Intracellular signaling pathways of Innate Immunity “to Toll-Like

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Intracellular signaling pathways of Innate Immunity “to Toll-Like Powered By Docstoc
					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                                                               30




                                                                                   Incidence/1,000 Population
        100,000          Number of cases                                      25
                         Incidence rate
         80,000                                                               20
Cases




         60,000                                                               15


        40,000                                                                10


        20,000                                                                5

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

                                          Age/Years
                  35% decrease in
I----27.8%---I    overall mortality
                 rate over 22 years




                    I----17.9%---I
     LPS                                 Mj


 Early Signaling Events
 of Innate Immunity




                               3’
     DNA                                 NFkB         nuclear
                                                    localization
                                                      sequence
                                    5’
5’
     3’




     Host response-antimicrobial
          defense programs
                                    TLR           LPS signaling pathways
                 LPS                 4
                                                  in human monocytes
     LBP               CD
                       14
                        MD2
                                           TRAM


                                                              IFNb
                 MyD88              Mal P
                    IRAK4          IRAK1
    “Fast” LPS
                                                  RIP-1
     signaling
                           TRAF6           TAB1,2
     pathway                                                      JAK
                    PI3K                   TAK1              “Slow” LPS
                            IKK     g                         signaling
                                                  TRAF6
            MKK6            a       b                         pathway P
                       NFkB                               IRAK1
                                        MKK7                         Stat 1
                       p65 p50
                                                           TBK1
                          IkB           JNK
P38, ERK1
                   p300
                                                          IRF-3
            P
                 p65 p50           c-Jun         p300
                                                p300
                                            IRF-3 IRF-3

                    Cytokines,
    CD80, CD83      APP, NOS                IFN-response genes
 OMP, PGN                                                        LPS
                           flagellin            TLR                                 Pathogen –
BLP         MALP           TLR                   4               RP                 associated
                            5                                   105                  Molecular
      TLR   TLR                                           CD
       2     6                                 MD2        14                  CD      pattern
                                                                              19
              CD                                                MD1                  receptors
TLR           36
 1
                                                                   B cells
 CD
 14

                                                                          Endosome
                           Cytosol              PGN-DAP
                                                                                       CpG DNA
                                                                 dsRNA
                        CARD     NOD          LRR                              ssRNA
             NOD1                                                TLR          ssRNA TLR
                                                                  3           TLR       9
             NOD2                                                             7/8
                                                    PGN-MDP
                                                                              m/h

                                         NFkB             JNK
                  p38
                                       p300
                                                                               IRF-3
                                  p65 p50               c-Jun        p300
               creb torc                                        IRF-3 IRF-3

                                         Cyokines,
                    CD80, CD83           APP, NOS           IFN-response genes
                    Polymorphisms in TLR4



  Hypothetical
 Model of TLR4
  With common
polymorphisms at
D299G and T399I

                    WT         Double mutant
Rallabhandi et al
   J Immunol
 2006;177:322
                          Docking
                           site?
                   Clotting and innate immunity are highly
                     integrated and contribute to sepsis




Hepatic Microcirculation-
        baseline
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

                                                 Diffuse vasodilation,
     Distributive
                                                 inflammation,
  hypoxia followed
                                                 intravascular fibrin, tissue
  by tissue dysoxia
                                                 hypoperfusion,
   and cytopathic
                                                 myocardial depression
       hypoxia




                                                       Arterial Hemoglobin-
Mixed venous
                                                       O2 saturation-Normal
hemoglobin-O2
                                                       > 95%
saturation (SVO2) <70%
                                                       O2 content high
O2 content very low

                            microcirculation
  Early Goal-Directed Therapy for Severe Sepsis/Septic Shock

                                 60
EGT in patients                                           Standard Therapy       EGT
  with severe                    50




                                      Mortality (%)
  sepsis produced                40
  the following:
   – 42%  in relative           30
     risk of 28-day
     mortality (P=0.009)         20
   – 33%  in relative
     risk of death at 60         10
     days (P=0.03)
• NNT to prevent 1                0
  death = 6-8                                          In-hospital   28-day mortality 60-day mortality
                                                      mortality (all
                                                        patients) SVO2 >70% and MAP 65 mm Hg in 6 hr


                                                      1o end-point
 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
(95% Confidence Interval)

                            100
   Odds Ratio of Death




                             10




                              1
                                  1-

                                        2-

                                              3-

                                                    4-

                                                           5-

                                                                   6-

                                                                        9-

                                                                              12

                                                                                       24

                                                                                             >3
                                   1.

                                         2.

                                               3.

                                                     4.

                                                              5.

                                                                   8.

                                                                         11

                                                                                  -2

                                                                                        -3

                                                                                                 6
                                    99

                                          99

                                                99

                                                         99

                                                              99

                                                                    99




                                                                                   3.

                                                                                            5.
                                                                             .9
                                                                              9

                                                                                       99

                                                                                             99
     (N=2731 ICU patients)
                                                         Time (hrs)
             Kumar et al. Crit Care Med 2006; 34: 1458
        Current targets for therapeutic intervention in sepsis

        1   PAMP’s         Microbial Mediators

                     Phospholipids
                                             Immune effector
                                                 cells
    Early host       Chemokines
2   mediators
                   Cytokines



    3    Platelet-fibrin
             clots                    Late host
                                  4   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;

• Hydrocortisone and Fludrocortisone for Septic Shock
    – JAMA 2002; 288:862-71; Corticus (unpublished data)

• 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 &                    MAP < 60
CVP or PAOP low               Low flow by exam or CI <2.5



  KIDNEY
                      CVP < 4
                                         Favors
                      PAOP < 8
                                          Dry
                                         LUNG
           Or the Liberal fluid strategy ?

                                Fluids

                FiO2 > 0.7          CI > 4.5

  Wet
                                           Favors
  LUNG                      CVP 10-14      Perfused
                            PAOP 14-18     KIDNEY
                                           (organs)


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


                                       p=0.006 (stratified log-rank test)
                     0
                           0          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                                                   Neutrophil
 C ascade
                                                       X       Adhesion
                             PAI-1
                         TAFI
                                   X
VIIIa                                                           M onocyte
        X          Increased F ibrinolysis                      Activation
                                               2                   X
 Va     X                   11                        3


Prothrom bin
                                  PC
            Th rom bin                                     4
                                                           4

                              Th rom bin           aPC P            EPCR
                    PAR                                S            CD1/
                            Th ro m b om od ulin                    MH C
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       NS ?Worse outcome in responders
      recovery for septic shock
       but no improvement in
         overall survival (the
          primary endpoint)




(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     •   Intensive insulin-
•   Rapidly culture and treat           euglycemia (if feasible)
    for likely pathogens            •   rhAPC (? Another trial)
•   Source control                  •   Stress dose steroids (low
                                        risk, low cost ?efficacy)
•   Optimize supportive care        •   Hemoperfusion,
    and monitoring                      diafiltration columns (?
•   Fluids, nutrition, DVT and          Needs to be studied)
    aspiration prevention           •   Participate in clinical trials-
                                        still 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 gram-
    negative 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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