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Educational WorkshopEW05: Bacteraemia and sepsisarranged with the ISC Working Group on Bloodstream Infections
Convenor: Evangelos J. Giamarellos-Bourboulisg(Athens, GR)
Faculty: Evangelos J. Giamarellos-Bourboulisy g(Athens, GR)Ralph Corey (Durham, US)Jos van der Meer (Nijmegen, NL)Steven Opal (Providence RI US)Steven Opal (Providence, RI, US)Pierre-François Laterre (Brussels, BE; nopresentation submitted)
Giamarellos-Bourboulis - A patient admitted with hypotension
A PATIENT ADMITTED WITH A PATIENT ADMITTED WITH HYPOTENSIONHYPOTENSION
E. J. GiamarellosE. J. Giamarellos--Bourboulis, MD, PhDBourboulis, MD, PhD
Assistant Professor of MedicineAssistant Professor of Medicine44thth Department of Internal MedicineDepartment of Internal Medicine
University of Athens, Medical School, Greece University of Athens, Medical School, Greece
DISCLOSURE OF INTERESTDISCLOSURE OF INTERESTI have received un-restricted educational grants from:• ABBOTT Laboratories• BRAHMS GmbH• Sanofi-Aventis• Virogates SA• Virogates SA• Wyeth-Ayest S.A.
I have participated in advisory boards of:• ASTELLAS SA • Novartis SA
CASECASE--HISTORYHISTORY• 53 yrs male patient• Admitted to the ER for dyspnoea
HISTORY• Fever up to 390C starting 48 hours prior admission• Aggravated by dyspnoea the last two hours
PHYSICAL EXAMINATION• 30 breaths/min; 110 beats/min• SBP: 80 mmHg• Fails to respond to commands • Hoarse crackles over the lower right lung field
3
Giamarellos-Bourboulis - A patient admitted with hypotension
HOW YOU SHOULD REACT?
1. Sampling for blood gases2. Administer vassopressors3. Administer oxygen via mask4 Administer fluids iv4. Administer fluids iv5. Ask for chest X-ray6. Answers 3 and 4
SEPSIS MANAGEMENT TEAM(www.sepsis.gr)
Coordinator
Resuscitation EvaluationSeverityUnderlying infection
IN YOUR OPINION, THE PATIENT PRESENTS WITH?
1. Uncomplicated sepsis2. Severe sepsis3. Septic shock4 None of the above4. None of the above
4
Giamarellos-Bourboulis - A patient admitted with hypotension
WHAT TESTS ARE ABSOLUTELY NECESSARY?
1. Blood gas2. Blood cultures3. Serum biochemistry4 Procalcitonin (PCT)4. Procalcitonin (PCT)5. All the above6. Answers 1 and 2
UNCOMPLICATED SEPSISUNCOMPLICATED SEPSISAny clinically or microbiologically documented
infection + ≥ 2:
• Temperature >380C or <360C• Pulse rate >90 beats/min• Breath rate >20/min or PaCO2 <32 mmHg• White blood cells >12000/mm3 or <4000 mm3
or >10% immature bands
Levy M, et al. Crit Care Med 2003; 31: 1250
SEVERE SEPSISSEVERE SEPSISSepsis hypoperfusion + ≥1 organ failure
ARDSPaO2/FiO2<200 + diffuse shadows in chest X-ray
Central nervous systemAbrupt change of mental status
Acute renal failureUrine output <0.5 ml/h/kg weight last 2 h + normal balance
Metabolic acidosispH <7.30 or base deficit > 5 mmol/l+ lactate > 2 x upper normal
Acute coagulopathyPLTs <100.000/mm3 or INR >1.5
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Giamarellos-Bourboulis - A patient admitted with hypotension
SEPTIC SHOCKSEPTIC SHOCK
Severe sepsis + SBP < 90 mmHg
despite adequate fluid resuscitationNEED FOR VASOPRESSORS
Levy M, et al. Crit Care Med 2003; 31: 1250
HOW YOU WOULD APPORACH INFECTION DIAGNOSIS?
1. Chest X-ray2. Abdominal ultrasound3. Urianalysis and culture4 Whole body CT scanning4. Whole body CT scanning5. All the above6. Answers 1, 2 and 3
ATTENTION!!!ATTENTION!!!The infection may be widespread +
Control of the infection site by the minimal invasive technique
Guided BUT not limited to what physical findings SUGGEST
Calandra & Cohen. Crit Care Med 2005; 33: 1639
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Giamarellos-Bourboulis - A patient admitted with hypotension
HOW YOU SHOULD IMMEDIATELY TREAT?
1. Place central catheter2. Administer vassopressors3. Administer lots of fluids iv 4 Administer lots of fluids iv and then administer4. Administer lots of fluids iv and then administer
antimicrobials5. Answers 1 and 3
EARLY GOALEARLY GOAL--DIRECTED THERAPYDIRECTED THERAPY(Rivers E, et al. (Rivers E, et al. N Engl J Med N Engl J Med 2001; 345: 1368)2001; 345: 1368)
• CVP: 8-12 cmH2O• SBP ≥90 mmHg or MAP ≥65 mmHg• Urine output ≥ 0.5ml/Kg/h• SatO2 ≥92%• SatVO2 ≥70%
EARLY ANTIMICROBIALS!!!EARLY ANTIMICROBIALS!!!(Kumar A, et al. (Kumar A, et al. Crit Care Med Crit Care Med 2006; 34: 1589)2006; 34: 1589)
%)
100
80
OutcomeCumulative effective antimicrobial therapy
Time (h) after hypotension
0-0.99 1-1.99 2-2.99 3-3.99 4-4.99 5-5.99 6-6.99
Sur
viva
l (% 80
60
40
20
0
7
Giamarellos-Bourboulis - A patient admitted with hypotension
HOW CAN YOU EVALUATE THE IMMUNE STATUS OF THIS PATIENT?
Sampling for:1. Procalcitonin (PCT)2. Lymphocyte subsets counts3. CD14/HLA-DR co-expression4. The ratio of circulating IL-10/TNFα5. All the above are of theoritical value
Phase 1: Hyper-inflammation
MONOCYTE
↑↑NFκBPRRPAMP TF
↑↑Pro-inflammatory cytokines
Clinical sepsis
Endothelium
Oedema
Hyper-coagulationHMGB1mtDNA
↓PC
Phase 2: Hypo-inflammation
MONOCYTE
↓↓NFκBPRRPAMP
↓↓Pro-inflammatory cytokines
↓↓Antigen-presentation (CD14/HLA-DR)TH1 <<< TH2 (IL-10/TNFα)
MODS
Antonopoulou & Giamarellos-Bourboulis. Immunotherapy 2011; 3: 117
THE INFLAMMASOMESTHE INFLAMMASOMES((Martinon F, et al. Martinon F, et al. Ann Rev Immunol Ann Rev Immunol 2009; 27: 229)2009; 27: 229)
MDP (Gram+); dsDNA; Oxygen radicalsIL-1β
Pro-caspase-1 Caspase-1
pro-IL-1β
IL-1βPYRIN NACHT LRRs
PYR
INN
AC
HT
LRR
s
PYR
INN
AC
HT
LRR
s
PYR
INN
AC
HT
LRR
s NALPs, IPAF, NODs
8
Giamarellos-Bourboulis - A patient admitted with hypotension
TLR4TLR4--INFLAMMASOME INTERACTIONSINFLAMMASOME INTERACTIONS
LPS
IL 1β
TLR4Gram (-)
NOD-2NALP3 inflammasome
Pro-caspase-1 Caspase-1
pro-IL-1β
IL-1βURATE
Giamarellos-Bourboulis EJ, et al. Ann Rheum DIs 2009; 68: 273Giamarellos-Bourboulis EJ, et al. Crit Care 2011; 15: R27
TRANSITION TO ADAPTIVE IMMUNITYTRANSITION TO ADAPTIVE IMMUNITY
ANTIGENMHC-II
Th-1 cytokines
ΤΝΤΝFFα, α, ILIL--2, IFN2, IFNγγNaiveT cell
APC
Th-2 cytokines
ILIL--44, , ΙΙLL--6, IL6, IL--1010
Netea MG, et al. J Immunol 2006; 172: 3712
IL-12/23T17 (IL-17) T regulatory cells
Th1 response
ΤΝΤΝFFα, α, ILIL--2, IFN2, IFNγγ
Th2 response
ILIL--44, , ΙΙLL--6, IL6, IL--1010
(-)
? anti-TNFs? age
Tregs
(-)
↑ inflammation↑ PMNs chemotaxis↑ phagocytosis
? co-morbidities
Antachopoulos & Roilides. Br J Hematol 2005; 129: 583Filler SG, et al. Clin Infect Dis 2005; 41 Suppl3: S208
T17 response
ILIL--1717
(+)
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Giamarellos-Bourboulis - A patient admitted with hypotension
APOPTOSIS AND SEVERE SEPSISAPOPTOSIS AND SEVERE SEPSIS(Vaki I, et al. (Vaki I, et al. J Leuk Biol J Leuk Biol 2011; 89: 343)2011; 89: 343)
Sampled serum <12 h (circulating factor)
CD4-LYMPHOCYTE CD14-MONOCYTE
↑↑↑↑CaspaseCaspase--88
APOPTOSIS
↑↑↑↑CaspaseCaspase--99
↑↑↑↑↑↑CaspaseCaspase--33
↓↓↓↓CaspaseCaspase--88
IMMORTAL
↓↓CaspaseCaspase--99
↓↓↓↓↓↓CaspaseCaspase--33
HETEROGENEITY OF PATIENTSHETEROGENEITY OF PATIENTS(Gogos C, et al. (Gogos C, et al. Crit Care Crit Care 2010; 14: R96)2010; 14: R96)
APOPTOSISCD14(+)/HLA-DR(+)
**
** **
**p<0.05 vs sepsis
*
** **
NKsAPOPTOSIS
NKT
** ** **
*p<0.05 vs other infections; **p<0.05 vs sepsis
APOPTOSIS
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Giamarellos-Bourboulis - A patient admitted with hypotension
APOPTOSISCD4(+)
CD8(+) * *
** **
APOPTOSIS( )
******
*p<0.05 vs other infections; **p<0.05 vs sepsis
B-lymphocytes
**
**p<0.05 vs sepsis
GOLDEN HOUR
• Fluids iv• Blood culture• Antimicrobials
• Physical examination• NecessaryLaboratory + radiological investigation
UNPREDICTABLE PATHOPHYSIOLOGY
11
Corey - Is bacteraemia always a septic condition?
G R l h C MDG. Ralph Corey, MDGary Hock Distinguished Professor
Duke University
Milan 2011
Bacteremia with sepsis Early - Organ(s) dysfunction/damage/deathLate – Metastatic infection
Bacteremia without sepsis Benign, self-limitedPersistenceMetastatic infection
SIRS Fever/hypothermiaTachycardiaTachypnea/hypocarbiaLeukocytosis/leukopeniay / p
Sepsis = SIRS induced by an infection – not necessarily an identified BSI!Severe sepsis = SIRs with ≥ 1 organ/system dysfunction Septic shock = severe SIRS with hypotension not easily reversible with fluids
ACCP/SCCM Consensus Conf Committee. Critical Care Med 1992; 20: 864.
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Corey - Is bacteraemia always a septic condition?
Sepsis: 30-50% no definite microbiological etiology foundOf the identified infections:
20% are polymicrobial50% GNR, 50% GPC
Many organisms cultured may not be causing the physiologic changes seen in the host
The SOAP Study. Vincent et al. Crit Care Med 2006
Bacterial Products involved in sepsis include exotoxins and cell wall products
Activation of innate immune system Toll-Like Receptors (TLRs) – first responders
Span cell membrane of effector cells (e.g. macrophages) Recognize:
Pathogen-associated molecular patterns (PAMPs )
TLRs Ligand PathogenTLR1 Lipopeptides Gram negative bacteriaTLR2 Lipoteichoic
acid/PeptidoglycanGram positive bacteria
acid/PeptidoglycanHeat shock proteins/HMGB1 Tissue Damage
TLR4 Lipopolysaccharide/Lipid AHeat shock proteins/HMGB1
Gram negative bacteriaTissue Damage
TLR5 Flagellin BacteriaTLR9 CpG-DNA Bacteria
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Corey - Is bacteraemia always a septic condition?
TLR activity after recognition of PAMPsActivate:
Effector cells like monocytes, macrophages, neutrophils, dendritic cells, NK cells.I t ll l i li thIntracellular signaling pathwaysTranscription factors (NF-kB, etc)Expression of immune response genes/release of cytokines – TNF, IL-1, IFN-v, MIF, HMGB1
Infectious Diseases. Jonathan Cohen. 2010
Type 1 toxins – superantigensS. aureus: TSST-1, enterotoxins A-FS. pyogenes: SPEA, SPEC, SMEZToxin links MHC II receptor on antigen presenting cells to Vβsubunit of T-cell receptorL l ti f T ll ti t d/ i Large population of T-cells activated/massive pro-inflammatory cytokine release
Type 1 toxin-induced sepsis depends on both bacterial and host factors:
Quantity of toxin (e.g. super-absorbent tampon)Pre-existing antibodiesComposition of host MHC moleculesHost T-lymphocyte repetoire of Vβ subunits
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Corey - Is bacteraemia always a septic condition?
Type 2 toxins MRSA: α-hemolysin, PVL, coagulase, DNAse, etcGAS: IL1β convertase, proteases, streptolysin-OC. difficile – α-toxin (mediates cell entry) and β toxin (cytoxic) –NAP1/027 (mutation of toxin suppressor gene) Many others
Infectious Diseases. Jonathan Cohen. 2010
The OrganismInnate characteristicsBacterial loadOriginOrigin
Source control
The HostGenetic characteristicsAcquired frailties
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Corey - Is bacteraemia always a septic condition?
Bacterial LoadOrganism growth – e.g. S. aureus USA300 – 30 min doubling time Timing of diagnosis
Outpatient vs. Inpatient onset Origin of BSI
Catheters – lower metastatic infection rate than non-CRBSI (14% vs. 33%)Concomitant illness – mortality of bacteremic pnx >> bacteremic skin infectionPulmonary and abdominal source are the most frequent origin of sepsis; source control is of primary importance
Fowler. Arch Int Med 2003. Rangel-Frausto. JAMA 1995
ElderlyBlunted immune response
Late diagnosis – e.g. less fever
DiabeticsMore severe sepsis, worse outcomesMore severe sepsis, worse outcomesPrimary infection is often more necrotizing
Emphysematous cholecystitis/pyelonephritisImmunocompromised
more acute sepsis if PMNs are absent
Meydani. JAMA 1997. Kourany. Scan J Med 2006. Shiel. Ann Hem 2003
Cytokines - severalMannose-binding protein - polymorphismsCD14 (LPS/PBP receptor) - polymorphismsToll-receptor gene mutations (e.g. TLR4)HLA II polymorphisms and response to superantigensIL1-beta SNP
Infectious Diseases. Jonathan Cohen/ William Powderly . P. 481. Vol 1; 2010Clark. Int Care Med 2006
16
Corey - Is bacteraemia always a septic condition?
Fibronectin Binding Protein polymorphismsResistance to Thrombin-induced Platelet
b d lMicrobicidal ProteinIntrinsic resistant profile
MRSAEnterococcusESBLs, etc
Dhawan. J Immun 1998. Vincent, SOAP Study. CCM 2006
Each bacterium appears to have unique characteristics guiding its ability to cause:
SepsispMetastatic infectionsPersistence
Contaminant Septic Shock Metastatic Infection Resistance
S. aureus Rare 2+ 4+ 4+
CoNS 4+ Rare 1+ * 4+
Organisms causing Bloodstream Infections
Virulent streptococci Rare 2-4+ 1+ 1+
Viridans group strep 3+ Rare 1+ 1+
Enterococcus 1+ 1+ 1+* 4+
Gram negative bacilli Rare 4+ 1+ 4+
* Primarily with intravascular foreign bodies
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Corey - Is bacteraemia always a septic condition?
Lowy, NEJM 1998.
Induces shock through 2 mechanismsSuperantigen related“Gram Negative Sepsis” Pathway - TLR2All comer mortality 24% at 12 weeks
MSSA/HA-MRSA/CA-MRSANo evidence of worse outcomes in ptswith USA300 PVL+ (except in pnx!) Agr – quorum sensing switch –adhesins to exotoxin expression
Lalani JCM 2008. Fowler Arch Int Med 2003
90% contaminants or of such low virulence minimal treatment is needed
Significant variation between strainsPrimary focus is adherence and biofilm production
No prominent virulence factors p
S. lugdenesis can act much like a second cousin to S. aureus (endocarditis) but most of the time is just another CoNS!
Toxins: delta-like hemolytic peptide, Dnase, agr locus
“No one dies of S. epi bacteremia”
Zinkernagel. Infection 36, 314, 2008. Elbright. Diag Micro ID 48, 17, 2004
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Corey - Is bacteraemia always a septic condition?
Group ASevere sepsis and shock are frequent
TSST-2 and other superantigens, Strep pyogenic exotoxins (Spe) which induce proinflammatory cytokines (TNF-a, IL-1B, IL-6)M protein (anti-phagocytic) Streptolysin O and S (pore forming/membrane damage)Streptolysin O and S (pore forming/membrane damage)25-35% mortality
C, GUncommon causes of bacteremia; skin origin and often cultured with S. aureus; primarily pts with diabetes, alcohol and malignancies M protein Streptolysin O20%-30% mortality;
Low virulence transient bacteremia; contaminants (20%)No endo or exotoxins
Dextran production and Fim A facilitate adherence Lipoteichoic acid adheres to fibronectin on damaged heart valves
Rarel induces TNF α production mimicks E coli sepsisRarely induces TNF-α production - mimicks E. coli sepsis
Prolonged bacteremia in neutropenia Mucositis with cancer RxCentral venous catheter25% have fulminant shock syndrome!
-S. mitis. 6-12% mortality
Tunkel. CID 1992. Marron ICCAC Abstract 1998
E. faecalis/E. faeciumCytolysin/hemolysin (in about 33% of EFS), gelatinase(important in IE), proteasesfsr quorum sensing system
Ace (Efs)/Acm (Efm), ElrA, pili are MSCRAMM family-facilitate attachment attachment Surface polyscchacharides – biofilm and antibody blocking
Bottom line: Sepsis is rare Bacteremia is common
Barbara Murray, personal communication
19
Corey - Is bacteraemia always a septic condition?
Most common causes of sepsis are E. coli, Klebsiella, and Pseudomonas. Long list of toxins, enzymes facilitating sepsis
Lipopolysaccharide/lipid A Hemolysin – E coliHemolysin – E. coliFimbriae, piliEnzyme secretion systemsMetalloprotease – C1’esterase inh.Plasmids – e.g. Shigatoxin, EHEC
Mortality is ~30%
Angus. CCM 2001
Blood Stream Infections result in a complex variety of pathogen and host interactionsFuture efforts will need to take into account many factors in determining prognosis:
P th h t i tiPathogen characteristicsAbility to cause septic shock (Gram negative bacilli)Ability to cause local tissue infection (S. aureus)Ability to evade host defenses (persistence – VRE, hVISA)
Host defenses/frailtiesTiming/Source of diagnosis
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van der Meer - How to choose the correct antibiotics
How to choose the correct antibiotics
Jos WM van der Meer MD PhD FRCP(Lon) FRCP (Edin)Professor of MedicineDept Internal MedicineDept Internal Medicine
Director of Nijmegen Institute for Infection Inflammation and Immunity
Radboud University Medical Center, NijmegenThe Netherlands
The problem with antibiotic therapy
• Antibiotic treatment schedules are not strongly evidence based.
• There are many underpowered trialsTh ld d h t b • The older drugs have not been investigated in modern RCTs
• Most of the clinical trials have been initiated and sponsored by industry and deal with new antibiotics
Sponsored vs. Non-sponsored RCTs
New drug superiorDjulbegovic, Lancet 2000
21
van der Meer - How to choose the correct antibiotics
The problem with antibiotic therapy
Trials have been directed towards demonstrating efficacy and virtually never towards the effects on emergence of resistanceemergence of resistance,and never bothered about antibiotic policy
The problem with antibiotic therapy
• The results of an RCT in one part of the world do not necessarily apply to other parts of the world
– US guidelines on CAP and sepsis do not – US guidelines on CAP and sepsis do not necessarily apply to Europe
– Sepsis guidelines within Europe should differ greatly
– Antimicrobial guidelines have to be updated at greater pace
PNSP MRSA< 1%1-5%5-<10%10-<25%25-<50%>50%
EARSS 2009
VRE 3dG CephR KP FQ-R KP
22
van der Meer - How to choose the correct antibiotics
2010The shit hit the fan
NDM-1 in Asia en UK
23
van der Meer - How to choose the correct antibiotics
Not only NDM-1!
• MRSA• VISA• VRE
• ESBL• Carbapenemase producing Klebsiella• ...
The crisis is there!
LANCET April 7, 2011, e pub
24
van der Meer - How to choose the correct antibiotics
The Netherlands
• Low resistance rates• Low AB usage rates
Recent dataRecent data• Pig MRSA• Rapidly increasing
ESBL• High use of AB in
veterinary/ agriculture
The Netherlands
• Corruptive practices of veterinarians and politicians?
I’m not going to eat vegetables! They contain resistant bacteria
• Resistance genes in soil, meat, poultry and vegetables
• Solutions??
Consequences for guidelines
• Each hospital should have its updated local guidelines– Based local epidemiology and susceptibility
datadata– Anchored in national consensus guidelines
[SWAB in the Netherlands]
And install governance in implementation! Who is allowed to prescribe which drug?
25
van der Meer - How to choose the correct antibiotics
GuidelinesBased on:• RCTs• Evidence from clinical studies• Clinical experience
‘we make the same mistake a thousand times and call it clinical experience’
• Extrapolation from in-vitro susceptibility data
How to select provisional antibiotics for treatment
The drug should:• be effective against the suspected causative
organism• reach adequate concentrations at the site of q
infection• not readily lead tot resistance (in the patient and
the environment)• be the least toxic• be available for the desired route of
administration• cheap
How to select provisional antibiotics for treatment
• Effective against the suspected organism– What does the guideline say?
What do clinical trials say?– What do clinical trials say?– What does recent surveillance say– Is there a reason to suspect resistance?
Previous antibiotics? Travel? Agriculture? Animals? Stay in health care facility?
26
van der Meer - How to choose the correct antibiotics
Streamlining more important than ever
• There are very few trials on streamlining
• If we start on broadspectrum treatment because of presumed treatment because of presumed resistance, rapid response to (rapid !?) microbiology is essential
• We should rapidly de-escalate (streamline) treatment
Carlet et al, Lancet 2011
We have watched too passively as the treasury of drugs that has served us well has been stripped of its value. We urge our collegues worldwide to take urge our collegues worldwide to take responsibility for the protection of this precious resource. There is no longer time for silence and complacency.
27
Opal - The need for immunomodulation
The need for immunomodulation in the Management of Sepsis:
New targets, new treatments?
Steven M. Opal MDESCMID meeting
Milan, ItalyMay 7, 2011
COI: institutional grants from Atoxbio, Sirtris, Astra-Zeneca, Agennix
LPS Mϕ
Sepsis induces disordered inflammation:
Rx should re-establish normal immune function
LPS Mϕ
nuclear localization sequence
3’5’ 5’
3’DNA NFκB
Host response-antimicrobial defense programs
DNA NFκB
MiMicroorganismscroorganisms
Immune cellsImmune cells
5 PRR5 PRRss
PAMPsPAMPs DAMPsDAMPs HSPHeparan
HyaluronateFibrinogenBiglycan
Surfactant AHMGB-1
HemeMRP8/14Histone
NLRs
HostHost--derived derived mmediaediatorstors
Caspase-1 & 5ASC
NALP1 & 3Pyrin
ASCNF-κB
TLRsNLRs
RLHs
Cinel and Opal CCM 2009;291 -courtesy of T. Calandra
CLRs CDRs
28
Opal - The need for immunomodulation
C. Nathan Cell 2010;140:871
Virulent pathogens (pneumococci, meningococcus, Group A strep, S. aureus, Clostrida spp.)
Pro-inflammatory markers-cytokines, chemokines C’
C, ROS RNS kinins, procoagulants
Early onset septic shock, MODS
• Invasive pathogens (pneumococcus, S. aureus, Group A strep, Clostridia, meningococci), rapid onset, in young previously healthy patients
• Proinflammatory mediators of innate immunity-cytokines, chemokines, procoagulants, kinins, ROI, RNI, C’
Traditional view of sepsis and its pathophysiology
(Hotchkiss and Karl N Engl J Med 2003;348:138)
Virulent pathogens (pneumococci, meningococcus, Group A strep, S. aureus, Clostrida spp.)
Pro-inflammatory markers-cytokines, chemokines C’
C, ROS RNS kinins, procoagulants
Early onset septic shock, MODS
•Less virulent pathogens: Stenotrophomonas,enterococci, Acinetobacter, CMV, Candida
•Anti-inflammatory state-cytokines, apoptosis, LPS reprogramming, Decreased HLA DR, TNFR, TLR4, expanded Treg cells, MDSCs, PMNs persist
• gradual deterioration and progressive organ
Realistic view of sepsis and its pathophysiology
Innate immunity
(Hotchkiss and Karl N Engl J Med 2003;348:138)
failure-fits most of our patients
Sepsis-induced immunosuppression
Hotchkiss, Karl N Engl J Med 2003;348:138
Adaptive immunity
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Opal - The need for immunomodulation
The main dimerization interfaceof the TLR4–MD-2–LPS complex.
Can Sepsis-induced immunosuppression be treated?
Φreprograming
BS Park et al. Nature 000, 1-5 (2009) doi:10.1038/nature07830
Hotchkiss and Opal N Engl J Med 2010 Hotchkiss and Opal N Engl J Med 2010;361(1):87
Regulate co-stimulators: CD28/80
Block co-inhibitors: PD1, BTLA, CTLA4
Support cells:IL-7,15, GM-CSF
Necrotic or Pyropoptic
cells
Fadok et al. JCI 2001;108:957
Apoptotic cells
Necrotic cells promote cytokine secretion while apoptotic cells attenuate cytokine generation
Cocco et al. MBC 2001;12:919
In the absence of LPS both necrotic and apoptotic cells were poor inducers of cytokines by Mφ
30
Opal - The need for immunomodulation
Role of IL-1α in necrosis versus apoptosis.Inflammatory signals by IL-1α after necrosis or apoptosis
IL-1α
IL-1α
Dinarello C A Blood 2011;117:3720-3732
IL-1RI
Pro-IL-1β IL-1β
Effect of apoptotic cells versus necrotic cells on survival following CLP
CLP-control
CLP+apoptotic cells
CLP+necrotic cells
Copyright ©2003 by the National Academy of SciencesHotchkiss, Richard S. et al. (2003) Proc. Natl. Acad. Sci. USA 100, 6724-6729
Necrotic cell protection is
IFN γ dependent
CLP+apoptotic cells
Th1 Th2IL-4IL-12
The role of Th1/Th2 and Th17/Treg cells in sepsis-immune dysregulation
TGFβ, IL-10
+ fibrogenesis
IL-1 +
Chemokines - fibrogenesis
31
Opal - The need for immunomodulation
1) Treat very early and try to abort the process before immune suppression develops
2) Reverse immune depression after initial resuscitation and promote recovery
3) Tissue hibernation, mitochondrial sparing, repair pro-resolution and regeneration strategies
(Hotchkiss and Karl N Engl J Med 2003;348:138)
Can we rapidly determine the immune status of the patient and intervene appropriately?
TCRCD28
ICOSCTLA4 PD1
BTLA
T cellEarly co-
stimulatory signals
Signal 1
Signal 2
B7-H2
CD80CD86
CD80CD86 PD-
L1 HVEM
MHCII
APC, monocyte/macrophage, some epithelial and endothelial cells
TCRCD28
ICOSCTLA4 PD1
BTLA
T cellEarly co-
stimulatory signals
Late co-inhibitory signals
B7-H2
CD80CD86
CD80CD86 PD-
L1 HVEM
MHCII
APC, monocyte/macrophage, some epithelial and endothelial cells
32
Opal - The need for immunomodulation
PDL1
CD28 mimetics
PD1
Anti-PD1
mimeticsAB 103
Pro-resolution events are active processes-not simply the lack of inflammatory signals
C. Nathan Cell 2010;140:871EET-Epoxyeicosatrienoic acid
Aspirin and statins promote the formation of 15-epi-LXA4Pro-resolving agents for sepsis?
Spite, M. Sherhan C. Circ Res 2010;107:1170-1184
33
Opal - The need for immunomodulation
Novel antiinflammatory and proresolving actions of lipoxins, resolvins, and protectins in the vasculature
Spite, M. and Sherhan Circ Res 2010;107:1170-1184
34