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Diagnosis and Management of Sepsis

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A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 38943

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Special Issue Editor

Dr. Daisuke Hasegawa

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Guest Editor

Department of Anesthesiology and Critical Care Medicine, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan
Interests: sepsis; precision medicine; sepsis-induced coagulopathy; blood purification

Special Issue Information

Dear Colleagues,

Sepsis, a dysregulated immune response, leads to multiple organ dysfunction and has high mortality rates despite recent therapeutic advancements. Accurate diagnosis and risk stratification are important for effective sepsis treatment. However, no decisive diagnostic or prognostic biomarkers are currently available. Moreover, much attention has recently been focused on the classification of sepsis for personalized treatment options, since sepsis is a syndrome with a heterogeneous disease state. Although most clinical trials on therapeutic interventions for sepsis have revealed inconclusive results, it is possible that specific therapeutic interventions can be effective for a specific population with similar phenotypes. However, there are still a lot of hurdles to overcome to make precision medicine available in this field. This Special Issue aims at gathering a collection of cutting-edge research from a basic, translational, and clinical viewpoint that helps to improve the quality of sepsis diagnosis and management. We welcome submissions on, but not limited to, the following topics:

Diagnostic or prognostic biomarkers (focusing on early detection is preferred);
Diagnostic or prognostic scoring (focusing on early detection is preferred);
Pathophysiology of organ dysfunction;
Sepsis-induced coagulopathy;
Disseminated intravascular coagulation;
Septic acute kidney injury;
Septic cardiomyopathy;
Acute respiratory distress syndrome;
Precision medicine;
Predictors of treatment responses;
Novel therapeutic intervention;
Blood purification;
Anticoagulation.

Dr. Daisuke Hasegawa
Guest Editor

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. Diagnostics 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

Diagnostic biomarkers
Prognostic biomarkers
Diagnostic scoring
Prognostic scoring
Multiple organ dysfunction
Sepsis-induced coagulopathy
Disseminated intravascular coagulation
Acute kidney injury
Septic cardiomyopathy
Acute respiratory distress syndrome
Precision medicine
Predictors of treatment responses
Novel therapeutic intervention
Blood purification
Anticoagulation

Published Papers (11 papers)

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Research

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14 pages, 2054 KiB

Open AccessArticle

Prognostic Impact of Parameters of Metabolic Acidosis in Critically Ill Children with Acute Kidney Injury: A Retrospective Observational Analysis Using the PIC Database

by Hikaru Morooka, Daisuke Kasugai, Akihito Tanaka, Masayuki Ozaki, Atsushi Numaguchi and Shoichi Maruyama

Diagnostics 2020, 10(11), 937; https://doi.org/10.3390/diagnostics10110937 - 11 Nov 2020

Cited by 9 | Viewed by 2984

Abstract

Acute kidney injury (AKI) is a major complication of sepsis that induces acid-base imbalances. While creatinine levels are the only indicator for assessing the prognosis of AKI, prognostic importance of metabolic acidosis is unknown. We conducted a retrospective observational study by analyzing a large China-based pediatric critical care database from 2010 to 2018. Participants were critically ill children with AKI admitted to intensive care units (ICUs). The study included 1505 children admitted to ICUs with AKI, including 827 males and 678 females. The median age at ICU admission was 22 months (interquartile range 7–65). After a median follow-up of 10.87 days, 4.3% (65 patients) died. After adjusting for confounding factors, hyperlactatemia, low pH, and low bicarbonate levels were independently associated with 28-day mortality (respective odds ratio: 3.06, 2.77, 2.09; p values: <0.01, <0.01, <0.01). The infection had no interaction with the three parameters. The AKI stage negatively interacted with bicarbonate and pH but not lactate. The current study shows that among children with AKI, hyperlactatemia, low pH, and hypobicarbonatemia are associated with 28-day mortality. Full article

(This article belongs to the Special Issue Diagnosis and Management of Sepsis)

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12 pages, 783 KiB

Open AccessArticle

Diagnostic Accuracy of Biomarkers for Early-Onset Neonatal Bacterial Infections: Evaluation of Serum Procalcitonin Reference Curves

by Hidetoshi Go, Nobuhiko Nagano, Daichi Katayama, Takuya Akimoto, Takayuki Imaizumi, Ryoji Aoki, Midori Hijikata, Ayako Seimiya, Ryota Kato, Aya Okahashi and Ichiro Morioka

Diagnostics 2020, 10(10), 839; https://doi.org/10.3390/diagnostics10100839 - 18 Oct 2020

Cited by 7 | Viewed by 2314 | Correction

Abstract

To date, no clinical studies have compared the accuracy of serum procalcitonin (PCT) reference curves. We aimed to validate the diagnostic accuracy of previously reported serum PCT reference curves and to determine which biomarkers among a cut-off value over the 95th percentile in the serum PCT reference curve, white blood cell (WBC) count, and C-reactive protein (CRP) and immunoglobulin M (IgM) levels, have the highest diagnostic accuracy for early-onset neonatal bacterial infections. This retrospective cohort study assessed 16 preterm and 23 term infants with suspected bacterial infections within 72 h after birth. Each infant group was divided into two subgroups: confirmed- and non-infection. The diagnostic accuracy was determined using the Youden index. The reference curves by Fukuzumi et al. in preterm and term infants had the highest Youden indexes: 1.000 and 0.324, respectively. Among preterm infants, the Youden index for PCT was 1.000. Among term infants, the Youden index for a combination of PCT, CRP, and WBC and/or IgM was 1.000. In conclusion, a serum PCT level over the 95th percentile on the reference curve for preterm infants and a combination of PCT and CRP levels with WBC count and/or IgM levels for term infants provided sufficient diagnostic accuracy. Full article

(This article belongs to the Special Issue Diagnosis and Management of Sepsis)

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7 pages, 201 KiB

Open AccessArticle

Impact of Blood Type O on Mortality of Sepsis Patients: A Multicenter Retrospective Observational Study

by Daisuke Hasegawa, Kazuki Nishida, Takahiro Kawaji, Yoshitaka Hara, Yasuyo Shimomura, Kazuhiro Moriyama, Daisuke Niimi, Naohide Kuriyama, Ayumi Shintani, Hidefumi Komura and Osamu Nishida

Diagnostics 2020, 10(10), 826; https://doi.org/10.3390/diagnostics10100826 - 15 Oct 2020

Cited by 8 | Viewed by 1705

Abstract

ABO blood groups have been implicated as potential risk factors for various diseases. However, no study has investigated the association between sepsis mortality and ABO blood types. We aimed to evaluate the impact of these blood types on mortality in patients with sepsis and septic shock. This retrospective observational study was conducted at two general hospitals in Japan. Patients diagnosed with sepsis or septic shock were included and divided into four groups based on blood type (O, A, B, and AB). The association between type O vs. other types and 28- and 90-day mortalities was evaluated using multivariate logistic regression analysis adjusted for age, sex, and Sequential (Sepsis-related) Organ Failure Assessment score. This study included 415 patients, of whom 131 (31.6%), 171 (41.2%), 81 (19.5%), and 32 (7.7%) had type O, A, B, and AB, respectively. Blood type O was not associated with 28-day (odds ratio: 1.7 p = 0.08) or 90-day mortality (odds ratio: 1.53, p = 0.091). However, type O was significantly associated with higher 90-day mortality (odds ratio: 3.26, p = 0.009) in patients with septic shock. The role of ABO blood type in risk stratification for septic shock and the mechanisms that potentially affect the prognosis of sepsis patients need further investigation. Full article

(This article belongs to the Special Issue Diagnosis and Management of Sepsis)

14 pages, 8356 KiB

Open AccessArticle

Sepsis Diagnostics: Intensive Care Scoring Systems Superior to MicroRNA Biomarker Testing

by Fabian Link, Knut Krohn, Anna-Maria Burgdorff, Annett Christel and Julia Schumann

Diagnostics 2020, 10(9), 701; https://doi.org/10.3390/diagnostics10090701 - 16 Sep 2020

Cited by 3 | Viewed by 2170

Abstract

Sepsis represents a serious medical problem accounting for numerous deaths of critically ill patients in intensive care units (ICUs). An early, sensitive, and specific diagnosis is considered a key element for improving the outcome of sepsis patients. In addition to classical laboratory markers, ICU scoring systems and serum miRNAs are discussed as potential sepsis biomarkers. In the present prospective observational study, the suitability of miRNAs in sepsis diagnosis was tested based on proper validated and normalized data (i.e., absolute quantification by means of Droplet Digital PCR (ddPCR)) in direct comparison to classical sepsis markers and ICU scores within the same patient cohort. Therefore, blood samples of septic intensive care patients (n = 12) taken at day of admission at ICU were compared to non-septic intensive care patients (n = 12) and a healthy control group (n = 12). Our analysis indicates that all tested biomarkers have only a moderate informative power and do not allow an unequivocal differentiation between septic and non-septic ICU patients. In conclusion, there is no standalone laboratory parameter that enables a reliable diagnosis of sepsis. miRNAs are not superior to classical parameters in this respect. It seems recommendable to measure multiple parameters and scores and to interpret them with regard to the clinical presentation. Full article

(This article belongs to the Special Issue Diagnosis and Management of Sepsis)

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9 pages, 236 KiB

Open AccessArticle

Haemogram-Derived Indices for Screening and Prognostication in Critically Ill Septic Shock Patients: A Case-Control Study

by Piotr S. Liberski, Michał Szewczyk and Łukasz J. Krzych

Diagnostics 2020, 10(9), 638; https://doi.org/10.3390/diagnostics10090638 - 27 Aug 2020

Cited by 10 | Viewed by 2256

Abstract

This study aimed (1) to assess the diagnostic accuracy of neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), monocyte-to-lymphocyte (MLR) and platelet count-to-mean platelet volume (PLT/MPV) ratios in predicting septic shock in patients on admission to the intensive care unit (ICU) and (2) to compare it with the role of C-reactive protein (CRP), procalcitonin (PCT) and lactate level. We also sought (3) to verify whether the indices could be useful in ICU mortality prediction and (4) to compare them with Acute Physiology and Chronic Health Evaluation II (APACHE II), Simplified Acute Physiology Score II (SAPS II) and Sequential Organ Failure Assessment (SOFA) scores. This retrospective study covered 138 patients, including 61 subjects with multi-organ failure due to septic shock (study group) and 77 sex- and age-matched controls. Septic patients had significantly higher NLR (p < 0.01) and NLR predicted septic shock occurrence (area under the ROC curve, AUROC = 0.66; 95% CI 0.58–0.74). PLR, MLR and PLT/MPV were impractical in sepsis prediction. Combination of CRP with NLR improved septic shock prediction (AUROC = 0.88; 95% CI 0.81–0.93). All indices failed to predict ICU mortality. APACHE II and SAPS II predicted mortality with AUROC = 0.68; 95% CI 0.54–0.78 and AUROC = 0.7; 95% CI 0.57–0.81, respectively. High NLR may be useful to identify patients with multi-organ failure due to septic shock but should be interpreted along with CRP or PCT. The investigated indices are not related with mortality in this specific clinical setting. Full article

(This article belongs to the Special Issue Diagnosis and Management of Sepsis)

8 pages, 462 KiB

Open AccessArticle

Platelet-Derived Microparticles Bearing PF4 and Anti-GAGS Immunoglobulins in Patients with Sepsis

by Maria Teresa Sartori, Chiara Zurlo, Maria Bon, Antonella Bertomoro, Raffaele Bendo, Irene Bertozzi, Claudia Maria Radu, Elena Campello, Paolo Simioni and Fabrizio Fabris

Diagnostics 2020, 10(9), 627; https://doi.org/10.3390/diagnostics10090627 - 24 Aug 2020

Cited by 13 | Viewed by 2450

Abstract

PF4 is a megakaryocyte-derived cationic chemokine that plays a part in innate immunity through its activity on the macrophages. In bacterial sepsis, PF4 binds to glycosaminoglycans (GAGs) on the surface of aerobic bacteria, giving rise to an antigenic complex that induces the early formation of anti-PF4 IgG-IgA-IgM. This triggers the immune response in patients receiving heparin therapy who develop heparin-induced thrombocytopenia (HIT). These antibodies have also been identified in patients with chronic Gram-negative infections. Given the complexity of this innate immune response network, our study on 45 patients with sepsis focused on the immune response mediated by platelet PF4. We analyzed the role of IgG-IgA-IgM against PF4-GAGs, and the presence of specific PF4-bearing platelet microparticles (PMPs). Anti-GAGs/PF4 IgG-IgA-IgM levels were significantly higher in septic patients than in control groups (healthy controls or acute patients without sepsis, p < 0.001). PF4-bearing PMP levels were only significantly higher in septic patients (p < 0.001). The occurrence of IgG-IgA-IgM against PF4-GAGs and PF4+ PMPs correlated with an improvement in patients’ sepsis. In conclusion, we demonstrated that, in the course of bacterial sepsis, platelet activation leads to the formation of specific PF4-bearing PMPs. These specific microparticles bind to polyanionic sequences on the surface of aerobic bacteria, giving rise to an antigenic complex that induces the early formation of IgG-IgA-IgM against PF4-GAGs as an innate immune response to infection. Full article

(This article belongs to the Special Issue Diagnosis and Management of Sepsis)

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16 pages, 2251 KiB

Open AccessArticle

Low Myostatin Serum Levels Are Associated with Poor Outcome in Critically Ill Patients

by Theresa H. Wirtz, Sven H. Loosen, Lukas Buendgens, Berkan Kurt, Samira Abu Jhaisha, Philipp Hohlstein, Jonathan F. Brozat, Ralf Weiskirchen, Tom Luedde, Frank Tacke, Christian Trautwein, Christoph Roderburg and Alexander Koch

Diagnostics 2020, 10(8), 574; https://doi.org/10.3390/diagnostics10080574 - 08 Aug 2020

Cited by 9 | Viewed by 2512

Abstract

Background: Growth differentiation factor 8, GDF-8 (Myostatin), is a protein released by myocytes inhibiting muscle growth and differentiation. Serum concentrations of Myostatin can predict poor survival in different chronic diseases, but its role in critical illness and sepsis is obscure. Our aim was to investigate Myostatin levels as a potential prognostic biomarker in critically ill patients with sepsis. Methods: We therefore measured Myostatin serum concentrations in 165 critically ill patients (106 with sepsis, 59 without sepsis) upon admission to the medical intensive care unit (ICU), in comparison to 14 healthy controls. Results: Myostatin levels were significantly decreased in ICU patients compared to controls but did not differ in patients with or without sepsis. However, Myostatin concentrations were significantly lower in patients requiring mechanical ventilation and indicated a trend towards dependency of intravenous vasopressors. Interestingly, we observed a negative correlation between Myostatin levels and markers of systemic inflammation. Strikingly, overall survival (OS) was significantly impaired in patients with low Myostatin levels in all critically ill patients. Low Myostatin levels at baseline turned out as an independent prognostic marker for OS in multivariate Cox-regression analysis (HR: 0.433, 95% CI: 0.211–0.889, p = 0.023). Conclusions: In summary, serum Myostatin concentrations are significantly decreased in critically ill patients and associated with disease severity. Low Myostatin levels also identify a subgroup of ICU patients that are more likely to face an unfavorable clinical outcome in terms of OS. Full article

(This article belongs to the Special Issue Diagnosis and Management of Sepsis)

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9 pages, 1002 KiB

Open AccessArticle

Different Biomarker Kinetics in Critically Ill Patients with High Lactate Levels

by Ryo Matsuura, Yohei Komaru, Yoshihisa Miyamoto, Teruhiko Yoshida, Kohei Yoshimoto, Yoshifumi Hamasaki, Masaomi Nangaku and Kent Doi

Diagnostics 2020, 10(7), 454; https://doi.org/10.3390/diagnostics10070454 - 04 Jul 2020

Cited by 2 | Viewed by 2627

Abstract

We evaluated the association of the kinetics of interleukin-6 (IL-6), neutrophil gelatinase-associated lipocalin (NGAL), and high-mobility group box 1 (HMGB1) with intensive care unit (ICU) mortality in critically ill patients with hyperlactatemia. This proof-of-concept study was conducted with prospectively enrolled patients admitted to a medical/surgical ICU with hyperlactatemia (lactate levels >4 mmol/L). Blood lactate, IL-6, NGAL, and HMGB1 were measured every 2 h until 6 h post ICU admission. The primary outcome was ICU mortality. Of thirty patients in this study, 14 patients (47%) had sepsis, and the ICU mortality was 47%. IL-6 and NGAL levels were significantly higher in septic patients than in non-septic patients. On kinetic analysis, the lactate levels were significantly decreased in survivors, and the NGAL levels were significantly increased in non-survivors. Among septic patients, a decline in IL-6 levels were observed in survivors. The HMGB1 levels were unchanged in survivors and non-survivors regardless of sepsis complication. Non-septic patients with higher reduction rate of lactate and HMGB1 had the lowest mortality than the others. ICU patients exhibited different kinetic patterns in lactate, NGAL, and IL-6, but HMGB1 did not seem to change over the 6-h duration. Further studies are necessary to evaluate the efficacy of the combination of the inflammatory biomarkers with lactate. Full article

(This article belongs to the Special Issue Diagnosis and Management of Sepsis)

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Review

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18 pages, 1483 KiB

Open AccessReview

Diagnosis and Management of Acute Respiratory Distress Syndrome in a Time of COVID-19

by Shayan Kassirian, Ravi Taneja and Sanjay Mehta

Diagnostics 2020, 10(12), 1053; https://doi.org/10.3390/diagnostics10121053 - 06 Dec 2020

Cited by 13 | Viewed by 14877

Abstract

Acute respiratory distress syndrome (ARDS) remains a serious illness with significant morbidity and mortality, characterized by hypoxemic respiratory failure most commonly due to pneumonia, sepsis, and aspiration. Early and accurate diagnosis of ARDS depends upon clinical suspicion and chest imaging. Coronavirus disease 2019 (COVID-19) is an important novel cause of ARDS with a distinct time course, imaging and laboratory features from the time of SARS-CoV-2 infection to hypoxemic respiratory failure, which may allow diagnosis and management prior to or at earlier stages of ARDS. Treatment of ARDS remains largely supportive, and consists of incremental respiratory support (high flow nasal oxygen, non-invasive respiratory support, and invasive mechanical ventilation), and avoidance of iatrogenic complications, all of which improve clinical outcomes. COVID-19-associated ARDS is largely similar to other causes of ARDS with respect to pathology and respiratory physiology, and as such, COVID-19 patients with hypoxemic respiratory failure should typically be managed as other patients with ARDS. Non-invasive respiratory support may be beneficial in avoiding intubation in COVID-19 respiratory failure including mild ARDS, especially under conditions of resource constraints or to avoid overwhelming critical care resources. Compared to other causes of ARDS, medical therapies may improve outcomes in COVID-19-associated ARDS, such as dexamethasone and remdesivir. Future improved clinical outcomes in ARDS of all causes depends upon individual patient physiological and biological endotyping in order to improve accuracy and timeliness of diagnosis as well as optimal targeting of future therapies in the right patient at the right time in their disease. Full article

(This article belongs to the Special Issue Diagnosis and Management of Sepsis)

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14 pages, 1416 KiB

Open AccessReview

The Role of Innate Lymphoid Cells in the Regulation of Immune Homeostasis in Sepsis-Mediated Lung Inflammation

by Yuichi Akama, Naoko Satoh-Takayama, Eiji Kawamoto, Atsushi Ito, Arong Gaowa, Eun Jeong Park, Hiroshi Imai and Motomu Shimaoka

Diagnostics 2020, 10(10), 808; https://doi.org/10.3390/diagnostics10100808 - 12 Oct 2020

Cited by 8 | Viewed by 3308

Abstract

Septic shock/severe sepsis is a deregulated host immune system response to infection that leads to life-threatening organ dysfunction. Lung inflammation as a form of acute lung injury (ALI) is often induced in septic shock. Whereas macrophages and neutrophils have been implicated as the principal immune cells regulating lung inflammation, group two innate lymphoid cells (ILC2s) have recently been identified as a new player regulating immune homeostasis. ILC2 is one of the three major ILC subsets (ILC1s, ILC2s, and ILC3s) comprised of newly identified innate immune cells. These cells are characterized by their ability to rapidly produce type 2 cytokines. ILC2s are predominant resident ILCs and, thereby, have the ability to respond to signals from damaged tissues. ILC2s regulate the immune response, and ILC2-derived type 2 cytokines may exert protective roles against sepsis-induced lung injury. This focused review not only provides readers with new insights into the signaling mechanisms by which ILC2s modulate sepsis-induced lung inflammation, but also proposes ILC2 as a novel therapeutic target for sepsis-induced ALI. Full article

(This article belongs to the Special Issue Diagnosis and Management of Sepsis)

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