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

Early detection is paramount

BUT.…

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

1

2

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

Enter the goose and the…

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

Damage Associated Molecular Patterns

Pathogen Associated Molecular Patterns

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

Procalcitonin

Procalcitonin

Procalcitonin

Procalcitonin in IFI

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

Procalcitonin and prognosis

Where next?

Cytokines

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

Leukocyte activation markers

Prognostic

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

Pentraxin-3

28-day progression

• Detects sepsis

– AUC 0.96

• Predicts progression

– AUC 0.87

– Sens 82% Spec 89% at 12ng/ml

• Did not predict mortality

Is it really that simple?

Obviously NOT!

The Future

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

Thank you