Sepsis Biomarkers

Reviewed and revised 20 December 2015

OVERVIEW

  • At least 178 different sepsis biomarkers have been described in the published medical literature, reflecting the complex pathophysiology of sepsis
    • e.g. coagulation, complement, contact system activation, inflammation, and apoptosis
    • also biomarkers of complications, e.g. troponin for myocardial dysfunction
  • None have well proven clinical utility
  • Most used are procalcitonin and CRP despite their limited ability to distinguish between sepsis and SIRS or to predict outcome
  • Only 5 biomarkers have studies reporting sensitivity and sensitivity >90% as diagnostic tests
  • Biomarkers have uses other than diagnosis (e.g. prognosis)

POTENTIAL USES OF SEPSIS BIOMARKERS

These include:

  • rule out sepsis
  • provide early intervention
  • guide antimicrobial therapy
  • assess response to therapy
  • differentiate gram positive and gram negative infection
  • distinguish bacterial from viral or fungal infection
  • predict outcome
  • distinguish local from systemic infection
  • predict multi-organ failure

TYPES OF SEPSIS BIOMARKERS

Acute Phase Reactants

  • amyloid
  • C-reactive peptide (CRP)
  • Erythrocycte sedimentation rate (ESR)
  • ferritin
  • procalcitonin
  • others

Cell Markers

  • CD types
  • mHLA-DR

Receptors

  • toll-like receptors
  • TNF receptors
  • IL-2 receptors
  • many others

Cytokines

  • interleukins (e.g. IL-27)
  • macrophage inflammatory proteins
  • monocyte protein
  • TNF
  • osteoponitin

Coagulation factors

  • APTT
  • protein C and S
  • fibrin
  • antithrombin
  • d-dimer
  • others

Miscellaneous

  • vascular endothelial damage markers
  • vasodilation markers
  • organ dysfunction markers
  • many others!

IMPORTANT SEPSIS BIOMARKERS 

Table adapted from Deranged Physiology — Sepsis Biomarkers

234
PhysiologyAdvantagesDisadvantages
Erythrocyte sedimentation rate (ESR)
  • 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
C-reactive protein (CRP)
  • ~ 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

 

Procalcitonin
  • 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
Pro-adrenomedullin
  • 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
Soluble triggering receptor expressed on myeloid cell 1 (sTREM-1)
  • 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
Presepsin (sCD14-st)
  • 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

 

PROBLEMS WITH THE USE OF SEPSIS BIOMARKERS

Problems include:

  • sepsis is a multisystem disease
  • varying effects in different patients
  • no gold standard to diagnose sepsis (cultures often negative)
  • cost
  • time
  • course of mediators released changes throughout disease process
  • most biomarkers have not yet been tested properly to assess assess reliability and validity

Combinations of biomarkers (e.g. procalcitonin and APTT waveform) may hold more promise


References and Links

LITFL

FOAM and web resources

Journal articles

  • Biron BM, Ayala A, Lomas-Neira JL. Biomarkers for Sepsis: What Is and What Might Be? Biomarker insights. 10(Suppl 4):7-17. 2015. [pubmed]
  • Cho SY, Choi JH. Biomarkers of sepsis. Infection & chemotherapy. 46(1):1-12. 2014. [pubmed]
  • Faix JD. Biomarkers of sepsis. Crit Rev Clin Lab Sci. 2013 Jan;50(1):23-36. doi: 10.3109/10408363.2013.764490. PubMed PMID: 23480440; PubMed Central PMCID: PMC3613962.
  • Kibe S, Adams K, Barlow G. Diagnostic and prognostic biomarkers of sepsis in critical care. J Antimicrob Chemother. 2011 Apr;66 Suppl 2:ii33-40. doi: 10.1093/jac/dkq523. Review. PubMed PMID: 21398306.
  • Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit Care. 2010;14(1):R15. doi: 10.1186/cc8872. Epub 2010 Feb 9. Review. PubMed PMID: 20144219; PubMed Central PMCID: PMC2875530.
  • Póvoa P, Salluh JI. Biomarker-guided antibiotic therapy in adult critically ill patients: a critical review. Ann Intensive Care. 2012 Jul 23;2(1):32. doi: 10.1186/2110-5820-2-32. PubMed PMID: 22824162; PubMed Central PMCID: PMC3475044.
  • Shankar-Hari M, Deutschman CS, Singer M. Do we need a new definition of sepsis? Intensive care medicine. 41(5):909-11. 2015. [pubmed] [free full text]
  • Singer M. Biomarkers in sepsis. Current opinion in pulmonary medicine. 19(3):305-9. 2013. [pubmed] [free full text]

CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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