GOLD Website Address http://www.goldcopd.org

Which of the following have been shown to reduce mortality in COPD? a) Long term inhaled corticosteroids in patients with FEV1 < 50 % b) Long term oxygen therapy for patients with baseline PaO2 < 55 mmHg, O2 sat < 88% c) Pulmonary rehabilitation for patients with moderate and severe disease d) Lung transplantation e) B and D

Burden of COPD Affects more than 5% of US population Third leading cause of death in US Twelfth leading cause of morbidity in US Costs: Direct medical costs about $29.5 billion/yr Total costs about $49.9 billion in 2010

Global Strategy for Diagnosis, Management and Prevention of COPD Definition of COPD COPD, a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients.

Mechanisms Underlying Airflow Limitation in COPD Global Strategy for Diagnosis, Management and Prevention of COPD Mechanisms Underlying Airflow Limitation in COPD Small Airways Disease Airway inflammation Airway fibrosis, luminal plugs Increased airway resistance Parenchymal Destruction Loss of alveolar attachments Decrease of elastic recoil AIRFLOW LIMITATION

Chronic Bronchitis Bronchiole Air passage narrowed by plugged and swollen mucous membrane Presence of chronic productive cough for 3 months in each of two successive years in a patient in whom other causes of chronic cough have been excluded Mucus and pus impede action of respiratory cilia

Emphysema Abnormal permanent enlargement of the air spaces distal to the terminal bronchioles accompanied by destruction of their walls and without obvious fibrosis Enlarged air sacs due to destruction of alveolar walls (bullae) Destruction of the alveolar wall damages pulmonary capillaries by tearing, fibrosis, or thrombosis Inelastic collapsible bronchioles Walls of individual sacs torn (repair not possible)

Aging Populations Risk Factors for COPD Genes Infections Global Strategy for Diagnosis, Management and Prevention of COPD Risk Factors for COPD Genes Infections Socio-economic status Aging Populations

Alpha-1-Antitrypsin Deficiency Genetic deficiency of the protective anti-protease alpha-1-antitrypsin, predisposing to emphysema (destruction of alveolar walls) due to the unopposed action of neutrophil (and other) elastases. Suspect in patients with: COPD in a never smoker COPD at a very young age Strong family history of COPD Emphysema more prominent in lung bases COPD with unexplained liver disease Diagnosis via serum level, genetic testing Treat with alpha-1-antitrypsin replacement therapy. Intermittent IV infusion slows the rate of decline in lung function in those with airflow obstruction

indoor/outdoor pollution Global Strategy for Diagnosis, Management and Prevention of COPD Diagnosis of COPD EXPOSURE TO RISK FACTORS SYMPTOMS shortness of breath tobacco chronic cough occupation sputum indoor/outdoor pollution è SPIROMETRY: Required to establish diagnosis

Spirometry: Obstructive Disease Normal 5 4 3 Volume, liters FEV1 = 1.8L FVC = 3.2L FEV1/FVC = 0.56 2 Obstructive 1 1 2 3 4 5 6 Time, seconds

Pulmonary Function Tests in COPD 8 6 4 2 -2 -4 -6 Peak expiratory flow rate Spirometry  FEV1  FEV1/FVC  FEF25-75% Lung Volumes May show Normal – mild disease Air trapping -  RV,  FRC,  RV/TLC Diffusing Capacity Low in emphysema Normal in chronic bronchitis Forced exhalation FEV1 (notch added by auto timer) Forced inhalation Normal COPD 1 2 3 4 Vital Capacity

Assess degree of airflow limitation using spirometry Global Strategy for Diagnosis, Management and Prevention of COPD Assessment of COPD Assess symptoms Assess degree of airflow limitation using spirometry Assess risk of exacerbations Assess comorbidities

Symptom Assessment

Chronic Obstructive Pulmonary Disease William P Sexauer, MD Division of Pulmonary and Critical Care Medicine Thomas Jefferson University

In patients with FEV1/FVC < 0.70: Global Strategy for Diagnosis, Management and Prevention of COPD Classification of Severity of Airflow Limitation in COPD* In patients with FEV1/FVC < 0.70: GOLD 1: Mild FEV1 > 80% predicted GOLD 2: Moderate 50% < FEV1 < 80% predicted GOLD 3: Severe 30% < FEV1 < 50% predicted GOLD 4: Very Severe FEV1 < 30% predicted *Based on Post-Bronchodilator FEV1

Global Strategy for Diagnosis, Management and Prevention of COPD Assess Risk of Exacerbations To assess risk of exacerbations use history of exacerbations and spirometry: Two or more exacerbations within the last year or an FEV1 < 50 % of predicted value are indicators of high risk.

COPD patients are at increased risk for: Cardiovascular diseases Global Strategy for Diagnosis, Management and Prevention of COPD Assess COPD Comorbidities COPD patients are at increased risk for: Cardiovascular diseases Osteoporosis Respiratory infections Anxiety and Depression Diabetes Lung cancer These comorbid conditions may influence mortality and hospitalizations and should be looked for routinely, and treated appropriately.

(C) (D) (B) (A) Risk Risk Symptoms Global Strategy for Diagnosis, Management and Prevention of COPD Combined Assessment of COPD 4 (C) (D) > 2 3 (Exacerbation history) Risk (GOLD Classification of Airflow Limitation) Risk 2 (A) (B) 1 1 mMRC 0-1 CAT < 10 mMRC > 2 CAT > 10 Symptoms (mMRC or CAT score))

Spirometric Classification Exacerbations per year Global Strategy for Diagnosis, Management and Prevention of COPD Combined Assessment of COPD When assessing risk, choose the highest risk according to GOLD grade or exacerbation history Patient Characteristic Spirometric Classification Exacerbations per year mMRC CAT A Low Risk Less Symptoms GOLD 1-2 ≤ 1 0-1 < 10 B More Symptoms > 2 ≥ 10 C High Risk GOLD 3-4 D

The term “BODE” refers to which of the following: a) a term used in discussing prognosis with patients and families b) a composite scoring system that describes prognosis in patients with COPD c) a world class skier with an ego and atitude to match his considerable talent d) all of the above

BODE Index Points 1 2 3 Body mass index (Kg/m2) >21 ≤21 1 2 3 Body mass index (Kg/m2) >21 ≤21 Obstructive airways disease (FEV, % pred) ≥ 65 50-64 36-49 ≤35 Dyspnea (MMRC scale) 0-1 4 Exercise (6-min walk dist, m.) ≥350 250-349 150-249 ≤149 Celli BR et al., NEJM 2004; 350:1005-12

BODE Index  Score of 5 to 6  Score of 7 to 10  Score of 0 to 2 Celli BR et al., NEJM 2004; 350:1005-12

Preventive/General Measures Smoking cessation: counseling pharmacologic aids - Avoid environmental/occupational exposures Vaccinations: influenza, pneumococcal Encourage physical activity

COPD Risk & Smoking Cessation 100 Never smoked or not susceptible to smoke 75 Smoked regularly and susceptible to effects of smoke Stopped smoking at 45 (mild COPD) FEV1 (% of value at age 25) 50 Disability Stopped smoking at 65 (severe COPD) 25 Death 25 50 75 Age (years) Adapted from Fletcher C et al. Br Med J. 1977;1:1645–1648.

Global Strategy for Diagnosis, Management and Prevention of COPD Therapeutic Options: COPD Medications Beta2-agonists Short-acting beta2-agonists Long-acting beta2-agonists Anticholinergics Short-acting anticholinergics Long-acting anticholinergics Combination short-acting beta2-agonists + anticholinergic in one inhaler Methylxanthines Inhaled corticosteroids Combination long-acting beta2-agonists + corticosteroids in one inhaler Systemic corticosteroids Phosphodiesterase-4 inhibitors

ICS+LABA and PDE4-inh. or Global Strategy for Diagnosis, Management and Prevention of COPD Manage Stable COPD: Pharmacologic Therapy (Medications in each box are mentioned in alphabetical order, and therefore not necessarily in order of preference.) Patient First choice Second choice Alternative Choices A SAMA prn or SABA prn LAMA LABA SABA and SAMA Theophylline B LAMA and LABA SABA and/or SAMA C ICS + LABA PDE4-inh. D ICS and LAMA or ICS + LABA and LAMA or ICS+LABA and PDE4-inh. or LAMA and LABA or LAMA and PDE4-inh. Carbocysteine

TORCH Study 6112 COPD patients (FEV1 < 60%) randomized to salmeterol/fluticasone (50/500), salmeterol, fluticasone, or placebo followed for 3 years. Primary outcome was all cause mortality. Results: 1. No signif difference in mortality between groups (S/F vs placebo, p=0.052) 2. All components reduced exacerbations compared to placebo 3. S/F and fluticasone improved HRQL vs placebo 4. All components improved lung function vs placebo 5. Both fluticasone groups had higher pneumonia rates than placebo NEJM 2007 356;8:775-789

COPD Interventions Shown to Reduce Mortality Smoking cessation for patients with early disease Home oxygen therapy for persistent baseline hypoxemia Lung Volume Reduction Surgery for very selected patients (upper lobe predominant emphysema, low exercise capacity after rehab)

“UPLIFT” Study 5993 COPD patients (FEV1 < 70%) randomized to tiotropium once daily vs placebo and followed for 4 years. LABA and ICS not excluded. Primary outcome measure was rate of decline in FEV1. Results: No signif difference in rate of FEV1 decline between groups Tiotropium improved: Pulmonary function – p < 0.001 HRQL (St George’s) – p < 0.001 Exacerbations – p < 0.001 Incidence of respiratory failure – p < 0.05 NEJM 2008 359;15:1543-54

Tiotropium vs Salmeterol NEJM 2011 364;12:1093-103

Azithromycin in COPD NEJM 365;8:689-698 8/25/11

Pharmacologic Interventions shown to reduce COPD Exacerbations Inhaled LA beta-agonists Inhaled LA anticholinergics Inhaled corticosteroids for patients with FEV1 < 50% Azithromycin Phosphodiesterase-4 inhibitor - roflumilast In select subgroup: chronic bronchitis phenotype FEV1 < 50% Frequent exacerbations

Other Therapies Oxygen: Non-invasive ventilation (NIV): Long term (home) oxygen if baseline PO2  55 mmHg, O2 Sat  88% As needed during acute exacerbations Non-invasive ventilation (NIV): 1. During acute or acute-on-chronic hypercapneic respiratory failure – avoid intubation 2. Part-time use (nocturnal) for chronic hypercapneic respiratory failure

Benefits of Pulmonary Rehabilitation Strength of Evidence* Reduction in dyspnea 1A Increased exercise ability Psychosocial benefits (reversal of anxiety and depression) 2B Improved quality of life Reduction in health care utilization Prolongation of life (?) -- *From Joint ACCP/AACVPR Evidence-Based Guidelines on Pulmonary Rehabilitation, 2007 Definition of Rating Scale: 1- Strong; 2 – Weak. A – High; Finding consistently supported by well-designed RCT’s; B – Moderate; Based on findings from RCT’s with inconsistent results or methodologic limitations; C – Low; Supported by observational studies

Surgical Options for COPD Lung Volume Reduction Surgery for Emphysema 1. Age < 75 2. Ex-smoker > 6 months 3. FEV1 < 45% pred; RV > 150% pred 4. Dyspnea despite max medical therapy, incl Pulmonary Rehab 5. *Emphysema with upper lobe predominance 6. *Low exercise capacity post-rehab (F < 25W, M < 40W) Bullectomy 1. Giant Bulla > 30% of hemithorax 2. Severe and/or progressive dyspnea despite maximal medical therapy 3. PFT evidence of air-trapping (RV > 150 % pred.) 4. CT evidence of compression of surrounding normal lung parenchyma

Lung Transplantation - COPD now the #2 indication for lung transplant in US - REFERRAL CRITERIA: BODE index of 7-10 or at least one of the following: a. FEV1 < 20% and either DLCO < 20% or homogenous distribution of emphysema b. Pulmonary hypertension/cor pulmonale despite O2 therapy c. History of hospitalization for exacerbation with acute hypercapnia (PCO2 > 50 mm Hg) Kotloff, Thabut AJRCCM 184:159-171 7/15/11