Download Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease
and Asthma Update
John L. Faul, MD FCCP
Assistant Professor,
Division of Pulmonary/Critical Care Medicine
Stanford University
COPD: Outline
1.
2.
3.
4.
5.
6.
Epidemiology
Definitions
Medical management
Hypoxia
Infections
Vaccination
Universal Problem
COPD: epidemiology
14 million in the US with COPD
12.5 million with chronic bronchitis
1.65 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
90
Rate/1,000 Population*
80
†
†
70
†
†
† †
†
†
†
†
†
†
†
†
†
60
50
40
Male
Female
Total
30
20
10
0
1980
1982
1984
1986
1988
1990
1992
1994
1996
1998
Year
*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.
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
Increased
AP diameter
Flat
diaphragms
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) an
ABG should be done
Home O2 costs in the US/yr: $ 2,400,000,000
Oxygen Dissociation Curve
__
100
At 80mmHg, 95% sat
At 60mmHg, 90% sat
__
80
__
Hemoglobin
Saturation % 60
__
40
__
20
__
0
At 40mmHg, 70% sat
i i i
40 60 80
PaO2 (mmHg)
Below PaO2 = 60mmHg, Hemoglobin rapidly loses oxygen carrying
capacity
(West: Textbook of Physiology)
Hypoxic Pulmonary Vasoconstriction
u
The lung regulates blood flow
according to its oxygen content
100
90
80
70
u
A low venous oxygen content
(low oxygen content in the
pulmonary artery) prevents
blood flow to the lung
Blood
Flow %
60
50
40
30
20
10
0
50
West: Textbook of Physiology
75
100
125
Air sack (Alveolar) Oxygen
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
300
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 included
asthma, 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 QID
she’s not sure this one helps, but maybe
theophylline 200 mg BID
some 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
HPI:
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
Exacerbation of COPD
If 2 of 3 following criteria are met:
increasing dyspnea
increased sputum
volume
increased sputum
purulence
Anthonisen et al,Ann Int Med 1987;106: 196
Saint et al, JAMA 1995;273(12):957
Exacerbation of COPD
Non 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 useful
Amsden 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 COPD
Annual 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
100
90
80
70
60
%
relapse free 50
40
30
20
10
0
*
*
*
Prednisone
Placebo
0
10
Day
n = 147, Pred 40/day for 10 days
20
30
Aaron SD. N Engl J Med. 2003;348 (26):2618-25.
Vlad the Inhaler
COPD: inhaled steroids and LABA
140
**
120
**
100
80
Change
In FEV1
(ml)
60
*
40
*
20
Placebo
FP(500)
Salmeterol
Sal/FP
0
-20
-40
-60
6months
n = 1465
1 year
Calverley P. Lancet. 2003 Feb 8;361(9356):449-56
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
100
90
80
70
% abstinence 60
Placebo
Bupropion
50
40
30
*
20
*
10
0
0
1month
1 year
Tonstad S. Eur Heart J. 2003 May;24(10):946-55.
COPD: advanced therapies
Surgery for emphysema:
Bullectomy
Lung volume reduction surgery (LVRS)
Transplantation
GOLD ’03 Classification of COPD
Stage
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
 50%  FEV1 < 80% predicted
COPD
 with or w/o chronic symptoms
III: Severe COPD  30%  FEV1 < 50% predicted
 with or w/o chronic symptoms
IV: Very severe  30%  FEV1 predicted or <50% pred
COPD
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
FEV1
II*:
Moderate
Normal
< 80% &
 80%
spirometry predicted  50%
III*:
Severe
< 50% &
 30%
IV*: Very
Severe
< 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
* FEV1/FVC < 70%
exacerbations
Gold Update 2003
Add O2
Consider
surgery
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
u
u
u
u
u
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.
Asthma Pathophysiology
Smooth Muscle
Dysfunction
• Bronchoconstriction
• Bronchial
Hyperreactivity
• Hypertrophy
• Hyperplasia
Airway
Inflammation
• Inflammatory Cell
Activation
• Mucosal Edema
• Proliferation
• Epithelial Damage
• B. Membrane
Thickening
Symptoms/Exacerbations
Spirometry
5
Pre-albuterol
Post-albuterol
Predicted
4
3
Flow
(l/s)
2
1
0
-2
1
2
-4
-6
Vol (l)
3
4
5
Eosinophils in Human Bronchi
Changes in EG2 during FP
therapy
2
p < 0.01
1.5
Cells per
Unit area
1
0.5
0
Baseline
2 week
8 week
Faul JL, Thorax 1998. 53, 753-61
Change in Mean Peak Flow with
therapy
490
480
470
460
Steroid
450
440
Steroid/placebo
430
Terbutaline
420
410
400
0
1
2
3
Haahtela T. N Engl J Med 1994, 331: 700
Change in Mean Peak Flow with
therapy
Greening AP. Lancet 1994, 344: 219-24
30
25
20
Steroid
St+Sal
15
10
5
0
Week 1
Week 9
Week 17
Comparison of Asthma Therapies
1.0
* 3%
0.8
11%
Probability 0.6
of Remaining
in the Study 0.4
35%
49%
Sal/FP 100/50
FP 100
Salmeterol 50
Placebo
0.2
0
7
14
21
28
35
42
49
56
63
70
77
Study Day
Kavuru M et al. J Allergy Clin Immunol. 2000;105:1108-1116.
Time to First Exacerbation
100
FP 88 mcg b.i.d. + Salmeterol
FP 220 mcg b.i.d.
95
*
90
Exacerbation-Free
Patients (%)
85
80
75
0
2
4
6
8
10 12 14 16 18
Time to First Exacerbation (weeks)
20
22
Matz J et al. J Allergy Clin Immunol. 2000;105:162S.
24
Patients Treated With ADVAIR™ Diskus® 100/50 had
a Significantly Greater Improvement in FEV1
Sal/FP 100/50
FP 100
Salmeterol 50
Placebo
30
25%
[0.51L] *
Mean Change 25
from Baseline
in FEV1 (%) 20
15%
[0.28L]
15
5%
[0.11L]
2%
[0.01L]
10
5
0
0
2
4
8
Week
*P0.008 vs FP 100, salmeterol 50, and placebo at endpoint.
Doses in mcg b.i.d.
Kavuru et al. J Allergy Clin Immunol. 2000;105:1108-1116.
Data on file, Glaxo Wellcome Inc.
6
10
12
Endpoint
Patients (15 Years) Not Controlled on PRN Beta-Agonists
Improved FEV1 (Study 1 and Extension)
30
Primary Study
Placebo
Montelukast
Beclomethasone
Cumulative Extension
25
FEV1 20
(%
Change 15
from
Baseline; 10
Mean
5
± SE)
0
-5
0
3
6
9
12
15 19 23 31 39 47 52 60 68 76
84 92 100 108 116 124 132 140
Study Weeks (Postrandomization)
Noonan et al. Am J Respir Crit Care Med. 1999;159(3):640.
Reiss et al. Arch Intern Med. 1998;158:1213-1220.
Patients (15 Years) Not Controlled on PRN Beta-Agonists
1
0.95
Proportion
of Patients
Without
Asthma Attack
Beclomethasone (n=248)
0.90
0.85
Montelukast (n=379)
0.80
0.75
Placebo (n=253)
0.70
0
10
20
30
40
50
60
70
80
90
Days Since Randomization
In this study, all patients benefited from
• mandatory use of spacers,
• enforced compliance, and
• rigorous monitoring of patients
P=0.006 Montelukast vs placebo
P=0.001 Beclomethasone vs placebo
P=0.129 Montelukast vs beclomethasone
Malmstrom et al. Ann Intern Med. 1999;130:487-495.
Anti-IgE Asthma Therapies ruhMAb
E-25
4.5
4
3.5
** **
3
NS
*
Placebo
Low-dose (2.5)
High-dose (5.8)
2.5
Sx
2
1.5
1
0.5
0
Baseline
Week 12
Week 20
Milgrom H. N Engl J Med. 1999 23;341(26):1966-73.
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 included
asthma, 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
HPI:
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
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
Long-Term Effects of Budesonide or
Nedocromil in Children with Asthma
Standing-height Velocity (cm/yr)
6.5
Standing Height (cm)
150
145
Budesonide
Nedocromil
Placebo
140
6.0
145
5.5
140
5.0
135
Budesonide
Nedocromil
Placebo
4.5
130
0
0.0
0
1
2
Time (yrs)
N Engl J Med 2000;343:1054-63.
3
4
0
1
2
Time (yrs)
3
4
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 GUIDLINES
STEP 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 corticosteroids
OR Leukotriene modifier, theophylline
2002 NAEPP GUIDELINES
Step 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 GUIDELINES
Step 4: Severe Persistent Asthma
• Continual Symptoms
• Exacerbations affect activity
• Nighttime symptoms frequent
• FEV1 and PEF < 60% predicted
• PEF variability >30%
High-dose inhaled corticosteroids
And Long-acting beta agonist
AND oral corticosteroids (2mg/kg/day)