-
Inmuno-fenotipos en la sepsis
Jesus F Bermejo-Martin, MD PhD
bio ∙sepsis
σήψιςHospital Clínico Universitario de Valladolid
-
Conflicts of interest
Assessment on biomarkers as
prognosis markers in sepsis
Thermo Fisher
Scientific
Patent on a biomarker for sepsis
diagnosis
Thermo Fisher
Scientificdiagnosis Scientific
Assessment on immunoglobulin
levels in sepsisBiotest AG
ψ
-
Colonization Infection
Sepsis
Resolution
Efficient
response
Mucosal
immunity
Memory
immunity
Innate
immunity
Adaptive
immunity
Sepsis
/death
Defficient
dysreg
response
-
“Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection”
-
IFN-γ
Antigen presentationT cell counts and function
presentation,
FID 1 to 5 quantitative and
qualitative alterations in
antigen presentation,
B, T , NK, lymphocytes ,
activation of PD1 Regulatory T cells
Poor control of
infection ?
Ageing
Co-
morbidities
Immature Neutrophils in non survivors
CNC
FID7: low
LTCD4
CD
28
CD4 LTCD8
CD
40L
CD8
CD
28
NK
T reg
Th0 MHCIITCR
B cell
PD1
FID6: low Iglevels
IgG IgMIgA
PD1
Viral reactivation?
Infection
leading
to sepsis
non survivors
MPOCTSG
ELANEAZU1
CEACAM
FID8: proinflamma. hyper-cytokinemia
FID7: low circulating counts of neutrophils and
increased immature forms in non
survivors
IL-6 IL-8
IL-10FID8: immunosup.hyper-cytokinemia
FID9: complement consumption C4 C3Factor B
Endothelial / Tissue damage ?
FID10: defective bacterial killing of
NETs
.
Neutrophil adhesion Neutrophil serine proteases
MCP-1 MIP1-β IFN-γ GM-CSF
-
Early hypersecretion of cytokines / hormokines
-
IL-8
IL-6
MCP-1
MIP-1b
IFN-g
GM-CSF
Symultaneous secretion of pro and anti-inflammatory cytokines
IL-10
p < 0.05
-
•Continuous hemodiafiltration using cytokine-adsorbing hemofilters such as polymethylmethacrylate (PMMA) and AN69ST membrane hemofilters
•Particularly useful for the treatment of septic shock and septic AKI.
-
11
0
-1
Inverse correlation between Igs and citokine levels
-
Biomarker/s score: Pro-adrenomedullin
-
Suboptimal expansion of neutrophil counts in non survivors
-
Discovery cohort: EXPRESS study Validation cohort: GRECIA study
p = 0.007p = 0.001
Neutrophil score
Bermejo-Martín JF, Tamayo E, Ruiz G, Andaluz-Ojeda D, Herrán-Monge R, Muriel-Bombín A, Fe Muñoz M, Heredia-Rodríguez M, Citores R, Gómez-Herreras J, Blanco J
-
Discovery Validation
Monocyte counts
n = 186n = 238
-
Mathias B et al, Medicine Volume 94, Number 50, December 2015
Meisel, C. et al. (2009). Am. J. Respir. Crit. Care Med. 180, 640–648
GM-CSF in patients with low HLA-DR expression:
Reduced the time on mechanical ventilationimproved APACHE-II and reduced length of both intrahospital and intensive
care unit stay
-
Immature neutrophil forms and neutrophil proteases are associated to bad outcome
-
1. Myelocyte 2. Metamyelocyte 3. Band cell
4. Mature Neutrophil
Earlier
mortality
-
Neutrophil Protease inhibitors?
-
Severe hypogammaglobulinemia is associated with prognosis
-
Frequent
Igs levels
Immunoglobulins are not like other drugs….we have them
in our body!
Frequent
finding in
sepsis
-
IgG
70% !IgG
hypogamma-globulinaemia
at diagnosis
…….but this finding did not identify a subgroup of
patients with a higher risk of death
70% !
-
IVIG: controversial role in sepsis
“Polyclonal IVIG reduced mortality among adults with sepsis
but this benefit was not seen in trials with low risk of bias….”
“We suggest against the use of IV immunoglobulins in
patients with sepsis or septic shock
(weak recommendation, low quality of evidence)…”
“We encourage conduct of large multicenter studies
to further evaluate the effectiveness of other IV polyclonal
immunoglobulin preparations in patients with sepsis”
-
But…who deserves treatment with IVIG…..?
It is necessary to
identify the
potential target potential target
population!
-
Is the predictive ability of
immunoglobulins different
depending on sepsis severity ?
-
GRECIA
ABISS - EDUSEPSIS
-
SOFA > 8 (n = 156)
278 patients admitted to the ICU with sepsis
Two
groups
SOFA < 8 (n = 122)
groups
-
SOFA > 8
p = 0.867 p = 0.912 p = 0.091
p = 0.554 p = 0.554 p = 0.660
-
SOFA < 8
p = 0.007 p = 0.005 p = 0.018
p = 0.026 p = 0.050 p < 0.001
-
Justel M, Socias L, Almansa R, Ramírez P, Gallegos MC, Fernandez V, Gordon M, Andaluz-Ojeda D, Nogales L, Rojo S, Vallés J, Estella A, Loza A, León C, Lopez-Mestanza C, Blanco J, Berezo JÁ, Rosich S, Cillòniz C, Torres A, de Lejarazu RO, Martin-Loeches I, Bermejo-Martin JF.
Combined score IgG2 + IgM
-
OK, large studies…..
but more oriented please…!
•SOFA score
•Basal levels of
IgG, IgA and IgM
“We encourage large multicenter studies to
further evaluate the
effectiveness of polyclonal
immunoglobulins in sepsis”IgG, IgA and IgM
Precision Medicine in Sepsis
http://liveclinic.com/blog/technology/hopeful-future-precision-medicine/
-
Complement activation: low levels of complement related proteins
-
Complement + Immunoglobulins kills
bacteria!
Complement can cause endothelial
/ tissue damage!
We need to asses complement factors levels and function!
Image from
bacteriemiaFactor B and properdin
-
Depressed lymphocyte mediated immunity
-
Low levels of T cells in sepsis
-
Severe sepsis –Septic Shock
Lymphopenia!
(< 1000 lymphocytes / mm3)
60-65 %
-
EXPRESS Study: Gene Expression in Sepsis
Septic shock
Severe sepsis
Healthy
SurgerySIRS
Sepsis
Healthycontrol
Anesthesiology Service + Research Support Unit,
Hospital Clínico Universitario de Valladolid
-
MMP8
LCN2/NGAL
PRTN3
MPO
CD40LG
LTF
HIGH EXPRESSION
CD40LG
HLA-II
CD28
ICOS
CD3E
LOW EXPRESSION
-
Inverse correlation between T cell markers
expression and SOFA score
-
Almansa et al. April 2014
SIRS SSs SSns
-
Derivation Validation
(n=1550 patients)
Multi-site: 14 hospitals
(n=2846 patients)
Single site
-
T cell response enhancers
-
Bristol-Myers Squibb
Nivolumab Phase 1 trial BMS-936559 Phase 1/2 trial
Immunotherapies move beyond cancer, with first foray into sepsis
https://www.statnews.com/2016/12/07/immunotherapy-sepsis/
Both drugs act on PD-1/PD-L1 pathway, resulting in the activation of T cells
-
New transcriptomic methods for profiling immunity in sepsis
-
Droplet Digital PCR
mRNA as a
biomarkerbiomarker
-
Immuno-transcriptomic scores
-
Immunological profiling to assess
disease severity and prognosis in CAP
www.thelancet.com/respiratory Vol 5 December 2017 e36
-
Systemic Immune dysfuction Syndrome (SIDS) and
Pre-sepsisPre-sepsis
-
Bermejo-Martin JF, Tamayo E, Andaluz-Ojeda D, Martín-Fernández M, Almansa RChest . 2017;151(2):518-519.
.
Immunoglobulin scores Transcriptomic scores
S istemic
I mmune
Cytokine scores
Biomarker scores
Lymphocyte score
Neutrophil score
I mmune
D ysfuction
S yndrom
-
Uncomplicated
infection
SOFA = 1SIDS
SOFA > 2
Pre-sepsis Sepsis -3
SOFA = 0
-
•Close monitoring of blood pressure
•Early instauration of liquid replacement
•Close monitoring of lactate, presence of altered
mentation and taquipnoea
•Active microbiological testing,
“Sepsis Alert”
Pre-sepsis•Active microbiological testing,
•Derivation to the hospital/ICU
•Early treatment with systemic antibiotics
-
Colonization Infection
Sepsis
Resolution
Efficient
response
Mucosal
immunity
Memory
immunity
Innate
immunity
Adaptive
immunity
Sepsis
/death
Defficient
dysreg
response
-
DeathDefficient /
dysreg
Response
Early Ab
treatment
Vital support
Progression of
immunological
dysfunction
New
opportunities for
diagnosis
Endothelial /
tissue damage
DIC
Response
(SIDS)
Early restauration
of immune
homeostasis
Progression of
organ failure
-
Death
New organ
failure
Early predictors:Time to act!
Late predictors: short of time to act!I
nfe
ctio
n
-
Identifying features of immunological dysfuction
Early detection of sepsis Early instauration of personalised treatment.
Precision Medicine in Sepsis
http://liveclinic.com/blog/technology/hopeful-future-precision-medicine/
-
bio ∙sepsisσήψις
Bermejo-Martin JF
@BioSepsis