Inflammatory and remodeling phenotypes in asthma James Martin Meakins Christie Laboratories Department of Medicine McGill University
Jan 29, 2016
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
B. Smith, unpublished results
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
McGill Difficult Asthma Program
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
B. Smith, unpublished results
Severe/Difficult/Refractory Asthma
Moore W, et al.AJRCCM 2010.
Cluster Moore Phenotypic Description
McGill Phenotypic Description
2 Increased health care utilization
Relatively infrequent HCU (28%)
B. Smith, unpublished results
Cluster SARP and McGill cohorts agreement
McGill Difficult Asthma Program
Moore W, et al. AJRCCM 2010.
Cluster Moore Phenotypic Description
McGill Phenotypic Description
3 Non-atopic Atopic
Cluster SARP and McGill cohorts agreement
B. Smith, unpublished results
McGill Difficult Asthma Program
Moore W, et al AJRCCM 2010
Cluster SARP and McGill cohorts agreement
B. Smith, unpublished results
McGill Difficult Asthma Program
Moore W, et al. AJRCCM 2010
Cluster SARP and McGill cohorts agreement
B. Smith, unpublished results
p=0.011
Human muscle specific alpha-actin
Clinical cluster and remodeling
B. Smith, unpublished results
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