Biomarkers in Sepsis Utility or Futility? Dr Andrew Ferguson Consultant in Intensive Care Medicine and Anaesthesia Craigavon Area Hospital
Biomarkers in SepsisUtility or Futility?
Dr Andrew FergusonConsultant in Intensive Care Medicine and Anaesthesia
Craigavon Area Hospital
Why give this your attention?• Microbes – the WMDs in your ICU• Sepsis is the main killer of general ICU patients
• Anything that helps you beat it is good news
• We need better diagnostic & prognostic tools
The clock is ticking - the first 12 hours…
Funk and Kumar, Crit Care Clinics 2011; 53-76.
For first 12 hours, 1% mortality per 5 minute delay
Early antibiotics
Szczepura A, Osipenko L. Point of Care Diagnostics for Sepsis: Health Economic Considerations. Available at https://connect.innovateuk.org/documents/3187680/3710018/Sepsis-TSB-27-07-12-Economic-slides.pdf/d805c6a6-ecdf-43c7-ac60-9e4da9d046fd;jsessionid=481FF37BC0ECFA0D6D41EC7474D20822.2
Conventional detection of sepsis
• 2 main strategies…• Detection of bacterial pathogen
– Slow and all too often negative• Detection of host response
– NEWS for fever, tachycardia, tachypnoea– “Conventional” lab tests (WBC, CRP etc)– The ICU eyeball test
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What’s wrong with that?• Physiological reserve determines presentation
• Physiological reserve determines trajectory• Misdiagnosis in patients with comorbidity• Recognition of severity is biased• Prognostication is weakened• There might not be an ICU eyeball
The biomarker paradigm…• Sepsis leads to
– Inflammation– Coagulation– Tissue damage and repair
• The sicker you are, the greater the changes• We can identify biomarkers for these processes
• We can measure these biomarkers• We can stratify severity based on biomarker levels
• We can prognosticate based on biomarker levels
Biomarker Candidates• Multiple, and growing all the time
• Some more common in the literature
• Linked to the main underlying processes– Inflammation– Coagulation– Tissue damage– Tissue repair
Examples• Acute phase proteins
– CRP– Procalcitonin– Pentraxin 3 (PTX3)– Lipopolysaccharide binding protein (LBP)
• Cytokines & chemokines– IL-1RA, IL-1b, IL-2, IL-6, MCP-1– TNF-a, TNFR1/2– HMGBP1
• Cell surface markers– Soluble CD14 (presepsin)– Neutrophil CD64 index (CD64in)– mHLA-DR (monocyte HLA-DR levels)– CD-163
• Receptor markers– VEGF– Soluble VEGF-receptor 1 (sFLT)– Soluble urokinase plasminogen activator (suPAR)
– sTREM-1– RAGE (soluble receptor for advanced glycation end products)
• Coagulation– Activated partial
thromboplastin time (aPTT) waveform analysis
– Protein C receptor– Thrombomodulin
• Endothelial damage– Heparin binding protein– E-selectin– Neopterin– ICAM-1, VCAM-1– Angiopoietin-1 and -2– Syndecan-1 and -2
• Vasodilation– Copeptin (AVP precursor)
• Cell damage– MicroRNA– Microparticles
• Cell repair– Procollagen III amino
propeptide
Questions to be answered
• Does the biomarker aid diagnosis?• Does it provide additional prognostic info?– For outcome– For progression/decline
• Better than the ICU eye?• Better than scoring systems?
Procalcitonin• Bacterial infections
– > ubiqitous CALC-1 gene expression– > release of PCT from all parenchymal tissues
– Procalcitonin (PCT) increases after 2-3 hours after induction e.g. by endotoxin
– Falls with successful treatment
Procalcitonin in IFI
“Fungi-related sepsis, even severe sepsis or septic shock, does not necessarily elicit a substantial increase in serum PCT”
DIAGNOSIS
Cytokines - IL-6• Can be reliably measured• Not specific for sepsis (hence
not diagnostic)• PROGNOSTIC tool
– Increased mortality as level rises– Increased risk of progression to severe sepsis/shock
Chemokines• IL-8• MCP-1 (monocyte chemoattractant protein 1)
• IL-8 can be used as diagnostic tool in sepsis
• MCP-1 can be used as PROGNOSTIC tool– Mortality risk
Pentraxin 3• Pentraxins are liquid-phase PAMP receptors
• “Short” pentraxins include CRP (bet you didn’t know that!) as is serum amyloid P component (SAP)
• Pentraxin-3 involved in:– complement activation– pathogen opsonisation– self versus modified-self versus non-self discrimination
• Detects sepsis– AUC 0.96
• Predicts progression– AUC 0.87– Sens 82% Spec 89% at 12ng/ml
• Did not predict mortality
PROGNOSI
S
Fatty acid b2 oxidation issue in non-survivors v survivors related to carnitine shuttle
(defective fatty acid transfer into mitochondria). Detectable at presentation.
Microparticles?• Small vesicles shed from membranes of apoptotic and stress-activated cells– Endothelial cells, RBCs, monocytes, platelets
Conclusion• Utility• Earlier detection of disease• Earlier detection of high risk sub-groups
• Earlier recognition of treatment success
• Earlier de-escalation• Adjunctive prognostication