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Personalized Diagnosis and Treatment of Patients with Sepsis

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A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Mechanisms of Diseases".

Deadline for manuscript submissions: closed (10 August 2021) | Viewed by 37521

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Special Issue Editors

Dr. Miroslav Průcha

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Guest Editor

Department of Clinical Biochemistry, Hematology and Immunology, Na Homolce Hospital, Prague, Czech Republic
Interests: sepsis; autoimmune diseases; vasculitis; ormond disease; personalized therapy

Prof. Dr. Michael Bauer

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Guest Editor

Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1,07747 Jena, Germany
Interests: differential gene expression; transcriptomics, proteomics and metabolomics in sepsis and organ failure; redox-sensitive transcription factors and cellular stress responses

Dr. Roman Zahorec

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Guest Editor

Department of Anesthesiology and Intensive Medicine, St. Elizabeth Cancer Institute Hospital, Comenius University, Bratislava, Slovakia
Interests: sepsis

Special Issue Information

Dear Colleagues,

Diagnostics and therapy of sepsis still represent the "Holy Grail" of 21st century medicine. The aim of this Special Issue is to provide information on the current and potential use of personalized medicine in sepsis. Sepsis is a multifactorial clinical syndrome with an extremely dynamic clinical course, and is very diverse with respect to clinical phenotype. Early diagnosis is of crucial importance for the final clinical outcome. Previous studies have not identified a biomarker with sufficient sensitivity and specificity for the diagnosis of sepsis. Identification of the infectious agents or the use of molecular biology, next-gene sequencing has not brought significant benefits for patients in terms of early diagnosis. Therefore, we are currently searching for biomarkers, through “omics” technologies with sufficient diagnostic specificity and sensitivity, that are able to predict the clinical course of the disease, and patient response to therapy. Current progress in the use of systems biology technologies brings us hope that by using big data from clinical trials, such biomarkers will be found.

Dr. Miroslav Průcha
Prof. Dr.Michael Bauer
Dr. Roman Zahorec
Guest Editor

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Keywords

sepsis
clinical phenotypes
diagnostics
genomics
transcriptomics
proteinomics
metabolomics
pharmacogenomics
personalized therapy

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review

3 pages, 191 KiB

Open AccessEditorial

Sepsis as a Challenge for Personalized Medicine

by Roman Zahorec and Miroslav Průcha

J. Pers. Med. 2022, 12(12), 1989; https://doi.org/10.3390/jpm12121989 - 1 Dec 2022

Viewed by 1516

Abstract

Sepsis is a clinical syndrome of systemic inflammation induced by infection, now defined as life-threatening organ dysfunction caused by a dysregulated immune response to infection [...] Full article

(This article belongs to the Special Issue Personalized Diagnosis and Treatment of Patients with Sepsis)

Research

Jump to: Editorial, Review

14 pages, 1944 KiB

Open AccessArticle

Plasma Levels of Mid-Regional Proadrenomedullin Accurately Identify H1N1pdm09 Influenza Virus Patients with Risk of Intensive Care Admission and Mortality in the Emergency Department

by Blanca Valenzuela-Méndez, Francisco Valenzuela-Sánchez, Juan Francisco Rodríguez-Gutiérrez, Rafael Bohollo-de-Austria, Ángel Estella, Pilar Martínez-García, María Ángela González-García and Jordi Rello

J. Pers. Med. 2022, 12(1), 84; https://doi.org/10.3390/jpm12010084 - 10 Jan 2022

Cited by 10 | Viewed by 2012

Abstract

Early identification of severe viral pneumonia in influenza virus A (H1N1pdm09) patients is extremely important for prompt admission to the ICU. The objective is to evaluate the usefulness of MR-proadrenomedullin (MR-proADM) compared to C reactive protein (CRP), procalcitonin (PCT), and ferritin in the prognosis of influenza A pneumonia. This prospective, observational, multicenter study included one hundred thirteen patients with confirmed influenza virus A (H1N1pdm09) admitted to an Emergency Department and ICUs of six hospitals in Spain. Measurements and Main Results: one-hundred thirteen patients with confirmed influenza virus A (H1N1pdm09) were enrolled. Seventy-five subjects (mortality 29.3%) with severe pneumonia caused by influenza A H1N1pdm09 virus (H1N1vIPN) were compared with 38 controls (CG).The median MR-proADM levels at hospital admission were 1.2 nmol/L (IQR (0.8–2.6) vs. 0.5 nmol/L (IQR 0.2–0.9) in the CG (p = 0.01), and PCT levels were 0.43 μg/L (IQR 0.2–1.2) in the H1N1vIPN group and 0.1 μg/L (IQR 0.1–0.2) in the CG (p < 0.01). CRP levels at admission were 15.5 mg/dL(IQR 9.2–24.9) in H1N1vIPN and 8.6 mg/dL(IQR 3–17.3) in the CG (p < 0.01). Ferritin levels at admission were 558.1 ng/mL(IQR 180–1880) in H1N1vIPN and 167.7 ng/mL(IQR 34.8–292.9) in the CG (p < 0.01). A breakpoint for hospital admission of MR-proADM of 1.1 nmol/L showed a sensitivity of 55% and a specificity of 90% (AUC-ROC0.822). Non-survivors showed higher MR-proADM levels: median of 2.5 nmol/L vs. 0.9 nmol/L among survivors (p < 0.01). PCT, CRP, and ferritin levels also showed significant differences in predicting mortality. The MR-proADM AUC-ROC for mortality was 0.853 (p < 0.01). In a Cox proportional hazards model, MR-proADM levels > 1.2 nmol/L at hospital admission were significant predictive factors for ICU and 90-day mortality (HR: 1.3). Conclusions: the initial MR-proADM, ferritin, CRP, and PCT levels effectively determine adverse outcomes and risk of ICU admission and mortality in patients with influenza virus pneumonia. MR-proADM has the highest potency for survival prediction. Full article

(This article belongs to the Special Issue Personalized Diagnosis and Treatment of Patients with Sepsis)

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19 pages, 27523 KiB

Open AccessArticle

Simultaneous Inhibition of Three Major Cytokines and Its Therapeutic Effects: A Peptide-Based Novel Therapy against Endotoxemia in Mice

by Hung-Jen Shih, Chao-Yuan Chang, Milton Chiang, Van Long Le, Hao-Jen Hsu and Chun-Jen Huang

J. Pers. Med. 2021, 11(5), 436; https://doi.org/10.3390/jpm11050436 - 20 May 2021

Cited by 7 | Viewed by 4041

Abstract

Three major cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6, mediate endotoxemia-induced liver injury. With the similar structures to the binding domains of the three cytokines to their cognate receptors, the novel peptide KCF18 can simultaneously inhibit TNF-α, IL-1β, and IL-6. We elucidated whether KCF18 can alleviate injury of liver in endotoxemic mice. Adult male mice (BALB/cJ) were intraperitoneally (i.p.) administered lipopolysaccharide (LPS, 15 mg/kg; LPS group) or LPS with KCF18 (LKCF group). Mice in the LKCF group received KCF18 (i.p.) at 2 h (0.6 mg/kg), 4 h (0.3 mg/kg), 6 h (0.3 mg/kg), and 8 h (0.3mg/kg) after LPS administration. Mice were sacrificed after receiving LPS for 24 h. Our results indicated that the binding levels of the three cytokines to their cognate receptors in liver tissues in the LKCF group were significantly lower than those in the LPS group (all p < 0.05). The liver injury level, as measured by performing functional and histological analyses and by determining the tissue water content and vascular permeability (all p < 0.05), was significantly lower in the LKCF group than in the LPS group. Similarly, the levels of inflammation (macrophage activation, cytokine upregulation, and leukocyte infiltration), oxidation, necroptosis, pyroptosis, and apoptosis (all p < 0.05) in liver tissues in the LKCF group were significantly lower than those in the LPS group. In conclusion, the KCF18 peptide–based simultaneous inhibition of TNF-α, IL-1β, and IL-6 can alleviate liver injury in mice with endotoxemia. Full article

(This article belongs to the Special Issue Personalized Diagnosis and Treatment of Patients with Sepsis)

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15 pages, 1988 KiB

Open AccessArticle

Myristic Acid Serum Levels and Their Significance for Diagnosis of Systemic Inflammatory Response, Sepsis, and Bacteraemia

by Roman Zazula, Michal Moravec, František Pehal, Tomáš Nejtek, Marek Protuš and Martin Müller

J. Pers. Med. 2021, 11(4), 306; https://doi.org/10.3390/jpm11040306 - 16 Apr 2021

Cited by 12 | Viewed by 3426

Abstract

Myristic acid is identified as a metabolite with the highest diagnostic sensitivity and specificity in the metabolome of patients with bacteraemia. Its significant decrease has been observed in patients with septic shock not responding to treatment. Another study has reported a close correlation of myristic acid levels with the outcome of severe trauma patients. Myristic acid concentrations were investigated in a cohort of septic patients and patients with Systemic Inflammatory Response Syndrome (SIRS) in 5 consecutive days following diagnosis and compared to healthy controls. The study population groups—Sepsis 34, SIRS 31, and Healthy Control 120 patients were included. Serum samples were analyzed using gas chromatography and mass spectrometry. The myristic acid levels in the Sepsis Group and SIRS Group were found to be significantly higher when compared to healthy controls. The serum concentration of myristic acid in septic patients with bacteraemia was higher than in septic patients without bacteraemia. Most patients with sepsis and SIRS had the highest levels of myristic acid within 24 h after an established diagnosis. Myristic acid should be considered as a new candidate marker of severe inflammation and sepsis. A simplified analysis and sufficient body of validated data are necessary steps towards the introduction of this metabolite into routine clinical practice. Full article

(This article belongs to the Special Issue Personalized Diagnosis and Treatment of Patients with Sepsis)

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13 pages, 962 KiB

Open AccessArticle

SOFA Score, Hemodynamics and Body Temperature Allow Early Discrimination between Porcine Peritonitis-Induced Sepsis and Peritonitis-Induced Septic Shock

by Mahmoud Al-Obeidallah, Dagmar Jarkovská, Lenka Valešová, Jan Horák, Jan Jedlička, Lukáš Nalos, Jiří Chvojka, Jitka Švíglerová, Jitka Kuncová, Jan Beneš, Martin Matějovič and Milan Štengl

J. Pers. Med. 2021, 11(3), 164; https://doi.org/10.3390/jpm11030164 - 28 Feb 2021

Cited by 3 | Viewed by 2574

Abstract

Porcine model of peritonitis-induced sepsis is a well-established clinically relevant model of human disease. Interindividual variability of the response often complicates the interpretation of findings. To better understand the biological basis of the disease variability, the progression of the disease was compared between animals with sepsis and septic shock. Peritonitis was induced by inoculation of autologous feces in fifteen anesthetized, mechanically ventilated and surgically instrumented pigs and continued for 24 h. Cardiovascular and biochemical parameters were collected at baseline (just before peritonitis induction), 12 h, 18 h and 24 h (end of the experiment) after induction of peritonitis. Analysis of multiple parameters revealed the earliest significant differences between sepsis and septic shock groups in the sequential organ failure assessment (SOFA) score, systemic vascular resistance, partial pressure of oxygen in mixed venous blood and body temperature. Other significant functional differences developed later in the course of the disease. The data indicate that SOFA score, hemodynamical parameters and body temperature discriminate early between sepsis and septic shock in a clinically relevant porcine model. Early pronounced alterations of these parameters may herald a progression of the disease toward irreversible septic shock. Full article

(This article belongs to the Special Issue Personalized Diagnosis and Treatment of Patients with Sepsis)

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14 pages, 1477 KiB

Open AccessArticle

A 33-mRNA Classifier Is Able to Produce Inflammopathic, Adaptive, and Coagulopathic Endotypes with Prognostic Significance: The Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis (ORANGES) Trial

by Jose Iglesias, Andrew V. Vassallo, Oliver Liesenfeld, Jerrold S. Levine, Vishal V. Patel, Jesse B. Sullivan, Joseph B. Cavanaugh, Yasmine Elbaga and Timothy E. Sweeney

J. Pers. Med. 2021, 11(1), 9; https://doi.org/10.3390/jpm11010009 - 23 Dec 2020

Cited by 11 | Viewed by 3714

Abstract

Background: Retrospective analysis of the transcriptomic host response in sepsis has demonstrated that sepsis can be separated into three endotypes—inflammatory (IE), adaptive (AE), and coagulopathic (CE), which have demonstrated prognostic significance. We undertook a prospective transcriptomic host response analysis in a subgroup of patients enrolled in the Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis (ORANGES) trial. Methods: Blood was obtained from 51 patients and profiled using a pre-established 33-mRNA classifier to determine sepsis endotypes. Endotypes were compared to therapy subgroups and clinical outcomes. Results: We redemonstrated a statistically significant difference in mortality between IE, AE, and CE patients, with CE patients demonstrating the highest mortality (40%), and AE patients the lowest mortality (5%, p = 0.032). A higher CE score was a predictor of mortality; coronary artery disease (CAD) and elevated CE scores were associated with an increase in mortality (CAD: HR = 12.3, 95% CI 1.5–101; CE score: HR = 15.5 95% CI 1.15–211). Kaplan–Meier (KM) analysis of the entire cohort (n = 51) demonstrated a decrease survival in the CE group, p = 0.026. KM survival analysis of hydrocortisone, ascorbic acid, and thiamine (HAT) therapy and control patients not receiving steroids (n = 45) showed CE and IE was associated with a decrease in survival (p = 0.003); of interest, there was no difference in survival in CE patients after stratifying by HAT therapy (p = 0.18). These findings suggest a possible treatment effect of corticosteroids, HAT therapy, endotype, and outcome. Conclusion: This subset of patients from the ORANGES trial confirmed previous retrospective findings that a 33-mRNA classifier can group patients into IE, AE, and CE endotypes having prognostic significance. A novel finding of this study identifying an association between endotype and corticosteroid therapy warrants further study in support of future diagnostic use of the endotyping classifier. Full article

(This article belongs to the Special Issue Personalized Diagnosis and Treatment of Patients with Sepsis)

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9 pages, 1252 KiB

Open AccessArticle

Presepsin as a Potential Prognostic Marker for Sepsis According to Actual Practice Guidelines

by Alice Nicoleta Drăgoescu, Vlad Pădureanu, Andreea Doriana Stănculescu, Luminița Cristina Chiuțu, Dan Nicolae Florescu, Ioana Andreea Gheonea, Rodica Pădureanu, Alex Stepan, Costin Teodor Streba, Andrei Ioan Drocaș, Adriana Mihaela Ciocâlteu-Ionescu, Valeriu Marin Șurlin and Octavian Petru Drăgoescu

J. Pers. Med. 2021, 11(1), 2; https://doi.org/10.3390/jpm11010002 - 22 Dec 2020

Cited by 18 | Viewed by 3432

Abstract

The 2016 Surviving Sepsis Campaign guidelines define sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection. This study had the objective of assessing the efficacy of presepsin in the prognosis of sepsis. This was a single-center prospective study, performed in Craiova Emergency Hospital, that included 114 patients admitted in the Intensive Care Unit (ICU) department between 2018 and 2019 fulfilling the sepsis criteria. Including criteria were: age ≥ 18, sepsis diagnosed by the Sequential Organ Failure Assessment (SOFA) score of pulmonary, abdominal, urinary, surgical or unknown origin, as well as lactate levels ≥ 2 mmol/l and need of vasopressors for mean arterial pressure (MAP) ≥ 65 mmHg, despite adequate volume resuscitations for patients with septic shock. Patients younger than 18, pregnant, immunocompromised, or with terminal illnesses were excluded. Based on disease severity, patients were distributed into two study groups: sepsis—76 patients and septic shock—38 patients. As expected, SOFA score and most of its components (PaO₂/FiO₂, platelets, and Glasgow Coma Score (GCS)) were significantly modified for patients with septic shock compared to those in the sepsis group and for survivors versus non-survivors. Overall death rate was 34.2%, with a significantly higher value for patients with septic shock (55.3% vs. 23.7%, p = 0.035). Sepsis marker presepsin was significantly elevated in all patients (2047 ng/mL) and significantly increased for the septic shock patients (2538 ng/mL, p < 0.001) and non-survivors (3138 ng/mL, p < 0.001). A significant correlation was identified between the SOFA score and presepsin (r = 0.883, p < 0.001). The receiver operating characteristics (ROC)-Area Under Curve (AUC) analysis showed significant prognostic values for presepsin regarding both sepsis severity (AUC = 0.726, 95% confidence interval CI = 0.635–0.806) and mortality risk (AUC = 0.861, 95%CI = 0.784–0.919). In conclusion, under the revised definition of sepsis, presepsin could be a useful marker for prognosis of sepsis severity and mortality risk. Additional data are required to confirm the value of presepsin in sepsis prognosis. Full article

(This article belongs to the Special Issue Personalized Diagnosis and Treatment of Patients with Sepsis)

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20 pages, 1869 KiB

Open AccessArticle

A Multi-mRNA Host-Response Molecular Blood Test for the Diagnosis and Prognosis of Acute Infections and Sepsis: Proceedings from a Clinical Advisory Panel

by James Ducharme, Wesley H. Self, Tiffany M. Osborn, Nathan A. Ledeboer, Jonathan Romanowsky, Timothy E. Sweeney, Oliver Liesenfeld and Richard E. Rothman

J. Pers. Med. 2020, 10(4), 266; https://doi.org/10.3390/jpm10040266 - 7 Dec 2020

Cited by 32 | Viewed by 6463

Abstract

Current diagnostics are insufficient for diagnosis and prognosis of acute infections and sepsis. Clinical decisions including prescription and timing of antibiotics, ordering of additional diagnostics and level-of-care decisions rely on understanding etiology and implications of a clinical presentation. Host mRNA signatures can differentiate infectious from noninfectious etiologies, bacterial from viral infections, and predict 30-day mortality. The 29-host-mRNA blood-based InSep^TM test (Inflammatix, Burlingame, CA, formerly known as HostDx^TM Sepsis) combines machine learning algorithms with a rapid point-of-care platform with less than 30 min turnaround time to enable rapid diagnosis of acute infections and sepsis, as well as prediction of disease severity. A scientific advisory panel including emergency medicine, infectious disease, intensive care and clinical pathology physicians discussed technical and clinical requirements in preparation of successful introduction of InSep into the market. Topics included intended use; patient populations of greatest need; patient journey and sample flow in the emergency department (ED) and beyond; clinical and biomarker-based decision algorithms; performance characteristics for clinical utility; assay and instrument requirements; and result readouts. The panel identified clear demand for a solution like InSep, requirements regarding test performance and interpretability, and a need for focused medical education due to the innovative but complex nature of the result readout. Innovative diagnostic solutions such as the InSep test could improve management of patients with suspected acute infections and sepsis in the ED, thereby lessening the overall burden of these conditions on patients and the healthcare system. Full article

(This article belongs to the Special Issue Personalized Diagnosis and Treatment of Patients with Sepsis)

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Review

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Open AccessReview

Individualized Hemodynamic Management in Sepsis

by Marcell Virág, Tamas Leiner, Mate Rottler, Klementina Ocskay and Zsolt Molnar

J. Pers. Med. 2021, 11(2), 157; https://doi.org/10.3390/jpm11020157 - 23 Feb 2021

Cited by 18 | Viewed by 8444

Abstract

Hemodynamic optimization remains the cornerstone of resuscitation in the treatment of sepsis and septic shock. Delay or inadequate management will inevitably lead to hypoperfusion, tissue hypoxia or edema, and fluid overload, leading eventually to multiple organ failure, seriously affecting outcomes. According to a large international survey (FENICE study), physicians frequently use inadequate indices to guide fluid management in intensive care units. Goal-directed and “restrictive” infusion strategies have been recommended by guidelines over “liberal” approaches for several years. Unfortunately, these “fixed regimen” treatment protocols neglect the patient’s individual needs, and what is shown to be beneficial for a given population may not be so for the individual patient. However, applying multimodal, contextualized, and personalized management could potentially overcome this problem. The aim of this review was to give an insight into the pathophysiological rationale and clinical application of this relatively new approach in the hemodynamic management of septic patients. Full article

(This article belongs to the Special Issue Personalized Diagnosis and Treatment of Patients with Sepsis)

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