immunodepression acquise en reanimation outils diagnostiques et perspectives thérapeutiques desc de...
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IMMUNODEPRESSION ACQUISE EN REANIMATION
Outils diagnostiques et perspectives thérapeutiques
DESC de Réanimation2011
Guillaume Monneret
Laboratoire d’Immunologie CellulaireHospices Civils de Lyon
Hôpital E. [email protected]
Hôpitaux de Lyon
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- Septic Syndromes : leading cause of death in ICU- 3rd cause of death after cardiovascular diseases and cancers- 2005 US figures : 800 000 cases / year- 2001 F figures : 70 000 cases / year
Sepsis as a starting point : Septic syndromes an increasing and significant healthcare challenge
NEJM 2003
Constant rise for many years
200,000
400,000
600,000
800,000
1,000,000
1,200,000
1,400,000
1,600,000
1,800,000
2001 2025 2050
Year
100,000
200,000
300,000
400,000
500,000
600,000
Severe Sepsis Cases
US Population
Sep
sis
Cas
es
To
tal
US
Po
pu
lati
on
/1,0
00
- Better care of co-morbidities- Increased longevity
future
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Hospitalization rate nearlydoubled from 1993 to 2003
Population-based mortality rate rose by two thirds.
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Wenzel 2002 - N Engl J Med
Incr
ea
sed
seve
rity
MultipleOrganfailure
DefinitionAssociation of an infection and a systemic inflammatory response syndrome (SIRS)
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Onset :germ(s) + site of infection + local inflammation
Amplification ?Lack of modulation ?
Pathophysiology :uncontrolled inflammatory
response
organ
systemic
DefinitionAssociation of an infection and a systemic inflammatory response syndrome (SIRS)
=> Sepsis is not caused by the infection itself but by the host response to this infection
(“The germ is nothing, the terrain is everything” - Pasteur L. - 1895)
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Decreased arterial pressureShock
Multiple organ failure
UncontrolledInflammatory
response
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Decreased arterial pressureShock
Multiple organ failure
UncontrolledInflammatory
response
Emergency symptomatic treatment :AntibiotherapyAgressive vascular resuscitationVasoactive agents
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Cytokines : TNF, IL-1, IL-6, IL-12Activation, amplification
Chemokines : IL-8, MIP-1, MCP-1Mobilize and activate leukocytes
Vasoactive hormones, Lipid mediators :PAF, PG’s, LK, TX, ADM, ANP…Multiple actions
Oxygen radicals :superoxide, nitric oxideAntimicrobial propertiesregulation vascular tone
« Cytokine storm »=> « Mediator storm » > 300 released mediators (Marshall, Nature Rev. 2003)
Extensive description for many years…..
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Uncontrolledinflammatory response
Anti-inflammatory drugs
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Failure of clinical trials testing anti-inflammatory therapies
38
35
39
45
40
40
37
39
…
381203433Total
35
36
50
41
38
40
35
…
2010
755
870
4132
688
514
1267
…
4
2
2
8
2
3
9
…
Anti-endotoxine
Anti-bradykinine
Anti-PAF
Anti-TNF
R solubles TNF
AINS
Stéroïdes
…
Mortality (%)
Placebo DrugNumber of
patientsNumber of
studiesDrug
Zeni et al, Crit Care Med, 1997
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Reasons for such a perfect disaster
1. Inappropriate animal models of sepsis
2. Heterogeneity of septic population (germs, virulence factors, co-morbidities, inflammatoryresponse, site of infection….)
1. Pathophysiology largely unknown
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> 70 % total mortality
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Resultant immune response at the systemic level = immunosuppression
Pro-inflammatory Response
Anti-inflammatory Response
Time
Simplified description of systemic pro- and anti-inflammatory immune responses over time after septic shock
Similar mechanisms each time SIRS occurs:trauma, surgery, pancreatitis, burns……
Onset ofAnti-inflammatory-based RCT
1. Inappropriate animal models of sepsis2. Heterogeneity of septic population3. Pathophysiology largely unknown
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Summarized view of sepsis-induced immunosuppression
immune functions
Innate Immunity
Monocyte / DCanergy
Adaptive Immunity
Lymphocyteanergy
IL-10(and soluble mediators)
Apoptosis(different mechanisms)
Endotoxintolerance
PNN chemotaxis and phagocytosisMonocyte deactivation:
- antigen presentation capacity- pro-inflammatory cytokine production- CX3CR1
dendritic cells nbr
Profound lymphopeniaTh2 shiftLymphocyte anergy apoptosis % Treg
Epigeneticregulation
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Consequences
- Decreased clearance of initial infection (Togersen 2009)- Increased nosocomial infections- Viral reactivation
=> May directly contribute to mortality
Diagnostic?
No clinical sign => biological monitoring
1. Functional testing2. Soluble mediators3. Cellular approach4. Genomics
outcomes: - mortality - occurrence of nosocomial infections
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- Because this directly measures ex vivo the capacity of a cell population to respondto an immune challenge, functional testing theoretically represents the method of reference
- Monocyte capacity to release TNF in response to LPS challenge- Lymphocyte proliferation in response to recall antigens or mitogens- Phagocytosis, chemotaxis….
- Time consuming (days of incubation for lymphocyte proliferation)- Home-made protocols => difficult to standardize
=> Not suitable for routine monitoring
- They remain essential to gain insights in the understanding of pathophysiology and to assess the validity of surrogate markers
1. Functional Testing
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2. Soluble mediators
- In septic shock, > 300 released mediators- Both pro- and anti-inflammatory mediators are elevated : not informative- A panel of markers is likely more desirable (or at least a ratio)
=> If a single one : IL-10- Potent immunosuppressive cytokine- Many studies have identified it as the most informative - Standardized measurement
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20
40
60
80
100
120
140
160
180
200
IL-10 pg/ml
1-2 3-4 5-7 8-15
**
**** **
Non-survivors 20
40
60
80
100
120
140
TNF pg/ml
1-2 3-4 5-7 8-15
Non-survivors
High IL-10 is associated with mortality – not TNF
2004
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=> Correlation with mortality but no data on nosocomial infections
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3. Cellular phenotyping
- monocytes- lymphocytes
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Monocytes
Gold standard = Decreased mHLA-DR
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- mHLA-DR expression level = Integrated Σ of the effects of numerous mediatorsIt is the true reflection of what force dominates at any given time-point
- Decreased mHLA-DR correlates with decreased functional testing (TNF release, Ag presentation)
Why using flow cytometry ? => example of mHLA-DR
100 % 0 %
Ting et al.
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(n = 120 septic shock patients)
30
40
50
0 - 48 h 48 – 96 h
% H
LA-D
R +
mon
ocyt
es
Survivors
Non-survivors
p : 0.2 p < 0.001
Monneret et al., Intensive Care Med 2006
(Control values > 90-100 %)
Low HLA-DR predicts mortality
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Survival curves stratified onmHLA-DR at 30 % at days 3-4
(n = 120 patients)
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Sex (F)
Age > 64 years
IGS II (onset) > 49
Type of admittance (surgery vs med.)
Comorbidity (≥ 1)
Type of infection (noso. vs commu.)
Infection site (pulm., abdo., others)
SOFA (≠ J1J2 vs J3J4) > 0
HLA-DR (J1-J2) < 30 %
HLA-DR (J3-J4) < 30 %
-
-
6.14
-
4.34
-
-
6.58
-
8.81
-
-
1.3 – 28.4
-
1.0 – 18.5
-
-
1.5 – 28.6
-
1.9 – 40.4
-
-
0.02
-
0.05
-
-
0.01
-
0.005
Odds ratio 95 % CI p
Multivariate analysis : mHLA-DR is an independent predictor of mortality(after adjustment for usual clinical confounders)
9-fold increased risk of death with mHLA-DR < 30 %
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- Multivariate analysis (including usual confonding factors):SOFA, SAPSII, Intubation, catheterization- Competitive risks
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Does mHLA-DR predict nosocomial infections in other ICU contexts ?
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HLA-DR expression and soluble HLA-DR levels in septic patients after traumaDitschkowski et al. Ann. Surg. 1999
Minor injuries
Severe injuries + secondary sepsis
Severe injuries withoutsecondary sepsis
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Normalvalues
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Recovery slope(> 1.2)
AUC : 0.8
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Low mHLA-DR predicts nosocomial infections after Day 15
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ROC Curves Analysis for the predictionsecondary infections
(AUC = 0.9)
According tosecondary infection(n = 29 non infected
n = 24 infected)
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Dendritic cells
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Persisting low circulating myeloid dendritic cells numberis associated with the development of nosocomial infections after septic shock
Days after shock
Pene, Chiche et al. (Société Réanimation Langue Française 2009)
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Lymphocytes
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Castelino et al.
From lab computer in a university hospital over a 3 month-periodLymphopenia when Ly < 600 / microL=> 1042 patients with lymphopenia
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Septicpatients
Septicpatients
Controls
Controls
Lymphocytes from septic patients do not proliferate upon antigen / mitogen challenge
Roth et al.,
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An increased circulating percentage of Treg is associatedwith a decreased cell proliferation in septic shock patients
FOXP3 inhibition restores lymphocyte proliferation
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Lymphocytes:
No recent data on correlation with motality and nosocomial infections
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n = 1211surgical
ICU patients
Skin testing(within 24 h after admission)
Positive30 %
(n = 369)
+/- 23 %
(n = 272)
Negative47 %
(n = 570)
Mortality
9 % (n = 31)
25 % (n = 55)
32 % (n = 184)
Nosocomialinfection
27 % (n = 99)
33 % (n = 91)
42 % (n = 237)
* p < 0.005
Skin testing with 5 antigens (positive if 2 reacted, +/- if solely 1 reacted, negative if none reacted)
**
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Cook CCM 2009
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4. Transcriptomic approach
(microarrays and qRT-PCR)
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Genes codingfor pro-inflammatory immune responseare decreasedwhile genes coding for apoptosisare increased
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Immunol Lett 2006. 106 (1) :63-71
SurvivorsNon-survivors
A cluster of 28 genesmostly linked with immunosuppression
differentiated S from NS
Septic shock patients > 48 h after the onset of shock31 patients (10 NS) + 7 patients in a prospective control study (3 NS)
HG-U133A oligonucleotide arrays (Affymetrix) – 14 500 genes
Among them, the decreased expression of the fractalkine receptor CX3CR1 mRNA was the most
interesting because of largest fold change between S and NS ( 8-fold decreased in survivors)
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CX3CR1 is mainly expressed on patroller monocytes that are the first to reach the site of secondary infections
to initiate immune response.
Due to decreased chemotaxis(and subsequent decreased inflammatory cytokines release),
the loss of this receptor might have a role inthe development of nosocomial infections
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Days after the onset of shock
Sur
viva
l dis
trib
utio
n fr
actio
n
CX3CR1 mRNA > 0.12
CX3CR1 mRNA < 0.12
p = 0.0002
Survival curves stratified on CX3CR1 mRNA level at day 1-2 (cut off: 0.12)
Confirmation cohort (N = 160 septic shock patients) : qRT-PCR in whole blood
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0,2
0,4
0,6
0,8
1
1,2
HL
A-D
RB
mR
NA
(ra
tio) p < 0.01
Days 1-3 Days 4-10
NS
S
SNS
Septic shock
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Cytokines / HLA-DR assessment by qRT-PCR in whole blood (Paxgen tubes)
Abe R et al.
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220 patients20 infected20 matched control group23 genes (PAXGENE) : TNF, IL1, IL10, IL18, SOCS3, CD3, CD69, Perforin, Granulysin, CCR3, KLRK1, IDO1, HLA-DRA, CD74,IL8, CXCL10, CCL3, CXCL1, HMOX1, S100A8, PF4, IL6
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Transcriptomic:
For now, few studies but promising resultsAdvantages :- mRNA (all components : intracellular, cell surface, soluble mediators => automated systems)- Panel of markers- MIP-Réa (800 patients)
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5. Conclusions and perspectives
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Representative examples
10
20
30
40
50
60
70
80
1 3 4 5 6 72
HLA
-DR
(%
+ m
onoc
ytes
)
Days post-shock
Survivor / non-infected
Non-survivor / infected
2 patients with septic shock – community acquired No comorbidity – first sample < 6 hours after the onset of shock
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Representative examples
10
20
30
40
50
60
70
80
1 3 4 5 6 72
HLA
-DR
(%
+ m
onoc
ytes
)
Days post-shock
Survivor / non-infected
Non-survivor / infected
2 patients with septic shock – community acquired No comorbidity – first sample < 6 hours after the onset of shock
Therapy ?
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10 20 30
days
20
40
60
80
100
Per
cent
sur
viva
l (%
)
Sepsis-induced immune failure(modified CLP models)
CLP (+ antibiotherapy and volume resuscitation)Sham
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10 20 30
days
20
40
60
80
100
Per
cent
sur
viva
l (%
)
Sepsis-induced immune failure (modified CLP models)
CLP + Infections with germs (Pseudomonas, Legionella, Candida, Aspergillosis)
CLP (+ antibiotherapy and volume resuscitation) + ØSham + ØSham + germs inoculation
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10 20 30
days
20
40
60
80
100
Per
cent
sur
viva
l (%
)
Sepsis-induced immune failure (modified CLP models)
Infectionswith germs
Immune stimulation (IL-7, IL-15, FLT3-L, DC, GITR mAbs…)
p < 0.05
Nascimento et al., Crit Care Med 2010Delano et al., J Immunol 2010Brahmamdam et al, J Leuko Biol 2010Unsinger et al. J Immunol 2010Inoue et al., J Immunol 2010Pene et al., J Immunol 2008Benjamin et al., Blood 2005
CLP (+ antibiotherapy and volume resuscitation) + ØSham + ØSham + germs inoculation
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Perspectives
Most ICU patients present with severe immune alterations after injury(sepsis, severe burn, trauma, pancreatitis, major surgery)
=>Immune failure should be considered as an important additional organ failure
=> Septic patients who do not recover normal immune functions are those who die
Biomarkers are readily available to monitor pro-/anti-inflammatory responses (- We now need multicentric clinical studies to validate and reinforce these promising preliminary results
- We need to establish standardized measurement protocols for each potential biomarker)
=> biomarker-based stratification=> individualized and targeted therapy
And beyond immuno-inflammation…..
THERANOSTIC
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Anti-inflammatory drugs
Anti-TNF stratified on IL-6 levels.Panacek EA et al., Crit Care Med. 2004 Nov;32(11):2173-82
New Strategies:- Close Monitoring (PCT ?) to detect asap the beginning of infections- Preventive antibacterial therapy (when possible / risk of resistance)- Immunotherapy to restore immune functions (pro-inflammatory drugs)
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Sepsis-induced immune dysfunctions
Innate Immunity
Monocyte anergy
Adaptive Immunity
Lymphocyte anergy
Immunotherapy to restore immune functions ?
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Immunotherapy to restore immune functions ?
Sepsis-induced immune dysfunctions
Innate Immunity
Monocyte anergy
Adaptive Immunity
Lymphocyte anergy
GM-CSFIFN-g
IL-7
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Docke WD et al. Nat Med. 1997;3:678-81
Monocyte deactivation in septic patients:restoration by IFN-gamma treatment
9 patients sepsis severe
HLA-DR < 30 %(2 jours de suite)
Interferon-gamma
Mortalité 33 % Mortalité 58 %
26 patients sepsis severe
HLA-DR < 30 %(2 jours de suite)Non randomisée
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Nakos G et al., Crit Care Med 2002;30:1488-1494
Immunoparalysis in patients with severe traumaand the effect of inhaled interferon-gamma
52 trauma patientsHLA-DR at day 3 (BAL)
HLA-DR > 30 % (n = 31)Usual monitoring
HLA-DR < 30 % (n = 21)
Placebo (n = 10)
Infection II : 550 %
Interferon-gamma (n = 11)
Infection II : 19 %
p < 0.05
Infection II : 310 %
Pas d’impact sur mortalité
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- No side effects- Significantly shorter time of ventilation (148 vs 208 h, p=0.04)- shorter length of intra-hospital stay (59 vs 69 days)- shorter length of ICU stay (41 vs 52)- 28-day mortality not different (trial not powered for mortality)
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GM-CSF
Stratified on ex vivo TNF releasebelow 160 pg/mL
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All ways may lead to immune suppression
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Vincent JL, Crit Care Med 2005 Cavaillon JM & Annane D, J Endotox Res 2007
To be kept in mindfor next years….
Effective early treatmentscannot avoid a risk
of immune suppression
Short term beneficial effectscan be hidden by deleterious effects
of immune suppressionwhen mortality is assessed at 28 days