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

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…

BIOMARKERS

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

DIAGNOSIS

Procalcitonin

DIAGNOSIS

Procalcitonin

DIAGNOSIS

Procalcitonin

DIAGNOSIS

Procalcitonin in IFI

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

DIAGNOSIS

PROGNOSIS

Procalcitonin and prognosis

PROGNOSIS

Where next?

Cytokines

Faix JD. Crit Rev Clin Lab Sci, 2013; 50(1): 23–36

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

Faix JD. Crit Rev Clin Lab Sci, 2013; 50(1): 23–36

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-3PROGNOSIS

28-day progressionPROGNOSIS

DIAGNOSIS

PROGNOSIS

• Detects sepsis– AUC 0.96

• Predicts progression– AUC 0.87– Sens 82% Spec 89% at 12ng/ml

• Did not predict mortality

PROGNOSIS

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

• Biomarkers have utility and potential• Earlier detection of disease• Earlier detection of high risk sub-groups• Earlier recognition of treatment success• Earlier de-escalation• Adjunctive prognostication