Biomarkers for sepsis: more than just fever and leukocytosis-a narrative review

Abstract

A biomarker describes a measurable indicator of a patient's clinical condition that can be measured accurately and reproducibly. Biomarkers offer utility for diagnosis, prognosis, early disease recognition, risk stratification, appropriate treatment (theranostics), and trial enrichment for patients with sepsis or suspected sepsis. In this narrative review, we aim to answer the question, "Do biomarkers in patients with sepsis or septic shock predict mortality, multiple organ dysfunction syndrome (MODS), or organ dysfunction?" We also discuss the role of pro- and anti-inflammatory biomarkers and biomarkers associated with intestinal permeability, endothelial injury, organ dysfunction, blood-brain barrier (BBB) breakdown, brain injury, and short and long-term mortality. For sepsis, a range of biomarkers is identified, including fluid phase pattern recognition molecules (PRMs), complement system, cytokines, chemokines, damage-associated molecular patterns (DAMPs), non-coding RNAs, miRNAs, cell membrane receptors, cell proteins, metabolites, and soluble receptors. We also provide an overview of immune response biomarkers that can help identify or differentiate between systemic inflammatory response syndrome (SIRS), sepsis, septic shock, and sepsis-associated encephalopathy. However, significant work is needed to identify the optimal combinations of biomarkers that can augment diagnosis, treatment, and good patient outcomes.

Keywords: Biomarker; Sepsis; Sepsis-associated encephalopathy; Septic shock; Systemic inflammatory response.

Fig. 1

Sepsis, septic shock, and sepsis-associated encephalopathy biomarkers. The infection triggers a cascade of signaling pathways that activate several transcription factors and promote proinflammatory mediators such as acute-phase proteins, cytokines, chemokines, and antimicrobial peptides necessary to eliminate the invading pathogens. The unbalanced host immune response triggers vascular endothelial damage, increasing gut and BBB permeability, culminating in organ dysfunction. Ang-2 (angiopoietin-2), APP (acute phase proteins), aPPT (activated partial thromboplastin), AST (astrocytes), AT (antithrombin), BBB (blood–brain barrier), C5aR (complement component 5a receptor), CD (cluster of differentiation), CD14-ST (soluble subtype of CD14), CRP (C reactive protein), DAMPs (damage-associated molecular patterns), GFAP (glial fibrillary acidic protein), HMGB-1 (high mobility group box 1), ICAM-1 (intercellular adhesion molecule 1), I-FABP (intestinal fatty acid binding protein), LBP (lipopolysaccharide binding protein), mHLA-DR (monocytic human leukocyte antigen DR), Mo (macrophage), NFL (neurofilament light), NSE (neuron specific enolase), NT-proBNP (N-terminal pro-brain natriuretic peptide), OCLN (occludin), OLG (oligodendrocyte), PAMPs (pathogen-associated molecular patterns), PCT (procalcitonin), PMNL (polymorphonuclear leukocytes), PT (prothrombin), PTX-3 (pentraxin-3), S100B (calcium-binding protein B), sFlt-1 (soluble fms-like tyrosine kinase 1), suPAR (soluble form of the urokinase plasminogen activator receptor), TNFR (tumor necrosis factor receptor type), TREM-1 (triggering receptor expressed on myeloid cells 1), VCAM-1 (vascular cell adhesion molecule 1), ZO-1 (zonula-occluden 1)