COPD A New Look at an Old Disease

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1 A New Look at an Old Disease Disclosures Research support to institution from Roche/Genentech, GSK, Astra Zeneca, Cheisi, Sunovion, Mylan, Boehringer Ingelheim Research support from the American Lung Association and NIH Nicola A. Hanania, MD, MS, FCCP, FRCP(C) Associate Professor of Medicine Pulmonary and Critical Care Medicine Director, Airway Clinical Research Center Consultant Roche/Genentech, Astra Zeneca, Boehringer Ingelheim, Novartis Speaker Bureau: Genentech, Sunovion GOLD: Global Initiative for Chronic Obstructive Lung Disease GOLD definition of 1 Common, preventable, treatable partially reversible Characterized by persistent airflow limitation Usually progressive and disabling Associated with enhanced chronic inflammatory response in airways/lung to noxious particles or gases is heterogeneous 2 Multiple risk factors, phenotypes, comorbidities Exacerbations and comorbidities contribute to severity The New Look of Epidemiology Pathophysiology Diagnosis and Assessment Management Novel targets for therapy 1. Global Initiative for Chronic Obstructive Lung Disease (GOLD) Goh F et al. Expert Rev RespirMed. 2013;7(6):

2 : The Old Look Perception 3,4,5 in Younger Patients and Women Is on the Rise Reality is a disease of the elderly 1 is a disease of men 2 Reality: afflicts the working age population. Reality: is also a disease of women. 1 Tinkelman, et al. Am J Manag Care. 2003;9: Chapman KR. Clin Chest Med. 2004;25: Rennard SI. New Engl J Med. 2004;350: Kleinschmidt P. Chronic obstructive pulmonary disease and emphysema. Available at 5 Rennard SI. New Engl J Med. 2004;305: Mannino, et al. MMWR. 2002; 51(6 suppl):1-16. Netter illustrations used with permission from Icon Learning Systems, a division of MediMedia USA, Inc. All rights reserved. The Impact of in the United States In 2010, accounted for million physician office visits/y 1.5 million ED visits 699,000 hospital discharges Costly 2 Direct: $27 billion/y Indirect: $20 billion/y 3rd leading cause of death 3 4th leading cause of hospital readmissions 4 The New Look of Epidemiology Pathophysiology Diagnosis and Assessment Management Novel targets for therapy 1. Ford ES et al. Chest. 2013;144(1): Morbidity & Mortality 2012 Chart Book. pdf. 3. HeronM. Natl Vital Stat Rep. 2012;60(6): Jencks SF et al. N Engl J Med. 2009; 360:

3 : The New Look Risk Factors for Exposure to inhaled particles: Tobacco smoke (active and passive) Occupational dusts, organic and inorganic Indoor air pollution from heating and cooking with biomass in poorly ventilated dwellings Outdoor air pollution Susceptibility genes Poor lung growth and development Oxidative stress Female gender Age Respiratory infections Low socioeconomic status Poor nutrition Co morbidities Agusti A, Vestbo J. AJRCCM 2011;184: : Oxidative Stress is Central to the Destruction of Pulmonary Tissue Inflammatory and Cellular Mechanisms in due to Cigarette Smoking Auto Barnes PJ. Clin Chest Med 35 (2014) Chung KF, et al. Eur Respir J. 2008;31:

4 : A Multicomponent Disease Pathophysiology of Mucus hypersecretion Reduced mucociliary transport Mucosal damage Increased numbers of inflammatory cells/ activation: CD8+ T-lymphocytes Monocytes/ macrophages Neutrophils Mast cells Elevated inflammatory mediators: IL-8, TNF-, LTB-4, and oxidants Protease/anti-protease imbalance Mucociliary dysfunction Airway inflammation Airflow limitation Structural changes Systemic component Goblet cell hyperplasia/ metaplasia Mucous gland hypertrophy Increased smooth muscle mass Airway fibrosis Alveolar destruction Poor nutritional status Reduced BMI Impaired skeletal muscle Weakness Wasting Loss of alveolar attachments Loss of elastic recoil Increased smooth muscle contraction Hyperinflation, central to the pathophysiology of (ie, increased airway resistance), correlates more directly with patient-reported outcomes Hypoxemia Anxiety Patientreported outcomes Tachypnea Dyspnea Airflow obstruction Air trapping Hyperinflation Ventilatory requirement Activity limitation Poor health-related quality of life Exacerbations Deconditioning Cooper CB. Respir Med. 2008;20:1-10. The New Look of is Underdiagnosed and Undertreated Epidemiology Pathophysiology Diagnosis and Assessment Management Novel targets for therapy 1. NIH, NHLBI. Morbidity and Mortality: 2009 Chartbook on Cardiovascular, Lung and Blood Diseases. 2.Make B et al. Int J Chron Obstruct Pulmon Dis. 2012;7: Mapel DW, et al. Int J Chron Obstruct Pulmon Dis. 2011; 6:

5 Natural History of Significant Drops in Lung Function Are Often Required for Patients to Become Severely Symptomatic PT # 1 59 y FEV1: 28 % PT # 2 63 y FEV1: 33 % PT # 3 70 y FEV1: 35 % PT # 4 72 y FEV1: 34 % MRC: 2/4 MRC: 2/4 MRC: 3/4 MRC: 4/4 FEV 1 (% predicted at age 25 years) Dyspnea, Cough Exercise Intolerance Exacerbations Hospitalizations Systemic Effects Respiratory Failure Pulm Hypertension PaO2: 70 mmhg 6MWD: 540 mt BMI: 30 PaO2: 57 mmhg PaO2: 66 mmhg 6MWD: 348mt 6MWD: 230 mt BMI: 21 BMI: 34 Heterogeneity PaO2: 60 mmhg 6MWD: 140 mt BMI: FEV1 < 35% predicted Courtesy of C.Cote, MD Recent Trials to Identify Phenotypes Airway Disease Emphysema BMI < 21 BMI >35 Sedentary Active 5

6 Phenotypes Disease attributes that describe the diverse symptoms and outcomes of patients Ideal Phenotypic Construct Frequent Exacerbations Systemic Inflammation Chronic Hypoxemia Exercise/ Activity Intolerance/ Hyperinflation Chronic Cough and Sputum Chronic Respiratory Failure Comorbidities Cardiac, Nutritional Radiologic Airway (CB, bronchiectasis), Emphysema Asthma Overlap Syndrome (ACOS) Symptom Burden Chen X et al. Front. Med. 2013;7(4): Oga T et al. Chest. 2005;128: Westwood M et al. Respir Res. 2011;12:40. Therapeutic implications Prognostic implications Han MK, et al. Am J Respir Crit Care Med. 2010;182(5): Assessment of Patient assessment criteria* Global Strategy for Diagnosis, Management and Prevention of : Assessment of Assess symptoms Airflow Limitation Spirometry for diagnosis and assessment Symptoms Validated patient questionnaires (mmrc and CAT) Exacerbation Risk History of exacerbations or spirometric classification *Pharmacological management of should also include an assessment of potential patient comorbidities mmrc: Modified Medical Research Council Dyspnea Scale CAT: Assessment Test Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease

7 Assessment of : Symptoms Assessment Test (CAT) Grade Description of Breathlessness 0 I only get breathless with strenuous exercise 1 I get short of breath when hurrying on level ground or walking up a slight hill 2 On level ground, I walk slower than people of the same age because of breathlessness, or have to stop for breath when walking at my own pace 3 I stop for breath after walking about 100 yards or after a few minutes on level ground 4 I am too breathless to leave the house or I am breathless when dressing Modified Medical Research Council Dyspnea Score 0 1 Symptoms More Severe GOLD Website. Updated December 2011 Global Strategy for Diagnosis, Management and Prevention of : Assessment of Assess symptoms Assess degree of airflow limitation using spirometry Severity of Obstruction Post-bronchodilator FEV 1 /FVC <70% Worse obstruction IV: Very Severe FEV 1 <30% III: Severe FEV 1 30% to 49% II: Moderate FEV 1 50% to 79% I: Mild FEV 1 80% Assessment of : Lung Function In patients with FEV 1 /FVC < 0.70: GOLD 1: Mild GOLD 2: Moderate GOLD 3: Severe FEV 1 > 80% predicted 50% < FEV 1 < 80% predicted 30% < FEV 1 < 50% predicted GOLD 4: Very Severe FEV 1 < 30% predicted *Based on Post-Bronchodilator FEV 1 GOLD Website. Updated December

8 Global Strategy for Diagnosis, Management and Prevention of : Assessment of Assess symptoms Assess degree of airflow limitation using spirometry Assess risk of exacerbations Lower quality of life Frequent Exacerbations Drive Disease Progression Increased inflammation Patients with frequent exacerbations Increased mortality rate Increased risk of recurrent exacerbations Faster disease progression Wedzicha JA & Seemungal TA. Lancet 2007;370: ,; Donaldson GC & Wedzicha JA. Thorax 2006;61: Increased likelihood of hospitalization Risk GOLD: Combined Assessment Assessment Using Symptoms, Breathlessness, Spirometric Classification, and Risk of Exacerbations a (GOLD Classification of Airflow Limitation) C High risk, Less symptoms A D High risk, More symptoms B 2 or 1 leading to hospital admission 1 (not leading to hospital admission) 1 Low risk, Less symptoms Low risk, More symptoms 0 CAT < 10 CAT 10 Symptoms mmrc 0 1 mmrc 2 Breathlessness Risk (Exacerbations/Year) Global Strategy for Diagnosis, Management and Prevention of : Assessment of Assess symptoms Assess degree of airflow limitation using spirometry Assess risk of exacerbations Assess comorbidities a When assessing risk, choose the highest risk according to GOLD grade or exacerbation history. 8

9 Comorbidities of Lung cancer Anxiety, depression Exploring the Links Between and Its Comorbidities Pulmonary hypertension Cardiovascular disease Anemia Diabetes Metabolic syndrome Cachexia Kao C, Hanania NA. in: Crapo J, ed. Philadelphia, PA: Current Medicine Group;2008. Peripheral muscle wasting and dysfunction Osteoporosis Peptic ulcers GI complications These comorbid conditions may influence mortality and hospitalizations; the patient should be assessed for them routinely and treated appropriately. Risk Factors Smoking and lifestyle factors Genetic susceptibility Chronic airway infection Acute exacerbations Mechanisms Airway and systemic inflammation Lung hyperinflation and endothelial dysfunction Oxidative stress Patel AR, Hurst JR. Expert Rev Respir Med. 2011;5(5): Comorbidities Ischemic heart disease Stroke and heart failure Hypertension and diabetes Muscle weakness and osteoporotic fractures Depression Outcomes Worse symptoms Worse health status Reduced activity Reduced survival Comorbidities of and Systemic Inflammation Assessing Comorbidities in Look for Comorbidities Look for If Smoker Barnes PJ. Clin Chest Med 35 (2014)

10 The New Look of Goals of Management Epidemiology Pathophysiology Diagnosis and Assessment Management Novel targets for therapy Airflow Limitation Symptom Burden Exacerbations Functional Limitations Reduce Hospital Admissions and Mortality Improve Lung Function Slow FEV1 Decline Improve Symptoms Prevent and Manage Exacerbations Improve Health Status and Exercise Tolerance Adapted from Global Initiative for Chronic Obstructive Lung Disease; (GOLD) Improving Outcomes in Early diagnosis and accurate assessment Identifying patients at risk Using appropriate diagnostic approaches, ruling out other mimickers Early treatment Implementing optimal management Reducing exposures to risk factors and triggers Non pharmacological approaches Pharmacological treatments Incorporating self management skills through education and collaboration with a health care team Improve adherence Nonpharmacologic Therapy To Manage Smoking Cessation Oxygen Therapy Patient Education Pulmonary Rehabilitation Vaccination Surgical and Nonsurgical Alternatives Rice K, et al. Clin Chest Med. 2014;35(2): ; Decramer M, et al. Respir Med. 2011;105(11): Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated

11 Non pharmacological Options for Patient Group Description Essential A Low risk, fewer symptoms GOLD 1 2 <1 Exacerbation mmrc 0 1 or CAT <10 B Low risk, more symptoms GOLD 1 2 <1 Exacerbation mmrc >2 or CAT >10 C High risk, fewer symptoms GOLD 3 4 >2 Exacerbations mmrc 0 1 or CAT <10 Smoking cessation for all patients who smoke The key intervention for smokers Can include pharmacologic treatment Pulmonary rehabilitation D High risk, more symptoms GOLD 3 4 >2 Exacerbations mmrc >2 or CAT >10 Exercise Training Involves the measurement of a number of physiologic variables, including maximum oxygen consumption, maximum heart rate, and maximum work performed Components of Pulmonary Rehabilitation Programs Pulmonary Rehabilitation Programs Nutrition Counseling Important determinant of symptoms, disability, and prognosis in ; a reduction in BMI is an independent risk factor for mortality in patients with Education Specific contributions of education to the improvements seen after pulmonary rehabilitation remain unclear Recommended Depending on local guidelines Physical activity Influenza vaccination Pneumococcal vaccination Assessment and Follow-up Adapted from Global Initiative for Chronic Obstructive Lung Disease; (GOLD) BMI=body mass index. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated Accessed April 9, Outcomes of Pulmonary Rehab in Reduces dyspnea Improves deconditioning, muscle fatigue Increases exercise capacity Improves quality of life Improves depression Reduces acute exacerbations. Reduces hospitalizations May reduce mortality Does not improve PFTs or ABGs Pharmacological Management of Guideline recommended treatment Improves lung function Minimizes symptoms Improves QoL Prevents exacerbations Wide variety of options including new agents Appropriate treatment selection hinges on GOLD staging Before stepping up/modifying treatment, re evaluate Treatment goals Clinical phenotype Comorbidities Adherence 1 British Thoracic Society. Thorax. 2001; 56: American Thoracic Society. Am J Respir Crit Care Med. 1999;159: Guell R, et al. Chest. 2000;117: Saey D, et al. Am J Respir Crit Care Med. 2003;168: Casaburi R. Am J Respir Crit Care Med. 2003;168: Casaburi R, et al. Am J Respir Crit Care Med. 1997;155: Griffiths TL, et al. Lancet. 2000;355: Cote CG, et al. Am J Respir Crit Care Med. 2003;167:A38. 11

12 Pharmacological Agents Approved in the U.S. Pharmacological Treatment Options Short acting β-agonists (SABA) Albuterol Pirbuterol Levalbuterol Bronchodilators Anticholinergic (SAMA) Ipratropium Long acting β-agonists (LABA) Salmeterol Formoterol Arformoterol Indacaterol Oladaterol Anticholinergic (LAMA) Tiotropium Aclidinium Umeclidinium Glycopyrrium LABA +LAMA Umeclidinium +Vilanterol Tiotropium + Oladaterol Glycopyrrinium _Indacaterol Anti Inflammatory ICS+LABA Fluticasone + Salmeterol Budesonide +Formoterol Fluticasone Fuorate +Vilanterol PDE 4 Inhibitors Roflumilast Systemic Steroids Prednisone Methylprednisolone Theophylline Adapted from: Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Inhaler Devices Available in the U.S. Strategies to Ensure Adherence A large proportion (49-76%) of patients use their inhalers incorrectly GOLD guidelines recommend rechecking inhaler technique at each patient visit Ellipta 1.Newman SP. Eur Respir Rev. 2005;14:96, Molimard M, et al. J Aerosol Med. 2003;16(3): Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease

13 The New Look of Epidemiology Pathophysiology Diagnosis and Assessment Management Novel targets for therapy Unmet Needs with Current Interventions Current pharmacotherapies do not change the natural history of Many patients remain symptomatic with current therapies Inadequate adherence with inhaled therapy is a major cause of poor clinical outcomes in the treatment of Cost, compliance, and safety are significant issues Novel Pharmacological Targets in Novel formulations of existing medications Ultra LABAs (indacaterol, oladaterol) Ultra LAMAs (aclidinium, umeclidinium, glycopyrinium) LABA/LAMA combinations (vilanterol/umeclidinium, indacaterol/glycopyrrolate, formoterol/glycopyrrolate) LABA/ICS combinations (vilanterol/fluticasone) Nebulized bronchodilators and combination therapies MABAs Drugs Used in Treatment of Comorbidities That May Be Useful in Macrolides Statins ACE Inhibitors Beta blockers Peroxisome proliferator activated receptor (PPAR) agonists 13

14 Smoking Cessation Nicotine antagonists Vaccination Inflammosome Inhibitors Anti proteases: Neutrophil elastase MMP9 inhibitors Chemokine Antagonists Antioxidants Reversal of Steroid Resistance PDE inhibitors Epigenetic modulators Mediator Antagonists (TNF, IL 17, IL5, IL 13 antibodies) Kinase inhibitors Antibiotics Phagocytosis Antifibrotic: Regeneration: Mucoregulators: Targeting TGFβ Stem Cell EGFR inhibitors PPR agonists Retinoic Acid Barnes PJ. Nature Rev Drug Discovery 2013; 12: 543 Flow regulation Tissue compression Bronchoscopic Approaches to LVR Zephyr Endobronchial Valves (EBV) PulmonX Intrabronchial Valves (IBV) Spiration RePneu Lung volume reduction coil (LVRC) PneumRx AeriSeal Polymeric Lung Sealant Aeris InterVapor Bronchoscopic Thermal Vapor Ablation (BTVA) Uptake One way valve leads to atelectasis. One way valve leads to atelectasis. Coil reduces lung volume by coiling and compressing disease tissue. Tissue sealant flows into alveolar compartment, polymerizes and seals target area. Heated water vapor produces thermal reaction with localized inflammation followed by fibrosis. Summary continues to be a major public health problem The pathophysiology of involves chronic airway inflammation and lung destruction driven by several inflammatory cells and mediators is a heterogenous disease with multiple phenotypes Phenotypic characterization of will improve personalized approach the disease Summary Clinical approach to includes assessment of symptoms, lung function, exacerbation risk and comorbidities Several non pharmacological and pharmacological interventions are available which should be implemented according to disease severity Multiple novel targets of therapy are being evaluated and may be available in the future 14