EW05 01 Giamarellos.ppt [Kompatibilitätsmodus]€¦ · Metabolic acidosis pH 5 mmol/l + lactate >...

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


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


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

5


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

6


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


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


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

(+)

9


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

10


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.

12


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

13


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

14


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

15


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


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

17


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

18


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


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

20

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



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 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


2010The shit hit the fan

NDM-1 in Asia en UK

23


Not only NDM-1!

• MRSA• VISA• VRE

• ESBL• Carbapenemase producing Klebsiella• ...

The crisis is there!

LANCET April 7, 2011, e pub

24


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


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


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


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


failure-fits most of our patients

Sepsis-induced immunosuppression

Hotchkiss, Karl N Engl J Med 2003;348:138

Adaptive immunity

29


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


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


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


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


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


Novel antiinflammatory and proresolving actions of lipoxins, resolvins, and protectins in the vasculature

Spite, M. and Sherhan Circ Res 2010;107:1170-1184

34

EW05 01 Giamarellos.ppt [Kompatibilitätsmodus]€¦ · Metabolic acidosis pH 5 mmol/l + lactate >...

Documents

Transcript of EW05 01 Giamarellos.ppt [Kompatibilitätsmodus]€¦ · Metabolic acidosis pH 5 mmol/l + lactate >...