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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 31  |  Issue : 4  |  Page : 1110-1115

Biomarkers in sepsis


1 Anesthesia, Intensive Care and Pain Management Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Cardiac Intensive Care Department Damietta Cardiology and Gastroenterology Center, Damietta, Egypt

Date of Submission08-Apr-2018
Date of Acceptance05-Jul-2018
Date of Web Publication14-Feb-2019

Correspondence Address:
Mohammed A. M. Ragab
Al Sheikh Dorgham, Damietta Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_145_18

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  Abstract 


Objectives
To perform a systematic review of the different categories of sepsis biomarkers including the new promising biomarkers and their role in diagnosis and prognosis of sepsis.
Data sources
Data were obtained from Medline databases (PubMed, Medscape, and Science Direct) and from materials available on the network from 2003 to April 2017.
Study selection
The initial search presented 30 articles. The research studies that met the inclusion criteria were 10 articles. All articles studied the role of biomarkers in diagnosis and prognosis of sepsis.
Data extraction
If the studies did not fulfill the inclusion criteria, they were excluded. Study quality assessment included whether ethical approval was gained, eligibility criteria specified, appropriate controls mentioned, adequate information provided, and assessment measures defined.
Data synthesis
Comparisons were made by structured review with the results tabulated.
Results
The use of combined biomarkers can be more efficient than using a single biomarker in diagnosis and prognosis of sepsis.
Conclusion
Biomarkers play a vital role for early diagnosis of sepsis, to predict outcome, and to guide choice of antibiotic therapy. In these modern times, clinicians encounter the laboratory results on a daily basis. Therefore, proper interpretation and wise use of biomarkers are necessary. Combination approaches of biomarkers with new techniques have shown promising results and need to be further evaluated.

Keywords: biomarkers, early diagnosis, prognosis, sepsis, systemic inflammatory response syndrome


How to cite this article:
Atalla HA, Abdelaziz AA, Ragab MA. Biomarkers in sepsis. Menoufia Med J 2018;31:1110-5

How to cite this URL:
Atalla HA, Abdelaziz AA, Ragab MA. Biomarkers in sepsis. Menoufia Med J [serial online] 2018 [cited 2019 Sep 20];31:1110-5. Available from: http://www.mmj.eg.net/text.asp?2018/31/4/1110/252024




  Introduction Top


Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Organ dysfunction can be identified as an acute change in total sequential organ failure assessment score more than or equal to two points consequent to the infection. In lay terms, sepsis is a life-threatening condition that arises when the body's response to an infection injures its own tissues and organs[1].

Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. Patients with septic shock can be identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain mean arterial pressure more than or equal to 65 mm Hg and having a serum lactate level more than 2 mmol/l (18 mg/dl) despite adequate volume resuscitation[1].

Sepsis remains one of the leading causes of mortality causing at least 19 million cases every year, mostly in low-income and middle-income countries[2]. Blood culturing diagnosis depends on growth of organisms, and it can take a long time to be positive. On the contrary, new biomarkers have been developed for rapid diagnosis of infection within minutes[3].

A biomarker is defined as a marker that is 'objectively measured as an indicator of a normal biological process, pathogenic process, or pharmacological response to a therapeutic intervention'[4]. Biomarkers play a vital role in early diagnosis of sepsis, predicting sepsis complications including the development of multiple organ dysfunctions, guiding antimicrobial therapy, and assessment of the response to therapy and recovery from sepsis[5].

Sepsis biomarkers can be classified in different manners. They can be classified according to their pathophysiological nature: (a) biomarkers of the proinflammatory phase: acute-phase mediators [procalcitonin (PCT) and C-reactive protein (CRP)], cell-surface biomarkers (presepsin), receptor biomarkers [triggering receptor expressed on myeloid cells-1 (TREM-1) and urokinase plasminogen activator (UPAR)], and cytokine/chemokine biomarkers; (b) biomarkers of the immunosuppressive phase: cytokines and cell-surface biomarkers; (c) vasodilation biomarkers: adrenomedullin and pro-adrenomedullin [ADM and mid-regional (MR) pro-ADM]; (d) cell damage biomarkers: micro-RNAs (mi-RNAs); (e) organ dysfunction biomarkers: brain natriuretic peptide (BNP); (f) coagulation biomarkers: activated partial thromboplastin time and protein C and S; (g) endothelial damage biomarkers: heparin-binding protein, E-selectin and L-selectin; and (h) other markers: neutrophil distribution width, and glutathione S-transferase.

They can also be classified according to their use as diagnostic or prognostic tools: (a) diagnostic biomarkers: CRP, tumor necrosis factor and interleukins (ILs): 1β, 6, 8, 11, 18; (b) prognostic biomarkers: UPAR and highly sensitive cardiac troponin T; and (c) diagnostic and prognostic biomarkers: calcitonin, pro-ADM, TREM-1, presepsin, BNP, and mi-RNAs[5].

Many studies have been performed about sepsis biomarkers. CRP, PCT, presepsin, the soluble form of urokinase-type plasminogen activator receptor (sUPAR), pro-ADM, and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) are probably the most studied among other biomarkers including various ILs, interferon-gamma, high mobility group box 1 protein, atrial natriuretic peptide, pro-atrial natriuretic peptide, eosinophil count, and pro-vasopressin[6].

Surviving sepsis campaign added CRP and PCT to the definition of sepsis in 2003. Then, in the early part of the past decade, surviving sepsis campaign approved the early goal-directed therapy, which include lactate level and lactate clearance in the early management and monitoring of patients of sepsis[7]. CRP biomarker has been used to indicate the presence of inflammatory or infectious disease especially in pediatrics because its levels rise significantly during acute inflammation[8].

Its main clinical use is screening of the early onset of sepsis in newborns (during the first 24 h of life), because it has a very high sensitivity in this context[9]. PCT has been shown to correlate closely with infection but it has some limitations. It is not detectable in certain cases of sepsis and it rises transiently in nonseptic conditions and systemic inflammatory response syndromes (SIRS), for example, trauma, heatstroke, and surgery[10].

The PCT test has been approved by the US Food and Drug Administration to assist in the risk assessment of critically sick people for progression to severe sepsis and septic shock in conjunction with other laboratory findings and clinical assessments. Serum PCT levels are elevated in patients with bacterial infections but are low in healthy individuals or in viral infections. This indicates that PCT is useful for the diagnosis of systemic bacterial infections[11]. PCT is superior to CRP in terms of accuracy at diagnosis and prognosis of sepsis. It is also a more sensitive and specific biomarker in the diagnosis of sepsis than other biomarkers including tumor necrosis factor alpha, lactate levels, IL-2, IL-6, IL-8, and IL-10[12].

We have searched for sepsis biomarkers that improve the clinical assessment, management, and patient outcome. A sepsis biomarker should meet the following demands: (a) it should save the time to (and) improve the diagnosis, (b) it should help in the differentiation between infectious and noninfectious causes of inflammation and its squealae of organ dysfunction or shock, and (c) it should reflect the effectiveness of antimicrobial treatment and other measures of source control more accurately than conventional clinical and laboratory signs.

Aim

The aim of this study was to perform a systematic review of the different categories of sepsis biomarkers including the new promising biomarkers and their role in diagnosis and prognosis of sepsis.


  Materials and Methods Top


Search strategy

We reviewed papers on the different categories of sepsis biomarkers including their diagnostic and prognostic role from Medline databases (PubMed, Medscape, and Science Direct) and also from materials available on the network. We used 'SIRS, biomarkers, sepsis, early diagnosis, and prognosis' as searching items in the title of the papers. The search was performed in the electronic databases from 2003 to April 2017.

Study selection

All the studies were independently assessed for inclusion criteria. They were included if they fulfilled the following criteria: published in English language, published in peer-reviewed journals, and focused on role of biomarkers in diagnosis and prognosis of sepsis. If a study had several publications on certain aspects, we used the latest publication giving the most relevant data.

Data extraction

Data from each eligible study were independently abstracted in duplicate using a data collection form to capture information on study characteristics, interventions, and quantitative results reported for each outcome of interest. Conclusion and comments on each study were made. Because of heterogeneity in the collected data, it was not possible to perform meta-analysis. Significant data were collected, then a structured review was performed with the results tabulated.

Quality assessment

The quality of all studies was assessed. Important factors were included such as study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.

Data synthesis

A structured systematic review was performed with the results tabulated [Table 1].
Table 1: Evaluation of new biomarkers with level of evidence-based medicine

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  Results Top


The selected articles were 10; these articles were deemed eligible by fulfilling the inclusion criteria. All of them presented data about diagnostic and prognostic role of biomarkers in sepsis. Of these 10 articles included in this review, one study presented data about presepsin, two studies presented data about pro-ADM, two studies presented data about sTREM-1, two studies presented data about sUPAR, one study presented data about mi-RNA (MiR-143), and two studies presented data about pro-BNP [Table 1].

Comparison was done to review the timing on which different inflammatory biomarkers come out in the site of inflammation including the time of onset and the peak time [Table 2].
Table 2: Comparison on the timing on which different inflammatory biomarkers come out at the site of inflammation

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  Discussion Top


This review discussed the new sepsis biomarkers: presepsin, pro-ADM, sTREM-1, sUPAR, MiR-143, and pro-BNP.

Presepsin

Cluster of differentiation 14 (CD14) is a 55-kDa glycosyl phosphatidyl inositol-anchored protein lacking a cytoplasmic domain. It is expressed on most innate immune response cells and exists either in an anchored membrane form (mCD14) or in a circulating soluble form (sCD14). The latter is a 43–53 kD glycoprotein that derives from either protease-mediated membrane CD14 shedding or liver synthesis as a type II acute-phase reactant. During inflammation, plasma protease activity generates CD14 fragments. The soluble CD14 subtype (sCD14-ST), a 13 kDa truncated N-terminal (NT) fragment of 64 amino acid residues, is called presepsin[23].

To evaluate the diagnostic and prognostic value of presepsin compared with other biomarkers, a prospective study enrolled 859 consecutive patients with at least two diagnostic criteria for SIRS in the emergency department (ED). Using a presepsin cutoff value of 317 pg/ml for diagnosing sepsis, the sensitivity was 70.8%, the specificity was 85.8%, the positive predictive value (PPV) was 93.2% and the negative predictive value (NPV) was 51.6%. Using a presepsin cutoff value of 550 pg/ml for predicting septic shock, the sensitivity was 85.7%, the specificity was 63.6%, the PPV was 28.5%, and the NPV was 96.3%[13].

Pro-adrenomedullin

ADM is a peptide hormone of 52 amino acids that was isolated in 1993 from extracts of a human pheochromocytoma. It has immune modulating, metabolic, and vasodilator activity. Its widespread production in the tissues helps to maintain a blood supply in every organ. ADM has bactericidal activity and could be helpful in the evaluation of sepsis diagnosis and prognosis and in monitoring such conditions[24]. Prohormone fragments (pro-ADM) are more stable than the complete peptide, and their levels can be measured in biological fluids by automated methods using the TRACE (Time-Resolved Amplified Cryptate Emission) method after immunocapture. The MR pro-ADM, included between amino acids 45 and 92, is the most stable part of the ADM, and it has been detected in plasma of patients with septic shock as a consequence of the ADM active peptide degradation[25].

To demonstrate the diagnostic value of pro-ADM in sepsis, a prospective study was conducted on 82 patients with acute infection admitted to the ED. When the cutoff value was 59.40 ng/l, the sensitivity was 80.7%, the specificity was 68.0%, the PPV was 85.2%, and the NPV was 60.7%[14]. Pro-ADM is also a biomarker of prognostic value. A prospective observational single-center study was performed in which a total of 120 consecutive patients with suspected severe sepsis were recruited to the ICU to evaluate the usefulness of MR pro-ADM levels in the prognosis of sepsis in patients admitted to the ICU. Patients with MR pro-ADM levels of 2.5 nmol/l and above or MR pro-ADM clearance less than 30% at the fifth day following admission in the ICU showed an enhancement in mortality and the sensitivity was 77%, the specificity was 97%, the PPV was 91%, and the NPV was 92%[15].

The soluble triggering receptor expressed on myeloid cells-1

TREM-1 is a group of cell-surface receptors that belong to the immunoglobulin superfamily. TREM-1 is expressed mainly on macrophages and neutrophils and has been identified as an amplifier of the immune response that strongly enhances leukocyte activation in the presence of microbial products. Levels of TREM-1 at the cell surface are up-regulated in the presence of bacteria or fungi. sTREM-1 can be found in body fluids, such as plasma, pleural fluid, bronchoalveolar lavage fluid, urine, and cerebrospinal fluid, where it can be assayed by enzyme-linked immunosorbent assay using commercial immunoassay kits[26].

Meta-analysis of 11 studies (1795 patients included) showed a pooled sensitivity and specificity of 79% [95% confidence interval (CI), 65–89] and 80% (95% CI, 69–88), respectively, with receiver operating characteristic curve of 0.87 (95% CI, 0.84–0.89). In this meta-analysis, for a prevalence of 62% of sepsis, the NPV was 0.7 and the PPV is 0.86. Finally, plasma sTREM-1 had a moderate diagnostic performance in differentiating sepsis from SIRS and was not sufficient for sepsis diagnosis in patients with SIRS[16]. Another meta-analysis of nine studies showed that the pooled sensitivity and specificity of sTREM-1 to predict mortality in sepsis were 74% (95% CI, 0.58–0.85) and 72% (95% CI, 0.62–0.80), respectively. The overall area under the Summary receiver operating characteristic curve was 0.78 (95% CI, 0.74–0.81)[17].

The soluble form of urokinase-type plasminogen activator receptor

The sUPAR is a biological marker of immunologic activation. It is expressed on many cell types and has different immunologic functions like migration, adhesion, and cell proliferation. UPAR is cleaved from the cell surface by proteases during inflammation to create the soluble form (sUPAR). The latter can be detected in urine, blood and cerebrospinal fluid[27].

A retrospective study included 140 patients with more than or equal to two SIRS criteria and clinical signs of infection presenting at the ED to evaluate the diagnostic accuracy of sUPAR to predict bloodstream infections upon admission to the ED. With sUPAR cutoff more than or equal to 7.5 ng/ml, the sensitivity was 80%, the specificity was 77%, PPV was 42%, and NPV was 95%[18]. In a prospective study that included 258 patients, during the week after ICU admission, serum sUPAR concentrations correlated with sequential organ failure assessment scores over time. High sUPAR levels on admission were a strong independent predictor for ICU and 28-day mortality. In the global population, a sUPAR level higher than 6.15 ng/ml had 66% sensitivity and 64% specificity for prediction of ICU mortality. This study concluded that in ICU patients, serum sUPAR concentrations have limited use for identifying sepsis, but their time course correlated with the degree of organ dysfunction, and they have prognostic value in septic and nonseptic populations[19].

Micro-RNAs

mi-RNAs represent a novel group of small RNA molecules (20–24 nucleotides) that regulate gene expression with no encoding for proteins. mi-RNAs play a vital role in the innate and adaptive immunity in pathological conditions like bacterial infection, so they might serve as biomarkers in sepsis[28]. MiR-143 is a subtype of mi-RNAs that was found to be associated with sepsis in human leukocytes after lipopolysaccharide infusion[29].

A retrospective study included 103 patients with sepsis and 95 patients with SIRS undergoing treatment at the Department of Critical Care Medicine to evaluate serum miR-143 levels in patients with sepsis or noninfectious SIRS. When using a cutoff level of 15.9 for serum miR-143, sensitivity was 78.6% (95% CI, 69.5–86.1) and specificity was 91.6% (95% CI, 84.1–96.3)[20].

B-type natriuretic peptide

B-type natriuretic peptide (BNP) is a 32-amino acid polypeptide. It has a vital role in fluid volume homeostasis. A gene in chromosome 1 encodes the prohormone pro-BNP. The latter is cleaved into the active BNP and the inactive NT pro-BNP which has higher stability and longer plasma half-life time. The measurement of NT pro-BNP has been introduced into routine clinical diagnostics[30].

A prospective study included 24 patients who were admitted to the Critical Care Medicine Department with a preliminary diagnosis of severe sepsis, and 12 healthy adults as volunteers were recruited into the study. With a cutoff point more than 108 pg/ml (as recommended by Youden's index), there was 95.8% sensitivity, 83.3% specificity, 92.0% PPV, and 90.91% NPV[21].

A recent meta-analysis was performed where 12 studies included a total of 1865 patients. Elevated natriuretic peptides were significantly associated with increased risk of mortality [odds ratio (OR), 8.65; 95% CI, 4.94–15.13; P < 0.00001). The association was consistent for BNP (OR, 10.44; 95% CI, 4.99–21.58; P < 0.00001) and NT pro-BNP (OR, 6.62; 95% CI, 2.68–16.34; P < 0.0001). The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were 79% (95% CI, 75–83), 60% (95% CI, 57–62), 2.27 (95% CI, 1.83–2.81), and 0.32 (95% CI, 0.22–0.46), respectively[22].


  Conclusion Top


Biomarkers play a vital role for early diagnosis of sepsis, to predict outcome, and to guide choice of antibiotic therapy. In these modern times, clinicians encounter the laboratory results on a daily basis. Therefore, proper interpretation and wise use of biomarkers are necessary. Combination approaches of biomarkers with new techniques have shown promising results and need to be further evaluated.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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