Inflammatory and remodeling phenotypes in asthma James Martin Meakins Christie Laboratories...

Inflammatory and remodeling phenotypes in asthma

James Martin

Meakins Christie Laboratories

Department of Medicine

McGill University

No conflicts to declare

“Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment.’’

GINA 2008.

Why is the definition so predominantly clinical?

Definition of asthma

Asthma Phenotypes

• A Phenotype is any observable characteristic or trait of a disease, such as morphology, development, biochemical or physiological properties, or behaviour, without any implication of a mechanism.

Is it realistic to anticipate distinct phenotypes?

Genes

Pathobiology

Clinical expression of disease

Response to treatment

Environment

Assessment of airway inflammation and remodeling in asthma

• Expectorated or induced sputum

• Airway biopsies

• Exhaled nitric oxide

• Breath condensate (8-isoprostane, pH, H2O2,leukotrienes, etc)

• Imaging

Inflammatory phenotypes based on sputum examination

Eos Neut Mixed Pauci Healthy

J Simpson et al, Respirology, 2006

Inflammatory phenotypes associate with age

J Simpson et al, Respirology, 2006

Clinical phenotypes of asthma

P. Haldar et al AJRCCM, 2008

Severe asthma phenotypes

G.P. Anderson Lancet 2008

Distinguishing severe asthma phenotypes: Role of age at onset and eosinophilic inflammation

Miranda et al JACI 2004

How stable are inflammatory phenotypes?

A-moderate B- severe

Only 1/3rd were stable phenotypes

Al Samri et al JACI 2010

Comparison of inflammation assessed from induced sputum and biopsies in moderate to

severe asthma?

Sputum but not tissue eosinophils correlate with frequency of exacerbationsIn severe asthmaNeutrophils are not correlated with clinical outcomes

C. Lemiere, JACI 2006

P Nair et al, NEJM 2009

Interim conclusions

• Sputum examination revealing eosinophilia identifies asthmatics at risk of exacerbation

• Sputum eosinophilia is usually a marker of steroid responsive disease

• Sputum neutrophilia is of uncertain significance• Generally inflammation is not well correlated

with the severity of disease• Persistent sputum eosinophilia in the presence

of oral corticosteroid treatment may drive the activity of disease and asthma may be IL-5 dependent

Airway wall remodeling on bronchial biopsies

•Epithelial (shedding, denudation)

•Subepithelial fibrosis

•Increase in ASM

•Epithelium to ASM distance reduced

ASM mass is related to disease severity

Pepe et al J Allergy Clin Immunol 2005

Severe asthma; variable and fixed obstruction

Kaminska et al, JACI 2009

fixed obstruction

variable obstruction

P<0.05

Airway remodeling is correlated with obstruction in children with

severe asthma

Tillie-Leblond et al. Allergy 2008

ASM remodeling is dynamic even in longstanding severe asthma

Hassan et al, JACI 2010

The relationship between ASM remodeling and clinical phenotypes

Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma

Research Program

Moore et al AJRCCM 2010

• Accuracy of clustering using 3 clinical variables

Moore et al AJRCCM 2010

Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma

Research Program

SARP versus McGill Difficult Asthma Program

Characteristic (SD) McGill SARP

Subjects – n 84 726

Age – years 45 (12) 37 (14)

Female – % 48 66

BMI 27 (5) 29 (8)

Age at asthma onset – years

24 (17) 15 (14)

Baseline FEV1 – %pred 71 (20) 74 (22)

Maximum FEV1 – %pred 81 (20) 87 (20)

Atopic – % 77 77

Mild – n/% 0/0 260/36

Moderate – n/% 27/32 157/22

Severe – n/% 57/68 304/42

B. Smith, unpublished results

McGill Difficult Asthma Program

Characteristic (SD) Cluster 1

Cluster 2

Cluster 3

Cluster 4

Cluster 5

Subjects – n 6 27 7 27 17

Base FEV1 – %pred 110 (8) 82 (8) 82 (9) 65 (10) 41 (10) p<0.01

Max FEV1 – %pred 123 (6) 89 (9) 95 (7) 75 (9) 52 (11) p<0.01

Age at onset – years 44 (15) 20 (12) 47 (3) 18 (15) 22 (17) p<0.01


McGill Difficult Asthma ProgramCharacteristic (SD) Cluster

1Cluster

2Cluster

3Cluster

4Cluster

5

Subjects – n 6 27 7 27 17

Female – % 80 64 43 38 31 p=0.11

BMI 24 (4) 27 (6) 31 (6) 28 (5) 26 (4) p=0.04

Duration – years 2 (1) 23 (13) 8 (5) 25 (18) 25 (15) p<0.01

Atopic – % 50 90 60 75 86 P=0.39

OCS Burst – % 0 18 43 70 55 p=0.01

ACQ – score 0.7 (0.9)

1.3 (0.8)

1.2 (0.8)

2.1 (1.0)

1.9 (0.7)

p=0.01

AQLQ – score 6.2 (0.5)

5.3 (1.1)

5.1 (1.2)

4.8 (1.2)

5.2 (1.0)

p=0.24

Asthma Control Questionnaire; Asthma-related Quality of Life Questionnaire:Minimal Clinically Important Difference: 0.5ACQ: Controlled: < 0.75; Uncontrolled >1.25; B. Smith, unpublished results


Moore W, et al. AJRCCM 2010; 181(4):315-323.

Cluster Moore Phenotypic Description

McGill Phenotypic Description

1 Early onset Later onset

1 Atopic Non atopic

Cluster SARP and McGill cohorts agreement


Severe/Difficult/Refractory Asthma

Moore W, et al.AJRCCM 2010.



2 Increased health care utilization

Relatively infrequent HCU (28%)




Moore W, et al. AJRCCM 2010.



3 Non-atopic Atopic




Moore W, et al AJRCCM 2010




Moore W, et al. AJRCCM 2010



p=0.011

Human muscle specific alpha-actin

Clinical cluster and remodeling


Asthma endotypes

• An Endotype is a subtype of a condition, which is defined by a distinct functional or pathobiological mechanism. Patients with a specific endotype may present themselves within phenotypic clusters of diseases.e.g. exercise-induced asthma and aspirin-induced asthma have relatively well-explained mechanisms for their triggers but they may also be represented within phenotypes such as atopic asthma and late-onset non-atopic asthma, respectively.

Open framework asthma endotype model

G.P. Anderson Lancet 2008

Conclusions

• Definition of asthma from endotypes is required

• Airway inflammation has a limited relationship to severity of disease

• Airway smooth muscle remodeling is linked to severity

• Dominant mechanisms need to be clarified

• Convenient biomarkers are required

Inflammatory and remodeling phenotypes in asthma James Martin Meakins Christie Laboratories...

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