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Asthma Endotypes Asthma Heterogeneity: Endotypes, Phenotypes and Choosing the Right TreatmentPresenter of Michael Wechsler, MD MMSc Reproduction Director, NJH Cohenfor Family Asthma PropertyInstitute Not Professor of Medicine National Jewish Health [email protected] Presenter of Reproduction for Property Not Dr. Wechsler has received consulting honoraria from AstraZeneca, Boehringer Ingelheim, Glaxosmithkline,Disclosures Novartis, Regeneron, Sanofi, Teva Asthma Defined Muscle • Asthma is a heterogeneous disease, characterized by chronic Healthy airway airway inflammation and history of respiratory symptoms Normal such as bronchial tube lining • Wheeze Presenter Tightened Asthma muscle • Shortness of breath of Inflamed • Chest tightness lining Reproduction Severely • Cough that varies over time and in intensity Severe tightened Asthma muscle • Variable airflow limitation for Excess Property mucus Not Inflamed lining Global strategy for asthma management and prevention. Global Initiative for Asthma website. https://ginasthma.org/wp‐content/uploads/2018/04/wms‐GINA‐2018‐report‐tracked_v1.3.pdf. Updated 2018. Accessed September 2018. Heterogeneity in Asthma—Not a New Concept Presenter of Reproduction for Property Not Spector SL, Farr RS. J Allergy Clin Immunol. 1976 May;57(5):499‐511. Asthma is Not a Clinically Homogeneous Condition • Multiple areas of difference: • Clinical presentations • Physiological characteristics Presenter • Responses to therapy of • Time of asthma development is a key factor: • Children—relatively homogeneous with a strong personal and family Reproduction allergic history of atopy for • Adults—very mixedProperty group of patients Not Basis for Disease is Present Early and Evolves Throughout Life Genetics , environment Presenter Proteins, biochemicalof pathways, cells Reproduction Physiology,for symptoms Property Not Factors That Can Contribute to Uncontrolled Asthma Disease-Related Factors Patient-Related Factors •Cyclical nature of disease •Increased disease severity •Comorbidities (eg, GERD Environmental Factors •Differing asthma phenotypes rhinosinusitis, depression) Presenter •Smoking •Passive smoking Uncontrolled Asthma •Frequent exposure to of •Obesity •Age traffic or air pollution Physician-Related Factors •Outdoor and indoor •Psychosocial issues allergens •Medication under-prescribingReproduction(eg, lower income, poor •Failure to assess adherence health literacy) •Failure to assessfor inhaler •Poor treatment adherence Propertytechnique •Inadequate inhaler technique •MisdiagnosisNot •Heterogeneity of treatment •Lack of asthma action plan response •Absence of specialty care •Failure to follow self- management plan •Side effects of other medications (eg, NSAIDs) The Asthma Patient Population is Segmented Based on Disease Severity Asthma Patient Population Presenter of Intermittent Mild Moderate Severe Reproduction for Property Persistent Asthma Not National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, Lung, and Blood Institute website. https://www.nhlbi.nih.gov/files/docs/guidelines/asthsumm.pdf. Published October 2007. Accessed September 2018. Evolution of Asthma Classification 1960’s- 1980’s- Early Late Present 1970’s 1990’s 2000’s 2000’s Presenter of Bronchoconstriction Inflammation Identification of Precision Precision therapy phenotypes and medicine: by endotype clustersReproductionidentification of endotypes and for mechanisms of disease including Property T2 vs. non-T2 Not Desai M, Oppenheimer J. Ann Allergy Asthma Immunol. 2016;116(5):394-401. Approach to Asthma Mangement 1. Assess adherence and make sure it’s asthma Presenter 2. Characterizeof the asthma- Reproduction what type offor asthma is it? Property Not 3. Treat the Asthma Asthma Phenotype vs Endotype Phenotype Endotype The set of observable A specific biologic characteristics of an mechanism that explains individual resulting from observable properties of the interaction of its Presenteran organism genotype with the of environment Reproduction for Different asthmaProperty phenotypes and endotypes may respond differentlyNot to targeted therapies Understanding Severe Asthma Heterogeneity Through Phenotyping and Endotyping Environment: Genes Allergies Gene expression Environment: Infections/ Presenter Severe Asthma Cytokines Irritants Phenotypeof and Endotype Immune Reproduction cells Meds/ for AdherenceProperty Airway Not Patient epithelium, factors smooth Comorbid muscle disease 1. Chung KF et al. Eur Respir J. 2014;43:343-373. Asthma Phenotypes Category Phenotype Trigger‐‐inducedinduced asthmaasthma • AllergicAllergic • NonallergicNon‐allergic • AspirinAspirin‐‐exacerbatedexacerbated respiratory respiratory disease disease (AERD) (AERD) • InfectionInfection • ExerciseExercisePresenter‐‐inducedinduced • OccupationalOccupationalof Asthma patientpatient characteristicscharacteristics • Smoking • ObesityReproduction • Elderly •forBlack Clinical presentation of asthmaProperty• Pre‐asthma wheezing in infants Not − Episodic (viral wheeze) − Multi‐trigger wheezing • Exacerbation‐prone asthma • Asthma associated with apparent irreversible airflow limitation Kim H, et al. Allergy Asthma Clin Immunol. 2017;13:48. Separation of Asthma Into Clinical Phenotypes • Unbiased hierarchical cluster analysis • Clinical characteristics (gender, age of onset, severity) • Physiology (lung function, airwayPresenter hyperresponsiveness) • Triggers (allergens, tobacco, ofoccupation) • Sputum inflammatory cells (eosinophils, neutrophils) • Sum total of characteristics areReproduction segregated into groups, with no single feature playingfor a predominant role in the classification Property Not Asthma Cluster Approaches and Eosinophilic Inflammation1 Discordant Monitoring inflammation Primary Care Secondary Care Symptoms allows down-titration of CS Asthma Asthma Early Symptom Predominant Early onset, atopic; normal BMI; high Concordant Disease symptom expression Symptom-based approach Obese Presenterto therapy titration may be Noneosinophilic sufficient Later onset, female of preponderance; Symptoms high symptom expression Reproduction for Monitoring inflammation Property allows targeted CS to lower exacerbation frequency Discordant Benign Asthma Inflammation Mixed middle-aged Not Inflammation Predominant cohort; well-controlled Late onset, greater proportion of symptoms and males; few daily symptoms but inflammation; benign active eosinophilic inflammation prognosis Eosinophilic Inflammation 1. Adapted from Haldar P et al. Am J Respir Crit Care Med. 2008;178:218-224. The Transition from Phenotyping and Endotyping to Genotyping Personalized approach to asthma Diagnosis Refractory asthma? CharacterizePresenter subtype of Phenotype/Cluster Endotypes (Th2 high vs. low) Genotype approach Blood SputumReproduction Other Gender biomarkers forbiomarkers Age IgEProperty Eosinophils FeNO Obesity Eosinophils Neutrophils Ethnicity/Race Not Periostin Cytokines Smoking Hx Cytokines Early vs. Late Onset Dunn and Wechsler 2015 TAILORED THERAPY 16 Asthma is Not Just One Disease Asthma Syndrome Symptoms of asthma, variable airflow obstruction Airway Wheeze, Lung Exacerbation Allergy inflammatio cough, other function s Presenter n symptoms Asthma Phenotypeof Characteristics Based on observable features with no direct relationship to a disease process (e.g., gender, age, obesity, ethnicity,Reproduction smoking history, early vs. late onset, etc.) Asthma Endotypes Distinct functional or pathophysiologicfor mechanisms that may be present in clusters of phenotypes; identifiedProperty by biomarkers (e.g., blood, sputum, urine, FeNO, exhaled Not breath) Endotype 1 Endotype 2 Endotype 3 Endotype 4 Endotype 5 Howard R, Rattray M, Prosperi M, Custovic A. Curr Allergy Asthma Rep. 2015;15(7):38. Lötvall J, Akdis CA, Bacharier LB, et al. J Allergy Clin Immunol. 2011;127(2):355‐60. Presenter of Reproduction for Property Not To personalize therapyWhy and Endotype? maximize drug response Biomarkers to Identify Asthma Phenotype Current • Sputum eosinophils • Circulating blood eosinophils • Exhaled nitric oxide • IgE Presenter of • Allergen skin testing ? Future Reproduction for • Periostin Property • Dipeptidyl peptidaseNot‐4 (DPP ‐4) • Eosinophil peroxidase • Urinary bromotyrosine IgE = Immunoglobulin E. Asthma Endotypes • Type 2 asthma • Non‐type 2 asthma – Eosinophilic Presenter– Neutrophilic – High nitric oxide of – Mediated by IL‐1, IL‐6, IL‐ – 17, and TNF High IgE Reproduction – Mediated by IL‐4, IL‐5, and IL‐13 for Property Not IL, interleukin; TNF, tumor necrosis factor. Chung KF, et al. Eur Respir J. 2014;43(2):343‐373; Kim H, et al. Allergy Asthma Clin Immunol. 2017;13:48. Presenter of Reproduction for Property Not Inflammatory, Immunologic, and Pathobiologic Features Leading to Severe Asthma Israel E, Reddel HK. N Engl J Med 2017;377:965-976 Inflammation, Endotypes, and Phenotypes in Severe Asthma are Heterogeneous Severe Asthma Disease burden: Exacerbations, symptoms, airflow obstruction/FEV1 impairment Type 2‐high Type 2‐low Endotype IL‐4, IL‐13, IL‐5‐ mediated IL‐6, IL‐17, TNF mediated Eosinophilia (eosinophilic asthma) Neutrophilia Biomarker Elevated IgE Presenter Paucigranulocytic Elevated FeNO of Early age of onset Later age of onset Phenotype Reproduction Allergic sensitization Obesity, infections, smokers for Chronic rhinosinusitis ± nasal polyps Comorbidities Property AtopicNot dermatitis Type 2 inflammation is prevalent in patients with uncontrolled persistent asthma, and these patients have
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