Sepsis Biomarkers

• Rate at which EDTA-treated diluted RBCs clump together in a vertical test tube
• Elevated in inflammatory conditions, mainly because of the increased amount of fibrinogen, which is an acute phase reactant

• Easy to perform
• Requires no special equipment, and minimal technical skill
• Uses widely available cheap reagents.
• Available in resource-poor environments

• Takes 1 hour to perform
• Unreliable due to variation with age, temperature, and test tube position
• Very poor specificity for sepsis

Non-infectious causes of elevation:

• Malignancy (eg. multiple myeloma)
• Inflammatory disease, eg. RA/PMR
• Chronic renal failure
• Vasculitis, eg. temporal arteritis

• ~ 115 kDa protein responsible for precipitating C-polysaccharide during the acute phase of Streptococcus pneumonia infection
• Produced by the liver
• acts as an opsonin: binds to soluble or particulate ligands and activates complement. Macrophages also have CRP receptors.
• CRP increases 4-6hrs after the start of an infection and then doubles every 8 h, reaching a peak at 36-50 h
• Half-life of 19 h

• Cheap
• Easy to perform
• Widely available
• As a marker for bacterial infections: sensitivity 68-92%, specificity 40-67%
• Correlates with severity of infection
• A rapid decrease in CRP levels suggests a good response to antibiotic therapy

• nonspecific marker of inflammation
• unreliable in patients with a dysfunctional liver
• not as good as procalcitonin in discriminating infectious from non-infectious causes of fever

non-infectious causes of elevation:

• Surgery, trauma
• Burns
• Myocardial infarctions
• Rheumatological disease

• prohormone of calcitonin, normally synthesised by the C-cells of the thyroid gland
• in sepsis it is produced ectopically by neuroendocrine cells in the lung and intestine
• 116-peptide molecule, 13 kDa
• Cleared by the parathyroid gland; renal clearance is minimal
• Synthesis is triggered by bacterial endotoxin and inflammatory cytokines
• Levels peak after 6 hours
• It has a half-life of 24-36 hours

• Useful in identifying occult infection; levels peak rapidly after the first appearance of endotoxin, i.e. before blood cultures have time to incubate
• Useful in discriminating between bacterial and non-infectious causes of inflammation, as its synthesis is triggered by bacterial endotoxin.
• Quick to perform
• More specific for bacterial sepsis than CRP
• Numerous trials, related to industry support

• Expensive
• Requires serial measurements (more expense)
• No value in assessment of fungal or viral infections
• No value in assessment of localised infections without a systemic response
• There is disagreement as to what the negative cutoff value should be
• For the discrimination of infectious from non-infectious cause of fever, the clinical judgement of an ED physician is at least equally accurate, if not better.

Non-infective causes of elevation:

• Burns
• Massive tissue necrosis
• Tumour lysis
• Cardiac or major abdominal surgery
• Multi-organ system failure
• Treatment with T-cell antibodies
• End-stage renal failure (procalcitonin is chronically elevated)
• Paraneoplastic production, eg. by medullary thyroid carcinoma or by small-cell lung cancer

• stable and physiologically inert mid-regional peptide fragment cleaved from the same precursor as adrenomedullin
• present in the bloodstream in stoichiometrically equivalent amounts to ADM
• Adrenomedullin (ADM) is produced during physiological stress; roles include vasodilation, anti-inflammatory and antimicrobial effects
• produced by numerous tissues: brain, lungs, heart, kidneys, endothelial cells and adipocytes
• ADM is rapidly cleared from the circulation (t12 = 22 minutes) but proADM has a longer half-life.

• ProADM is higher in patients with sepsis than with SIRS
• In febrile neutropenia patients, proADM can distinguish sepsis from non-infectious SIRS
• Unlike procalcitonin, proADM rises in localised infectious processes (eg. abscesses)
• Also it seems to be superior to procalcitonin as a predictor of bloodstream infection, and of non-response to therapy
• ProADM predicts mortality in patients with CAP and COPD (in some of the studies)

• Expensive
• Not widely available
• Levels do not seem to correlate very strongly with severity

Non infectious causes of elevation:

• Congestive heart failure
• Acute heart failure

• TREM-1 is a glycopeptide receptor expressed on the surface of myeloid cells
• Expression of sTREM-1 increases in bacterial and fungal sepsis

• Probably as accurate as procalcitonin (if not better at a high cut-off) in the diagnosis of bacterial sepsis
• For bacterial infections: sensitivity 82%, specificity 86%
• Admission sTREM-1 levels are independently associated with mortality
• Rapid decrease of sTREM-1 associated with a better outcome

• Expensive
• Not widely available
• A more recent meta-analysis has down-estimated its sensitivity and specificity
• Also elevated in acute MI
• Assay method significantly affects accuracy

• 13kDa soluble N-terminal fragment of CD14 (a part of the LPS receptor from myeloid cells)
• During inflammation, plasma protease activity generates these CD14 fragments
• Increases at 2 hours post insult, and has a half-life of 4-5 hours

• Detects both systemic and localised bacterial infections: Sensitivity 87.8%, Specificity 81.4%
• Rises very early: useful for early (ED) diagnosis of sepsis
• Prognostically important: presepsin levels associated with outcome in the ALBIOS study
• Unlike procalcitonin, presepsin is not elevated in severe burns
• Even though it is derived from WCCs, neutropenic patients with sepsis still develop high presepsin levels

• Expensive
• Not widely available
• Enthusiasm among researchers may have the effect of obscuring the potential disadvantages
• Levels did not seem to increase in UTI
• Affected by antimyeloid drugs: lower levels are seen after chemotherapy

Elevated in non-septic patients:

• Neutropenic mucositis
• Hepatitis (chronic HepB)
• Febrile but culture-negative patients
• Psoriasis