COPD or not COPD, that is the question.

COPD or not COPD, that is the question. Asthma-COPD Overlap Syndrome: ACOS Do we really need this? Michelle Harkins

Disclosure Slide Slide help - William Busse, MD Organizational Interests ATS, ACCP, ACP FDA: PADAC Research Interest - No current industry sponsored clinical trials but have worked with several industries in asthma trials

Introduction and Goals Asthma and COPD share many disease features including symptoms, time of onset of disease, and airflow obstruction Features of asthma and COPD may co-exist, especially in older patients, to complicate the recognition of underlying airway diseases and its treatment, particularly in the face of smoking. Discuss Obstructive lung disease classifications Overlap syndrome (ACOS) Approaches to recognition and treatment? Is it a necessary diagnosis

Chronic obstructive pulmonary diseases Traditional View Asthma COPD Distinct Diseases

Traditional views British hypothesis Dutch hypothesis Spectrum of disease, 1961

Obstructive defect A disproportionate reduction of maximal airflow with respect to the maximal lung volume FEV 1 decreases more than FVC FEV 1 /FVC is decreased, should be primary guide

Spirometry: Flow-Volume Loops in Demonstrating Non-obstructed Pattern & Reversal of Airflow Obstruction Following a Beta-Agonist 5 Flow (l/s) 4 3 2 1 0-2 -4-6 1 2 3 4 5 Volume (l) Pre-albuterol Post-albuterol Predicted

Obstructive Diseases Asthma reversible airflow obstruction, different phenotypes, inflammation prominent Emphysema (COPD) permanent, enlargement/destruction of the respiratory bronchioles Chronic Bronchitis sputum production 3 months/year for 2 years

Interrelationship of Diseases Causing Airways Obstruction

What is ACOS? A specific definition for ACOS can not be developed until more evidence is available about clinical phenotypes and underlying mechanisms. GINA/GOLD Joint Statement www.gina.org

AKA ACOS or COAS ACO Wheezy bronchitis Eosinophilic COPD Neutrophilic Asthma Reversible COPD

Some Proposals for Criteria- ACOS Fixed airway obstruction Previous history of asthma Bronchodilator reversibility Blood eosinophils >5%, Immunoglobulin E >100 IU

Patient case A 62-year-old Caucasian woman presents with a chief complaint of cough and shortness of breath that has become progressively more severe over the past two years. She is now having shortness of breath with minimal exercise, occasionally at night, and with respiratory infections.

Past medical history: Hypertension on hydrochlorothiazide Hx of asthma while in grade school, but was not treated Had hay fever as a child, but outgrew this Recently had normal dobutamine stress echocardiogram Social history: History professor at local university Currently a nonsmoker, but smoked roughly 1 1.5 packs of cigarettes daily through college, graduate school, and the early part of her career with a 15 20 pack-year history No pets Family history: Father was a long-term smoker and died of lung cancer aged 73 years Mother has exercise-induced asthma and is still living at 87 years

Office spirometry FVC: 3.2 L (84% predicted) FEV 1 : 2.0 L (69% predicted) FEV 1 :FVC ratio: 63% predicted FEV 1, forced expiratory volume in 1 s; FVC, forced vital capacity.

What are the key points in this patient s history and findings? Older patient (>60 years) Past history of allergies and asthma Smoking history Escalating respiratory symptoms Obstructive lung disease What does she have? Asthma vs COPD

Postma DS; Rabe K. N Engl J Med 2015;373:1241-9

Hypothetical Course of Lung Function in Chronic Obstructive Pulmonary Disease and Asthma Postma DS; Rabe K. N Engl J Med 2015;373:1241-9.

Differentiating asthma vs COPD Asthma COPD Symptoms before age 40 Common Rare Smoking status Possible ~90% are ex-smokers Nighttime awakenings Common Rare Chronic productive cough Uncommon Common Breathlessness Variable Persistent Atopy Common Possible Day-to-day variability in symptoms Common Uncommon (except during exacerbations) Response to bronchodilator More Less

Spirometric measures in asthma, COPD, and ACOS Spirometric variable Asthma COPD ACOS Normal FEV 1 /FVC + Post-BD FEV 1 /FVC <0.7 + + + FEV 1 80% predicted + + + FEV 1 <80% predicted + + + Post-BD increase in FEV 1 12% and 200 ml from baseline (reversible airflow limitation) Post-BD increase in FEV 1 12% and 400 ml from baseline (marked reversibility) + +/ + + + BD, bronchodilator; FEV 1, forced expiratory volume in 1 s; FVC, forced vital capacity. Global Initiative for Asthma. Global strategy for Asthma Management and Prevention. Updated 2015. http://www.ginasthma.org.

Four Examples of Patients with Obstructive Airway Disease Postma DS; Rabe K. N Engl J Med 2015;373:1241-9.

The Overlap Syndrome As many as 50% of older adults with obstructive airway disease have overlapping diagnoses of asthma and COPD This percentage increases linearly with age These patients are often excluded from clinical studies for asthma (because of smoking history) and for COPD (because of at least a partial reversibility of airflow obstruction) Leads to questions for recommended treatment regimens of individual patients with symptom overlap Gibson PG and Simpson JL. Thorax 2009;64:728 735.

The effect of age on the presence of The Overlap Syndrome Gibson PG and Simpson JL. Thorax 2009;64:728 735.

Defining Asthma COPD Overlap Syndrome (ACOS) Asthma COPD overlap syndrome is characterized by: Persistent airflow limitation Several features usually associated with asthma Several features usually associated with COPD ACOS is identified by the features it shares with both asthma and COPD, and treatment is directed towards the dominant underlying airway disease

Chronic obstructive pulmonary diseases Newer View Asthma COPD 1 2 3 4 5 A B C D Phenotypes Phenotypes

CLUSTER ANALYSIS: 5 CLUSTERS Cluster 1 n=110 Cluster 2 n=321 Cluster 3 n=59 Cluster 4 n=120 Cluster 5 n=116 P-value Age at Enrollment 27 33 50 38 49 <0.0001 Gender (%female) 80 67 71 53 63 0.0006 Race (% Cauc/AAOther) 62/29/9 63/30/7 73/22/5 62/33/5 68/20/12 0.17 Body Mass Index (BMI) 27 28 33 31 31 <0.0001 Age of Asthma Onset (yrs) 11 11 42 8 21 <0.0001 Asthma Duration (yrs) 15 22 9 30 29 <0.0001 Baseline Lung Function* FEV1 % Predicted 102 82 75 57 43 <0.0001 FVC % Predicted 112 93 80 72 60 <0.0001 FEV1/FVC 0.78 0.74 0.74 0.64 0.57 <0.0001 Maximal Lung Function FEV1 % Predicted 113 94 84 76 58 <0.0001 FVC % Predicted 117 100 87 89 75 <0.0001 Atopy: % with 1 pos 85% 78% 64% 83% 66% 0.0008 skin test *Pre-bronchodilator values (>6 hours withhold of bronchodilators). Post-bronchodilator values after 6-8 puffs of albuterol Moore et al. AJRCCM 2010; 181:315-323.

CLUSTER ANALYSIS: 5 CLUSTERS Cluster 1 n=110 Cluster 2 n=321 Cluster 3 n=59 Cluster 4 n=120 Cluster 5 n=116 P-value Corticosteroid Use (%) None Low-moderate dose ICS High dose ICS* Oral or Systemic CS** 45% 38% 10% 11% 31% 40% 28% 10% 14% 37% 49% 17% 15% 18% 63% 39% 5% 16% 78% 47% <0.0001 Total Controllers(%) None 2 3 41% 41% 19% 26% 46% 29% 10% 35% 54% 12% 33% 56% 4% 28% 67% <0.0001 Health Care Utilization Pst Yr None 1 Urgent Visit and/or ED 3 Oral CS burst/yr Hospitalization 67% 20% 11% 7% 61% 25% 19% 9% 41% 34% 36% 15% 38% 39% 46% 23% 32% 42% 42% 28% <0.0001 * High dose ICS dose equivalent to 1000 fluticasone propionate daily; **Chronic oral corticosteroids (OCS) 20 mg daily or other systemic steroids in the past 3 months. Controllers include LTRA, ICS, LABA, theophyllines, OCS, omalizumab. P value from Chi-Square Analysis of ranked ordinal composite variables. Moore et al. AJRCCM 2010; 181:315-323.

Smoking and Asthma In asthma, smoking can: Make airway inflammation more neutrophilic (Thomson et al. Clin Exp All 2003, Boulet et al. Chest 2006) Make asthma more difficult to control (Polosa et al. ERJ 2012, Boulet et al. Chest 2006) Reduce symptom perception (Kleis S, et a. Respir Med. 2007) Reduce response to asthma drugs (Livingston et al. Drugs 2005) Accelerate loss of pulmonary function and induce fixed airway obstruction (Lange NEJM 1998)

Model of symptom/risk of evaluation of COPD Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated 2015. www.goldcopd.org

The Eosinophilic Phenotype? Some patients have elevated levels of eosinophils in bloodno features of asthma; a predictive biomarker of ICS responsiveness. FLAME trial1: patients on LABA+LAMA QD had fewer exacerbations and hospitalizations than BID ICS. WISDOM trial 2 :withdrawal of ICS did not increase exacerbations of COPD. But chance of exacerbating off ICS greater when eosinophil count >300 cells/mcl Question: Non-eosinophilic type of COPD no ICS? Eosinophilic Phenotpe of COPD early ICS? 1. Manussen et al NEJM 2014 2. Wedzicha et al NEJM 2016

The characteristics of patients with asthma, COPD, and the overlap phenotype AHR, airway hyperresponsiveness. Postma DS et al. Clin Chest Med 2014;35:143 56.

Hardin M et al. The clinical features of the overlap between COPD and asthma. Respir Res 2011;12:127 Cross-sectional study comparing subjects with COPD and asthma to subjects with COPD alone Hardin M et al. Respir Res 2011;12:127.

Characteristics of COPD cases (GOLD stage 2 or greater) with and without physician-diagnosed asthma COPD only COPD and asthma p-value Total subjects 796 119 Gender male 53.1% 53.1% Age, years 64.7 61.3 0.001 Pack-years of smoking 55.1 43.7 <0.0001 Current smoker 34.2% 38.7% 0.35 BMI kg/m 2 27.8 28.1 GOLD Stage 2 3 4 51.3 31.5 17.2 51.3 31.9 16.8 BODE index 2.1 1.9 0.28 Severe exacerbations 17.6% 32.8% 0.0003 Frequent exacerbations 18.0% 42.7% <0.0001 Hay fever 27.8% 57.0% <0.0001 FEV 1 % predicted 49.4 49.2 FVC % predicted 76.6 78.3 FEV 1 /FVC 0.48 0.48 0.99 BMI, body mass index; FEV 1, forced expiratory volume in 1 s; FVC, forced vital capacity. Hardin M et al. Respir Res 2011;12:127.

Subjects (%) Exacerbations: Percentage of frequent and severe exacerbations among subjects with COPD compared with subjects with COPD and asthma Frequent exacerbations Severe exacerbations 50 42.7%* 50 40 40 32.8%* 30 30 20 18% 20 17.6% 10 10 0 COPD COPD & asthma **p<0.0001 for the difference between COPD and COPD with asthma. 0 COPD COPD & asthma Hardin M et al. Respir Res 2011;12:127.

Health Care Utilization Numerous studies suggest ACOS associated with lower health-related quality of life Increased exacerbations, hospitalizations More rapid decline of lung function Greater health burden relative to asthma or COPD alone

Approaches to Diagnosis of Overlap Syndrome 1. Does the patient have chronic airways disease? 2. If so, is it asthma, COPD, or the overlap syndrome in adults Predominantly asthma Predominantly COPD Global Initiative for Asthma. Global strategy Asthma Management and Prevention. Revised Aug. 2014. http://www.ginasthma.org

Asthma vs. COPD Clinical Differentiation Between Asthma and COPD Asthma COPD Symptoms Before Age 40 Common Rare Smoking Status Possible ~90% are ex-smokers Nighttime Awakenings Common Rare Chronic Productive Cough Uncommon Common Breathlessness Variable Persistent Atopy Common Possible Day to Day Variability in Symptoms Common Response to Bronchodilator More Less Uncommon (Except during exacerbations)

Approaches to Diagnosis of Overlap Syndrome 1. Does the patient have chronic airways disease? 2. If so, is it asthma, COPD, or the overlap syndrome in adults Predominantly asthma Predominantly COPD 3. Spirometry Essential Global Initiative for Asthma. Global strategy Asthma Management and Prevention. Revised Aug. 2014. http://www.ginasthma.org

Characteristics of the Overlap Syndrome Gibson PG and Simpson JL. Thorax 2009;64:728 735.

Approaches to Diagnosis of Overlap Syndrome 1. Does the patient have chronic airways disease? 2. If so, is it asthma, COPD, or the overlap syndrome in adults Predominantly asthma Predominantly COPD 3. Spirometry Essential 4. Specialized evaluations Global Initiative for Asthma. Global strategy Asthma Management and Prevention. Revised Aug. 2014. http://www.ginasthma.org

Specialized investigations to distinguish asthma and COPD Asthma COPD Lung function tests DLCO Normal (so slightly elevated) Often reduced Arterial blood gases Normal between exacerbations May be chronically abnormal between exacerbations in more severe forms of COPD Airway hyperresponsiveness (AHR) Not useful on its own in distinguishing asthma form COPD, but high levels of AHR favor asthma Imaging High resolution CT Cscn Inflammatory biomarkers Test for atopy (specific IgE and/or skin prick tests) FeNO Usually normal but air trapping and increased bronchial wall thickness may be observed Modestly increases probability of asthma; not essential for diagnosis A high level (>50 ppb) in non-smokers supports a diagnosis of eosinophilic airway inflammation Low attenuation areas denoting either air trapping or emphysematous change can be quantitated; bronchial wall thickening and features of pulmonary hypertension may be seen Conforms to background prevalence; does not rule out COPD Usually normal. Low in current smokers Blood eosinophilia Supports asthma diagnosis May be present during exacerbations Sputum inflammatory cell analysis Not established in large populations Global Initiative for Asthma. Global strategy Asthma Management and Prevention. Revised Aug. 2014. http://www.ginasthma.org

CT scanning CT scan pre and post bronchodilators in ACOS patients vs COPD lower extent of emphysema and different distribution (Upper predominance) Greater post BD variation in air trapping Suggesting ACOS is a different phenotype from COPD. Gao, J et al. International J of COPD 2016 11:2457-2465

Approaches to Diagnosis of Overlap Syndrome 1. Does the patient have chronic airways disease? 2. If so, is it asthma, COPD, or the overlap syndrome in adults Predominantly asthma Predominantly COPD 3. Spirometry Essential 4. Specialized evaluations 5. Initiate treatment Predominantly asthma combination therapy Predominantly COPD (bronchodilators or combination therapy not ICS alone) Global Initiative for Asthma. Global strategy Asthma Management and Prevention. Revised 2014. http://www.ginasthma.org

Patient case A 62-year-old Caucasian woman presents with a chief complaint of cough and shortness of breath that has become progressively more severe over the past two years. She is now having shortness of breath with minimal exercise, occasionally at night, and with respiratory infections.

Treatment approaches to ACOS Asthma COPD COPD Anti-inflammatory Rx Asthma Bronchodilators (LABAs, LAMAs)

In Summary A specific definition for ACOS can not be developed until more evidence is available about clinical phenotypes and underlying mechanisms. GINA/GOLD Joint Statement www.gina.org

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References Postma, DS and Rabe KF. The Asthma-COPD Overlap Syndrome. NEJM 2015 373:1241-9 Bonten TN et al Defining asthma-copd overlap syndrome: a population-based study. Eur Respir J 2017 49:1602008 Jo, Yong Suk et al. Different prevalence and clinical characteristic of asthma-chronic obstructive pulmonary disease overlap syndrome according to accepted criteria. Ann Allergy Asthma Immunol 2017 118:696-703 Rodrigue, C. et al. Characterization of Asthma-Chronic Obstructive pulmonary disease overlap syndrome: A qualitative analysis. J of COPD 2107 14:330-338 Cosio BG. Et al. Th-2 signature in chronic airway diseases: towards the extinction of asthma- COPD overlap syndrome? Eur Respir J 2017 49: 1602397 Timmola M, et al. Differences between asthma-copd overlap syndrome and adult-onset asthma. Eur Respir J 2017 49:1602383 Hines, KL and Peebles, RS. Management of the Asthma-COPD Overlap Syndrome (ACOS): a review of the evidence. Curr Allergy Asthma Rep 2017 17:15 Fragoso, C et al. Asthma-COPD overlap syndrome in the US: a prospective population-based analysis of patient-reported outcomes and health care utilization. International J of COPD 2017 12:517-527 Gao, J et al. Characterization of sputum biomarkers for asthma-copd overlap syndrome. International J of COPD 2016 11:2457-2465 Cazzola M and Rogliani P. Do we really need asthma-chronic obstructive pulmonary disease overlap syndrome? JACI 2016 138:977-983