Sepsis - the use of modulators of the

inflammatory response

Dr CM ShevlinAugust 2013

Sepsis

Characterised by systemic cytokine-mediated pro-inflammatory response to invading pathogen

Extensive research/clinical trials

New targets in pro-inflammatory response emerging at rapid rate

Increasing evidence for extensive cross-talk between pro-inflammatory response, anti-inflammatory response, immunomodulation and coagulation cascade

• While PAMPs initiate, dysregulated host response amplifies = cellular injury, SIRS and MOF

• Rich source of potential targetsCohen, J. Clin Microbiol Infect 2009; 15: 302–307

Targets for modification

The established...corticosteroids...

And the aspirational...

Cytokines

Activated Protein C

Renal replacement therapies

And many others...

Corticosteroids

Substantial evidence that inability to mount appropriate HPA axis response plays a role in systemic inflammation and host inability to suppress

Still controversial benefit vs risk...?

Not clear whether our current approach to steroid therapy is evidence-based, aimed at “replacement therapy” or modest immunosuppression

Rationale for steroids

Evidence for over-activity of pro-inflammatory pathways relative to endogenous glucocorticoid activity

Glucocorticoids molecular mechanism of action fits with the pathophysiology of sepsis...

Restores cardiovascular stability in sepsis

retention of sodium and water

synergistic with inotropes

Evidence for steroids

Schumer (1976): short course of high dose steroids

Cronin et al (1995), Bollaert PE et all (1998), Briegel et al (1999): meta-analyses and large double blind trials = lower dose of hydrocortisone

Annane (multiple, 2000-2006)... Became standard of care [fludrocortisone, ACTH test]

CORTICUS (2008)

Now...? Surviving sepsis guidelines (2013)

Where do we stand?

Which patients?

Should we performing an ACTH test?

When should they given?

How long for?

How should it be given? IV/PO...Bolus/Infusion

Cytokines

Functional class of small protein mediators which affect activation of immune response

“Pro-inflammatory” (TNF, IL-1, IL-6, IL12, MIF) activate innate/adaptive immune response and ‘cytokine cascade’

“Anti-inflammatory” (IL-10, TGF, IL-4) attempt to restore immunological equilibrium

Redundancy in the system may make targeted therapy ineffective... not simple division into pro- and anti but complex network

Specific cytokine targets

TNF probably best example of mediator that has been extensively investigated as a therapeutic target

encouraging preclinical evidence, several large phase III clinical trials - no strategy has succeeded

IL-1, IL-6 and MIF

Anti-inflammatory cytokines - IL10, IL4, TGF

Specific cytokine targets II

New players:

IL-17

high-mobility group box-1 protein

myeloid related proteins

Unclear why human trials so far unsuccessful

Activated Protein C

aPC developed on basis of Protein C - naturally occurring anticoagulant -consumed in sepsis (correlated with outcome)

Additional anti-inflammatory action = preventing excessive generation of thrombin. May prevent production of pro-inflammatory cytokines

PROWESS and PROWESS-SHOCKThe PROWESS phase 3 clinical trial subsequently showed that the treatment of severe sepsis with rhAPC reduced the relative and absolute death risk by 19.4 and 6.1%, respectively. By what mechanism?

Renal replacement therapies

If targeted therapies don’t work... would whole “blood purification”?

Rationale: non-selective removal of inflammatory mediators/bacterial products

Promising results (case series only) with all techniques - haemofiltration/dialysis, variety adsorption mediums...

Ongoing randomised trials

Renal replacement therapies II

No large-scale studies with answers to timing, duration, frequency of therapies

At least 1 RCT did not demonstrate improvement in clearance or outcome

Currently insufficient data to support use of haemofiltration in absence of renal failure

Targets still under investigation

Toll-like receptors

Beta-adrenergic modulation

Anti-microbial peptides

Gene inhibition

Statin therapy

Melatonin

Selenium

Conclusion

Reducing mortality in sepsis a clinical need that remains unmet

Designing appropriate therapies has been particularly challenging

Many contributing factors to this

Approaching fifty years of widespread knowledge of existence of inflammatory response to sepsis

Still only one licensed drug available - corticosteroids