THE COPD-ASTHMA OVERLAP SYNDROME

THE COPD-ASTHMA OVERLAP SYNDROME NICOLA A. HANANIA, MD, MS, FRCP(C), FCCP, FACP ASSOCIATE PROFESSOR OF MEDICINE DIRECTOR OF ASTHMA & COPD CLINICAL RESEARCH CENTER BAYLOR COLLEGE OF MEDICINE HOUSTON, TX Nicola A. Hanania, MD, MS is Associate Professor of Medicine in the Section of Pulmonary and Critical Care Medicine and Director of the Asthma and COPD Clinical Research Center at the Baylor College of Medicine in Houston, Texas, USA. He completed his medical training at the University of Jordan followed by residency in internal medicine and a fellowship in pulmonary medicine at the University of Toronto, Canada. He subsequently completed a fellowship in critical care medicine at Baylor College of Medicine, where he later earned a master s degree in clinical investigation. As a Fellow of the American College of Chest Physicians, Dr. Hanania has served on the Board of Regents and as Chair of the Clinical Pulmonary, Airways Networks and Council of Networks for this organization. He has been on the Board of Trustees of the Chest Foundation since 2012. In addition, he is a current member of the Health Policy Committee of the American Thoracic Society, the European Respiratory Society, the Society of Critical Care Medicine and a fellow of the Royal College of Physicians and Surgeons of Canada. He has served on several guideline and workshop panels including the ACP/ATS/ACCP/ERS Clinical Practice guidelines on COPD and the CTS/ACCP COPD exacerbations guidelines. Dr. Hanania has received multiple awards including the ACCP s Distinguished Scholar in Respiratory Health, ACCP Humanitarian Award, Career Investigator Award (K23) from the NIH, Fulbright and Jaworski s Faculty Excellence Award for Teaching and Evaluation and the Award for Excellence in Teaching from the Department of Medicine at Baylor. Baylor also named him to the Academy of Distinguished Educators for 2003-2010. Dr. Hanania is a deputy editor of Respiratory Medicine and is Associate Editor of Therapeutic Advances in Respiratory Disease, Current Opinion in Pulmonary Medicine (Asthma Section) and Pulmonary Pharmacology and Therapeutics. Dr. Hanania s research interests focus on the pharmacology and management of asthma and COPD. He has published more than 200 peer-reviewed papers, book chapters, editorials and reviews on these topics. He is actively involved in clinical trials investigating novel treatments. He is Principal Investigator for the American Lung Association Airway Clinical Research Center at Baylor College of Medicine, as well as Principal Investigator or Co-Investigator in several clinical trials in asthma and COPD. He has been invited and has lectured widely at local, regional, national and international meetings.

OBJECTIVES: Participants should be better able to: 1. Describe current knowledge about Asthma-COPD Overlap Syndrome (ACOS); 2. Discuss Clinical Scenarios of Patients with ACOS; 3. Compare Impact of Asthma, COPD and ACOS; 4. Review Guidelines and Consensus Definition and Diagnostic and Management Strategies for ACOS; 5. Outline Future Research Needs. SATURDAY, MARCH 25, 2017 10:30 AM

Asthma COPD Overlap Syndrome (ACOS) Nicola A. Hanania, MD, MS, FCCP Associate Professor of Medicine Pulmonary and Critical Care Medicine Director, Asthma Clinical Research Center Baylor College of Medicine, Houston, Texas Disclosure Information Advisor/ Consultant: - Roche/ Genentech, AstraZeneca, BI, Sanofi/Regeneron, Teva Member, Board of Trustee, CHEST Foundation Research grant support (to institution): - NHLBI, ALA - GSK, BI, Roche/Genentech, AstraZeneca 1

Learning Objectives Describe current knowledge about Asthma COPD Overlap Syndrome (ACOS) Discuss Clinical Scenarios of Patients with ACOS Compare Impact of Asthma, COPD and ACOS Review Guidelines and Consensus Definition and Diagnostic and Management Strategies for ACOS Outline Future Research Needs Case 56 years old White woman with 20 pack.year smoking history presents with increasing dyspnea, wheezing and cough. History of asthma since childhood which has been stable until recently History of allergic rhinitis, GERD and hypertension P/E: audible wheezing and prolonged expiratory sounded Spirometry: - Post bronchodilator FEV1: 65% predicted, - FEV1/FVC 0.68, 22% reversibility 2

Question 1 A. Significant bronchodilator response (12% and 200 ml change) can distinguish asthma from COPD and ACOS B. Smoking history of >20 pack.year suggests a diagnosis of COPD C. Presence of allergic rhinitis in this patient suggests a diagnosis of Asthma D. A post bronchodilator FEV1/FVC ratio <0.7 rules out the diagnosis of ACOS E. None of the above Question 1 A. Significant bronchodilator response (12% and 200 ml change) can distinguish asthma from COPD and ACOS B. Smoking history of >20 pack.year suggests a diagnosis of COPD C. Presence of allergic rhinitis in this patient suggests a diagnosis of Asthma D. A post-bronchodilator FEV1/FVC ratio <0.7 rules out the diagnosis of ACOS E. None of the above 59% 15% 19% 7% 0% A. B. C. D. E. 3

Question 2 A. ACOS leads to more significant health status impairment, increased exacerbations and increased hospitalizations than COPD B. Comorbidities in ACOS can contribute to impairment C. Patients with ACOS may have increase in eosinophils or neutrophils, or both, in sputum. D. There is limited evidence for treatment recommendations because ACOS patients are excluded from randomized controlled trials E. All the above Question 2 A. ACOS leads to more significant health status impairment, increased exacerbations and increased hospitalizations than COPD B. Comorbidities in ACOS can contribute to impairment C. Patients with ACOS may have increase in eosinophils or neutrophils, or both, in sputum D. There is limited evidence for treatment recommendations because ACOS patients are excluded from randomized controlled trials E. All of the above 3% 3% 0% 3% 91% A. B. C. D. E. 4

The Dutch Hypothesis The Dutch Hypothesis Common Disease? Professor Dick Orie Groningen, NL Common Mechanisms Asthma CNSLD.COPD Orie et al. Bronchitis II Second International Symposium. Assen, Netherlands: Royal Van Gorcum; 1964:398 99 Host (Genetic) factors (Atopy, AHR) The Dutch Hypothesis Asthma Endogenous factors (Sex, age) Bronchial Inflammation COPD CNSLD Environmental factors (Allergens, infection, smoking, air pollution) Orie et al. Bronchitis II Second International Symposium. Assen, Netherlands: Royal Van Gorcum; 1964:398 99 Postma DS, Boezen HM. Chest 2004; 126: 96 104S Postma DS et al. J Allergy Clin Immunol 2015; 136:521 9 5

The Dutch Hypothesis The Dutch Hypothesis Common Disease? Professor Dick Orie Groningen, NL Common Mechanisms Asthma CNSLD.COPD Orie et al. Bronchitis II Second International Symposium. Assen, Netherlands: Royal Van Gorcum; 1964:398 99 The Debate Continues The Dutch Hypothesis The British Hypothesis Common Disease? Professor Dick Orie Groningen, NL Common Mechanisms Asthma CNSLD.COPD Orie et al. Bronchitis II Second International Symposium. Assen, Netherlands: Royal Van Gorcum; 1964:398 99 Allergies Different Diseases Asthma Professor Charles Fletcher, London, UK Different Mechanisms COPD Irritants/ Smoking 6

The Overlap Between Asthma and COPD Traditional View Am J Respir Crit Care Med. 1995;152(5 pt 2):S77 S121. Soriano JB, et al. Chest. 2003;124:474 481. Jeffery PK. Am J Respir Crit Care Med. 2001;152:S28 S38. COPD: A Heterogenous Disease CV comorbidity CBI Muscle alterations Bronchiect. Osteoporosis Chronic sputum Exacerbations Enphysema Hyperinsuf. Rhinitis Revers. Dyspnea Pulmonary HTN Eosinophil. Low weight BHR 7

COPD: A Heterogenous Disease CV comorbidity CBI Muscle alterations Bronchiect. Osteoporosis Chronic sputum Exacerbations Enphysema Hyperinsuf. Rhinitis Revers. Dyspnea Pulmonary HTP Eosinophil. Low weight BHR Asthma COPD Overlap Syndrome? eno & Sputum Eosinophils in Reversible COPD Exhaled NO Sputum eos Papi A et al: AJRCCM 2000 Reversible: >15% in FEV 1 after b/d 8

Can Sputum Neutrophils and Eosinophils Differentiate COPD vs. ACOS? Kitaguchi et al, International Journal of COPD 2012:7 283 289 Eur Respir J 2014; 43: 421 429 9

Eur Respir J 2014; 43: 421 429 Clinically, ACOS can be Defined as 1 of 2 Phenotypes Asthma with partially reversible airflow obstruction with or without emphysema or reduced DLCO COPD accompanied by reversible or partially reversible airflow obstruction with or without environmental allergies (elevated IgE or eosinophils) Postma DS, Rabe KF. N Engl J Med 2015;373:1241 9. 10

Clinical Scenarios When Asthma and COPD may Overlap COPD (Post Bronchodilator FEV1/FVC <0.7) with One or More of the Following: a. Past or Current Diagnosis of Asthma b. Clinical Features of Asthma Episodic symptoms Allergic Triggers and comorbidities (Rhinitis, sinusitis) Elevated IgE, Antigen Specific IgE sensitization c. Variable Airflow Obstruction Significant acute bronchodilator response, Diurnal variability in PEFR Airway hyperresponsiveness d. Evidence of Eosinophilic Airway Inflammation Elevated eno, elevated blood or sputum eosinophils Late Onset Asthma with Partially Reversible Airway Obstruction Asthma with Current or Past History of Heavy Smoking Bujarski S, Parulekar A, Hanania NA. Curr Allergy Asthma Rep (2015) 15: 7 The Overlap Between Asthma and COPD Emerging View: Is this ACOS?? Other COPD Phenotypes Emphysema Airflow obstruction Other Asthma Phenotypes 11

Prevalence of Overlap Syndrome Increases with Age Gibson P G, and Simpson J L Thorax 2009;64:728 735 de Marco R et al. PLoS ONE 2013: 8: e62985. Predictors of Asthma Among Subjects with COPD Multivariate Logistic Regression ACOS more likely to be younger, African-American, and have less smoking history N = 915 Hardin et al. Respiratory Research 2011, 12:127 12

ACOS vs. COPD in ECLIPSE Keele E. European Respiratory Journal 2016 47: 1559 1562 Prevalence of Respiratory Symptoms or Conditions de Marco R et al. PLoS ONE 2013: 8: e62985. 13

More Exacerbations in Patients with ACOS and COPD Hardin et al. Respiratory Research 2011, 12:127 Exacerbation Rate in Patients with ACOS International Journal of COPD 2015:10 1443 1454 14

Health Care Utilization and Clinical Implications of ACOS Patients with COPD and asthma use more health care services and incur higher costs than those with COPD without the presence of asthma 1 1 Blanchette CM et al. J Manag Care Pharm. 2008;14(2):176 85 Menezes AMB et al. CHEST 2014; 145(2):297 304 Impact of ACOS on Physical Activity and Health Status Marc Miravitlles et al. Respiratory Medicine (2013) 107, 1053 1060 15

Clinical Characteristics of Patients with ACOS vs. COPD Kitaguchi et al, International Journal of COPD 2012:7 283 289 Prevalence of Co morbidities in ACOS vs. Asthma and COPD Postma DS. Clin Chest Med 35 (2014) 143 156 16

Prevalence of Comorbidities in Patients with ACOS in Primary Care Adjusted OR ACOS (n=5093) vs. COPD (n= 22778) Allergic Rhinitis 1.81, 95% CI: 1.63 2.00 Anxiety 1.18, 95% CI: 1.1 1.27 GERD 1.18, 95% CI: 1.04 1.33 Osteoporosis 1.14, 95% CI: 1.04 1.26 Chronic kidney disease 0.79, 95% CI: 0.66 0.95 Ischemic heart disease 0.88, 95% CI: 0.79 0.98 Van Boven J, et al. ERS 2015 Comorbidities in Patients with ACOS 17

Fu J J et al. Allergy Asthma Immunol Res. 2014 July;6(4):316 324 Fu J J et al. Allergy Asthma Immunol Res. 2014 July;6(4):316 324 18

Spanish Respiratory Society Criteria for ACOS - Very positive bronchodilator test (increse in FEV 1 15% y 400 ml, over baseline) - Sputum eosinophilia - Personal history of asthma (history before the age of 40) - High total IgE - Personal history of atopy -Positive bronchodilator test on 2 or more occasions (increase in FEV 1 12% y 200 ml, over baseline) Major Minor Diagnostic criteria 2 major criteria or 1 major + 2 minor Soler Cataluña JJ, et al. Arch Bronconeumol 2012; 48: 331 7 19

Asthma-COPD overlap syndrome (ACOS) [a description] Asthma-COPD overlap syndrome (ACOS) is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD. ACOS is therefore identified by the features that it shares with both asthma and COPD. A specific definition for ACOS cannot be developed until more evidence is available about its clinical phenotypes and underlying mechanisms. STEP 1 DIAGNOSE SYNDROMIC CHRONIC DIAGNOSIS AIRWAYS DISEASE IN ADULTS STEP 2 Do symptoms suggest chronic airways disease? (i) Assemble the features for asthma and for COPD that best describe the patient. (ii) Compare number of features in favour of each diagnosis and select a diagnosis Features: Yes if present suggest - No Consider other diseases first ASTHMA COPD Age of onset Before age 20 years After age 40 years Pattern of symptoms Variation over minutes, hours or days Worse during the night or early morning Persistent despite treatment Good and bad days but always daily symptoms and exertional dyspnea Triggered by exercise, emotions including laughter, dust or exposure to allergens Chronic cough & sputum preceded onset of dyspnea, unrelated to triggers Lung function Lung function between symptoms Past history or family history Record of variable airflow limitation (spirometry or peak flow) Normal Previous doctor diagnosis of asthma Family history of asthma, and other allergic conditions (allergic rhinitis or eczema) Record of persistent airflow limitation (FEV 1 /FVC < 0.7 post-bd) Abnormal Previous doctor diagnosis of COPD, chronic bronchitis or emphysema Heavy exposure to risk factor: tobacco smoke, biomass fuels Time course No worsening of symptoms over time. Variation in symptoms either seasonally, or from year to year May improve spontaneously or have an immediate response to bronchodilators or to ICS over weeks Symptoms slowly worsening over time (progressive course over years) Rapid-acting bronchodilator treatment provides only limited relief Chest X-ray Normal Severe hyperinflation NOTE: These features best distinguish between asthma and COPD. Several positive features (3 or more) for either asthma or COPD suggest that diagnosis. If there are a similar number for both asthma and COPD, consider diagnosis of ACOS DIAGNOSIS CONFIDENCE IN DIAGNOSIS Asthma Asthma Some features of asthma Asthma Features of both Could be ACOS Some features of COPD Possibly COPD COPD COPD 20

QUESTION 3 The following statement is correct A. Post bronchodilator FEV1/FVC <0.7 is compatible with either COPD or ACOS B. Post bronchodilator increase in FEV1 >12% and 400 ml is commonly seen in COPD and ACOS C. Sputum eosinophils >2% is diagnostic of ACOS D. FeNO > 25 is diagnostic of ACOS QUESTION 3 The following is correct A. Post bronchodilator FEV1/FVC <0.7 is compatible with either COPD or ACOS B. Post bronchodilator increase in FEV1 >12% and 400 ml is commonly seen in COPD and ACOS C. Sputum eosinophils >2% is diagnostic of ACOS D. FeNO > 25 is diagnostic of ACOS 77% 20% 3% 0% A. B. C. D. 21

STEP 3 PERFORM SPIROMETRY Marked reversible airflow limitation (pre-post bronchodilator) or other proof of variable airflow limitation FEV 1 /FVC < 0.7 post-bd Spirometric variable Asthma COPD ACOS Normal FEV 1 /FVC pre- or post-bd Compatible with asthma Post-BD - FEV 1 /FVC <0.7 Indicates airflow limitation; may improve FEV 1 80% predicted Compatible with asthma (good control, or interval between symptoms) FEV 1 <80% predicted Compatible with asthma. A risk factor for exacerbations Post-BD - increase in Usual at some time in FEV 1 >12% and 200mL course of asthma; not from baseline (reversible always present airflow limitation) Post-BD - increase in High probability of FEV 1 >12% and 400mL asthma from baseline Not compatible with diagnosis (GOLD) Required for diagnosis by GOLD criteria C ompatible with GOLD category A or B if post- BD FEV 1 /FVC <0.7 Indicates severity of airflow limitation and risk of exacerbations and mortality Common in COPD and more likely when FEV 1 is low Unusual in COPD. Consider ACOS Not compatible unless other evidence of chronic airflow limitation Usual in ACOS Compatible with mild ACOS Indicates severity of airflow limitation and risk of exacerbations and mortality Common in ACOS, and more likely when FEV 1 is low Compatible with diagnosis of ACOS Clinical and Physiological Characteristics of Asthma, Overlap and COPD Gibson P G, and Simpson J L Thorax 2009;64:728-735 22

Pulmonary Function in Patients with COPD and ACOS Kitaguchi et al, International Journal of COPD 2012:7 283 289 Goals of Management Airflow Limitation Symptom Burden Exacerbations Functional Limitations Reducing Impairment Reduce Hospital Admissions and Mortality Improve Lung Function Slow FEV1 Decline Improve Symptoms Prevent and Manage Exacerbations Reducing Risk Improve Health Status and Exercise Tolerance 23

Model of Disease Components and Individualized Treatment Approach to Obstructive Airway Disease. Gibson PG et al. The Lancet 2010; 376: 803 813 Therapeutic Targets 24

STEP 4 INITIAL TREATMENT* Asthma drugs No LABA monotherapy Asthma drugs No LABA monotherapy ICS and consider LABA +/or LAMA COPD drugs COPD drugs QUESTION 4 Initial treatment of a patient should include: A. Inhaled Corticosteroids B. Long acting beta2 agonists C. Long acting anti cholinergics D. LABA/LAMA Combination 25

QUESTION 4 Initial treatment of a patient should include: A. Inhaled Corticosteroids B. Long-acting beta2-agonists C. Long-acting anti-cholinergics D. LABA/LAMA Combination 64% 27% 0% 9% A. B. C. D. Therapeutic Implications Response to Beta 2 Agonists ad ics Kitaguchi et al, International Journal of COPD 2012:7 283 289 26

Therapeutic Implications The recognition of individuals with shared characteristics of asthma and COPD (ACOS) has important implications for disease management. In these patients, the disease will respond to ICSs irrespective of the severity of airflow obstruction. Conversely, patients with COPD but without any features of asthma will have a poor response to ICSs, and treatment with these drugs should be reassessed. Targeted Approach to Airway Diseases Barnes PJ. JACI 2015 27

Investigation Asthma COPD DLCO Normal or slightly elevated Often reduced Arterial blood gases Normal between exacerbations In severe COPD, may be abnormal between exacerbations Airway hyperresponsiveness High resolution CT scan Tests for atopy (sige and/or skin prick tests) FENO Not useful on its own in distinguishing asthma and COPD. Higher levels favor asthma Usually normal; may show air trapping and increased airway wall thickness Not essential for diagnosis; increases probability of asthma If high (>50ppb) supports eosinophilic inflammation Air trapping or emphysema; may show bronchial wall thickening and features of pulmonary hypertension Conforms to background prevalence; does not rule out COPD Usually normal. Low in current smokers Blood eosinophilia Supports asthma diagnosis May be found during exacerbations Sputum inflammatory cell Role in differential diagnosis not established in large populations analysis GINA 2016, Box 5-5 What do we currently know about ACOS? B. Ding & A Enstone. Expert Rev Respir Med 2016; 10:3, 363 371, 28

ACOS Take Home Messages Asthma COPD Overlap syndrome is not a disease entity but a term applied to patients with clinical features of both asthma and COPD ACOS is associated with greater morbidity than Asthma and COPD alone and with relative treatment refractoriness, but information is sparse about its course since most clinical studies have excluded such patients Current recommendations based on consensus suggest that patients with suspected ACOS should be given both a long acting bronchodilator; the cornerstone of COPD treatment and an inhaled corticosteroids; the cornerstone of asthma treatment What do we need to know about ACOS? Consensus definition and to understand the clinical context, size of the problem and reanalysis of population data Large longitudinal (non interventional) studies, or retrospective observational studies to understand the clinical and natural history of ACOS. Understand the molecular mechanisms of ACOS and its related phenotypes; Large longitudinal data are required to discover novel molecular pathways involved in ACOS. Understand the role of inhaled corticosteroids in ACOS; prospective clinical trials are required to validate (or refute) response to ICS and the cost effectiveness of this approach. Examine the role of biologic therapy on clinical course and outcomes 29