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

No conflicts to declare

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.

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 Environment Pathobiology Response to treatment Clinical expression of disease

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 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

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 exacerbations In severe asthma Neutrophils 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 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.

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

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

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 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

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

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

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

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):315-323. B. Smith, unpublished results

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

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

McGill Difficult Asthma Program Cluster SARP and McGill cohorts agreement Moore W, et al AJRCCM 2010 B. Smith, unpublished results

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 AJRCCM 2010 B. Smith, unpublished results

Clinical cluster and remodeling p=0.011 B. Smith, unpublished results Human muscle specific alpha-actin

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