1. Inflammatory and remodeling phenotypes in asthma
James Martin
Meakins Christie Laboratories
Department of Medicine
McGill University

2. No conflicts to declare

3. Why is the definition so predominantly clinical?
Definition of asthma
“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?
Asthma is not a single entity but the convergence of multiple mechanisms of airway narrowing, mucus hypersecretion, nerve irritation, inflammation and remodeling. The diversity of asthma in its clinical presentations is well recognized as well as unequal treatment responses prompting a consideration of asthma phenotypes.

4. 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.

5. Is it realistic to anticipate distinct phenotypes?
Genes
Environment
Pathobiology
Response to treatment
Clinical expression of disease

6. 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

7. Inflammatory phenotypes based on sputum examination
Eos Neut Mixed Pauci Healthy
J Simpson et al, Respirology, 2006

8. Inflammatory phenotypes associate with age
J Simpson et al, Respirology, 2006

9. Clinical phenotypes of asthma
P. Haldar et al AJRCCM, 2008

10. Severe asthma phenotypes
G.P. Anderson Lancet 2008

11. Distinguishing severe asthma phenotypes: Role of age at onset and eosinophilic inflammation
Bal and bronchoscopy performed on around 75 persons. Late onset had slightly more eos. No evidence for Th2 inflammation in late onset.
Miranda et al JACI 2004

12. How stable are inflammatory phenotypes?
A-moderate B- severe
Only 1/3rd were stable phenotypes
Al Samri et al JACI 2010

13. Comparison of inflammation assessed from induced sputum and biopsies in moderate to severe asthma?
Sputum but not tissue eosinophils
correlate with frequency of exacerbations
In severe asthma
Neutrophils are not correlated with clinical
outcomes
C. Lemiere, JACI 2006

14. P Nair et al, NEJM 2009

15. 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

16. Airway wall remodeling on bronchial biopsies
Epithelial (shedding, denudation)
Subepithelial fibrosis
Increase in ASM
Epithelium to ASM distance reduced
Where does our interest in ASM growth come from? It is of course based on the longstanding observation that airways from asthmatic subjects show remodeling involving the epithelium, the subepithelial space and the airway smooth muscle. Histological evidence of an increase in ASM has been reported by numerous authors going back to the 1920s with Huber and Kossler. ON this biopsy you can see the prominent muscle bundles. Interestingly these bundles are more superficially located suggesting that they may have proliferated on the luminal side of the airway.

17. ASM mass is related to disease severity
Pepe et al J Allergy Clin Immunol 2005

18. Severe asthma; variable and fixed obstruction
variable obstruction
P<0.05
fixed obstruction
Kaminska et al, JACI 2009

19. Airway remodeling is correlated with obstruction in children with severe asthma
Tillie-Leblond et al. Allergy 2008

20. ASM remodeling is dynamic even in longstanding severe asthma
Hassan et al, JACI 2010

21. The relationship between ASM remodeling and clinical phenotypes

22. Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program
Moore et al AJRCCM 2010

23. Accuracy of clustering using 3 clinical variables
Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program
Accuracy of clustering using 3 clinical variables
Moore et al AJRCCM 2010

24. 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
Mild – n/%
0/0
260/36
Moderate – n/%
27/32
157/22
Severe – n/%
57/68
304/42
B. Smith, unpublished results

25. McGill Difficult Asthma Program
Characteristic (SD)
Cluster 1
Cluster 2
Cluster 3
Cluster 4
Cluster 5
Subjects – n 6 27 7 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)
Age at onset – years
44 (15)
20 (12)
47 (3)
18 (15)
22 (17)
B. Smith, unpublished results

26. McGill Difficult Asthma Program
Characteristic (SD)
Cluster 1
Cluster 2
Cluster 3
Cluster 4
Cluster 5
Subjects – n 6 27 7 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 – % 18 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)
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
MCID: AQLQ 0.5
Asthma Control Questionnaire; Asthma-related Quality of Life Questionnaire:
Minimal Clinically Important Difference: 0.5
ACQ: Controlled: < 0.75; Uncontrolled >1.25;
B. Smith, unpublished results

27. McGill Difficult Asthma Program
Cluster SARP and McGill cohorts agreement
Cluster
Moore Phenotypic Description
McGill Phenotypic Description 1
Early onset
Later onset
Atopic
Non atopic
Moore W, et al. AJRCCM 2010; 181(4):
B. Smith, unpublished results

28. Severe/Difficult/Refractory Asthma
Cluster SARP and McGill cohorts agreement
Cluster
Moore Phenotypic Description
McGill Phenotypic Description 2
Increased health care utilization
Relatively infrequent HCU (28%)
Moore W, et al.AJRCCM 2010.
B. Smith, unpublished results

29. McGill Difficult Asthma Program
Cluster SARP and McGill cohorts agreement
Cluster
Moore Phenotypic Description
McGill Phenotypic Description 3
Non-atopic
Atopic
Moore W, et al. AJRCCM 2010.
B. Smith, unpublished results

30. McGill Difficult Asthma Program
Cluster SARP and McGill cohorts agreement
Moore W, et al AJRCCM 2010
B. Smith, unpublished results

31. McGill Difficult Asthma Program
Cluster SARP and McGill cohorts agreement
Moore W, et al. AJRCCM 2010
B. Smith, unpublished results

32. Clinical cluster and remodeling
p=0.011
B. Smith, unpublished results
Human muscle specific alpha-actin

33. 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.

34. Open framework asthma endotype model
G.P. Anderson Lancet 2008

35. 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