1. Chronic Obstructive Pulmonary Disease (COPD)
Jaime Palomino, MD
Pulmonary/CCM
Tulane University

2. INTRODUCTION COPD is the most important lung disease in U.S.
25% of ED visits for Dyspnea
4th cause of death

3. Definition
Disease state characterized by airflow obstruction that is no longer fully reversible and is usually progressive
Accelerated declined in FEV1 from 30ml/year after 30y to 60ml
“Preventable and treatable”

5. Epidemiology COPD is the fourth leading cause of death in the US.1
>25 million people in US have impaired lung fxn
Annual cost of COPD in the US ~ $30.4 billion (ALA)
office visits, diagnostic procedures, medications, and emergency and hospital services
1.Centers for Disease Control and Prevention. Mortality patterns—US, MMWR. 1999;48:

7. COPD – Pathogenesis Cosio et al. NEJM 2009;360:2445-54
In the specimen of the small airways (membranous bronchioles) from the healthy lung of a nonsmoker (Panel A), the airway walls are thin, and intact alveoli are attached along its circumference. In a comparable specimen from the lung of a smoker with COPD (Panel B), the diameter of the airway is narrowed, the airway wall is thickened, and many of the alveolar attachments are broken. CD8+ T lymphocytes (in red) infiltrate the airway wall in the specimen from the smoker with COPD (Panel B) but not in the specimen from the nonsmoker (Panel A) (immunostaining with antihuman CD8; counterstained with hematoxylin). Images courtesy of Dr. Fiorella Calabrese.
Cosio et al. NEJM 2009;360:

8. A 100-μm slice from the whole lung shows centrilobular emphysema, which is more prominent in the upper lobes (no staining). The square inset shows centrilobular destruction and enlargement (hematoxylin and eosin). The oval inset shows a severe inflammatory infiltrate, consisting of alveolar macrophages, CD8+ T lymphocytes (immunostaining with antihuman CD8; counterstained with hematoxylin), and other cells, involving the alveolar wall and surrounding air spaces.
Cosio et al. NEJM 2009;360:

9. COPD – Immunology Cosio et al. NEJM 2009;360:2445-54
Cigarette smoke injures epithelial cells, which release “danger signals” that act as ligands for toll-like receptors (TLRs) in the epithelium.
These actions trigger the production of chemokines and cytokines, which results in an innate inflammation. Products from the inflammatory
cells may injure the extracellular matrix, leading to the release of TLR ligands and consequent TLR activation, which will promote
further inflammation, tissue injury, and the production of antigenic substances. This chain of events may cause dendritic cells to mature
and migrate to local lymph organs, where, if the conditions are favorable, T-cell activation may result, with progression of the disease. If
the innate inflammation in step 1 is minimized or controlled, the inflammation will not progress to adaptive immunity, and the disease
may be arrested. These processes are typical of smokers who have neither COPD nor Gold stage 1. GM-CSF denotes granulocyte–macrophage
colony-stimulating factor, HSP heat-shock protein, ICAM-1 intercellular adhesion molecule 1, MCP-1 monocyte chemoattractant protein 1, and TNF tumor necrosis factor.
Cosio et al. NEJM 2009;360:

10. When step 1 is successful, mature dendritic cells migrate to local lymphatic organs, whereupon stimulation by toll-like receptors (TLRs) leads to the expression of CD80–CD86 and cytokines, creating a propitious milieu for Tcell antigen presentation and proliferation into effector CD4+ type 1 helper
(Th1) T cells and cytolytic CD8+ T cells. Interleukin-6, secreted by the dendritic cells, favors the production of effector T cells by overcoming the signals
from regulatory T (Treg) cells. Upon activation, effector T cells express tissue-specific chemokine receptors. Immune regulation or tolerance mechanisms
will determine at this stage the degree of proliferation of T-cell effectors, homing, and eventually, disease severity. An absence of tolerance is
associated with Gold stage 3 or stage 4, moderate tolerance with Gold stage 2, and full tolerance with Gold stage 1. MHC denotes major histocompatibility
Complex.
Cosio et al. NEJM 2009;360:

11. With the failure of tolerance or immune regulation in step 2, an adaptive immune inflammation (autoimmune) develops in the lung, consisting of CD4+ type 1 helper (Th1) T cells, cytolytic CD8+ T cells, and IgG-producing B cells. Regulatory T cells (Treg) and γδ CD8+ T cells could modulate the severity of the adaptive immune inflammation. The resulting immune inflammation, induced by CD4+ Th1 T cells and consisting of activated innate immune cells
producing oxidative stress and proteinases, along with cytolytic CD8+ T cells and B cells, leads to cellular necrosis and apoptosis, immune and complement deposition, tissue injury with airway remodeling, and emphysema, as well as the release of additional antigenic material, which perpetuates the process. In step 3, the full autoimmune process has developed, producing the most severe disease (Gold stage 3 and stage 4). NO denotes nitric oxide, and ROS reactive oxygen species.
Cosio et al. NEJM 2009;360:

12. COPD – Pathogenesis
Sethi et al. NEJM 2008;359:

13. COPD – Risk Factors
ACCP Pulmonary Board Review. 2007

14. Diagnosis of COPD History Spirometry: FEV1, FEV1/FVC
Smoking, occupational history
Spirometry: FEV1, FEV1/FVC
6 minute walk to monitor fxnl status
distance a patient can walk on a flat path in 6 minutes
practical and reliable way to measure level of everyday impairment and exercise tolerance

17. COPD Severity (GOLD Guidelines)
ACCP Pulmonary Board Review. 2007

23. ACCP Pulmonary Board Review. 2007

26. Celli et al. CHEST 2008;133:

27. Medications – Anticholinergics
Short-Acting:
Ipratropium: Inhaled, nebs, (Atrovent- HFA®)
Long-Acting:
Tiotropium (Spiriva®)

28. Medications – Beta Agonists
Short-Acting:
Albuterol (ProAir-HFA®, Proventil-HFA®, Ventolin-HFA®)
Pirbuterol (Maxair®)
Metaproterenol (nebs)
Levalbuterol (Xopenex® nebs, Xopenex-HFA®)
Long-Acting:
Arformoterol (Brovana® nebs)
Formoterol (Foradil®, Perforomist® nebs)
Salmeterol (Serevent Diskus®)

29. Medications – ICS Flunisolide (Aerobid®) Ciclesonide (Alvesco®)
Mometasone (Asmanex Twisthaler®)
Triamcinolone (Azmacort®)
Fluticasone (Flovent Diskus®, Flovent HFA®)
Budesonide (Pulmicort Flexhaler®, Pulmicort Respules® nebs)
Beclomethasone (QVAR®)

30. Medications – Combinations
SABA + SAMA:
Albuterol/Ipratropium (Combivent®, Duoneb®)
LABA + ICS:
Fluticasone/Salmeterol (Advair Diskus®, Advair HFA®)
Budesonide/Formoterol (Symbicort®)
SAMA: short-acting muscarinic-antagonist

31. Medications – Others
Theophylline (Theo-24®, Uniphyl®)

32. Calverley et al. NEJM 2007;356:775-89
TORCH = Towards a Revolution in COPD Health
Randomized, double-blind trial: Sameterol(50mcg)+Fluticasone(500mc) bid Vs Placebo Vs salmeterol alone Vs fluticasone alone
F/u x 3years
Primary outcome: death from any cause
Age ~ 65
Current smoker ~ 43% Pack-years: 47-49
FEV1:1.22L (44%pred)
Calverley et al. NEJM 2007;356:775-89

33. Calverley et al. NEJM 2007;356:775-89
No difference in all-cause mortality and COPD-mortality among groups, except for combination Vs fluticasone alone (worse mortality in latter)
Calverley et al. NEJM 2007;356:775-89

34. Calverley et al. NEJM 2007;356:775-89
Less exacerbations and better quality of life in combination group, also slower decline in FEV1 in combination group
Calverley et al. NEJM 2007;356:775-89

35. Figure 2. Adjusted means at each visit and rate of decline (ml/yr) in post-bronchodilator FEV1 by treatment (random coefficients model).
The slope over time was calculated from Week 24 to Week 156, as indicated by the arrows, and was significantly steeper in the patients
receiving placebo versus those receiving active therapies. FP 5 fluticasone propionate; SAL 5 salmeterol; SFC 5 salmeterol/fluticasone
propionate combination. *P < compared with placebo. Note: Vertical bars represent standard errors of the adjusted means at each
visit. The number of patients at each clinic visit with FEV1 measurements is shown below the graph.
Celli et al. AJRCCM 2008;178:

36. Calverley et al. NEJM 2007;356:775-89
TORCH Trial
Calverley et al. NEJM 2007;356:775-89

37. Drummond et al. JAMA 2008;300:

38. Figure 1: Kaplan-Meier estimate of risk of pneumonia as an (A) adverse event or (B) serious adverse event between patients given inhaled budesonide or control treatment (formoterol or placebo).
Data pooled from 7 trials: Budesonide w/wo formoterol Vs placebo or formoterol in patients with stable COPD and at least f/u x 6months
Primary outcome: risk of pneumonia as an adverse event or serious adverse event
Conclusion: No difference in risk of pneumonia btwn budesonide group and control group (F/u x 12 months)
FEV1: L (36-80% pred) Total: 1.34L (46% pred)
51% current smokers
Budesonide is more rapidly cleared from airways than fluticasone, difference magnified in extensive airflow obstruction. Therefore less down-regulation of local immunity and less bacterial proliferation with budesonide (Hypothesis)
Serious adverse event: adverse event that resulted in death or hospital admission.
Sin et al. Lancet 2009;374:712-19

39. UPLIFT = Understanding Potential Long-Term Impacts on Function with Tiotropium
Randomized, double-blind trial, follow up 4 years
Tiotropium Vs placebo in patients with COPD who were permited to use all respiratory medications except inhaled anticholinergic drugs.
Primary endpoint: Rate of decline in the mean FEV1
5993 patients, FEV1: 1.32L (48%pred)
Tashkin et al. NEJM 2008;359:

40. Panel A shows the probability of treatment discontinuation in the tiotropium group and the placebo group. Panel B shows the estimated
mean forced expiratory volume in 1 second (FEV1) before and after bronchodilation from day 30 to the end of the study. Before bronchodilation,
the annual rates of decline were the same in the tiotropium group and the placebo group: 30±1 ml per year. After bronchodilation,
the annual rate of decline was 40±1 ml per year in the tiotropium group, as compared with 42±1 ml per year in the placebo group.
Panel C shows the mean forced vital capacity (FVC) before and after bronchodilation from day 30 to the end of the study. Before bronchodilation,
the annual rate of decline was 43±3 ml per year in the tiotropium group and 39±3 in the placebo group. After bronchodilation,
the annual rates of decline were the same in the tiotropium group and the placebo group: 61±3 ml per year. Panel D shows the healthrelated
quality-of-life score from month 6 to the end of the study, as measured on St. George’s Respiratory Questionnaire (SGRQ), which
ranges from 0 to 100, with lower scores indicating improvement. The annual rate of change was 1.25±0.09 units per year in the tiotropium
group, as compared with 1.21±0.09 units in the placebo group. Repeated-measure analysis of variance was used to estimate means.
Means are adjusted for baseline measurements. For FEV1 and FVC, patients with three or more acceptable pulmonary-function tests
afterday 30 and no missing baseline values were included in the analysis. For the SGRQ total score, patients with two or more acceptable
scores after month 6 and no missing baseline values were included in the analysis. The I bars represent standard errors, and the
horizontal dashed lines represent baseline levels. Asterisks denote P<0.001, the dagger P = 0.002, and the double dagger P = 0.04.
Conclusion: Tiotropium did not significantly reduce the rate of decline in FEV1, but was associated with improvements in lung function, quality of life and exacerbations during 4-year period.
Tashkin et al. NEJM 2008;359:

41. Tashkin et al. NEJM 2008;359:

42. Kaplan–Meier curves show the cumulative incidence estimate of the probability of COPD exacerbation (Panel A) and of death from any cause at day 1470 for all patients for whom data were available regarding vital status (Panel B). The numbers of patients who continued to receive a study drug (including those at 30 days after the last dose) are listed for each time point, with the study period truncated at 48 months. All patients who received at least one dose of a study drug were included in the analysis. P values were calculated with use of the log-rank test.
Tashkin et al. NEJM 2008;359:

43. Lee et al. Arch Intern Med. 2009;169:1403-1410

44. 12-week, randomized, double blind, parallel group. Multicenter
660 subjects
62yr, 75% male, FEV1:1.1L (38%)
Tiotropium(18mcg/d) + Budesonide/Formoterol(320/9mcg bid) Vs Tiotropium + Placebo(bid)
Primary outcome: Clinic predose FEV1
Secondary outcomes: Clinic postdose FEV1, pre & postdose FVC, IC, health status, home symptoms, exacerbations, tolerability
Sponsor: Astra-Zeneca
Welte et al. AJRCCM.2009;180:

45. Number of Severe Exacerbations Changes in Lung Function
Improvement in FEV1 in triple therapy group as well as less exacerbations
Figure 4. Change in lung function. (A) Predose FEV1 at the clinic: visit geometric means and percentage mean change from baseline. (B)
Onset of effect, measured by FEV1 at bedside in the morning at Weeks 1 and 12. BUD/FORM5 budesonide/formoterol; PBO 5 placebo; TIO 5
tiotropium. Circles represent BUD/FORM1 TIO; squares represent PBO 1 TIO. The graphs illustrate absolute pre- and postdose values at Weeks 1
and 12. The onset was calculated as change from predose to 5 and 15 minutes postdose, corresponding to differences between treatments
of 70 and 90 ml, respectively, at Week 1 and 100 ml at both time points at Week 12 in favor of budesonide/formoterol added to
tiotropium versus tiotropium alone (P , 0.001).
Welte et al. AJRCCM.2009;180:

46. Lee et al. Ann Intern Med 2008;149:380-390
VA study
Nested case-control study in a cohort
32130 case patients, controls
Lee et al. Ann Intern Med 2008;149:

47. Inhaled anticholinegics are associated with a significantly increased risk of CV death, MI, or Stroke among patients with COPD.
Singh et al. JAMA 2008;300:

48. UPLIFT Trial
Tashkin et al. NEJM 2008;359:

49. Medications Theophylline or PDE Inhibitors May have a “come-back”
Lower levels (8-13 mg/dL)
Improvement in corticosteroid resistance (HDAC2)
Phosphodiesterase E4 inhibitors
Inflammation (oxidative + nitrative stress)  reduction in HDAC2  Increased acetylation of glucocorticoid receptor  decreased inhibition of NF-KB-driven inflammation
Low doses of theophylline increase HDAC2 expression in alveolar macrophages  restoration of steroid-responsiveness

50. Calverley et al. Lancet 2009;374:685-694

51. Smoking cessation
Smoking cessation: single most effective way to improve clinical outcomes in patients at all stages of COPD (asx-severe).1-4
After cessation, FEV1 rate of decline may decrease to the rate found in healthy nonsmokers.5,6
35% abstinent at 1 year, 22% at 5 years
1. The National COPD Awareness Panel (NCAP). Guidelines for early detection and management of COPD. J Resp Dis. 2000;21(suppl):S5-S21.
2. Centers for Disease Control and Prevention. The Surgeon General’s 1990 report on the health benefits of smoking cessation: executive summary – introduction, overview, conclusions. MMWR. 1990;39(RR-12):2-10.
3. Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an inhaled bronchodilator on the rate of decline in FEV1: the Lung Health Study. JAMA. 1994;272:
4. Kanner RE. Early intervention in chronic obstructive pulmonary disease: a review of the Lung Health Study results. Med Clin North Am. 1996;80:
5. Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ. 1977;1:
6. Higgins MW, Enright PL, Kronmal RA, et al. Smoking and lung function in elderly men and women. JAMA. 1993;269:

52. Smoking cessation Ask: every patient, during each clinic visit
Advise: urge to quit
Assess: willingness to quit
Assist: quit plan, counseling, social support, pharmacotherapy
Arrange: follow-up contract

53. Vaccination
Pneumococcal vaccination
Annual influenza vaccination

55. Pulmonary Rehabilitation
Exercise training does not improve lung function, but it does ease other manifestations of COPD, increasing exercise tolerance, reducing dyspnea, and improving quality of life. Improved skeletal-muscle function is related, in part, to a reversal of deconditioning. Exercise training improves aerobic function of the muscles of ambulation. Dyspnea is mitigated by the reduction in dynamic hyperinflation that occurs when exercise induced increases in the rate and depth of breathing result in inadequate time for full expiration, given the high expiratory airflow resistance. End-expiratory lung volume rises, and exercise is terminated when end inspiratory lung volume approaches levels at which the high elastic work of breathing causes severe dyspnea. Exercise training reduces the ventilatory requirement and respiratory rate during heavy exercise, prolonging the time allowed for expiration and reducing dynamic hyperinflation. Desensitization to dyspnea occurs centrally as a result of exercise training; the underlying mechanism is uncertain. Decreased anxiety and depression are thought to result from increased exercise capacity and consequent increases in activities of daily living, coupled with feelings of mastery.
Casaburi et al. NEJM 2009;360:

56. Pulmonary Rehabilitation
Improves (better than other COPD therapies):
Exercise capacity
Severity of dyspnea
Health-related quality of life
Reductions in hospitalization
Improvements in cost-effectiveness
Reduction in depression and anxiety
Improves cognitive function and self-efficacy
Survival benefit has not been demonstrated
Reimbursement varies
Casaburi et al. NEJM 2009;360:

57. Pulmonary Rehabilitation
Indications:
GOLD Stage 3 or 4
3 times/week. 3-4 hrs/session. 6 – 12 weeks
Endurance exercise leg muscles
Walking, stationary cycling, treadmill
Resistance-exercise component
Upper extremities exercise
Bronchodilators, oxygen, NIPPV, heliox, anabolic steroids
Education, smoking cessation, nutrition
Casaburi et al. NEJM 2009;360:

58. Treatment - COPD Lung Transplant LVRS (pneumoplasty) < 65 y/o
High BODE index
Effects on survival remains controversial
LVRS (pneumoplasty)
Upper lobe disease
Limited exercise performance after pulmonary rehabilitation
FEV1 : % predicted
Bronchoscopic placement of one-way valves or biological substances

59. Tillie-Leblond et al. Ann Intern Med. 2006;144:390-396
3 factors: h/o thromboembolism, malignant disease, decrease of paCo2 of at least 5 mmHg
Tillie-Leblond et al. Ann Intern Med. 2006;144:

60. Rizkallah et al. CHEST 2009;135:786-793

61. Zvezdin et al. CHEST 2009;136:

62. Treatment - NPPV
NPPV  fewer intubations, decreased mortality, and shortened MICU admissions
Indications for NPPV
pH < 7.20
RR > 25
MS change
worsening hypercapnia