Inflammatory and remodeling phenotypes in asthma

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

2. No conflicts to declare

3. 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?

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 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

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. 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 B. Smith, unpublished results

25. McGill Difficult Asthma Program B. Smith, unpublished results

26. McGill Difficult Asthma Program 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 ClusterSARP and McGill cohorts agreement Moore W, et al. AJRCCM 2010; 181(4):315-323. B. Smith, unpublished results

28. Severe/Difficult/Refractory Asthma ClusterSARP and McGill cohorts agreement Moore W, et al.AJRCCM 2010. B. Smith, unpublished results

29. McGill Difficult Asthma Program ClusterSARP and McGill cohorts agreement Moore W, et al. AJRCCM 2010. B. Smith, unpublished results

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 McGill Difficult Asthma Program ClusterSARP and McGill cohorts agreement Moore W, et al AJRCCM 2010 B. Smith, unpublished results

31. McGill Difficult Asthma Program ClusterSARP 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