Chronic Obstructive Pulmonary Diseaseand Asthma Update

John L. Faul, MD FCCPAssistant Professor,

Division of Pulmonary/Critical Care Medicine

Stanford University

COPD: Outline

1. Epidemiology

2. Definitions

3. Medical management

4. Hypoxia

5. Infections

6. Vaccination

Universal Problem

COPD: epidemiology

14 million in the US with COPD12.5 million with chronic bronchitis1.65 million with emphysema

4th leading cause of death in US

3rd most frequent diagnosis of patients receiving home care

Prevalence of COPD in the US

*Age-adjusted to 2000 US population.†Represents a statistically significant difference from rate among males.

Mannino et al. MMWR. 2002;51(SS-6):1-16.

Rat

e/1,

000

Po

pu

lati

on

*

0

20

30

40

50

60

70

80

90

1980 1982 1984 1986

Year

MaleFemaleTotal10

1988 1990 1992 1994 1996 1998 2000

• Since 1987, the prevalence of COPD among women has been significantly higher than that among men

† †† †

†

†

††

††

††

†

†

†

COPD:The Usual Suspects

COPD: risk factors

tobacco smoking accounts for 80-90% of the risk of developing COPD

age of starting, total pack-years and current smoking status are predictive of mortality

only 15% of smokers develop clinically significant COPD

alpha1-antitrypsin deficiency (accounts for less than 1% of all COPD cases)

occupational exposures to dusts and fumes

Lung function declines with age

Elastic tissue is lost in emphysema

COPD: definitions

Chronic bronchitis---a clinical definition:“the 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”

Emphysema---a pathologic definition:“abnormal permanent enlargement of the

airspaces distal to the terminal bronchioles accompanied by destruction of their walls”

Pink puffers &Blue bloaters

COPD: Hyperinflation

Increased retrosternal

airspace

Flatdiaphragms

IncreasedAP diameter

COPD

COPD: Oxygen therapy

Oxygen therapy in COPD: extends life in hypoxemic patients

NOTT trial, Ann Int Med 1980;93: 391-398

MRC trial, Lancet 1981; 1: 681-685

strengthens cardiac function, improves exercise performance and ADLs

when FEV1< 1.0 L (or < 50% predicted) anABG should be done

Home O2 costs in the US/yr: $ 2,400,000,000

Oxygen Dissociation Curve

100

80

60

Below PaO2 = 60mmHg, Hemoglobin rapidly loses oxygen carrying capacity (West: Textbook of Physiology)

HemoglobinSaturation %

40 60 80

__

__

__

__

__

40

__20

0 i i i

At 80mmHg, 95% satAt 60mmHg, 90% sat

At 40mmHg, 70% sat

PaO2 (mmHg)

Hypoxic Pulmonary Vasoconstriction

The lung regulates blood flow according to its oxygen content

A low venous oxygen content (low oxygen content in the pulmonary artery) prevents blood flow to the lung

0

10

20

30

40

50

60

70

80

90

100

50 75 100 125 300

BloodFlow %

Air sack (Alveolar) OxygenWest: Textbook of Physiology

Oxygen-sensitive chemoreceptors located in the pulmonary arteriole are the dominant controllers of pulmonary vascular tone

Fishman AP: Hypoxia on the pulmonary circulation. How and where it acts. Circ Res 1976; 38:221–231

COPD: a case in point

CC: Mrs. H. is a 67 y.o female with worsening dyspnea x several years who presents for 2nd opinion regarding diagnoses, and management, of her “breathing problem”

her past diagnoses have includedasthma, bronchitis, and emphysema

she wants to know exactly what she has...

COPD: a case in point

Her dyspnea is much worse in the last year, to the point that she can no longer bathe or cook without help...

She has an occasional cough, productive of scant sputum...

She smoked 2 ppd x 40 years but quit 6 years ago...

COPD: a case in point

She takes the following medications:albuterol MDI 2-4 puffs QID and prn

this is her “favorite” medicine

atrovent MDI 2 puffs QIDshe’s not sure this one helps, but maybe

theophylline 200 mg BIDsome doctor gave her this “years ago”

prednisone 10 mg QD continuously for 3 years with occasional increases

she’s never taken any estrogen replacement

COPD: a case in point

She’s takes antibiotics 6-7 times/year when her breathing “gets really bad”

She’s been on oxygen but doesn’t like it

She’s too short of breath to do any exercise

She has been in the hospital 4 times in the last year and was intubated once, 6 months ago

HPI:

Exacerbation of COPD

Anthonisen et al,Ann Int Med 1987;106: 196Saint et al, JAMA 1995;273(12):957

If 2 of 3 following criteria are met:If 2 of 3 following criteria are met:

increasing dyspneaincreased sputum

volumeincreased sputum

purulence

Exacerbation of COPDNon infectious and infectious

Infections include viral

Controversial if all sputum cultures are causative

For patients with 2 or especially 3 cardinal features, antibiotics are useful

Short courses of antibiotics are usefulAmsden GW et al., Chest 2003: 123:772-777

Antimicrobial Therapy

Oral agents used earlier in therapy

Monotherapy used whenever possible

Patient compliance (once-daily dosing)

Comprehensive disease management

Vaccinations and COPDAnnual influenza vaccine:

Reductions in exacerbation rates particularly within 3 weeks. No evidence of an effect of intranasal live attenuated virus when this was added to inactivated intramuscular vaccination.

Pneumococcal vaccine every 5 years

No evidence that pneumococcal vaccine reduces the severity of COPD

Poole PJ. Cochrane Database Syst Rev. 2000;(4):CD002733.Leech JA. CMAJ. 1987: 136(4):361-5.

COPD: oral steroids for ER discharges

0102030405060

708090

100

0 10 20 30

Prednisone

Placebo

Aaron SD. N Engl J Med. 2003;348 (26):2618-25.

% relapse free

Dayn = 147, Pred 40/day for 10 days

* * *

Vlad the Inhaler

COPD: inhaled steroids and LABA

Calverley P. Lancet. 2003 Feb 8;361(9356):449-56

-60

-40

-20

0

20

40

60

80

100

120

140

6months 1 year

PlaceboFP(500)SalmeterolSal/FP

Change In FEV1

(ml)

n = 1465

*

****

*

Peak Flow Rates

Tiotropium versus Salmeterol

Donohue JF Chest 2002.122:47-55.

COPD: smoking cessation

Tobacco smoking is the most important factor in COPD,

and stopping smoking is the only intervention known to modify the natural history of airways

obstruction.

COPD: smoking cessation

0

10

20

30

40

50

60

70

80

90

100

0 1month 1 year

Placebo

Bupropion

% abstinence

**

Tonstad S. Eur Heart J. 2003 May;24(10):946-55.

COPD: advanced therapies

Bullectomy

Lung volume reduction surgery (LVRS)

Transplantation

Surgery for emphysema:

GOLD ’03 Classification of COPDStage Characteristics

0: At Risk normal spirometry chronic sx (cough, sputum)

I: Mild COPD FEV1/FVC < 70% (for stages I-IV) FEV1 80% predicted with or w/o chronic symptoms

II: Moderate COPD

50% FEV1 < 80% predicted with or w/o chronic symptoms

III: Severe COPD 30% FEV1 < 50% predicted with or w/o chronic symptoms

IV: Very severe COPD

30% FEV1 predicted or <50% pred plus chronic respiratory failure*

* respiratory failure: PaO2 < 60 mm Hg with or w/o PaCO2 > 50 mm Hg

Therapy at Each Stage of COPD 0: At Risk I*: Mild II*:

Moderate III*: Severe

IV*: Very Severe

FEV1 Normal spirometry

80% predicted

< 80% & 50%

< 50% & 30%

< 30%

Avoidance of risk factor(s); influenza vaccination

Add short-acting bronchodilators when needed

Add regular Rx c 1 long-acting bronchodilator. Add rehabilitation

Add ICS if repeated exacerbations

Add O2 Consider surgery

Gold Update 2003

* FEV1/FVC < 70%

COPD: management

Stop smoking

Long-term oxygen

Inhaled steroids and long-acting beta agonists

Diet and exercise

Treat acute exacerbations

Monitor lung function

Vaccinate

Asthma Facts in the United States

Annual number of hospitalizations: 478,000 Annual number of deaths from asthma: 4,657 Annual number of work days lost: 14.5 million Annual number of school days lost: 14 million Estimated direct and indirect medical costs: $16

billion (needs validation)

Morb Mortal Wkly Rep. 2002 March 29; 51:1-13.

Smooth Muscle Dysfunction

AirwayInflammation

• Inflammatory Cell Activation

• Mucosal Edema• Proliferation• Epithelial Damage• B. Membrane

Thickening

• Bronchoconstriction• Bronchial

Hyperreactivity• Hypertrophy• Hyperplasia

Symptoms/Exacerbations

Asthma Pathophysiology

Flow

(l/s)

Vol (l)

-2

0

-4

1

3

2

4

5

21 3 4 5

-6

Pre-albuterolPost-albuterolPredicted

Spirometry

Eosinophils in Human Bronchi

Changes in EG2 during FP therapy

Faul JL, Thorax 1998. 53, 753-61

0

0.5

1

1.5

2

Baseline 2 week 8 week

Cells per Unit area

p < 0.01

400

410

420

430

440

450

460

470

480

490

0 1 2 3

Steroid

Steroid/placebo

Terbutaline

Change in Mean Peak Flow with therapy

Haahtela T. N Engl J Med 1994, 331: 700

0

5

10

15

20

25

30

Week 1 Week 9 Week 17

Steroid

St+Sal

Change in Mean Peak Flow with therapy Greening AP. Lancet 1994, 344: 219-24

Study Day

Probability of Remainingin the Study

1.0

0.8

0.6

0.4

0.2

Sal/FP 100/50FP 100Salmeterol 50Placebo

* 3%

0 7 14 21 28 35 42 49 56 63 70 77

11%

35%

49%

Comparison of Asthma Therapies

Kavuru M et al. J Allergy Clin Immunol. 2000;105:1108-1116.

Time to First Exacerbation

*

100

95

90

85

80

750 2 4 6 8 10 12 14 16 18 20 22 24

Time to First Exacerbation (weeks)

Exacerbation-FreePatients (%)

FP 88 mcg b.i.d. + Salmeterol FP 220 mcg b.i.d.

Matz J et al. J Allergy Clin Immunol. 2000;105:162S.

Kavuru et al. J Allergy Clin Immunol. 2000;105:1108-1116.Data on file, Glaxo Wellcome Inc.

Week

Mean Change from Baseline

in FEV1 (%)

30

25

20

15

10

5

00 2 4 6 8 10 12 Endpoint

15% [0.28L]

5% [0.11L]2%

[0.01L]

Sal/FP 100/50FP 100Salmeterol 50Placebo

25% [0.51L] *

*P0.008 vs FP 100, salmeterol 50, and placebo at endpoint.Doses in mcg b.i.d.

Patients Treated With ADVAIR™ Diskus® 100/50 had a Significantly Greater Improvement in FEV1

Noonan et al. Am J Respir Crit Care Med. 1999;159(3):640.Reiss et al. Arch Intern Med. 1998;158:1213-1220.

FEV1

(% Change

from Baseline;

Mean± SE)

Study Weeks (Postrandomization)

30

25

20

15

10

5

0

-50 3 6 9 12 15 19 23 31 39 47 52 60 68 76 84 92 100 108 116 124 132 140

Cumulative Extension PlaceboMontelukastBeclomethasone

Primary Study

Patients (15 Years) Not Controlled on PRN Beta-Agonists

Improved FEV1 (Study 1 and Extension)

Proportionof Patients

WithoutAsthma Attack

Days Since Randomization

Beclomethasone (n=248)

Montelukast (n=379)

Placebo (n=253)

P=0.006 Montelukast vs placeboP=0.001 Beclomethasone vs placeboP=0.129 Montelukast vs beclomethasone

1

0.95

0.90

0.85

0.80

0.75

0.700 10 20 30 40 50 60 70 80 90

Patients (15 Years) Not Controlled on PRN Beta-Agonists

Malmstrom et al. Ann Intern Med. 1999;130:487-495.

In this study, all patients benefited from • mandatory use of spacers, • enforced compliance, and • rigorous monitoring of patients

Anti-IgE Asthma Therapies ruhMAb E-25

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Baseline Week 12 Week 20

Placebo

Low-dose (2.5)

High-dose (5.8)

** ** NS *

Milgrom H. N Engl J Med. 1999 23;341(26):1966-73.

Sx

ASTHMA: a case in point

CC: Ms. B. is a 22 y.o female with episodic dyspnea x 2 years who presents for 2nd opinion regarding diagnoses, and management, of her “breathing problem”

her past diagnoses have includedasthma, bronchitis, and allergies

she wants to know exactly what she has...

ASTHMA: a case in point

Her dyspnea is much worse in the last year, to the point that she occasionally has to skip class and once she has had to go to the ED...

She has an occasional cough, productive of green sputum...

She never smoked she is allergic to pollen and cats ...

She’s a Stanford student who eats a “healthy diet and takes lots of vitamins”

A case in point

She takes the following medications:albuterol MDI 2-4 puffs QID and prn

this is her “favorite” medicine

prednisone 10 mg QD she is just finishing a steroid taper that was

prescribed after her most recent Emergency Room visit

she’s never taken any steroid inhaler, because they don’t work and she’s fearful of their adverse effects

COPD: a case in point

She’s takes antibiotics 5 times/year when her breathing “gets really bad”

She sometimes wheezes after exercise

She has been in the ED 4 times in her lifetime, was admitted once, but has not been intubated

HPI:

Considerations in Asthma Therapy

1. Efficacy

2. Convenience

3. Control

4. Adverse effects

Adverse effects of Asthma Therapy

1. Beta agonists: tremor, tachycardia

2. Inhaled steroids: Voice, Bones, ?Metabolic

3. LKRAs: Headache

4. Prednisone: Cushing’s syndrome

0 1 2 3 40

130

135

140

145

140

145

150

0 1 2 3 4

6.5

6.0

5.5

5.0

4.5

0.0

Time (yrs) Time (yrs)

Standing Height (cm) Standing-height Velocity (cm/yr)

N Engl J Med 2000;343:1054-63.

BudesonideNedocromilPlacebo

BudesonideNedocromilPlacebo

Long-Term Effects of Budesonide or Nedocromil in Children with Asthma

The Rule of Twos(Who Needs Controller Therapy)

Two beta-agonist canisters/year Two doses of beta-agonist/week Two nocturnal awakenings/month Two unscheduled visits/year Two prednisone bursts/year

2002 NAEPP GUIDLINESSTEP 1: Mild Intermittent Asthma

• Symptoms Present <2days/week• Brief Exacerbations• Nighttime Symptoms <2nights/month• Asymptommatic with normal lung function between exacerbations• FEV1 and PEF >80% predicted• PEF variability <20%

•No daily medication•Severe exacerbations may occur – a course of oral corticosteroids

2002 NAEPP GUIDELINES

Step 2: Mild Persistent Asthma• Symptoms present >2x/week but <1x/day• Exacerbations may affect activity• Nighttime symptoms >2x/month• FEV1 and PEF 80% predicted• PEF variability 20-30%Daily low-dose inhaled corticosteroidsOR Leukotriene modifier, theophylline

2002 NAEPP GUIDELINESStep 3: Moderate Persistent Asthma

• Symptoms daily• Exacerbations affect activity• Nighttime symptoms >1x/week• FEV1 and PEF 60-80% predicted• PEF variability >30%Low-medium dose inhaled corticosteroids with long-acting Beta agonist OR Leukotriene modifier, theophylline

2002 NAEPP GUIDELINESStep 4: Severe Persistent Asthma

• Continual Symptoms • Exacerbations affect activity• Nighttime symptoms frequent• FEV1 and PEF < 60% predicted• PEF variability >30%High-dose inhaled corticosteroidsAnd Long-acting beta agonistAND oral corticosteroids (2mg/kg/day)