Download - Sepsistargets
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