Markers for Sepsis Diagnosis: What is Useful?

Humoral and cellular host response

Sepsis biomarkers are derived from the complex host response to an infectious stimulus. Among others, bacterial toxins or membrane surface antigens (pathogen- associated molecular patterns) can initiate activation of plasmatic (complement system, coagulation cascade, kallikrein-kinin-system, eicosanoids) and cellular pathways (granulocytes, thrombocytes, macrophages, endothelial cells), releasing different mediators and molecules (cytokines, chemokines, acute-phase proteins).

C-reactive protein

C-reactive protein (CRP) is an acute-phase protein that is released from hepatic cells after stimulation by inflammatory mediators like interleukin (IL)-6 and IL-8 [7]. CRP has both pro- and anti-inflammatory properties. It activates the complement system after binding bacterial polysaccharides or fragments of cell membranes. CRP prevents the adhesion of granulocytes on endothelial cells and the synthesis of superoxides. It stimulates the production of IL-1 receptor antagonists. Some studies

Cytokines

Increased plasma levels of cytokines are the primary host response to an inflammatory insult. Cytokines are glycoproteins released by macrophages, monocytes, lymphocytes, and endothelial cells. Their binding to specific receptors leads to defined reactions. Proinflammatory cytokines and anti-inflammatory cytokines may be elevated depending on the stage of sepsis. In clinical routine, however, they play only a minor role, because cytokines have a short half-life of a few minutes and receptor

Procalcitonin

PCT is a 13-kd propeptide of calcitonin. In healthy individuals, levels of PCT are below 0.1 ng/mL. In patients with sepsis, PCT levels may increase up to 5000 to 10,000 times with calcitonin still in the normal range [27]. In contrast to the short half-life of calcitonin (10 minutes), the half-life of PCT is approximately 24 hours [9], [28].

The physiologic role of PCT and its site of production are not completely understood. Bacterial endotoxins are a major stimulus for PCT induction [28] but

Endotoxin (lipopolysaccharide) and endotoxin activity essay

Endotoxin is an essential structure of the outer cell membrane of gram-negative bacteria. The Limulus amoebocyte lysate assay showed methodologic problems with variations of more than 50%, low specificity because of differences in the endotoxin structure in several gram-negative bacteria, and interactions with plasma proteins and antibiotics leading to differing results in clinical studies. Endotoxin measurement did not play a role in the clinical setting [48]. Recently, however, a highly

Surface and soluble triggering receptor expressed on myeloid cells-1

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a recently identified cell surface molecule, a member of the immunoglobulin superfamily, which is expressed on human neutrophils and monocytes and triggers secretions of proinflammatory mediators, such as IL-8, tumor necrosis factor-α, and IL-1β [51]. Human TREM-1 is strongly expressed in acute inflammatory lesions caused by bacteria and fungi but not in lesions derived from noninfectious inflammatory diseases, such as psoriasis,

Adrenomedullin

Adrenomedullin (AM) is a 52–amino acid peptide identified in 1993 with strong and sustained hypotensive effects [58]. It belongs to a superfamily of peptides including calcitonin gene-related peptide, calcitonin, and amylin, which are structurally related peptides with N-terminal 6– to 7–amino acid ring structures linked by a disulfide bridge and with amidated C-termini [59]. AM is expressed in a large variety of tissues in addition to the adrenal gland for which it was originally named [60].

Atrial and brain natriuretic peptides

Natriuretic peptides play an important role in the regulation of fluid volume and are markers of congestive heart failure. They are released by atrial distention. In patients with septic shock, elevated levels of atrial natriuretic peptide were associated with increased mortality by myocardial depression [76]. A recent observational study of critically ill patients admitted to the ICU showed that mid proatrial natriuretic peptide levels were significantly higher in survivors than in

Lipopolysaccharide-binding protein

Lipopolysaccharide-binding protein was first described in 1990 [79]. It is a 58-kd class-1 acute-phase protein that mediates the endotoxin-induced activation of monocytes by the CD14-receptor and the production of IL-6. Lipopolysaccharide-binding protein is mainly synthesized by hepatocytes, intestinal, and pulmonary epithelial cells. The normal plasma level for lipopolysaccharide-binding protein ranges from 5 to 15 μg/mL. In patients with febrile neutropenia, lipopolysaccharide-binding protein

Protein C

Derangement of the coagulation system correlates with increased mortality in severe sepsis and septic shock [83], [84]. Protein C (PrC), which plays an important role in the clotting cascade, is activated by interaction with thrombin-thrombomodulin and exerts antithrombotic, profibrinolytic, and anti-inflammatory activities [85]. PrC activation in sepsis may be impaired by inflammatory cytokines [86] and reduced levels of PrC in septic patients are associated with poor clinical outcome [87],

Endocan

Endocan or endothelial cell-specific molecule-1 is a soluble 50-kd dermatan sulfate proteoglycan that is secreted by the vascular endothelial cells of lung and kidney in response to proinflammatory cytokines [90]. In a prospective observational pilot study, patients with sepsis showed on average fourfold higher endocan levels at admission to ICU than healthy subjects or patients with systemic inflammatory response syndrome. Endocan levels were higher in patients with septic shock than in

Complement 3a

Complement 3a is a proinflammatory mediator, derived from the α-chain of C3 after activation of the classical and alternative pathway of the complement cascade. The assay for complement 3a by column chromatography is complicated and expensive. It is known that systematic inflammation leads to 40-fold elevated levels of complement 3a [93]; however, large sample size studies in critically ill patients have not been undertaken. A recently published study showed plasma concentration of complement

Neopterin

Neopterin is a substance of low molecular weight released from human monocytes after immune stimulation mainly by the macrophage-activating factor interferon and is biosynthetically derived from guanosine triphosphate. The function of neopterin is probably associated with the cytotoxic reactivity of activated macrophages [95], [96]. Because elevated plasma levels are found in all infectious and noninfectious inflammations and in malignant diseases, the specificity of neopterin as a marker of

HLA-DR

HLA-DR is a surface antigen expressed on monocytes. Sepsis and severe infections suppress the HLA-DR expression. This status of immune paralysis characterizes a high-risk patient population. The degree of suppression of the monocytic HLA-DR expression correlates with the severity and the outcome of sepsis [99], [100]. This occurs only in a subgroup of septic patients, however, and may also be found in patients after major surgery [101], [102]. Apart from some value for outcome prediction,

Summary

Requirements for the clinical use of a sepsis marker demand that the test results are able significantly to alter clinical decision making at the bedside. To date, only a few markers are able to fulfill such requirements. This is the case for IL-6 and IL-8, which are used to some degree in pediatrics and neonatology. PCT has gained growing clinical acceptance during the last years for the reasons given later. In the meanwhile, it has been approved by the Food and Drug Administration as a tool