This document discusses potential targets for modulating the inflammatory response in sepsis. It summarizes research on cytokines like TNF and IL-1 that have been investigated as therapeutic targets but with unsuccessful human trials so far. Activated protein C is discussed as having shown a reduction in death risk in clinical trials by preventing excessive thrombin generation. Corticosteroids are established as standard of care based on evidence from several trials. Renal replacement therapies also show promise but require more large-scale studies. In conclusion, reducing sepsis mortality remains a challenge despite decades of research into modulating the inflammatory response.

1. Sepsis - the use of modulators
of the inflammatory response
Dr CM Shevlin
August 2013

2. 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

3. • While PAMPs initiate, dysregulated host response
amplifies = cellular injury, SIRS and MOF
• Rich source of potential targets
Cohen, J. Clin Microbiol Infect 2009; 15: 302–307

4. Targets for modification
The established...corticosteroids...
And the aspirational...
Cytokines
Activated Protein C
Renal replacement therapies
And many others...

5. 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

6. 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

7. 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)

8. 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

9. 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

10. 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

11. Specific cytokine targets II
New players:
IL-17
high-mobility group box-1 protein
myeloid related proteins
Unclear why human trials so far unsuccessful

12. 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-SHOCK
The 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?

13. 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

14. 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

15. Targets still under investigation
Toll-like receptors
Beta-adrenergic modulation
Anti-microbial peptides
Gene inhibition
Statin therapy
Melatonin
Selenium

16. 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