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

jfbermejo@saludcastillayleon.es

Bermejo-Martin JF

@BioSepsis