Early Diagnosis and Prognosis of Postoperative Sepsis by Presepsin and Syndecan-1

Millions of patients die around the world every year because of sepsis. 1%-2% of patients admitted to hospital and 25% of Intensive Care Units (ICU) patients suffer from sepsis. One of the most important principles of sepsis management is early diagnosis and treatment as Surviving Sepsis Campaign recommends Hour-1 bundle use.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection and organ dysfunction can be identified as an acute change in total Sepsis related Organ Failure Assessment (SOFA) score ≥ 2 points consequent to the infection.

The baseline SOFA score can be zero in patients not known to have pre-existing organ dysfunction. A SOFA score 2 reflects an overall mortality risk of approximately 10% in a general hospital population with suspected infection. Patients with suspected infection who are likely to have a prolonged ICU stay or die in the hospital can be promptly identified at the bedside with quick SOFA score (qSOFA) i.e. (HAT ie, Hypotension with systolic blood pressure ≤100 mm Hg, Alteration in mental status, or Tachypnea with respiratory rate ≥22/min.

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 blood pressure (MAP) ≥65 mm Hg and having a serum lactate level >2 mmol/L (18 mg/dL) despite adequate volume resuscitation. With these criteria, hospital mortality is in excess of 40%.

As blood culture is needed to confirm diagnosis of sepsis it requires 48-72 hours to be performed, and positive rate is low. No single clinical or biological marker indicative of sepsis has been approved.

There is a need for biomarkers with a high sensitivity and specificity for early diagnosis and prognosis. They also should be positively correlating with Acute Physiology and Chronic Health Evaluation II (APACHE II) and SOFA scores.

Many known reported old biological markers as Procalcitonin (PCT), Interleukins, Pro-Vasopressin and C-Reactive Protein (CRP) have been studied and new markers were detected as Presepsin [(soluble CD14 (sCD-14)] and Syndecan-1 from Glycocalyx shedding.

One of the key molecular causes of gram-negative septicemia is a component of the outer membrane of gram-negative bacteria, lipopolysaccharide (LPS). It binds with high affinity to LPS-binding glycoproteins and activates Toll-like receptor (TLR)-4 and co-receptor cluster of differentiation 14 (CD14) expressed on monocytes/macrophages and endothelial cells to induce the secretion of proinflammatory cytokines. This is not the only main pathogenic mechanism of lipopolysaccharide (LPS). An alternative intracellular LPS-sensing pathway, bypassing TLR4, that activates caspases 4 and 5 in humans resulting in inflammasome(it is an intracellular multimeric protein complex that contains (1) a pattern recognition receptor (PRR), (2) an adaptor protein and (3) an effector enzyme (caspase), and catalyses a cellular reaction to protect against an immediate danger via cytokine secretion and cell death) induced pyroptosis has been considered to be the main pathogenic mechanism of sepsis.

Presepsin is an N-terminal fragments of 13kDa of soluble CD14 (sCD14). subtype (sCD14-ST). sCD14 is seen in plasma, and is produced by membrane-bound CD14 (mCD14) fall-off or cell secretion. Cluster of Differentiation 14 (CD14) is the receptor of lipopolysaccharide-lipopolysaccharide binding protein (LPS-LBP) complexes. CD14 has two forms: membrane-bound CD14 (mCD14) and soluble CD14 (sCD14). Presepsin is released after the binding of lipopolysaccharides (LPS) to monocytes, causing an enhanced immune response. mCD14 has a high affinity to LPS, and is mainly expressed on the cell surface of monocytes/macrophages or distributed a little bit on the cell surface of neutrophils. Two kinds of sCD14 could be detected in the plasma of healthy people at microgram level: 49KD and 55KD. sCD14 plays an important role in mediating the immune responses to LPS of CD14-negative cells such as endothelial cells and epithelial cells. sCD14 is cleaved by Cathepsin D and other proteases in plasma.

Since presepsin is produced immediately after the onset of an infection it can be detected early in the development of sepsis.its value as sepsis biomarker was shown in the diagnosis and evaluation of sepsis.

Syndecan-1 is one of components of Glycocalyx layer. This is a layer lining luminal surface of the vascular endothelium, which acts as a protective layer to maintain its permeability and a key factor in leukocyte migration and preventing intravascular coagulation.This is made of glycoproteins, proteoglycans, glycosaminoglycans and other plasma proteins especially hyaluronan and syndecans (a proteoglycan) are the principle component for its integrity.

Early pathophysiologic changes in sepsis concern the endothelium including degradation of the glycocalyx through proteinases produced by pathogens that lead to increase permeability to plasma proteins and fluids subsequently tissue edema formation and organ failure. The damaged glycocalyx layer becomes thinner and releases its components (such as syndecan-1, heparan sulfate, hyaluronan, chondroitin sulfates) into the plasma via enzymes including heparanase that cleaves the heparan sulfate and matrix metalloproteinase (MMPs) A disintegrin and metalloproteases (ADAMs). ADAM17 is inducible, cleaves syndecan-4,while ADAM10 is expressed constitutively, sheds syndecan-1 from proteoglycans. which could be used as a sepsis biomarker.