Biomarkers in sepsis

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Biomarkers in sepsis

  1. 1. Biomarkers in Sepsis Utility or Futility? Dr Andrew Ferguson Consultant in Intensive Care Medicine and Anaesthesia Craigavon Area Hospital
  2. 2. 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
  3. 3. The clock is ticking - the first 12 hours… For first 12 hours, 1% mortality per 5 minute delay Funk and Kumar, Crit Care Clinics 2011; 53-76.
  4. 4. 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-ecdf43c7-ac60-9e4da9d046fd;jsessionid=481FF37BC0ECFA0D6D41EC7474D20822.2
  5. 5. Early detection is paramount BUT.…
  6. 6. Conventional detection of sepsis • 2 main strategies… 1 • Detection of bacterial pathogen – Slow and all too often negative 2 • Detection of host response – NEWS for fever, tachycardia, tachypnoea – “Conventional” lab tests (WBC, CRP etc) – The ICU eyeball test
  7. 7. 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
  8. 8. Enter the goose and the…
  9. 9. 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
  10. 10. Damage Associated Molecular Patterns
  11. 11. Pathogen Associated Molecular Patterns
  12. 12. 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
  13. 13. Examples • Acute phase proteins – – – – • Cytokines & chemokines • • Soluble CD14 (presepsin) Neutrophil CD64 index (CD64in) mHLA-DR (monocyte HLA-DR levels) CD-163 Receptor markers – – – – – Endothelial damage – – – – – – Cell surface markers – – – – Coagulation – Activated partial thromboplastin time (aPTT) waveform analysis – Protein C receptor – Thrombomodulin CRP Procalcitonin Pentraxin 3 (PTX3) Lipopolysaccharide binding protein (LBP) – IL-1RA, IL-1b, IL-2, IL-6, MCP-1 – TNF-a, TNFR1/2 – HMGBP1 • • • VEGF Soluble VEGF-receptor 1 (sFLT) • Soluble urokinase plasminogen activator (suPAR) sTREM-1 RAGE (soluble receptor for advanced glycation end products) • 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
  14. 14. 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?
  15. 15. 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
  16. 16. Procalcitonin
  17. 17. Procalcitonin
  18. 18. Procalcitonin
  19. 19. Procalcitonin
  20. 20. Procalcitonin in IFI “Fungi-related sepsis, even severe sepsis or septic shock, does not necessarily elicit a substantial increase in serum PCT”
  21. 21. Procalcitonin and prognosis
  22. 22. Where next?
  23. 23. Cytokines
  24. 24. 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
  25. 25. 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
  26. 26. Leukocyte activation markers Prognostic
  27. 27. 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
  28. 28. Pentraxin-3
  29. 29. 28-day progression
  30. 30. • Detects sepsis – AUC 0.96 • Predicts progression – AUC 0.87 – Sens 82% Spec 89% at 12ng/ml • Did not predict mortality
  31. 31. Is it really that simple?
  32. 32. Obviously NOT!
  33. 33. The Future
  34. 34. Fatty acid b2 oxidation issue in non-survivors v survivors related to carnitine shuttle (defective fatty acid transfer into mitochondria). Detectable at presentation.
  35. 35. Microparticles? • Small vesicles shed from membranes of apoptotic and stress-activated cells – Endothelial cells, RBCs, monocytes, platelets
  36. 36. Conclusion • • • • • • Utility Earlier detection of disease Earlier detection of high risk sub-groups Earlier recognition of treatment success Earlier de-escalation Adjunctive prognostication
  37. 37. Thank you

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