Marqueurs de l'inflammation et sévérité clinique: le cas des complications pulmonaires

Marthe-Sandrine Eiymo Mwa Mpollo, PhD

November 5th, 2016

Sickle Cell Disease SymposiumConnecting inflammatory biomarkers and

SCD clinical severity : the lung complications perspective

Sickle Cell Disease (SCD)

Hemolysis

Vasoocclusion

Steinberg, NEJM 2009

Treatment strategies• Management of vaso-occlusive crisis• Management of chronic pain syndromes• Management of chronic hemolytic anemia• Prevention and treatment of infections• Management of the complications and the various organ damage syndromes associated

with the disease• Prevention of stroke• Detection and treatment of pulmonary hypertension

Beyond RBC sickling, hemolysis other features/organ

complications of SCD include

RBCSickling/anemia

Lung Com-

plications

Other organs

Bones/jointsBone marrow hyperplasiaAvascular necrosiesDactilytis

OsteomyelitisAplastic crisis

GallbladderGallstonesKidney

HypostenuriaPapillary necrosis

Renal failure

AsthmaAirway Hyper-

reactivity

PHAcute chest

syndrome

HeartCardiomyopathy

Premature coronary

and artery disease

What is the connection between thissingle defect in RBC and those multi-organ complications?

1) Produce by sickled red blood cells

2) Correlate with the severity of the disease pathophysiology

Assumptions:

The Biomarkers Definitions Working Group (2001) defined a biomarker as ‘a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention’.

Rees, British Journal of Haematology 2011 156, 433–445.

Inflammation, VOCPerelman…Blood 03

Pulmonary Endothelium / Monocytes / Mast Cells

PLGFBone Marrow

Erythroid Cells

EpoEry. Hyperplasia

Reactive Airways

Acute Chest Syndrome

(Clinical Trials, Murine Studies)

Patel.. Blood 09

Eiymo.., JCI 2015

Pulmonary

HypertensionSundaram..Blood 10

Patel… Blood 08

Placenta Growth Factor is produced by immature

erythroid and not other hematopoietic cells

• Pulmonary hypertension: Incidence is 30% (Gladwin MT et al, 2004).

• Airway hyperreactivity and asthma – reported to be 17% to 77% (Boyd JH. et al, 2006)

• Acute Chest syndrome (ACS) : with an incidence rate of 50%, ACS is estimated to be responsible for 25% of SCD related deaths (Castro, Blood 1994; Platt, Blood Principles and Practice of Hematology 1995).

• Inflammation: Activated leukocytes have been shown to initiate vaso-occlusion (Wun T. et al, 2001).

“From a clinical perspective, pulmonary complications —

namely, the acute chest syndrome and pulmonary

hypertension — are the most common causes of death in

patients with sickle cell disease.”Gladwin, NEJM 2008

Is PlGF a biomarker for pulmonaryhypertension (PH)?

Variable n r p

RBC_COUNT 123 -0.28 0.0017

Hemoglobin 123 -0.27 0.0024

Absolute Reticulocyte count 123 0.07 0.4233

LDH 116 0.22 0.0153

ESR 115 0.19 0.0465

CRP 114 0.30 0.0012

WBC count 122 0.19 0.0376

Endothelin-1 117 0.24 0.0087

TRJV 123 0.38 P<0.0001

PlGF is elevated in adult patients with SCD and is associated with

features of PH.

Sundaram, Blood 2010

PlGF overexpression in WT mice induces right

ventricular hypertrophy and pulmonary hypertension

Sundaram, Blood 2010

Could PlGF be a biomarker for AcuteChest Syndrome (ACS)?

Leukotrienes: PlGF target genes are strongly associated with ACS

0

0,05

0,1

0,15

0,2

0,25

0,3

0,35

Lower Middle Upper

Me

an r

ate

of

AC

S/ye

ar

Leukotriene E4 Tertiles

PlGFPlGF Bone Marrow Erythroid

Cells

Erythroid

Hyperplasia

LeukotrienesEiymo, JCI 2015

ACS

Field, Am J Hematol 2008

• ACS: lung complication believed to result from vaso-occlusions in the pulmonary circulation

• The leukotrienes, powerful inflammatory molecules, are potent vasoconstrictors in the pulmonary circulation.

PlGF-induced airway hyper-reactivity is associated with ACS

None Mild Mod/Sev0

1

2

3

4

# of Admits for Sickle Crisis

# Acute Chest Syndrome Episodes

***

*

Airway Hyper-Reactivity

No

. o

f S

ickle

C

ell

Re

late

d

Morb

idity E

ve

nts

PlGFPlGF Bone Marrow Erythroid Cells

Erythroid

Hyperplasia

Reactive Airway Diseases

Patel, Blood 09

Eiymo, JCI 2015

LeukotrienesEiymo, JCI 2015

ACS

No Severe0

1.010 -7

2.010 -7

3.010 -7

4.010 -7*

LT

D4 (

pg/m

l)

SCD patients

AHR

PlGF inhibition reduces both leukotrienes and airway

hyperreactivity, ACS associated features

0 50 1000

5

10

15

Chi-HbS-HDM ( PlGF)Chi-HbS-HDM (Zileuton)

Methacholine (mg/ml)

Chi-HbS-HDM (Vehicle)

##

Res

ista

nce

(cm

H2O

.s/m

l)

Chi-BL/6

***

#

Chi-BL/6 Chi-HbSChi-HbSChi-HbS104

105

106106.5

107

VehiclePlGFZileuton

****

***

CystLT (pg/ml)Eiymo, JCI 2015

AHR

Acute Chest Syndrome

(Clinical Trials, Murine Studies)

PlGF

Bone Marrow

Erythroid Cells

EpoEry. Hyperplasia

Hemolysis

SummaryPlGF, an inflammatory mediator released by the sickle RBC connect the seemingly unrelated many diseases activities in SCD

LeukotrienesEiymo, JCI 2015

Pulmonary Hypertension

(Cross-sectional studies, Murine

Studies)

Other organs

Lung Com-plications

PlGF , and like factors

HbF, MCH, HbSHemolysis

Vasoocclusion

Beyond RBC sickling, hemolysis other features/organ

complications of SCD include

Lung Acute chest syndromeAirway Hyper-reactivityPulmonary hypertensionOngoing fibrosispneumonia

Vascular damagePainStroke (brain)Central artery damageRetinal and artery occlusion/retinopathy

SpleenSplenic sequestration of RBCAutosplenectomyChronic hypersplenectomyImpaired immunity

KidneyHypostenuriaPapillary necrosisRenal failure

GenitalsPriapism

HeartCardiomyopathyPremature coronaryand artery disease

GallbladderGallstones

Bones/jointsBone marrow hyperplasiaAvascular necrosiesDactilytisOsteomyelitisAplastic crisis