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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 2022) | Viewed by 43196

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Prof. Dr. Marcello Ciaccio

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Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, 90127 Palermo, Italy
Interests: biomarkers; molecular genetics; sepsis; neurodegenerative diseases; cardiovascular diseases; diabetes; laboratory medicine
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Special Issue Information

Dear Colleagues,

Sepsis is a highly complex disease caused by a deregulated host response to infection. It has been recently recognised as a global health priority by the World Health Organization due to its high mortality and morbidity. The rapid detection of sepsis is crucial in order to prevent adverse outcomes and reduce mortality by promptly starting the treatment. Indeed, it has been estimated that each hour of treatment delay is associated with a 7–10% increase in sepsis-related mortality. However, the early diagnosis of sepsis remains challenging because it is characterised by no specific signs and symptoms. Thus, many efforts have been made to identify reliable biomarkers for screening patients at high risk of sepsis. Additionally, sepsis biomarkers could provide information on prognosis and guide and monitor therapy. Thus, sepsis biomarkers represent a precious tool for clinical decision-making and for improving patient management.

This Special Issue will address the current advances in biomarkers in sepsis.

Prof. Dr. Marcello Ciaccio
Guest Editor

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Keywords

biomarkers
sepsis
diagnosis
prognosis
therapy

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review, Other

3 pages, 170 KiB

Open AccessEditorial

Biomarkers of Sepsis

by Luisa Agnello and Marcello Ciaccio

Diagnostics 2023, 13(3), 435; https://doi.org/10.3390/diagnostics13030435 - 25 Jan 2023

Cited by 5 | Viewed by 1978

Abstract

Sepsis is a highly complex disease caused by a deregulated host’s response to infection [...] Full article

(This article belongs to the Special Issue Biomarkers of Sepsis)

Research

Jump to: Editorial, Review, Other

12 pages, 1125 KiB

Open AccessArticle

Clusterin Plasma Concentrations Are Decreased in Sepsis and Inversely Correlated with Established Markers of Inflammation

by Eray Yagmur, Samira Abu Jhaisha, Lukas Buendgens, Nadezhda Sapundzhieva, Jonathan F. Brozat, Philipp Hohlstein, Maike R. Pollmanns, Ger H. Koek, Ralf Weiskirchen, Christian Trautwein, Frank Tacke, Theresa H. Wirtz and Alexander Koch

Diagnostics 2022, 12(12), 3010; https://doi.org/10.3390/diagnostics12123010 - 1 Dec 2022

Cited by 7 | Viewed by 1694

Abstract

Clusterin is a multifunctional protein that is recognized to mediate cellular stress response associated with organ failure, systemic inflammation, and metabolic alterations. The aim of this study was to determine the value of clusterin as a clinical biomarker in critical ill patients with or without sepsis. We analyzed clusterin plasma concentrations in 200 critically ill patients (133 with sepsis, 67 without sepsis) on admission to the medical intensive care unit (ICU). The results were compared with 66 healthy controls. Clusterin plasma concentration was significantly elevated in critically ill patients compared to healthy subjects. Clusterin levels were significantly higher in non-septic ICU patients than in patients with sepsis. Clusterin correlated inversely with routinely used biomarkers of inflammatory response. Furthermore, clusterin levels were higher in ICU patients with pre-existing obesity and type 2 diabetes. Clusterin was not associated with disease severity, organ failure, or mortality in the ICU. This study highlights significantly elevated clusterin levels in critically ill patients, predominantly in non-sepsis conditions, and associates circulating clusterin to inflammatory and metabolic dysfunctions. Full article

(This article belongs to the Special Issue Biomarkers of Sepsis)

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11 pages, 1098 KiB

Open AccessArticle

Weaning Failure in Critically Ill Patients Is Related to the Persistence of Sepsis Inflammation

by Anna Kyriakoudi, Nikoletta Rovina, Ourania Koltsida, Eirini Kostakou, Elissavet Konstantelou, Matina Kardara, Maria Kompoti, Anastasios Palamidas, Georgios Kaltsakas and Antonia Koutsoukou

Diagnostics 2022, 12(1), 92; https://doi.org/10.3390/diagnostics12010092 - 31 Dec 2021

Cited by 6 | Viewed by 2192

Abstract

Introduction: Septic patients undergoing mechanical ventilation (MV) often experience difficulty in weaning. Th aim of this study was to determine whether inflammatory biomarkers of sepsis could be indicative of the failure or success of spontaneous breathing trial (SBT) in these patients. Methods: Sixty-five patients on MV (42 septic and 23 intubated for other reasons) fulfilling the criteria for SBT were included in the study. Blood samples were collected right before, at the end of (30 min) and 24 h after the SBT. Serum inflammatory mediators associated with sepsis (IL-18, IL-18BP, TNF) were determined and correlated with the outcome of SBT. Results: A successful SBT was achieved in 45 patients (69.2%). Septic patients had a higher percentage of SBT failure as compared to non-septic patients (85% vs. 15%, p = 0.026), with an odds ratio for failing 4.5 times (OR = 4.5 95%CI: 1.16–17.68, p 0.022). IL-18 levels and the relative mRNA expression in serum were significantly higher in septic as compared to non-septic patients (p < 0.05). Sepsis was independently associated with higher serum IL-18 and TNF levels in two time-point GEE models (53–723, p = 0.023 and 0.3–64, p = 0.048, respectively). IL-18BP displayed independent negative association with rapid shallow breathing index (RSBI) (95% CI: −17.6 to −4, p = 0.002). Conclusion: Sustained increased levels of IL-18 and IL-18BP, acknowledged markers of sepsis, were found to be indicative of SBT failure in patients recovering from sepsis. Our results show that, although subclinical, remaining septic inflammation that sustaines for a long time complicates the weaning procedure. Biomarkers for the estimation of the septic burden and the right time for weaning are needed. Full article

(This article belongs to the Special Issue Biomarkers of Sepsis)

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14 pages, 2626 KiB

Open AccessArticle

Pentraxin-3 Is a Strong Biomarker of Sepsis Severity Identification and Predictor of 90-Day Mortality in Intensive Care Units via Sepsis 3.0 Definitions

by Huan Chen, Tao Li, Shanshan Yan, Meidong Liu, Ke Liu, Huali Zhang, Min Gao and Xianzhong Xiao

Diagnostics 2021, 11(10), 1906; https://doi.org/10.3390/diagnostics11101906 - 15 Oct 2021

Cited by 12 | Viewed by 2252

Abstract

Background: Sepsis is the leading cause of mortality in intensive care units (ICUs). However, early diagnosis and prognosis of sepsis and septic shock are still a great challenge. Pentraxin-3 (PTX3) was shown to be associated with the severity and outcome of sepsis and septic shock. This study was carried out to investigate the diagnostic and prognostic value of PTX3 in patients with sepsis and septic shock based on Sepsis 3.0 definitions. Methods: In this single-center prospective observational study, all patients’ serum was collected for biomarker measurements within 24 h after admission. Logistic and Cox regression analyses were used to identify the potential biomarkers of diagnosis, severity stratification, and prediction. Results: Serum levels of PTX3 were significantly increased on the first day of ICU admission, while septic shock patients had highest PTX3 levels than other groups. A combination between PTX3 and procalcitonin (PCT) could better discriminate sepsis and septic shock, and PTX3 was an independent predictor of mortality in sepsis and septic shock patients. Conclusion: PTX3 may be a robust biomarker to classify the disease severity and predict the 90-day mortality of sepsis and septic shock based on the latest Sepsis 3.0 definitions. Full article

(This article belongs to the Special Issue Biomarkers of Sepsis)

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14 pages, 1201 KiB

Open AccessArticle

Application of Peak Glucose Range and Diabetes Status in Mortality Risk Stratification in Critically Ill Patients with Sepsis

by Kai-Yin Hung, Yi-Hsuan Tsai, Chiung-Yu Lin, Ya-Chun Chang, Yi-Hsi Wang, Meng-Chih Lin and Wen-Feng Fang

Diagnostics 2021, 11(10), 1798; https://doi.org/10.3390/diagnostics11101798 - 29 Sep 2021

Cited by 7 | Viewed by 2056

Abstract

The effects of diabetes and glucose on the outcomes of patients with sepsis are somewhat conflicting. This retrospective study enrolled 1214 consecutive patients with sepsis, including a subpopulation of 148 patients with immune profiles. The septic patients were stratified according to their Diabetes mellitus (DM) status or peak glucose level (three-group tool; P1: ≤140 mg/dL, P2: 141–220 mg/dL, P3: >220 mg/dL) on day 1. Although the DM group had a lower hazard ratio (HR) for 90-day mortality compared to non-DM patients, the adjusted HRs were insignificant. The modified sequential organ failure assessment-glucose (mSOFA-g) score can predict 90-day survival in patients with and without diabetes (β = 1.098, p < 0.001; β = 1.202, p < 0.001). The goodness of fit of the mSOFA-g score was 5% higher than the SOFA score of the subgroup without diabetes. The SOFA score and human leukocyte antigen-D-related (HLA-DR) expression were comparable between the groups. The P3 group had lower HLA-DR expression on days 1 and 3 and a higher 90-day mortality. The three-group tool was useful for predicting 90-day mortality in patients with separate Kaplan-Meier survival curves and mortality HRs in the construction and validation cohorts. The peak glucose level, instead of diabetes status, can be used as an easy adjunctive tool for mortality risk stratification in critically ill septic patients. Full article

(This article belongs to the Special Issue Biomarkers of Sepsis)

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9 pages, 321 KiB

Open AccessArticle

Red Cell Distribution Width as a Prognostic Factor and Its Comparison with Lactate in Patients with Sepsis

by Tsung-Han Wang and Yin-Chou Hsu

Diagnostics 2021, 11(8), 1474; https://doi.org/10.3390/diagnostics11081474 - 14 Aug 2021

Cited by 9 | Viewed by 2589

Abstract

Sepsis remains the leading cause of death in critically ill patients. Thus, regular measurement of lactate levels has been proposed in sepsis guidelines. Elevated red cell distribution width (RDW) is associated with mortality risk in patients with sepsis. This study aimed to investigate the association between RDW and the risk of other adverse outcomes in patients with sepsis and to compare the mortality discriminative ability between lactate and RDW levels. This is a single-centered, retrospective, case-control study that included 504 adult patients with sepsis in the emergency department between 1 January 2020 and 31 December 2020. Eligible patients were divided into normal (RDW ≤ 14.5%) and high (RDW > 14.5%) groups. The baseline characteristics and adverse outcomes were recorded and compared. Compared with the normal RDW group, the patients in the high RDW group had a significantly higher rate of ICU admission (48.8% vs. 32.4%, p = 0.03), septic shock (39.2% vs. 23.5%, p < 0.01), and 30-day in-hospital mortality (32.0% vs. 20.7%, p < 0.01). Furthermore, the RDW (area under curve (AUC) = 0.71) had superior mortality discriminative ability compared to lactate (AUC = 0.63) levels (p = 0.02). Clinicians could rely on this simple and rapid parameter for risk stratification to initiate prompt treatment for patients with sepsis. Full article

(This article belongs to the Special Issue Biomarkers of Sepsis)

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7 pages, 547 KiB

Open AccessArticle

Independent Validation of Sepsis Index for Sepsis Screening in the Emergency Department

by Luisa Agnello, Alessandro Iacona, Salvatore Maestri, Bruna Lo Sasso, Rosaria Vincenza Giglio, Silvia Mancuso, Anna Maria Ciaccio, Matteo Vidali and Marcello Ciaccio

Diagnostics 2021, 11(7), 1292; https://doi.org/10.3390/diagnostics11071292 - 19 Jul 2021

Cited by 11 | Viewed by 2762

Abstract

(1) Background: The early detection of sepsis is still challenging, and there is an urgent need for biomarkers that could identify patients at a high risk of developing it. We recently developed an index, namely the Sepsis Index (SI), based on the combination of two CBC parameters: monocyte distribution width (MDW) and mean monocyte volume (MMV). In this study, we sought to independently validate the performance of SI as a tool for the early detection of patients at a high risk of sepsis in the Emergency Department (ED). (2) Methods: We enrolled all consecutive patients attending the ED with a request of the CBC. MDW and MMV were measured on samples collected in K3-EDTA tubes on the UniCel DxH 900 haematology analyser. SI was calculated based on the MDW and MMV. (3) Results: We enrolled a total of 703 patients stratified into four subgroups according to the Sepsis-2 criteria: control (498), infection (105), SIRS (52) and sepsis (48). The sepsis subgroup displayed the highest MDW (median 27.5, IQR 24.6–32.9) and SI (median 1.15, IQR 1.05–1.29) values. The ROC curve analysis for the prediction of sepsis showed a good and comparable diagnostic accuracy of the MDW and SI. However, the SI displayed an increased specificity, positive predictive value and positive likelihood ratio in comparison to MDW alone. (4) Conclusions: SI improves the diagnostic accuracy of MDW for sepsis screening. Full article

(This article belongs to the Special Issue Biomarkers of Sepsis)

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Review

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20 pages, 666 KiB

Open AccessReview

Non-Coding RNA Networks as Potential Novel Biomarker and Therapeutic Target for Sepsis and Sepsis-Related Multi-Organ Failure

by Domenico Di Raimondo, Edoardo Pirera, Giuliana Rizzo, Irene Simonetta, Gaia Musiari and Antonino Tuttolomondo

Diagnostics 2022, 12(6), 1355; https://doi.org/10.3390/diagnostics12061355 - 31 May 2022

Cited by 5 | Viewed by 2785

Abstract

According to “Sepsis-3” consensus, sepsis is a life-threatening clinical syndrome caused by a dysregulated inflammatory host response to infection. A rapid identification of sepsis is mandatory, as the extent of the organ damage triggered by both the pathogen itself and the host’s immune response could abruptly evolve to multiple organ failure and ultimately lead to the death of the patient. The most commonly used therapeutic strategy is to provide hemodynamic and global support to the patient and to rapidly initiate broad-spectrum empiric antibiotic therapy. To date, there is no gold standard diagnostic test that can ascertain the diagnosis of sepsis. Therefore, once sepsis is suspected, the presence of organ dysfunction can be assessed using the Sepsis-related Organ Failure Assessment (SOFA) score, although the diagnosis continues to depend primarily on clinical judgment. Clinicians can now rely on several serum biomarkers for the diagnosis of sepsis (e.g., procalcitonin), and promising new biomarkers have been evaluated, e.g., presepsin and adrenomedullin, although their clinical relevance in the hospital setting is still under discussion. Non-codingRNA, including long non-codingRNAs (lncRNAs), circularRNAs (circRNAs) and microRNAs (miRNAs), take part in a complex chain of events playing a pivotal role in several important regulatory processes in humans. In this narrative review we summarize and then analyze the function of circRNAs-miRNA-mRNA networks as putative novel biomarkers and therapeutic targets for sepsis, focusing only on data collected in clinical settings in humans. Full article

(This article belongs to the Special Issue Biomarkers of Sepsis)

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19 pages, 2778 KiB

Open AccessReview

The Value of a Complete Blood Count (CBC) for Sepsis Diagnosis and Prognosis

by Luisa Agnello, Rosaria Vincenza Giglio, Giulia Bivona, Concetta Scazzone, Caterina Maria Gambino, Alessandro Iacona, Anna Maria Ciaccio, Bruna Lo Sasso and Marcello Ciaccio

Diagnostics 2021, 11(10), 1881; https://doi.org/10.3390/diagnostics11101881 - 12 Oct 2021

Cited by 62 | Viewed by 20483

Abstract

Sepsis represents an important global health burden due to its high mortality and morbidity. The rapid detection of sepsis is crucial in order to prevent adverse outcomes and reduce mortality. However, the diagnosis of sepsis is still challenging and many efforts have been made to identify reliable biomarkers. Unfortunately, many investigated biomarkers have several limitations that do not support their introduction in clinical practice, such as moderate diagnostic and prognostic accuracy, long turn-around time, and high-costs. Complete blood count represents instead a precious test that provides a wealth of information on individual health status. It can guide clinicians to early-identify patients at high risk of developing sepsis and to predict adverse outcomes. It has several advantages, being cheap, easy-to-perform, and available in all wards, from the emergency department to the intensive care unit. Noteworthy, it represents a first-level test and an alteration of its parameters must always be considered within the clinical context, and the eventual suspect of sepsis must be confirmed by more specific investigations. In this review, we describe the usefulness of basic and new complete blood count parameters as diagnostic and prognostic biomarkers of sepsis. Full article

(This article belongs to the Special Issue Biomarkers of Sepsis)

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Other

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12 pages, 421 KiB

Open AccessSystematic Review

The Expression Levels and Concentrations of PD-1 and PD-L1 Proteins in Septic Patients: A Systematic Review

by Mutiara Indah Sari and Syafruddin Ilyas

Diagnostics 2022, 12(8), 2004; https://doi.org/10.3390/diagnostics12082004 - 19 Aug 2022

Cited by 14 | Viewed by 2365 | Correction

Abstract

Sepsis is a series of life-threatening organ dysfunction caused by an impaired host response to infection. A large number of molecular studies of sepsis have revealed complex interactions between infectious agents and hosts that result in heterogeneous manifestations of sepsis. Sepsis can cause immunosuppression and increase the expression of checkpoint inhibitor molecules, including programmed death protein (PD-1) and programmed death ligand 1 (PD-L1), and thus PD-1 and PD-L1 are thought to be useful as diagnostic and prognostic tools for sepsis. PD-1 is an inhibitor of both adaptive and innate immune responses, and is expressed on activated T lymphocytes, natural killer (NK) cells, B lymphocytes, macrophages, dendritic cells (DCs), and monocytes, whereas PD-L1 is expressed on macrophages, some activated T and B cells, and mesenchymal stem cells as well as various non-hematopoietic cells. This systematic review aims to assess the PD-1 and PD-L1 protein expression levels and concentrations in septic and other infectious patients. Full article

(This article belongs to the Special Issue Biomarkers of Sepsis)

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