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Sepsis: Immunopathology, Patient Classification and Clinical Management

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

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 69816

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Special Issue Editor

Dr. Brendon P. Scicluna

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Guest Editor

1. Amsterdam UMC, University of Amsterdam, Center for Experimental Molecular Medicine, Amsterdam Infection and Immunity, Amsterdam, The Netherlands
2. Amsterdam UMC, University of Amsterdam, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam, The Netherlands
Interests: genomics; immunity; sepsis; infectious diseases; precision medicine; computational biology

Special Issue Information

Dear colleagues,

Sepsis is a multifaceted syndrome that is understood to be initiated by an abnormal reaction to infection, leading to life-threatening organ dysfunction. Despite empirical antimicrobial therapy and advances in intensive care, it is expected that sepsis will remain a major healthcare problem (it was recently recognized by the World Health Assembly and WHO, who made it a global health priority in 2017). More than 100 clinical trials have evaluated drugs targeting specific components of the host immune response to infection but to no avail. Those failures have been ascribed to the marked heterogeneity in the clinical presentation and immunopathology of sepsis, which hinders the identification of patients who would benefit from specific treatment. For decades, an abnormal inflammatory response to infection was considered to be central to the pathogenesis of sepsis. It is now evident that the host response is altered in a more complex way, involving persistent excessive inflammation, immune suppression, and a failure to restore normal homeostasis. It may be argued that those alterations may reflect a fundamental reorganization of immune and metabolic cell processes; however, it remains difficult to create an overarching framework of the key drivers in sepsis immunopathology versus changes that are secondary and less decisive to patient outcome. Improving our understanding of sepsis pathophysiology is critical for the development of precise therapeutics and patient management. Therefore, this Special Issue is dedicated to advances in sepsis immunopathology, patient classification, and clinical management.

Dr. Brendon P Scicluna
Guest Editor

Manuscript Submission Information

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Keywords

sepsis
immunopathology
heterogeneity
risk stratification
diagnosis

Published Papers (13 papers)

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22 pages, 4217 KiB

Open AccessArticle

Differential Gene Expression in Circulating CD14⁺ Monocytes Indicates the Prognosis of Critically Ill Patients with Sepsis

by Anke Liepelt, Philipp Hohlstein, Hendrik Gussen, Jia Xue, Anna C. Aschenbrenner, Thomas Ulas, Lukas Buendgens, Klaudia T. Warzecha, Matthias Bartneck, Tom Luedde, Christian Trautwein, Joachim L. Schultze, Alexander Koch and Frank Tacke

J. Clin. Med. 2020, 9(1), 127; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9010127 - 02 Jan 2020

Cited by 15 | Viewed by 3838

Abstract

Critical illness and sepsis are characterized by drastic changes in the systemic innate immune response, particularly involving monocytes. The exact monocyte activation profile during sepsis, however, has remained obscure. Therefore, we prospectively analyzed the gene expression profile of circulating CD14⁺ monocytes from healthy volunteers (n = 54) and intensive care unit (ICU) patients (n = 76), of which n = 36 had sepsis. RNA sequencing of selected samples revealed that monocytes from septic ICU patients display a peculiar activation pattern, which resembles characteristic functional stages of monocyte-derived macrophages and is distinct from controls or non-sepsis ICU patients. Focusing on 55 highly variable genes selected for further investigation, arachidonate 5-lipoxygenase-activating protein (ALOX5AP) was highly upregulated in monocytes of ICU patients and only normalized during 7 days in the ICU in non-sepsis patients. Strikingly, low monocytic guanine nucleotide exchange factor 10-like protein (ARHGEF10L) mRNA expression was associated with the disease severity and mortality of ICU patients. Collectively, our comprehensive analysis of circulating monocytes in critically ill patients revealed a distinct activation pattern, particularly in ICU patients with sepsis. The association with disease severity, the longitudinal recovery or lack thereof during the ICU stay, and the association with prognosis indicate the clinical relevance of monocytic gene expression profiles during sepsis. Full article

(This article belongs to the Special Issue Sepsis: Immunopathology, Patient Classification and Clinical Management)

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13 pages, 2238 KiB

Open AccessArticle

Erastin Inhibits Septic Shock and Inflammatory Gene Expression via Suppression of the NF-κB Pathway

by Byung Moo Oh, Seon-Jin Lee, Gyoung Lim Park, Yo Sep Hwang, Jeewon Lim, Eun Sun Park, Kyung Ho Lee, Bo Yeon Kim, Yong Tae Kwon, Hee Jun Cho and Hee Gu Lee

J. Clin. Med. 2019, 8(12), 2210; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8122210 - 14 Dec 2019

Cited by 43 | Viewed by 5645

Abstract

Sepsis is a life-threatening condition that is caused by an abnormal immune response to infection and can lead to tissue damage, organ failure, and death. Erastin is a small molecule capable of initiating ferroptotic cell death in cancer cells. However, the function of erastin in the inflammatory response during sepsis remains unknown. Here, we showed that erastin ameliorates septic shock induced by cecal ligation and puncture or lipopolysaccharides (LPS) in mice, which was associated with a reduced production of inflammatory mediators such as nitric oxide, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β. Pretreatment with erastin in bone marrow-derived macrophages (BMDMs) significantly attenuated the expression of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α, and IL-1β mRNA in response to LPS treatment. Furthermore, we also showed that erastin suppresses phosphorylation of IκB kinase β, phosphorylation and degradation of IκBα, and nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in LPS-stimulated BMDMs. Our findings suggest that erastin attenuates the inflammatory response by suppressing the NF-κB signaling pathway, resulting in inhibition of sepsis development. This study provides new insights regarding the potential therapeutic properties of erastin in sepsis. Full article

(This article belongs to the Special Issue Sepsis: Immunopathology, Patient Classification and Clinical Management)

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10 pages, 1603 KiB

Open AccessArticle

Predictive Validity of the qSOFA Score for Sepsis in Adults with Community-Onset Staphylococcal Infection in Thailand

by Supaksh Gupta, Kristina E. Rudd, Sarunporn Tandhavanant, Pornpan Suntornsut, Ploenchan Chetchotisakd, Derek C. Angus, Sharon J. Peacock, Narisara Chantratita and Timothy Eoin West

J. Clin. Med. 2019, 8(11), 1908; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8111908 - 07 Nov 2019

Cited by 4 | Viewed by 2908

Abstract

The quick sequential organ failure assessment (qSOFA) score has had limited validation in lower resource settings and was developed using data from high-income countries. We sought to evaluate the predictive validity of the qSOFA score for sepsis within a low- and middle-income country (LMIC) population with culture-proven staphylococcal infection. This was a secondary analysis of a prospective multicenter cohort in Thailand with culture-positive infection due to Staphylococcus aureus or S. argenteus within 24 h of admission and positive (≥2/4) systemic inflammatory response syndrome (SIRS) criteria. Primary exposure was maximum qSOFA score within 48 h of culture collection and primary outcome was mortality at 28 days. Baseline risk of mortality was determined using a multivariable logistic regression model with age, gender, and co-morbidities significantly associated with the outcome. Predictive validity was assessed by discrimination of mortality using area under the receiver operating characteristic (AUROC) curve compared to a model using baseline risk factors alone. Of 253 patients (mean age 54 years (SD 16)) included in the analysis, 23 (9.1%) died by 28 days after enrollment. Of those who died, 0 (0%) had a qSOFA score of 0, 8 (35%) had a score of 1, and 15 (65%) had a score ≥2. The AUROC of qSOFA plus baseline risk was significantly greater than for the baseline risk model alone (AUROC_qSOFA = 0.80 (95% CI, 0.70–0.89), AUROC_baseline = 0.62 (95% CI, 0.49–0.75); p < 0.001). Among adults admitted to four Thai hospitals with community-onset coagulase-positive staphylococcal infection and SIRS, the qSOFA score had good predictive validity for sepsis. Full article

(This article belongs to the Special Issue Sepsis: Immunopathology, Patient Classification and Clinical Management)

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12 pages, 870 KiB

Open AccessArticle

The Effect of the Intelligent Sepsis Management System on Outcomes among Patients with Sepsis and Septic Shock Diagnosed According to the Sepsis-3 Definition in the Emergency Department

by Juhyun Song, Hanjin Cho, Dae Won Park, Sejoong Ahn, Joo Yeong Kim, Hyeri Seok, Jonghak Park and Sungwoo Moon

J. Clin. Med. 2019, 8(11), 1800; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8111800 - 27 Oct 2019

Cited by 12 | Viewed by 4016

Abstract

We developed a novel computer program, the Intelligent Sepsis Management System, based on Sepsis-3 definitions and 2016 Surviving Sepsis Campaign guidelines and performed a quasi-experimental pre-post study to assess its effect on compliance with the Surviving Sepsis Campaign guidelines and outcomes in patients with sepsis and septic shock. During the pre-period, patients were managed with usual care. During the post-period, patients were managed using the Intelligent Sepsis Management System upon arrival at the emergency department. A total of 631 patients were enrolled (pre-period, 316; post-period, 315). The overall compliance with the Surviving Sepsis Campaign guidelines’ bundle improved (pre-period 10.8% vs. post-period 54.6%; p < 0.001). The post-period showed significantly lower 30-day mortality than the pre-period (pre-period 37.3% vs. post-period 29.5%; p = 0.037), but was not a protective factor for 30-day mortality, with an adjusted hazard ratio (95% confidence interval) of 0.75 (0.55–1.04) (p = 0.151). The associated factors for 30-day mortality were age, sequential organ failure assessment score, overall compliance, and lactate levels. The 30-day mortality was significantly lower in the compliance group than in the non-compliance group (27.2% vs. 36.5%; p = 0.002). After implementation of the Intelligent Sepsis Management System, overall compliance with the Surviving Sepsis Campaign guidelines improved and was associated with reduced 30-day mortality. However, we could not verify the causal effect of this system on 30-day mortality. Full article

(This article belongs to the Special Issue Sepsis: Immunopathology, Patient Classification and Clinical Management)

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18 pages, 2562 KiB

Open AccessArticle

TSLP Exacerbates Septic Inflammation via Murine Double Minute 2 (MDM2) Signaling Pathway

by Na-Ra Han, Phil-Dong Moon, Hyung-Min Kim and Hyun-Ja Jeong

J. Clin. Med. 2019, 8(9), 1350; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8091350 - 01 Sep 2019

Cited by 19 | Viewed by 3458

Abstract

Thymic stromal lymphopoietin (TSLP) is crucial for Th2-mediated inflammation. Sepsis is a serious systemic inflammatory reaction with organ dysfunction by infection. However, the function of TSLP during sepsis is poorly understood. Thus, we investigated a role and regulatory mechanism of TSLP during sepsis. Sepsis was induced by lipopolysaccharides (LPS) or Escherichia coli DH5α injection in mice. TSLP levels were measured in human subjects, mice, and macrophages. TSLP deficiency or murine double minute 2 (MDM2) deficiency was induced using siRNA or an MDM2 inhibitor, nutlin-3a. We found that TSLP levels were elevated in serum of patients and mice with sepsis. TSLP deficiency lowered liver damage and inflammatory cytokine levels in mice with sepsis. TSLP was produced by the MDM2/NF-κB signaling pathway in LPS-stimulated macrophages. TSLP downregulation by an MDM2 inhibitor, nutlin-3a, alleviated clinical symptoms and septic inflammatory responses. Pharmacological inhibition of TSLP level by cisplatin reduced the septic inflammatory responses. Altogether, the present results show that TSLP exacerbates septic inflammation via the MDM2 signaling pathway, suggesting that TSLP may be a potential target for the treatment of sepsis. Full article

(This article belongs to the Special Issue Sepsis: Immunopathology, Patient Classification and Clinical Management)

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Graphical abstract

11 pages, 635 KiB

Open AccessArticle

Real World Patterns of Antimicrobial Use and Microbiology Investigations in Patients with Sepsis outside the Critical Care Unit: Secondary Analysis of Three Nation-Wide Point Prevalence Studies

by Maja Kopczynska, Ben Sharif, Harry Unwin, John Lynch, Andrew Forrester, Claudia Zeicu, Sian Cleaver, Svetlana Kulikouskaya, Tom Chandy, Eshen Ang, Emily Murphy, Umair Asim, Bethany Payne, Jessica Nicholas, Alessia Waller, Aimee Owen, Zhao Xuan Tan, Robert Ross, Jack Wellington, Yahya Amjad, Vidhi Unadkat, Faris Hussain, Jessica Smith, Sashiananthan Ganesananthan, Harriet Penney, Joy Inns, Carys Gilbert, Nicholas Doyle, Amit Kurani, Thomas Grother, Paul McNulty, Angelica Sharma and Tamas Szakmany Show full author list Hide full author list

J. Clin. Med. 2019, 8(9), 1337; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8091337 - 29 Aug 2019

Cited by 9 | Viewed by 5862

Abstract

Recent description of the microbiology of sepsis on the wards or information on the real-life antibiotic choices used in sepsis is lacking. There is growing concern of the indiscriminate use of antibiotics and omission of microbiological investigations in the management of septic patients. We performed a secondary analysis of three annual 24-h point-prevalence studies on the general wards across all Welsh acute hospitals in years 2016–2018. Data were collected on patient demographics, as well as radiological, laboratory and microbiological data within 48-h of the study. We screened 19,453 patients over the three 24 h study periods and recruited 1252 patients who fulfilled the entry criteria. 775 (64.9%) patients were treated with intravenous antibiotics. Only in 33.65% (421/1252) of all recruited patients did healthcare providers obtain blood cultures; in 25.64% (321/1252) urine cultures; in 8.63% (108/1252) sputum cultures; in 6.79% (85/1252) wound cultures; in 15.25% (191/1252) other cultures. Out of the recruited patients, 59.1% (740/1252) fulfilled SEPSIS-3 criteria. Patients with SEPSIS-3 criteria were significantly more likely to receive antibiotics than the non-septic cohort (p < 0.0001). In a multivariable regression analysis increase in SOFA score, increased number of SIRS criteria and the use of the official sepsis screening tool were associated with antibiotic administration, however obtaining microbiology cultures was not. Our study shows that antibiotics prescription practice is not accompanied by microbiological investigations. A significant proportion of sepsis patients are still at risk of not receiving appropriate antibiotics treatment and microbiological investigations; this may be improved by a more thorough implementation of sepsis screening tools. Full article

(This article belongs to the Special Issue Sepsis: Immunopathology, Patient Classification and Clinical Management)

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13 pages, 2972 KiB

Open AccessArticle

Overexpression of IL-10 Enhances the Efficacy of Human Umbilical-Cord-Derived Mesenchymal Stromal Cells in E. coli Pneumosepsis

by Mirjana Jerkic, Claire Masterson, Lindsay Ormesher, Stéphane Gagnon, Sakshi Goyal, Razieh Rabani, Gail Otulakowski, Haibo Zhang, Brian P. Kavanagh and John G. Laffey

J. Clin. Med. 2019, 8(6), 847; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8060847 - 13 Jun 2019

Cited by 35 | Viewed by 3375

Abstract

Enhancing the immunomodulatory effects of mesenchymal stromal cells (MSCs) may increase their effects in sepsis. We tested the potential for overexpression of Interleukin-10 (IL-10) in human umbilical cord (UC) MSCs to increase MSC efficacy in Escherichia coli (E. coli) pneumosepsis and to enhance human macrophage function. Pneumonia was induced in rats by intratracheal instillation of E. coli ((2.0–3.0) × 10⁹ Colony forming units (CFU)/kg). One hour later, animals were randomized to receive (a) vehicle; (b) naïve UC-MSCs; or (c) IL-10 overexpressing UC-MSCs (1 × 10⁷ cells/kg). Lung injury severity, cellular infiltration, and E. coli colony counts were assessed after 48 h. The effects and mechanisms of action of IL-10 UC-MSCs on macrophage function in septic rodents and in humans were subsequently assessed. Survival increased with IL-10 (9/11 (82%)) and naïve (11/12 (91%)) UC-MSCs compared to vehicle (9/15 (60%, p = 0.03). IL-10 UC-MSCs—but not naïve UC-MSCs—significantly decreased the alveolar arterial gradient (455 ± 93 and 520 ± 81, mmHg, respectively) compared to that of vehicle animals (544 ± 52, p = 0.02). Lung tissue bacterial counts were significantly increased in vehicle- and naïve-UC-MSC-treated animals but were not different from sham animals in those treated with IL-10 overexpressing UC-MSCs. IL-10 (but not naïve) UC-MSCs decreased alveolar neutrophils and increased alveolar macrophage percentages compared to vehicle. IL-10 UC-MSCs decreased structural lung injury compared to naïve UC-MSC or vehicle therapy. Alveolar macrophages from IL-10-UC-MSC-treated rats and from human volunteers demonstrated enhanced phagocytic capacity. This was mediated via increased macrophage hemeoxygenase-1, an effect blocked by prostaglandin E2 and lipoxygenase A4 blockade. IL-10 overexpression in UC-MSCs enhanced their effects in E. coli pneumosepsis and increased macrophage function. IL-10 UC-MSCs similarly enhanced human macrophage function, illustrating their therapeutic potential for infection-induced acute respiratory distress syndrome (ARDS). Full article

(This article belongs to the Special Issue Sepsis: Immunopathology, Patient Classification and Clinical Management)

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10 pages, 1243 KiB

Open AccessArticle

Impact of Lymphocyte and Neutrophil Counts on Mortality Risk in Severe Community-Acquired Pneumonia with or without Septic Shock

by Estel Güell, Marta Martín-Fernandez, Mari C. De la Torre, Elisabet Palomera, Mateu Serra, Rafael Martinez, Manel Solsona, Gloria Miró, Jordi Vallès, Samuel Fernández, Edgar Cortés, Vanessa Ferrer, Marc Morales, Juan C. Yébenes, Jordi Almirall and Jesús F. Bermejo-Martin

J. Clin. Med. 2019, 8(5), 754; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8050754 - 27 May 2019

Cited by 17 | Viewed by 3785

Abstract

Background: Community-acquired pneumonia (CAP) is a frequent cause of death worldwide. As recently described, CAP shows different biological endotypes. Improving characterization of these endotypes is needed to optimize individualized treatment of this disease. The potential value of the leukogram to assist prognosis in severe CAP has not been previously addressed. Methods: A cohort of 710 patients with CAP admitted to the intensive care units (ICUs) at Hospital of Mataró and Parc Taulí Hospital of Sabadell was retrospectively analyzed. Patients were split in those with septic shock (n = 304) and those with no septic shock (n = 406). A single blood sample was drawn from all the patients at the time of admission to the emergency room. ICU mortality was the main outcome. Results: Multivariate analysis demonstrated that lymphopenia <675 cells/mm³ or <501 cells/mm³ translated into 2.32- and 3.76-fold risk of mortality in patients with or without septic shock, respectively. In turn, neutrophil counts were associated with prognosis just in the group of patients with septic shock, where neutrophils <8850 cells/mm³ translated into 3.6-fold risk of mortality. Conclusion: lymphopenia is a preserved risk factor for mortality across the different clinical presentations of severe CAP (sCAP), while failing to expand circulating neutrophils counts beyond the upper limit of normality represents an incremental immunological failure observed just in those patients with the most severe form of CAP, septic shock. Full article

(This article belongs to the Special Issue Sepsis: Immunopathology, Patient Classification and Clinical Management)

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11 pages, 528 KiB

Open AccessArticle

Lack of an Association between the Functional Polymorphism TREM-1 rs2234237 and the Clinical Course of Sepsis among Critically Ill Caucasian Patients—A Monocentric Prospective Genetic Association Study

by Julius Runzheimer, Caspar Mewes, Benedikt Büttner, José Hinz, Aron-Frederik Popov, Michael Ghadimi, Katalin Kristof, Tim Beissbarth, Joel Schamroth, Mladen Tzvetkov, Bastian Schmack, Michael Quintel, Ingo Bergmann and Ashham Mansur

J. Clin. Med. 2019, 8(3), 301; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8030301 - 03 Mar 2019

Cited by 8 | Viewed by 3008

Abstract

Sepsis is a life-threatening condition and a significant challenge for those working in intensive care, where it remains one of the leading causes of mortality. According to the sepsis-3 definition, sepsis is characterized by dysregulation of the host response to infection. The TREM-1 gene codes for the triggering receptor expressed on myeloid cells 1, which is part of the pro-inflammatory response of the immune system. This study aimed to determine whether the functional TREM-1 rs2234237 single nucleotide polymorphism was associated with mortality in a cohort of 649 Caucasian patients with sepsis. The 90-day mortality rate was the primary outcome, and disease severity and microbiological findings were analyzed as secondary endpoints. TREM-1 rs2234237 TT homozygous patients were compared to A-allele carriers for this purpose. Kaplan–Meier survival analysis revealed no association between the clinically relevant TREM-1 rs2234237 single nucleotide polymorphism and the 90-day or 28-day survival rate in this group of septic patients. In addition, the performed analyses of disease severity and the microbiological findings did not show significant differences between the TREM-1 rs2234237 genotypes. The TREM-1 rs2234237 genotype was not significantly associated with sepsis mortality and sepsis disease severity. Therefore, it was not a valuable prognostic marker for the survival of septic patients in the studied cohort. Full article

(This article belongs to the Special Issue Sepsis: Immunopathology, Patient Classification and Clinical Management)

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Review

Jump to: Research

18 pages, 1681 KiB

Open AccessReview

A Physiologic Approach to Hemodynamic Monitoring and Optimizing Oxygen Delivery in Shock Resuscitation

by Amy Russell, Emanuel P. Rivers, Paresh C. Giri, Anja K. Jaehne and H. Bryant Nguyen

J. Clin. Med. 2020, 9(7), 2052; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9072052 - 30 Jun 2020

Cited by 13 | Viewed by 8302

Abstract

The approach to shock resuscitation focuses on all components of oxygen delivery, including preload, afterload, contractility, hemoglobin, and oxygen saturation. Resuscitation focused solely on preload and fluid responsiveness minimizes other key elements, resulting in suboptimal patient care. This review will provide a physiologic and practical approach for the optimization of oxygen delivery utilizing available hemodynamic monitoring technologies. Venous oxygen saturation (SvO₂) and lactate will be discussed as indicators of shock states and endpoints of resuscitation within the framework of resolving oxygen deficit and oxygen debt. Full article

(This article belongs to the Special Issue Sepsis: Immunopathology, Patient Classification and Clinical Management)

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9 pages, 961 KiB

Open AccessReview

A Systematic Summary of Systematic Reviews on Anticoagulant Therapy in Sepsis

by Shuhei Murao and Kazuma Yamakawa

J. Clin. Med. 2019, 8(11), 1869; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8111869 - 04 Nov 2019

Cited by 20 | Viewed by 3389

Abstract

Many systematic reviews have been published regarding anticoagulant therapy in sepsis, among which there is substantial heterogeneity. This study aimed to provide an overview of existing systematic reviews of randomized controlled trials by using a comprehensive search method. We searched MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews. Of 895 records screened, 19 systematic reviews were included. The target agent was as follows: antithrombin (n = 4), recombinant thrombomodulin (n = 3), heparin (n = 3), recombinant activated protein C (n = 8), and all anticoagulants (n = 1). Antithrombin did not improve mortality in critically ill patients but indicated a beneficial effect in sepsis-induced disseminated intravascular coagulation (DIC), although the certainty of evidence was judged as low. Recombinant thrombomodulin was associated with a trend in reduced mortality in sepsis with coagulopathy with no increased risk of bleeding, although the difference was not statistically significant and the required information size for any declarative judgement insufficient. Although three systematic reviews showed potential survival benefits of unfractionated heparin and low-molecular-weight heparin in patients with sepsis, trials with low risk of bias were lacking, and the overall impact remains unclear. None of the meta-analyses of recombinant activated protein C showed beneficial effects in sepsis. In summary, a beneficial effect was not observed in overall sepsis in poorly characterized patient groups but was observed in sepsis-induced DIC or sepsis with coagulopathy in more specific patient groups. This umbrella review of anticoagulant therapy suggests that characteristics of the target populations resulted in heterogeneity among the systematic reviews. Full article

(This article belongs to the Special Issue Sepsis: Immunopathology, Patient Classification and Clinical Management)

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10 pages, 265 KiB

Open AccessReview

Back to Basics: Recognition of Sepsis with New Definition

by Jan Horak, Vendula Martinkova, Jaroslav Radej and Martin Matejovič

J. Clin. Med. 2019, 8(11), 1838; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8111838 - 01 Nov 2019

Cited by 13 | Viewed by 4165

Abstract

Patients with serious infections at risk of deterioration represent highly challenging clinical situations, and in particular for junior doctors. A comprehensive clinical examination that integrates the assessment of vital signs, hemodynamics, and peripheral perfusion into clinical decision making is key to responding promptly and effectively to evolving acute medical illnesses, such as sepsis or septic shock. Against this background, the new concept of sepsis definition may provide a useful link between junior doctors and consultant decision making. The purpose of this article is to introduce the updated definition of sepsis and suggest its practical implications, with particular emphasis on integrative clinical assessment, allowing for the rapid identification of patients who are at risk of further deterioration. Full article

(This article belongs to the Special Issue Sepsis: Immunopathology, Patient Classification and Clinical Management)

16 pages, 1151 KiB

Open AccessReview

Advance in the Management of Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulation

by Toshiaki Iba, Jerrold H. Levy, Aditya Raj and Theodore E. Warkentin

J. Clin. Med. 2019, 8(5), 728; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8050728 - 22 May 2019

Cited by 117 | Viewed by 17266

Abstract

Coagulopathy commonly occurs in sepsis as a critical host response to infection that can progress to disseminated intravascular coagulation (DIC) with an increased mortality. Recent studies have further defined factors responsible for the thromboinflammatory response and intravascular thrombosis, including neutrophil extracellular traps, extracellular vesicles, damage-associated molecular patterns, and endothelial glycocalyx shedding. Diagnosing DIC facilitates sepsis management, and is associated with improved outcomes. Although the International Society on Thrombosis and Haemostasis (ISTH) has proposed criteria for diagnosing overt DIC, these criteria are not suitable for early detection. Accordingly, the ISTH DIC Scientific Standardization Committee has proposed a new category termed “sepsis-induced coagulopathy (SIC)” to facilitate earlier diagnosis of DIC and potentially more rapid interventions in these critically ill patients. Therapy of SIC includes both treatment of the underlying infection and correcting the coagulopathy, with most therapeutic approaches focusing on anticoagulant therapy. Recently, a phase III trial of recombinant thrombomodulin was performed in coagulopathic patients. Although the 28-day mortality was improved by 2.6% (absolute difference), it did not reach statistical significance. However, in patients who met entry criteria for SIC at baseline, the mortality difference was approximately 5% without increased risk of bleeding. In this review, we discuss current advances in managing SIC and DIC. Full article

(This article belongs to the Special Issue Sepsis: Immunopathology, Patient Classification and Clinical Management)

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