. It has been suggested that intense infection may induce irreversible metabolic reprogramming cells. As critical arm protection vertebrates, alterations adaptive system devastating repercussions. Indeed, marked depletion lymphocytes observed sepsis, correlating with increased mortality. Such sepsis-induced lymphopenia profound consequences on how T cells respond but equally humoral both elicited B supported distinct CD4+ follicular helper (TFH) cell subsets. The immunosuppressive state further exacerbated functional impairments remaining lymphocyte population, including presence expressing dysfunctional or exhausted phenotypes. This review will specifically focus destabilises system, closer examination TFH affected corresponding impact immunity.

Language: Английский

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microRNA-124-3p attenuates myocardial injury in sepsis via modulating SP1/HDAC4/HIF-1α axis

Cell Death Discovery, Journal Year: 2022, Volume and Issue: 8(1)

Published: Jan. 28, 2022

Sepsis-induced cardiac dysfunction can lead to death in sepsis. In this case, we targeted explore detail the relative mechanism of microRNA (miR)-124-3p sepsis-induced myocardial injury via specific protein 1/histone deacetylase 4/hypoxia-inducing factor 1α (SP1/HDAC4/HIF-1α) axis. Septic rats were modeled by cecal ligation puncture while vitro septic cardiomyocyte H9C2 induced lipopolysaccharide (LPS). miR-124-3p/SP1/HDAC4/HIF-1α expression levels tissues and LPS-treated cells measured. miR-124-3p overexpression SP1 silencing assays implemented on theirs actions inflammation, oxidative stress cell apoptosis. The interactions miR-124-3p, SP1, HDAC4 testified. was lowly expressed HDAC4, HIF-1α highly Upregulation ameliorated stress, apoptosis cells. Silencing improved LPS-induced damage cardiomyocytes. interacted with SP1. antagonized upregulation-induced improvements damage. This study illustrates that improves through regulation mediate HDAC4/HIF-1α.

Language: Английский

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Current perspectives in the management of sepsis and septic shock

Frontiers in Medicine, Journal Year: 2024, Volume and Issue: 11

Published: Aug. 15, 2024

Within patients with sepsis, there exists significant heterogeneity, and while all should receive conventional therapy, are subgroups of who may benefit from specific therapies, often referred to as rescue therapies. Therefore, the identification these patient is crucial lays groundwork for application precision medicine based on development targeted interventions. Over years, efforts have been made categorize sepsis into different subtypes clinical characteristics, biomarkers, or underlying mechanisms. For example, can be stratified phenotypes predominant dysregulated host response. These range hyperinflammatory states immunosuppressive even mixed phenotypes. Each phenotype require therapeutic approaches improve outcomes. Rescue strategies septic shock encompass various interventions, such immunomodulatory extracorporeal support (e.g., ECMO), therapies at molecular cellular pathways involved in pathophysiology sepsis. In recent has growing interest identification. Precision aims tailor treatments each individual their unique characteristics disease

Language: Английский

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Sepsis-induced immunosuppression: mechanisms, biomarkers and immunotherapy

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 29, 2025

Sepsis, a life-threatening organ dysfunction resulting from dysregulated host response to infection, initiates complex immune that varies over time, characterized by sustained excessive inflammation and immunosuppression. Sepsis-induced immunosuppression is now recognized as major cause of septic death, identifying effective strategies counteract it poses significant challenge. This results the disruption homeostasis, abnormal death effector cells, hyperproliferation suppressor release anti-inflammatory cytokines, expression checkpoints. Preclinical studies targeting immunosuppression, particularly with checkpoint inhibitors, have shown promise in reversing immunocyte dysfunctions establishing resistance pathogens. Here, our review highlights mechanisms sepsis-induced current diagnostic biomarkers, well immune-enhancing evaluated patients therapeutics under investigation.

Language: Английский

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Intravenous immunoglobulin treatment for patients with severe COVID-19: a retrospective multicentre study

Clinical Microbiology and Infection, Journal Year: 2021, Volume and Issue: 27(10), P. 1488 - 1493

Published: May 19, 2021

Language: Английский

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Intravenous IgM-enriched immunoglobulins in critical COVID-19: a multicentre propensity-weighted cohort study

Critical Care, Journal Year: 2022, Volume and Issue: 26(1)

Published: July 7, 2022

Abstract Background A profound inflammation-mediated lung injury with long-term acute respiratory distress and high mortality is one of the major complications critical COVID-19. Immunoglobulin M (IgM)-enriched immunoglobulins seem especially capable mitigating inflicted inflammatory harm. However, efficacy intravenous IgM-enriched preparations in critically ill patients COVID-19 largely unclear. Methods In this retrospective multicentric cohort study, 316 laboratory-confirmed were treated ten German Austrian ICUs between May 2020 April 2021. The primary outcome was 30-day mortality. Analysis performed by Cox regression models. Covariate adjustment propensity score weighting using machine learning-based SuperLearner to overcome selection bias due missing randomization. addition, a subgroup analysis focusing on different treatment regimens patient characteristics performed. Results Of ICU patients, 146 received 170 cases did not, which served as controls. There no survival difference two groups terms at 30 days overall (HR adj : 0.83; 95% CI: 0.55 1.25; p = 0.374). An improved without mechanical ventilation time immunoglobulin not reach statistical significance 0.23; 0.05 1.08; 0.063). Also, statistically significant observed when daily dose ≥ 15 g duration 3 applied 0.65; 0.41 1.03; 0.068). Conclusions Although we cannot prove reliable effect immunoglobulins, confidence intervals may suggest clinically relevant certain subgroups. Here, an early administration (i.e. but yet mechanically ventilated patients) for least confer beneficial effects concerning safety issues. these findings need be validated upcoming randomized clinical trials. Trial registration DRKS00025794 , Clinical Trials Register, https://www.drks.de . Registered 6 July

Language: Английский

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Efficacy and safety of trimodulin in patients with severe COVID-19: results from a randomised, placebo-controlled, double-blind, multicentre, phase II trial (ESsCOVID)

European journal of medical research, Journal Year: 2024, Volume and Issue: 29(1)

Published: Aug. 13, 2024

Trimodulin (human polyvalent immunoglobulin [Ig] M ~ 23%, IgA 21%, IgG 56% preparation) has previously been associated with a lower mortality rate in subpopulation of patients severe community-acquired pneumonia on invasive mechanical ventilation (IMV) and clear signs inflammation. The hypothesis for the ESsCOVID trial was that trimodulin may prevent inflammation-driven progression coronavirus disease 2019 (COVID-19) to critical or even death. Adults COVID-19 were randomised receive intravenous infusions placebo 5 consecutive days addition standard care. primary efficacy endpoint composite clinical deterioration (Days 6–29) 28-day all-cause 1–29). One-hundred-and-sixty-six received (n = 84) 82). Thirty-three died, nine during treatment phase. Overall, 84.9% 76.5% completed follow-up, respectively. reported 33.3% 34.1% (P 0.912). No differences observed proportion recovered Day 29, ventilation, intensive care unit-free days. Rates treatment-emergent adverse events comparable. A post hoc analysis conducted early systemic inflammation by excluding those high CRP (> 150 mg/L) and/or D-dimer (≥ 3 low platelet counts (< 130 × 109/L) at baseline. Forty-seven group 49 met these criteria. difference 15.5 percentage points favour (95% confidence interval: −4.46, 34.78; P 0.096). Although there no outcome overall population, observations subgroup suggest have potential this setting warrants further investigation. NCT04576728

Language: Английский

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