1. Management of COPD & Asthma

3. Leading Causes of Death, US (1998) Causes of Death 1. Heart disease 2. Cancer 3. Cerebrovascular disease (stroke) 4. COPD and allied conditions 5. Accidents 6. Pneumonia and influenza 7. Diabetes 8. Suicide 9. Nephritis 10. Chronic liver disease All other causes of death Number 724,269 538,947 158,060 114,381 94,828 93,307 64,574 29,264 26,295 24,936 469,314 Global Obstructive Lung Disease (GOLD) Initiative website (www.goldcopd.com), accessed April 2, 2001.

4. Percent Increases in Adjusted Death Rates, US, 1965 – 1998 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Coronary Heart Disease Stroke Other CVD COPD All Other Causes - 59% - 64% - 35% + 163% - 7% 1965–1998 1965–1998 1965–1998 1965–1998 1965–1998 Proportion of 1965 Rate Global Obstructive Lung Disease (GOLD) Initiative website (www.goldcopd.com), accessed April 2, 2001.

5. Risk Factors

6. Risk Factors in COPD:

8. Differential Diagnosis Chronic Bronchitis Emphysema Asthma COPD Airflow Obstruction

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

11. Chronic Bronchitis Presence of chronic productive cough for 3 months in each of 2 successive years in a patient in whom other causes of chronic cough have been excluded Air passage narrowed by plugged and swollen mucous membrane Bronchiole Mucus and pus impede action of respiratory cilia

13. Asthma Is A Disease Of The Large & COPD The Small Airways Asthma Emphysema Bronchitis Bronchitis trachea bronchi alveoli

14. Disease Pathology Asthma COPD Reversible airflow obstruction + ++ + Airway inflammation + + + + + Mucus hypersecretion + + + + Goblet cell metaplasia + + + Impaired mucus clearance + + + + Epithelial damage ++ — Alveolar destruction — ++ Smooth muscle hypertrophy + + — Basement membrane thickening +++ —

17. Inflammatory Cell Levels in Ex-Smokers With COPD (>1 Year of Smoking Cessation) Rutgers et al. Thorax. 2000;55:12-18. Values are expressed as percentages of the total number of nonsquamous cells. The role of these cells in COPD is not fully understood. Sputum Neutrophils (%) Sputum Lymphocytes and Eosinophils (%) Neutrophils P =0.0001 Patients with COPD Healthy controls Lymphocytes P =0.0161 Eosinophils P =0.0083 100 90 80 70 60 50 40 30 20 10 0 10 8 6 4 2 0

19. Asthma Sensitizing agent COPD Noxious agent Asthmatic airway inflammation CD4+ T-lymphocytes Eosinophils COPD airway inflammation CD8+ T-lymphocytes Macrophages Neutrophils Airflow limitation Completely reversible Completely irreversible

24. Relationship Between Initial Histamine Threshold and Annual Rate of Decline in FEV 1 16 127 ± 59 < 2 50 77 ± 42 2-3 15 47 ± 22 > 4 Patients (n) Decline in FEV1 (ml/yr) Log Histamine Threshold Postma, Am Rev Respir Dis 1986: 134:276-280

25. Level Of BHR And Mortality From COPD During 30 Years of Follow Up RR (95% CI) COPD mortality Threshold histamine dose n (n=60 ) > 32 mg/ml 998 1 32 mg/ml 391 3.83 (0.97 - 15.10) 16 mg/ml 286 4.40* (1.16 - 16.67) 8 mg/ml 191 4.78* (1.27 - 18.00) 4 mg/ml 103 6.69* (1.71 - 26.13) 1 mg/ml 39 15.8* (3.72 - 67.13) * p  0.05 Hospers, et al. Lancet 2000; 356:1313-1317

26. Changes in Responder Classification After Albuterol and Ipatroprium Bromide

27. Bronchodilator Response: COPD vs. Asthma Higgins BG, Eur Resp J; 1991 p415

28. Assessment/Diagnosis

30. COPD Risk and Smoking Cessation FEV 1 (% of value at age 25) Age (years) Adapted from Fletcher C et al. Br Med J . 1977;1:1645–1648. 0 25 50 75 100 25 50 75 Death Disability Never smoked or not susceptible to smoke Smoked regularly and susceptible to effects of smoke Stopped smoking at 45 (mild COPD) Stopped smoking at 65 (severe COPD)

38. Augmentation Therapy: Impact on Mortality 0 6 12 18 24 30 36 42 48 54 60 Never (n = 162) Partially (n = 285) Always (n = 316) Time (months) FEV 1 < 50% Predicted Alpha-1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med . 1998;158:49–59. 50 40 30 20 10 0

45. Long-Term Oxygen Therapy: Guidelines Indications Absolute Pa O 2 ≤55 mm Hg or Sa O 2 ≤88% In patients with cor pulmonale Pa O 2 55–59 mm Hg or Sa O 2 ≥89% ECG evidence of P pulmonale, hematocrit >55%, and CHD Specific Indications Nocturnal hypoxemia Sleep apnea with nocturnal desaturation not corrected by constant positive airway pressure or bilevel positive airway pressure No hypoxemia at rest, but desaturation during exercise or sleep (PaO 2 <55 mm Hg) Treatment Goals Pa O 2 ≥60 mm Hg or Sa O 2 ≥90%; Appropriately adjusted O 2 dose during sleep and exercise Same as above Appropriately adjusted O 2 dose during sleep Appropriately adjusted O 2 dose during sleep Same as above

46. Effects of Tiotropium Day 1 and Day 92 0.85 0.90 0.95 1.00 1.05 1.10 1.15 1.20 1.25 1.30 1.35 -1 -0.5 0 0.5 1 1.5 2 2.5 3 Day 1 Day 92 Tiotropium (N = 276) Placebo (N = 188) FEV 1 (L) Hours following drug administration Casaburi R, et al. Chest . 2000;118:1294–1302.

47. Salmeterol/Fluticasone Combination Change From Baseline Pre-Dose FEV 1 Time (weeks) * P <0.05 vs. placebo; † P <0.05 vs. SAL; ‡ P <0.05 vs. FP Data on file, GlaxoSmithKline. FEV 1 (mL) *†‡ *†‡ * * * PBO SAL50/FP250 350 300 250 200 150 100 50 0 -50 0 2 4 6 8 12 16 20 24 EP SAL50 FP250 FP500 SAL50/FP500

48. Serial FEV 1 Day 1 Baseline FEV 1 FSC- 1.31L IP/ALB- 1.26L 0 50 100 150 200 250 300 1 2 3 4 5 6 Time (hrs) Change in FEV 1 (mL) 1 2 3 4 5 6 Time (hrs) Change in FEV 1 (mL) FSC IP/ALB 1 2 3 4 5 6 Day 1 Week 8 † † * * * † † FSC vs. IP/ALB: p<0.001 * IP/ALB vs FSC p  0.002 -50 0 50 100 150 200 250 300

49. Predose FEV 1 FSC IP/ALB Endpoint * p <0.001 vs. IP/ALB * 0 * * Week 8 Week 1 * Week 4

52. AECOPD Proposed Classification of Patients Adapted from Wilson R. Chest . 1995;108:53S–57S. Baseline Clinical Status I. Acute tracheo- bronchitis Criteria/ Risk Factors No underlying structural disease Pathogens Usually viral Suggested Therapy None; consider macrolide or tetracycline

53. Viral Pathogens Associated With Acute COPD Exacerbations RSV = respiratory syncytial virus. Sethi S. Infect Dis Clin Pract . 1998;7:S300–S308. 10% 10% 18% 20% 25% 35% 0 10 20 30 40 Influenza Parainfluenza Rhinovirus Coronavirus Adenovirus RSV Proportion of Acute Viral Exacerbations

54. AECOPD Proposed Classification of Patients (cont’d) * Possible beta-lactam resistance. Baseline Clinical Status II. Simple chronic bronchitis Criteria/ Risk Factors FEV 1 >50% increased sputum volume/ purulence Pathogens H influenzae M catarrhalis S pneumoniae* Suggested Therapy Amoxicillin Adapted from Wilson R. Chest . 1995;108:53S–57S.

55. AECOPD Proposed Classification of Patients (cont’d) * Resistance to beta-lactams common. Baseline Clinical Status III. Complicated chronic bronchitis Criteria/ Risk Factors As for Class II + any one of: FEV 1 <50%, advanced age, ≥4 exacerbations/yr, significant co- morbidity Pathogens H influenzae M catarrhalis S pneumoniae * Suggested Therapy Quinolone Penicillin +  -lactamase inhibitor 2nd- or 3rd-gen. cephalosporin 2nd-gen. macrolide Adapted from Wilson R. Chest . 1995;108:53S–57S.

56. AECOPD Proposed Classification of Patients (cont’d) Baseline Clinical Status IV. Chronic bronchial infection Criteria/ Risk Factors Class III + continuous sputum throughout the year Pathogens H influenzae M catarrhalis S pneumoniae Enterobacteriae spp P aeruginosa Suggested Therapy Quinolone Adapted from Wilson R. Chest . 1995;108:53S–57S.

57. “ The Downward Spiral” COPD Airway obstruction Exacerbation Mucus hypersecretion Continued smoking Lung inflammation Alveolar destruction Impaired mucus clearance Submucosal gland hypertrophy Exacerbation Exacerbation Hypoxemia DEATH

58. Asthma Management Step Symptoms Day/Night FEV1 & PEF (% predicted) PEF variability Medication PRN SABA ≥ 80% <20% < 2 days per week/Nocturnal symptoms < 2 nights per month 1 Mild Intermittent Low-dose ICS ≥ 80% 20-30% >2 x per week but <1 time day/Nocturnal symptoms >2 nights/month 2 Mild Persistent LABA + low to moderate dose ICS  60%  80% >30% Daily/Nocturnal symptoms  1 per week 3 Moderate LABA + high-dose ICS Consider LTM corticosteroids as needed (taper to lowest dose)  60%  30% Continual daytime/frequent nocturnal symptoms 4 Severe

59. Importance of early treatment with inhaled corticosteroids in asthma <2 2-3 3-5 >5 Annual change in FEV 1 %pred Agertoft & Pedersen. Respir Med 1994; 88:373-81 Years that symptoms started before treatment

60. Relative Risk of Hospitalization in the United States Donahue et al. JAMA . 1997;277:887-891. Prescriptions per Person-Year Relative Risk None 1-2 2-3 3-5 5-8 8+ 0-1  2 -Agonists Total ICS 0 1 2 3 4 5 6 7 8 Age 0-17 Age 18-44 Age 45+ Total Age 0-17 Age 18-44 Age 45+

62. Beclomethasone Comparison Study: FEV 1 Placebo Montelukast sodium Beclomethasone Weeks in active treatment 0 3 6 9 12 15 0 5 10 15 Mean change in FEV 1 (%) Washout * P < 0.01 beclomethasone vs montelukast and placebo. † P < 0.001 vs placebo. * † Malmstrom K, et al. Ann Intern Med. 1999;130:487-495.

64. Patients Treated With ADVAIR ™ Diskus ® 250/50 Had a Significantly Greater Improvement in FEV 1 Mean  in FEV 1 from Baseline (%) *Differs from FP 250, salmeterol 50, placebo at endpoint; P  0.003 Doses in mcg b.i.d. Shapiro G, et al. Am J Respir Crit Care Med. 2000;161:527-534. 30 25 20 15 10 5 0 -5 Endpoint Week -5% [-0.11L] ADVAIR 250/50 FP 250 Salmeterol 50 Placebo 23% [0.48L] * 13% [0.25L] 4% [0.05L] 2 4 6 8 10 12

65. Patients Treated With ADVAIR ™ Diskus ® 250/50 Were Less Likely to be Withdrawn for Worsening Asthma *Differs from FP 250, salmeterol 50, placebo; P  0.002 Doses in mcg b.i.d. Shapiro G, et al. Am J Respir Crit Care Med. 2000;161:527-534. 1.0 0.8 0.6 0.4 0.2 0 0 7 14 21 28 35 42 49 56 63 70 77 84 Study Day Placebo FP 250 ADVAIR 250/50 Salmeterol 50 Probability of Remaining in Study 4% * 22% 38% 62%