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Intracellular signaling pathways of Innate Immunity

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					The Treatment of Sepsis: Slow progress, but continued hope

S. M. Opal, MD ID noon time lecture Aug 27, 2007

Martin et al. N Engl J Med 2003;348:1546

3 fold increase

21 yr CDC study: 10 million cases of severe sepsis in USA

Incidence of Severe Sepsis by Age
120,000
100,000 30

Number of cases Incidence rate

25 20 15 10 5 0

Cases

80,000 60,000
40,000 20,000 0 <1 1 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85+

Age/Years

Incidence/1,000 Population

I----27.8%---I

35% decrease in overall mortality rate over 22 years

I----17.9%---I

LPS
Early Signaling Events of Innate Immunity

Mj

DNA

3’

NFkB
5’



nuclear localization sequence

3’ Host response-antimicrobial defense programs

5’

LPS LBP
CD 14 MD2

TLR 4

LPS signaling pathways in human monocytes
TRAM

IFNb
MyD88

“Fast” LPS signaling pathway

IRAK4 TRAF6 PI3K IKK

Mal P IRAK1 RIP-1 TAB1,2 TAK1 TRAF6 MKK7

g b

MKK6

NFkB
p65 p50

a

IRAK1

JAK “Slow” LPS signaling pathway P Stat 1

IkB
P38, ERK1 P
p300

TBK1

JNK IRF-3
c-Jun p300 p300 IRF-3 IRF-3

p65 p50

CD80, CD83

Cytokines, APP, NOS

IFN-response genes

OMP, PGN BLP TLR 2 TLR 1
CD 14

flagellin
MALP TLR 6
CD 36

TLR 5

TLR 4
CD 14

LPS
RP 105
MD1 CD 19

MD2

Pathogen – associated Molecular pattern receptors

B cells

Cytosol
NOD1 NOD2
CARD NOD

Endosome
PGN-DAP LRR

dsRNA TLR 3
PGN-MDP

CpG DNA

ssRNA ssRNA TLR

TLR 7/8 m/h

9

NFkB p38
p300 creb torc

JNK IRF-3
c-Jun p300 IRF-3 IRF-3

p65 p50

CD80, CD83

Cyokines, APP, NOS

IFN-response genes

Polymorphisms in TLR4

Hypothetical Model of TLR4 With common polymorphisms at D299G and T399I WT Rallabhandi et al J Immunol 2006;177:322 Docking site? Double mutant

Clotting and innate immunity are highly integrated and contribute to sepsis

Hepatic Microcirculationbaseline

30 min post sublethal dose LPS

Intravascular fibrin

PMN-platelet aggregates

Receptor downregulation (TLR 4, TNFR, HLA-DR) Soluble (sIL1,6,TNFr) and decoy receptors (IL-1R2) Receptor antagonists (IL-1ra)

Anti-inflammatory cytokines (IL-4,10,13)
Intracellular inhibitors (SOCS, IkB, Tollip, MyD88s) Cellular apoptosis of B cells CD4 T cells and FDCs

Sepsis-induced immunosuppression

(Hotchkiss and Karl N Engl J Med 2003;348:138)

The Diagnosis of Sepsis
• No single lab test, biomarker, clinical finding or hemodynamic event is sufficient to make a unequivocal diagnosis for sepsis • Clinical Diagnosis of an invasive infection (with or without bloodstream invasion) + a deleterious host response - fever (or hypothermia), leukocytosis (or neutropenia), tissue hypoperfusion with or without systemic hypotension – multiorgan involvement- DIC, ATN, ARDS, CNS dysfunction, Lactic acidosis, hepatic dysfunction – Shock- fluid non-responsive hypotension (BP<90/60) with early hyperdynamic cardiovascular response (high CO, normal Lt Atrial filling pressure, Low SVR)

Surviving Sepsis Campaign - Evidence based review of the medical literature - 2007 Initial evaluation and resuscitation (The golden Six Hours)

• Measure blood lactate • Blood cultures before antibiotics • Broad spectrum antibiotics to cover likely pathogens within 1 hour of presentation • If systolic BP<90 mmHg, or MAP<65 mmHg or lactate >4 mmolar, initial fluid resuscitation with 20-40 ml/kg • Vasopressors for hypotension during & after initial fluid resuscitation • Inotropic agents (and/or PRBCs if Hct <30%) delivered for ScVO2<70% if CVP>8

• 6 hour Goals: CVP 8-12 mmHg; ScVO2>70%; MAP>65 mmHg and blood Lactate normalizing

Septic Shock: Flow-dependent O2 Uptake in the
microcirculation-failure of autoregulation
Distributive hypoxia followed by tissue dysoxia and cytopathic hypoxia Diffuse vasodilation, inflammation, intravascular fibrin, tissue hypoperfusion, myocardial depression

Mixed venous hemoglobin-O2 saturation (SVO2) <70% O2 content very low

Arterial HemoglobinO2 saturation-Normal > 95% O2 content high

microcirculation

Early Goal-Directed Therapy for Severe Sepsis/Septic Shock
60 Standard Therapy EGT 50 40 30 20 10 0
In-hospital 28-day mortality 60-day mortality mortality (all patients) SVO2 >70% and MAP 65 mm Hg in 6 hr

– 42%  in relative risk of 28-day mortality (P=0.009) – 33%  in relative risk of death at 60 days (P=0.03)

• NNT to prevent 1 death = 6-8

Mortality (%)
1o end-point

EGT in patients with severe sepsis produced the following:

Rivers E, et al. N Engl J Med 2001;345:1368-77

5-10% increase in mortality for every hour delay of antibiotic Rx after onset of septic shock

Odds Ratio of Death (95% Confidence Interval)

100

10

1

(N=2731 ICU patients)
Kumar et al. Crit Care Med 2006; 34: 1458

11.

22.

33.

44.

55.

68.

911

12

24

6 >3 99 5. -3

3. -2

99

99

99

99

Time (hrs)

99

99

.9 9

99

Current targets for therapeutic intervention in sepsis

1

PAMP’s

Microbial Mediators
Phospholipids

2

Early host mediators

Immune effector cells

Chemokines Cytokines

3

Platelet-fibrin clots

4

Late host mediators
MIF HMGB-1 Proteases

5

24 Hour Sepsis Bundle:
• Intensive Insulin Rx in Critically Ill Patients
– NEJM 2001;345:1359-67; NEJM 2006;354:449

• Low T V ventilation; keep the lungs dry post-resuscitation
– NEJM 2000;342:1301-8; NEJM 2006;354:2564

• Activated Protein C for Severe Sepsis

– NEJM 2001; 344:699-709; NEJM 2005;353:1332; Lancet 2007; – JAMA 2002; 288:862-71; Corticus (unpublished data)

• Hydrocortisone and Fludrocortisone for Septic Shock • Remove septic focus and source control asap • Feed early and enterally if possible • Provide DVT prophylaxis and elevate the head of the bed

The next 24 hr. - Conservative fluid strategy

Furosemide
UOP < 0.5 ml/kg/h & CVP or PAOP low MAP < 60 Low flow by exam or CI <2.5

KIDNEY

CVP < 4 PAOP < 8

Favors Dry LUNG

Or the Liberal fluid strategy ?

Fluids
FiO2 > 0.7 CI > 4.5 Favors Perfused KIDNEY (organs)

Wet LUNG

CVP 10-14 PAOP 14-18

FACTT trial-favors dry lung (NEJM 2006:354:2564)

Intensive Insulin Therapy in Critically Ill Patients

Van den Berghe et al. Intensive Insulin in Critically Ill Patients. NEJM 2001;345:1359

All patients

If in ICU>3 days

(Van den Berghe et al. NEJM 2006;354:449)

rh Activated Protein C in severe sepsis (PROWESS)
100
Bernard et al. NEJM 2001; 344:699

Percent Survivors

90 Drotrecogin Alfa (activated) (N=850)

80
Placebo (N=840) 70

0 0

p=0.006 (stratified log-rank test)

7

14

21

28

Days from Start of Infusion to Death

The ADDRESS trial – rhAPC in severe sepsis at low risk of death (NEJM 2005;353:1332)

Placebo did better the rhAPC even when APACHE 2 > 24

Additional clinical trials with rhAPC: ENHANCE (no placebo); ADDRESS low risk of death study; Xpress trial (rhAPC+/-heparin); RESOLVE trial placebo-controlled trial in pediatrics

Activated Protein C - Mechanisms of Activity
Co agulation C ascade VIIIa
Va

PAI-1 X TAFI
Increased F ibrinolysis

X

Neutrophil Adhesion
M onocyte Activation

X X

1 1

2

3

X

Prothrom bin Th rom bin

PC

4 4
aPC P S
EPCR CD1/ MH C

Th rom bin
PAR
Th ro m b om od ulin

Fibrin/Platelets A PC Receptor

Cell activation

Anti-apoptotic

Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients With Septic Shock
But: the Corticus trial (n=600) Significantly improved recovery for septic shock but no improvement in overall survival (the primary endpoint)
NS ?Worse outcome in responders

(Annane et al. JAMA 2002; 288:862)

Therapy for severe sepsis/septic shock in 2007
Standard care for sepsis
• •

Consider for sepsis
• • •

Early goal directed therapy Rapidly culture and treat for likely pathogens Source control Optimize supportive care and monitoring Fluids, nutrition, DVT and aspiration prevention

• •

•

•

•

Intensive insulineuglycemia (if feasible) rhAPC (? Another trial) Stress dose steroids (low risk, low cost ?efficacy) Hemoperfusion, diafiltration columns (? Needs to be studied) Participate in clinical trialsstill lots of room for improvement

Current overall mortality 25-35% severe sepsis- 40-45% for septic shock managed in the ICU

MKSAP questions: #1
• 30 yo man with no significant PMH presents with a 1 day hx of increasing pain in right leg 2 days after a splinter was removed from his rt thigh. Initial exam is unremarkable other than marked thigh tenderness. Lab studies in ER normal expect CT scan evidence FB in thigh with some stranding and edema rt thigh. He now develops acute deterioration BP 60/0 and renal and hepatic insufficiency. • The most appropriate empiric antibiotic choice at this point is ?:
– – – – – 1) Nafcillin and aztreonam 2) Nafcillin and clindamycin 3) Nafcillin and piperacillin-tazabactam 4) Vancomycin and clindamycin 5) Piperacillin-tazabactam and gentamicin

• Correct answer is 4

MKSAP questions: #2
• 15 yo boy with no significant PMH presents with swelling and pain after abrading his arm in a high school football game. He rapidly develops fever, confusion, and orthostatic hypotension. Initial exam shows marked erthyema, edema tenderness in the right arm and an area of pale gray skin suggestive of dermal necrosis. Lab studies show multisystem dysfunction and blood cultures are positive for gram-positive cocci in chains. Which of the following prophylactic agents should be offered to the household contacts ?:
– – – – – 1) oral Penicillin V (PCN) 2) IM benzathine PCN 3) Throat cultures followed by oral PCN 4) Throat cultures followed by clindamycin 5) No prophylaxis indicated

•

•

Correct answer is 5

MKSAP questions: #3
• 35 yo man presents to the ER with acute onset fever, dyspnea, nausea, vomiting, malaise, watery sputum with occasional hemoptysis. He works as a veterinarian at a local zoo. His mother, with whom he lives, died of an unknown type of pneumonia 4 days earlier.The USA has just issued a code red terrorism risk in the past 7 days. Exam shows fever, tachypnea, tachycardia and mild hypotension. Physical exam and radiographic findings confirm a dense right sided consolidation without any significant hilar lymphadenopathy. Therapy with ceftriaxone and clarithromycin is not effective and the patient dies from septic shock, DIC and respiratory failure. The laboratory calls to report the blood cultures are now positive for an unidentified gramnegative rod. The most likely bacterial pathogen is ?:
– – – – – 1) Yersinia pestis 2) Bacillus anthracis 3) Haemophilus influenzae 4) Francisella tularensis 5) Coxiella burnetti

•

•

Correct answer is 1


				
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