Post on 29-May-2022
ATHENS 2019GREECE | 27-29 JUNE
Eosinophils in COPD: Myths and reality
Stelios Loukides MD Phd FCCP FERSERS educational council
University of Athens Medical School
ATHENS 2019GREECE | 27-29 JUNE
Conflicts
§AstraZeneca §Boehringer Ingelheim§Chiesi§GlaxoSmithKline§Elpen§Menarini§Novartis§Sanofi
MCQ 1Only one of the following is trueA. The most stable phenotype in COPD is the eosinophilic oneB. Biologics targeting IL-5 or IL-5R are effective at a level of > 300 AC
eosinophilsC. Blood or sputum eosinophilia are inflammatory variables at ACO defined
processD. In a COPD patient treated with LAMA & LABA and having >2
exacerbations the cut off value for the identification of eosinophilic endotype is 150AC.
MCQ 1Only one of the following is trueA. The most stable phenotype is the eosinophilic oneB. Biologics targeting IL-5 or IL-5R are effective at a level of > 300 AC
eosinophilsC. Blood or sputum eosinophilia are inflammatory variables at ACO defined
processD. In a COPD patient treated with LAMA & LABA and having >2
exacerbations the cut off value for the identification of eosinophilic endotype is 150AC.
§ Some introductory remarks. The eosinophil
Design
Travers J et al Mucosal Immunology (2015) 8, 464-475;
Eosinophil: A key regulatory cell
Nixon J et al Pharmacology & Therapeutics, 2016
Is it different in COPD?
Eosinophils are multivalent leukocytes that contribute to a variety of
immune responses in physiological and pathological conditionsEosinophils contribute to protection against parasitic, microbial and
viral infections1
§ Eosinophils are commonly associated with protection against helminths
§ Associated with protective response to respiratory viruses
§ Interact with dendritic cells to promote immune responses
§ In vitro, eosinophils release mitochondrial DNA in response to LPS
Eosinophils contribute to the inflammatory response as:
§ Response to allergens2
§ Tissue repair and remodeling1
§ Asthma1,2
§ Eosinophilic oesophagitis1
§ Hyperosinophilic syndrome1
§ Increasing evidence now suggests eosinophils are involved in COPD3,4
Antigen-specificinteractions
# Proliferation andcytokine production
Th2 cellrecruitment
#Superoxide#IL-8$CR3
Maintains alternativelyactivated macrophages
in adipose tissue
Histamine release#Survival
#Maturation
#Survival
#IgMproduction
T cell
Co-stimulatorymolecules
MBP Neutrophil
MHC class II
CCL17,CCL22
Th2 cell
Priming
B cell
Bone marrowplasmablast
APRIL,IL-6 EDN CpG DNA
Mast cell
MacrophageMBP, ECP,EPX, NGF
IL-4,IL-13
Eosinophil
DC
§ Some introductory remarks. The eosinophil§ Endotyping
Design
Inflammatory endotypes in COPD: The eosinophilic part
Barnes PJ Allergy, First published: 04 March 2019, DOI: (10.1111/all.13760)
Remodeling in COPD: How eosinophilic it is?
RespirologyVolume 20, Issue 4, pages 667-670, 27 JAN 2015 DOI: 10.1111/resp.12475http://onlinelibrary.wiley.com/doi/10.1111/resp.12475/full#resp12475-fig-0001
Eosinophils directly modulate alveolar macrophage production of matrix metalloprotease (MMP)-12 through interleukin (IL)-13-dependent mechanisms
Alfred D. Doyle et al. Eur Respir J 2019;53:1801291
• Some introductory remarks. The eosinophil• Endotyping • Phenotyping
Design
Microbiome and eosinopenia
Marco Contoli et al. Eur Respir J 2017
Blood and sputum eosinophils in COPD; relationship with bacterial load
Colsum U et al Resp Research 2017
Eosinopenia and Emphysema
Papaioannou A et al COPD 2018
Predicting airway eosinophilia
Florence Schleich et al. Eur Respir J 2016;47:1562-1564
Phenotyping ECOPD: The T2 approach
Bafadhel M et al Am J Respir Crit Care Med. 2011
Asthma-chronic obstructive pulmonary disease overlap: Diagnostic stability and inflammatory characteristics
Patentalakis G et al Allergy, First published: 11 May 2019, DOI: (10.1111/all.13865)
• Some introductory remarks. The eosinophil• Endotyping • Phenotyping• Outcomes
Design
Eosinopenia in ECOPD
Steer J et al. Thorax 2012;67:970-976
From: Eosinophils in COPD Exacerbations Are Associated With Increased Readmissions
Chest. 2017;151(2):366-373. doi:10.1016/j.chest.2016.10.003
Friend or foe?
Ciro Casanova et al. Eur Respir J 2017;50:1701162
Low and High Blood Eosinophil Counts as Biomarkers in Hospitalized ECOPD
McDonald Mi et al Chest 2019
Bafadhel M et al Chest 2016
Exacerbation COPD: outcome
Published in: Signe Vedel-Krogh; Sune F. Nielsen; Peter Lange; Jørgen Vestbo; Børge G. Nordestgaard; Am J Respir Crit Care Med 193, 965-974.2016
Predicting rate of ECOPD: Remains controversial
Signe Vedel-Krogh et al Am J Respir Crit Care Med 2016 193, 965-974.
Selecting the better?
• Some introductory remarks. The eosinophil• Endotyping • Phenotyping• Outcomes• Stability
Design
Blood Eosinophils: How stable they are?
Oshagbemi OA et al AJRCCM 2017
Stability of the Blood Eosinophilic Phenotype in Stable and ECOPD
Schumann DM et al Chest 2019
• Some introductory remarks. The eosinophil• Endotyping • Phenotyping• Outcomes• Stability• Treatment decisions
Design
MCQ 2
A 56 year old woman was referred to our department. She has COPD [treated with triple therapy ICS, LAMA & LABA]. CAT 10, mMRC 1. FEV1 69% pred, ratio 65%. 1 exacerbation in the last year. No signs of Asthma. Absolute eosinophilic count 150 measured twice, The patient is eligible for: A. ICS withdrawal B. Keeping the same treatment strategyC. None of the aboveD. I need further information
MCQ 2
A 56 year old woman was referred to our department. She has COPD [treated with triple therapy ICS, LAMA & LABA]. CAT 10, mMRC 1. FEV1 69% pred, ratio 65%. 1 exacerbation in the last year. No signs of Asthma. Absolute eosinophilic count 150 measured twice, The patient is eligible for: A. ICS withdrawal B. Keeping the same treatment strategyC. None of the aboveD. I need further information
Siva R et al ERJ 2007
Eosinophil-guided treatment strategy in COPD
COPD initial treatment: The eosinophilic part?
GOLD 2019
GOLD 2019
COPD follow up: The eosinophilic part?
Bafadhel M, et al. Lancet Resp Med 2018
4528 patients from 3 RCT BUD/FOR vs FOR
The eosinophilic part of the GOLD guidelines
Magnussen H, NEJM 2014
ICS withdrawal…
12-month, double-blind, parallel-group study - 2485 patients with a history of ≥1 AECOPD in he previous year - FEV1 <50% pred.Triple therapy TIO 18 μg once daily + SALM 50 μg twice daily + FP 500 μg twice daily during a 6-week run-in periodRCT: continued triple therapy vs. withdrawal of fluticasone in three steps over a 12-week period.Primary end point: time to the first moderate or severe COPD exacerbation
-38 mL-43 mL
ICS and eosinophils in COPD: Exacerbations -Wisdom
Watz H et al Lancet Respiratory 2016
Neil C. Barnes et al. Eur Respir J 2016;47:1374-1382
A different view of the Isolde study : A different FEV1 decline
SUNSET another trial for ICS withdrawal
Chapman KR, et al. AJRCCM 2018; 198: 329-339.
SUNSET: The eosinophilic sign
Chapman KR, et al. AJRCCM 2018; 198: 329-339.
The Impact study: Triple therapy superiority Irrespective of eosinophils?
Lipson D, et al. NEJM 2018
Who drives the eosinophilic inflammation in COPD?
Samy Suissa, and Amnon Ariel Eur Respir J 2018;52:1801848
LABA-ICS versus LAMA as initial treatment in COPD targeted by blood eosinophils: a population-based cohort study.
Suissa S et al Lancet Resp Med 2018
ICS recommendations
Agusti A, et al. Eur Respir J 2018; 52: 1801219
↑age, ↓ BMI,
greater overall fragility,
blood eosinophils <100 cells·μL−1,
pts receiving higher ICS doses
Αnti- IL-5 : Not yet for COPD
Pavord ID et al. N Engl J Med ;377:1613-1629
Benralizumab for COPD
Criner CJ et al NEJM 2019
Take home messages
§ Eosinophils are multifunctional cells that contribute to both innate and adaptive immunity.
§ Eosinophils have a critical role in asthma pathogenesis. Still questioning in COPD
§ Different cellular and molecular mechanisms drive eosinophilia in COPD§ Eosinophil represents an “ideal” biomarker to optimise steroid therapy
(personalised medicine) in asthma –but not yet in COPD..§ Still searching their predictive role§ Eosinophilic inflammation improves responses to targeted therapies in
asthma but not in COPD. § To be continued…..