This document discusses the potential utility of biomarkers for diagnosing and prognosing sepsis. It begins by explaining why improving diagnostic and prognostic tools for sepsis is important, as it is a leading cause of death in ICU patients. It then discusses how early detection and treatment are paramount but current detection strategies are limited. The document introduces the biomarker paradigm for sepsis, where biomarkers can identify inflammation, coagulation, tissue damage and repair processes to better stratify severity and prognosticate outcomes. Several candidate biomarkers are discussed, such as procalcitonin, cytokines, chemokines, and pentraxin 3. The document considers how biomarkers may help with diagnosis, prognostication, and identifying high-risk patients and treatment response. It concludes the future

1. Biomarkers in Sepsis
Utility or Futility?
Dr Andrew Ferguson
Consultant in Intensive Care Medicine and Anaesthesia
Craigavon Area Hospital

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. 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. 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. Early detection is paramount
BUT.…

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. 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

9. Enter the goose and the…

10. The biomarker paradigm…
• Sepsis leads to
– Inflammation
– Coagulation
– Tissue damage and repair
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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

11. Damage Associated Molecular Patterns

12. Pathogen Associated Molecular Patterns

13. 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

14. Examples
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Acute phase proteins
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Cytokines & chemokines
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Soluble CD14 (presepsin)
Neutrophil CD64 index (CD64in)
mHLA-DR (monocyte HLA-DR levels)
CD-163
Receptor markers
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Endothelial damage
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Cell surface markers
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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
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VEGF
Soluble VEGF-receptor 1 (sFLT)
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Soluble urokinase plasminogen activator (suPAR)
sTREM-1
RAGE (soluble receptor for advanced glycation
end products)
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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

15. 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?

16. 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

17. Procalcitonin

18. Procalcitonin

19. Procalcitonin

20. Procalcitonin

21. Procalcitonin in IFI
“Fungi-related sepsis, even severe sepsis or septic shock, does not necessarily elicit a
substantial increase in serum PCT”

23. Procalcitonin and prognosis

24. Where next?

25. Cytokines

26. 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

27. Chemokines
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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

28. Leukocyte activation markers
Prognostic

29. 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

30. Pentraxin-3

31. 28-day progression

34. • Detects sepsis
– AUC 0.96
• Predicts progression
– AUC 0.87
– Sens 82% Spec 89% at 12ng/ml
• Did not predict mortality

35. Is it really that simple?

36. Obviously NOT!

37. The Future

38. Fatty acid b2 oxidation issue in non-survivors v survivors related to carnitine shuttle
(defective fatty acid transfer into mitochondria). Detectable at presentation.

39. Microparticles?
• Small vesicles shed from membranes of
apoptotic and stress-activated cells
– Endothelial cells, RBCs, monocytes, platelets

40. Conclusion
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Utility
Earlier detection of disease
Earlier detection of high risk sub-groups
Earlier recognition of treatment success
Earlier de-escalation
Adjunctive prognostication

41. Thank you