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)