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SIRS and Sepsis: Novel Aspects of Modern Research on Hyperinflammation

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Intensive Care".

Deadline for manuscript submissions: closed (22 March 2023) | Viewed by 22334

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Special Issue Editors

Dr. Andreas Hecker

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Guest Editor

Department of General, Visceral, Thoracic, Transplant and Pediatric Surgery, University Hospital of Giessen, Giessen, Germany
Interests: abdominal sepsis; peritonitis; PBMCs; abdominal compartment syndrome (ACS); SEPSIS-3; NLRP3 inflammasome; innate immunity
Special Issues, Collections and Topics in MDPI journals

Dr. Matthias Hecker

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Guest Editor

Medical Clinic II, University Hospital of Giessen, Giessen, Germany
Interests: ARDS; SIRS; Sepsis; PBMCs; mitochondria; innate immunity; pneumonia
Special Issues, Collections and Topics in MDPI journals

Dr. Martin Reichert

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Guest Editor

Department of General, Visceral, Thoracic, Transplant and Pediatric Surgery, University Hospital of Giessen, Giessen, Germany
Interests: surgical oncology; emergency surgery; transplant surgery; innate immunity; abdominal sepsis

Special Issue Information

Dear Colleagues,

In 2020, our first Special Issue on “Sepsis: Current Clinical Practices and New Perspectives” was launched (https://www.mdpi.com/journal/jcm/special_issues/Sepsis_Clinical_Practice). We were able to collect a large number of expert manuscripts on the whole spectrum of research on SIRS and sepsis underlining the importance of JCM as one important platform for researchers worldwide. Part I covered both clinical and basic immunological research on hyperinflammation and was such a success that we have decided to edit another Special Issue as an update for the last edition. In part II, we aim to unite research manuscripts including reviews, original manuscripts, and case reports on both basic immunology, stimulating retrospective and prospective randomized clinical trials and case series, which will be able to shed some light on new diagnostic and therapeutic aspects of hyperinflammation.

We welcome articles providing new insights into a) new pharmacological pathways and targets in innate immunity, b) new tools for the rapid diagnosis of SIRS and sepsis (also including COVID-19-testing), and c) novel therapeutic approaches for inflammatory disorders, postoperative inflammation, and complication management.

COVID-19 is one key target of research worldwide. Researchers with new ideas to elucidate its immunological characteristics are explicitly and cordially invited to submit their work.

We welcome both solicited and unsolicited submissions that will contribute to this goal.

Dr. Andreas Hecker
Dr. Matthias Hecker
Dr. Martin Reichert
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

SIRS/sepsis
Innate immunity
Critical care medicine
Damage control surgery
Peritonitis
Pneumonia
ARDS

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Related Special Issue

Sepsis: Current Clinical Practices and New Perspectives in Journal of Clinical Medicine (15 articles)

Published Papers (8 papers)

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Research

Jump to: Review, Other

13 pages, 2421 KiB

Open AccessArticle

The Prognostic Value of a Liver Function Test Using Indocyanine Green (ICG) Clearance in Patients with Multiple Organ Dysfunction Syndrome (MODS)

by Franz Haertel, Sebastian Nuding, Diana Reisberg, Martin Peters, Karl Werdan, P. Christian Schulze and Henning Ebelt

J. Clin. Med. 2024, 13(4), 1039; https://doi.org/10.3390/jcm13041039 - 11 Feb 2024

Viewed by 1949

Abstract

Background: Multiple organ dysfunction syndrome (MODS) is common in intensive care units (ICUs) and is associated with high mortality. Although there have been multiple investigations into a multitude of organ dysfunctions, little is known about the role of liver dysfunction. In addition, clinical and laboratory findings of liver dysfunction may occur with a significant delay. Therefore, the aim of this study was to investigate whether a liver function test, based on indocyanine green (ICG)-clearance, contains prognostic information for patients in the early phase of MODS. Methods: The data of this analysis were based on the MODIFY study, which included 70 critically ill patients of a tertiary medical ICU in the early phase of MODS (≤24 h after diagnosis by an APACHE II score ≥ 20 and a sinus rhythm ≥ 90 beats per minute, with the following subgroups: cardiogenic (cMODS) and septic MODS (sMODS)) over a period of 18 months. ICG clearance was characterized by plasma disappearance rate = PDR (%/min); it was measured non-invasively by using the LiMON system (PULSION Medical Systems, Feldkirchen, Germany). The PDR was determined on the day of study inclusion (baseline) and after 96 h. The primary endpoint of this analysis was 28-day mortality. Results: ICG clearance was measured in 44 patients of the MODIFY trial cohort, of which 9 patients had cMODS (20%) and 35 patients had sMODS (80%). Mean age: 59.7 ± 16.5 years; 31 patients were men; mean APACHE II score: 33.6 ± 6.3; 28-day mortality was 47.7%. Liver function was reduced in the total cohort as measured by a PDR of 13.4 ± 6.3%/min At baseline, there were no relevant differences between survivors and non-survivors regarding ICG clearance (PDR: 14.6 ± 6.1%/min vs. 12.1 ± 6.5%/min; p = 0.21). However, survivors showed better liver function than non-survivors after 96 h (PDR: 21.9 ± 6.3%/min vs. 9.2 ± 6.3%/min, p < 0.05). Consistent with these findings, survivors but not non-survivors show a significant improvement in the PDR (7.3 ± 6.3%/min vs. −2.9 ± 2.6%/min; p < 0.01) within 96 h. In accordance, receiver-operating characteristic curves (ROCs) at 96 h but not at baseline show a link between the PDR and 28-day mortality (PDR at 96 h: AUC: 0.87, 95% CI: 0.76–0.98; p < 0.01. Conclusions: In our study, we found that ICG clearance at baseline did not provide prognostic information in patients in the early stages of MODS despite being reduced in the total cohort. However, improvement of ICG clearance 96 h after ICU admission is associated with reduced 28-day mortality. Full article

(This article belongs to the Special Issue SIRS and Sepsis: Novel Aspects of Modern Research on Hyperinflammation)

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13 pages, 2476 KiB

Open AccessArticle

The Effects of Heparan Sulfate Infusion on Endothelial and Organ Injury in a Rat Pneumosepsis Model

by Daan P. van den Brink, Derek J. B. Kleinveld, Annabel Bongers, Jaël Vos, Joris J. T. H. Roelofs, Nina C. Weber, Jaap D. van Buul and Nicole P. Juffermans

J. Clin. Med. 2023, 12(20), 6438; https://doi.org/10.3390/jcm12206438 - 10 Oct 2023

Viewed by 1157

Abstract

Septic shock is characterized by endothelial dysfunction, leading to tissue edema and organ failure. Heparan sulfate (HS) is essential for vascular barrier integrity, possibly via albumin as a carrier. We hypothesized that supplementing fluid resuscitation with HS would improve endothelial barrier function, thereby reducing organ edema and injury in a rat pneumosepsis model. Following intratracheal inoculation with Streptococcus pneumoniae, Sprague Dawley rats were randomized to resuscitation with a fixed volume of either Ringer’s Lactate (RL, standard of care), RL supplemented with 7 mg/kg HS, 5% human albumin, or 5% human albumin supplemented with 7 mg/kg HS (n = 11 per group). Controls were sham inoculated animals. Five hours after the start of resuscitation, animals were sacrificed. To assess endothelial permeability, 70 kD FITC-labelled dextran was administered before sacrifice. Blood samples were taken to assess markers of endothelial and organ injury. Organs were harvested to quantify pulmonary FITC-dextran leakage, organ edema, and for histology. Inoculation resulted in sepsis, with increased lactate levels, pulmonary FITC-dextran leakage, pulmonary edema, and pulmonary histologic injury scores compared to healthy controls. RL supplemented with HS did not reduce median pulmonary FITC-dextran leakage compared to RL alone (95.1 CI [62.0–105.3] vs. 87.1 CI [68.9–139.3] µg/mL, p = 0.76). Similarly, albumin supplemented with HS did not reduce pulmonary FITC-dextran leakage compared to albumin (120.0 [93.8–141.2] vs. 116.2 [61.7 vs. 160.8] µg/mL, p = 0.86). No differences were found in organ injury between groups. Heparan sulfate, as an add-on therapy to RL or albumin resuscitation, did not reduce organ or endothelial injury in a rat pneumosepsis model. Higher doses of heparan sulfate may decrease organ and endothelial injury induced by shock. Full article

(This article belongs to the Special Issue SIRS and Sepsis: Novel Aspects of Modern Research on Hyperinflammation)

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13 pages, 1902 KiB

Open AccessArticle

Effect of CytoSorb Coupled with Hemodialysis on Interleukin-6 and Hemodynamic Parameters in Patients with Systemic Inflammatory Response Syndrome: A Retrospective Cohort Study

by Vanja Persic, Alexander Jerman, Marija Malgaj Vrecko, Jernej Berden, Vojka Gorjup, Adela Stecher, Milica Lukic, Matjaz Jereb, Gordana Taleska Stupica and Jakob Gubensek

J. Clin. Med. 2022, 11(24), 7500; https://doi.org/10.3390/jcm11247500 - 18 Dec 2022

Cited by 9 | Viewed by 2136

Abstract

Excessive release of cytokines during systemic inflammatory response syndrome (SIRS) often leads to refractory hypotension and multiple organ failure with high mortality. Cytokine removal with hemoadsorption has emerged as a possible adjuvant therapy, but data on interleukin-6 (IL-6) reduction and outcomes in clinical practice are scarce. We aimed to evaluate the effect of CytoSorb hemoadsorption on laboratory and clinical outcomes in shocked patients with SIRS. We designed a retrospective analysis of all patients with SIRS treated with CytoSorb in intensive care units (ICU). IL-6, laboratory and hemodynamic parameters were analyzed at approximate time intervals during CytoSorb treatment in the whole cohort and in a subgroup with septic shock. Observed and predicted mortality rates were compared. We included 118 patients with various etiologies of SIRS (septic shock 69%, post-resuscitation shock 16%, SIRS with acute pancreatitis 6%, other 9%); in all but one patient, CytoSorb was coupled with renal replacement therapy. A statistically significant decrease in IL-6 and vasopressor index with an increase in pH and mean arterial pressure was observed from 6 h onward. The reduction of lactate became significant at 48 h. Results were similar in a subgroup of patients with septic shock. Observed ICU and in-hospital mortalities were lower than predicted by Sequential Organ Failure Assessment (SOFA) (61% vs. 79%, p = 0.005) and Acute Physiology and Chronic Health Evaluation (APACHE) II (64% vs. 78%, p = 0.031) scores. To conclude, hemoadsorption in shocked patients with SIRS was associated with a rapid decrease in IL-6 and hemodynamic improvement, with improved observed vs. predicted survival. These results need to be confirmed in a randomized study. Full article

(This article belongs to the Special Issue SIRS and Sepsis: Novel Aspects of Modern Research on Hyperinflammation)

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15 pages, 1193 KiB

Open AccessArticle

Peak Plasma Levels of mtDNA Serve as a Predictive Biomarker for COVID-19 in-Hospital Mortality

by Fabian Edinger, Sophia Edinger, Christian Koch, Melanie Markmann, Matthias Hecker, Michael Sander and Emmanuel Schneck

J. Clin. Med. 2022, 11(23), 7161; https://doi.org/10.3390/jcm11237161 - 1 Dec 2022

Cited by 12 | Viewed by 1338

Abstract

Several predictive biomarkers for coronavirus disease (COVID-19)-associated mortality in critically ill patients have been described. Although mitochondrial DNA (mtDNA) is elevated in patients with COVID-19, the association with coagulation function and its predictive power for mortality is unclear. Accordingly, this study investigates the predictive power of mtDNA for in-hospital mortality in critically ill patients with COVID-19, and whether combining it with thromboelastographic parameters can increase its predictive performance. This prospective explorative study included 29 patients with COVID-19 and 29 healthy matched controls. mtDNA encoding for NADH dehydrogenase 1 (ND1) was quantified using a quantitative polymerase chain reaction analysis, while coagulation function was evaluated using thromboelastometry and impedance aggregometry. Receiver operating characteristic (ROC) curves were used for the prediction of in-hospital mortality. Within the first 24 h, the plasma levels of mtDNA peaked significantly (controls: 65 (28–119) copies/µL; patients: 281 (110–805) at t₀, 403 (168–1937) at t₂₄, and 467 (188–952) copies/µL at t₇₂; controls vs. patients: p = 0.02 at t₀, p = 0.03 at t₂₄, and p = 0.44 at t₇₂). The mtDNA levels at t₂₄ showed an excellent predictive performance for in-hospital mortality (area under the ROC curve: 0.90 (0.75–0.90)), which could not be improved by the combination with thromboelastometric or aggregometric parameters. Critically ill patients with COVID-19 present an early increase in the plasma levels of ND1 mtDNA, lasting over 24 h. They also show impairments in platelet function and fibrinolysis, as well as hypercoagulability, but these do not correlate with the plasma levels of fibrinogen. The peak plasma levels of mtDNA can be used as a predictive biomarker for in-hospital mortality; however, the combination with coagulation parameters does not improve the predictive validity. Full article

(This article belongs to the Special Issue SIRS and Sepsis: Novel Aspects of Modern Research on Hyperinflammation)

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13 pages, 958 KiB

Open AccessArticle

Characteristics of Interleukin-6 Signaling in Elective Cardiac Surgery—A Prospective Cohort Study

by Jürgen Puchinger, Sylvia Ryz, Larissa Nixdorf, Maximilian Edlinger-Stanger, Andrea Lassnigg, Dominik Wiedemann, Michael Hiesmayr, Andreas Spittler and Martin H. Bernardi

J. Clin. Med. 2022, 11(3), 590; https://doi.org/10.3390/jcm11030590 - 25 Jan 2022

Cited by 8 | Viewed by 2745

Abstract

Interleukin-6 (IL-6) can cause pro- and anti-inflammatory effects via different signaling pathways. This prospective study investigated the perioperative kinetics of IL-6, soluble IL-6 receptor (sIL-6R), and soluble glycoprotein 130 (sgp130) in elective patients undergoing cardiopulmonary bypass (CPB). IL-6, sIL-6R, and sgp130 were measured simultaneously and consecutively at 19 timepoints until the 10th postoperative day (POD). The proportion of pro- and anti-inflammatory pathways were determined by calculating sIL-6R/IL-6 and sIL-6R/sgp130 ratios. We analyzed 93 patients. IL-6 increased during surgery with reaching a plateau two hours after CPB and peaking on POD 1 (188.5 pg mL⁻¹ (IQR, 126.6; 309.2)). sIL-6R decreased at the beginning of the surgical procedure, reaching a nadir level on POD 2 (26,311 pg mL⁻¹ (IQR, 22,222; 33,606)). sgp130 dropped immediately after CPB initiation (0.13 ng mL⁻¹ (IQR, 0.12; 0.15)), followed by a continuous recovery until POD10. The sIL-6R/IL-6 ratio decreased substantially at the beginning of the procedure, reaching a nadir on POD 1 (149.7 (IQR, 82.4; 237.4)), while the sIL-6R/sgp130 ratio increased simultaneously until 6 h post CPB (0.219 (IQR 0.18; 0.27)). In conclusion, IL-6 exhibited high inter-individual variability reflecting an inhomogeneous inflammatory response. Pro-inflammatory effects and overwhelming inflammation were rare and predominantly anti-inflammatory effects were found. Full article

(This article belongs to the Special Issue SIRS and Sepsis: Novel Aspects of Modern Research on Hyperinflammation)

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12 pages, 677 KiB

Open AccessArticle

Effect of the Lymphocyte Activation Gene 3 Polymorphism rs951818 on Mortality and Disease Progression in Patients with Sepsis—A Prospective Genetic Association Study

by Caspar Mewes, Tessa Alexander, Benedikt Büttner, José Hinz, Ayelet Alpert, Aron-F. Popov, Tim Beißbarth, Mladen Tzvetkov, Marian Grade, Michael Quintel, Ingo Bergmann and Ashham Mansur

J. Clin. Med. 2021, 10(22), 5302; https://doi.org/10.3390/jcm10225302 - 15 Nov 2021

Cited by 9 | Viewed by 1842

Abstract

(1) Background: Sepsis is a leading cause of death and a global public health problem. Accordingly, deciphering the underlying molecular mechanisms of this disease and the determinants of its morbidity and mortality is pivotal. This study examined the effect of the rs951818 SNP of the negative costimulatory lymphocyte-activation gene 3 (LAG-3) on sepsis mortality and disease severity. (2) Methods: 707 consecutive patients with sepsis were prospectively enrolled into the present study from three surgical ICUs at University Medical Center Goettingen. Both 28- and 90-day mortality were analyzed as the primary outcome, while parameters of disease severity served as secondary endpoints. (3) Results: In the Kaplan–Meier analysis LAG-3 rs951818 AA-homozygote patients showed a significantly lower 28-day mortality (17.3%) compared to carriers of the C-allele (23.7%, p = 0.0476). In addition, these patients more often received invasive mechanical ventilation (96%) during the course of disease than C-allele carriers (92%, p = 0.0466). (4) Conclusions: Genetic profiling of LAG-3 genetic variants alone or in combination with other genetic biomarkers may represent a promising approach for risk stratification of patients with sepsis. Patient-individual therapeutic targeting of immune checkpoints, such as LAG-3, may be a future component of sepsis therapy. Further detailed investigations in clinically relevant sepsis models are necessary. Full article

(This article belongs to the Special Issue SIRS and Sepsis: Novel Aspects of Modern Research on Hyperinflammation)

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Review

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23 pages, 417 KiB

Open AccessReview

Treatment Advances in Sepsis and Septic Shock: Modulating Pro- and Anti-Inflammatory Mechanisms

by Adriana Marques, Carla Torre, Rui Pinto, Bruno Sepodes and João Rocha

J. Clin. Med. 2023, 12(8), 2892; https://doi.org/10.3390/jcm12082892 - 15 Apr 2023

Cited by 21 | Viewed by 5560

Abstract

Sepsis is currently defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection, and it affects over 25 million people every year. Even more severe, septic shock is a subset of sepsis defined by persistent hypotension, and hospital mortality rates are higher than 40%. Although early sepsis mortality has greatly improved in the past few years, sepsis patients who survive the hyperinflammation and subsequent organ damage often die from long-term complications, such as secondary infection, and despite decades of clinical trials targeting this stage of the disease, currently, no sepsis-specific therapies exist. As new pathophysiological mechanisms have been uncovered, immunostimulatory therapy has emerged as a promising path forward. Highly investigated treatment strategies include cytokines and growth factors, immune checkpoint inhibitors, and even cellular therapies. There is much to be learned from related illnesses, and immunotherapy trials in oncology, as well as the recent COVID-19 pandemic, have greatly informed sepsis research. Although the journey ahead is a long one, the stratification of patients according to their immune status and the employment of combination therapies represent a hopeful way forward. Full article

(This article belongs to the Special Issue SIRS and Sepsis: Novel Aspects of Modern Research on Hyperinflammation)

Other

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9 pages, 629 KiB

Open AccessBrief Report

Evaluation of Dose Requirements Using Weight-Based versus Non-Weight-Based Dosing of Norepinephrine to Achieve a Goal Mean Arterial Pressure in Patients with Septic Shock

by Ashley R. Selby, Nida S. Khan, Tara Dadashian and Ronald G. Hall 2nd

J. Clin. Med. 2023, 12(4), 1344; https://doi.org/10.3390/jcm12041344 - 8 Feb 2023

Cited by 2 | Viewed by 4274

Abstract

No consensus exists regarding optimal dosing of norepinephrine in septic shock. We aimed to evaluate if weight-based dosing (WBD) lead to higher norepinephrine doses when achieving goal mean arterial pressure (MAP) than non-weight-based dosing (non-WBD). This was a retrospective cohort study conducted after standardization of norepinephrine dosing within a cardiopulmonary ICU. Patients received non-WBD prior to standardization (November 2018–October 2019) and WBD afterwards (November 2019–October 2020). The primary outcome was the norepinephrine dose needed to attain goal MAP. Secondary outcomes included time to goal MAP, duration of norepinephrine therapy, duration of mechanical ventilation, and treatment-related adverse effects. A total of 189 patients were included (WBD 97; non-WBD 92). There was a significantly lower norepinephrine dose at goal MAP (WBD 0.05, IQR 0.02, 0.07; non-WBD 0.07, IQR 0.05, 0.14; p < 0.005) and initial norepinephrine dose (WBD 0.02, IQR 0.01, 0.05; non-WBD 0.06, 0.04, 0.12; p < 0.005) in the WBD group. No difference was observed in achievement of goal MAP (WBD 73%; non-WBD 78%; p = 0.09) or time until goal MAP (WBD 18, IQR 0, 60; non-WBD 30, IQR 14, 60; p = 0.84). WBD may lead to lower norepinephrine doses. Both strategies achieved goal MAP with no significant difference in time to goal. Full article

(This article belongs to the Special Issue SIRS and Sepsis: Novel Aspects of Modern Research on Hyperinflammation)

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