Transcript Cardinal Concepts in the Management and Control of Asthma

Cardinal Concepts in the
Management and Control of Asthma
Presented by
MICHAEL B. FOGGS, MD, FACAAI, FCCP
Chair-Elect
ALLERGY, ASTHMA, & IMMUNOLOGY SECTION
NATIONAL MEDICAL ASSOCIATION (NMA)
Member
ASTHMA AND ALLERGY RESCUE PROJECT, NMA
Chief of Allergy & Immunology
ADVOCATE HEATLH CENTERS, ADVOCATE HEALTH CARE
CHICAGO, IL
Member: NHLBI/NAEPP EXPERT PANEL 3
Guidelines for the Diagnosis & Treatment of Asthma
General Statistics
• 26,000,000 Americans with asthma
• 5000 deaths each year in the United States
• 25, 000 deaths worldwide annually?
• 1/3 of All lost school days in America
• Annual cost > 14 billion dollars
Chicago Distinction….#1 in Asthma Epidemic
Definition Of Asthma
A generic, waste-basket term
“Chronic inflammatory disease of the lungs
characterized by bronchial hyperresponsiveness &
bronchoconstriction”
Chronic “eosinophilic desquamative” bronchitis
WHAT IS ASTHMA?
persistence of
inflammatory
cells
inflammatory
cell
recruitment
vascular
permeability
& edema
inflammatory
cell
activation
inflammatory
mediator
release
mucus secretion
&
bronchoconstriction
activation of
fibroblasts
& macrophages
tissue
repair &
remodeling
decreased
apoptosis
release of
cytokines
and growth factors
smooth muscle
& mucus gland
proliferation
increased
bronchial
hyperreactivity
Modified from Bousquet et al., Am. J. Respir. Crit. Care Med., 2000
epithelial cell
activation &
shedding
Pathophysiological Features Associated
with Asthma
• Bronchoconstriction
• Mucus hypersecretion
• Variable airflow obstruction – Goblet cell metaplasia
• Cough
• Airway inflammation
– Eosinophils
– Mast cells
– Lymphocytes
– Neutrophils
• Edema
• Airway hyperresponsivity
– Submucosal gland
hypertrophy
• Impaired mucus clearance
• Smooth muscle
hypertrophy/ hyperplasia
• Subepithelial matrix protein
deposition
• Collagen deposition
Components of Asthma
Asthma Triggers
Allergens
Exercise
Irritants
Viruses
Weather
Smooth Muscle
Dysfunction
Inflammation
Mucus
Secretion
Hypertrophy
Hyperplasia
Architectural
Changes
Inflammatory
Mediator
Release
Bronchial Constriction
Bronchial Hyperreactivity
Symptoms
Adapted from Creticos. Adv Stud Med. 2002;2(14):499-503.
Epithelial
Damage
Edema
Impaired
Ciliary
Function
Inflammatory Cell Infiltration
Incidence of Allergic Asthma
Asthma & allergies are related:
90% - 100% in children
80% in adults
IgE-Dependent Release of
Inflammatory Mediators
Allergens
IgE
FcRI
FcRI
binding site
Over Hours
Immediate Release
Granule contents:
Histamine, TNF-,
Proteases, Heparin
Sneezing
Nasal congestion
Itchy, runny nose
Watery eyes
Cytokine production:
Specifically IL-4, IL-13
Over Minutes
Lipid mediators:
Prostaglandins
Leukotrienes
Wheezing
Bronchoconstriction
Mucus production
Eosinophil recruitment
Immediate and Late Phase IgEMediated Hypersensitivity
Responses
Immediate Phase
Response
Late Phase Response
Adapted from Hadley JA. Med Clin North Am. 1999;83(1):13-25.
Dykewicz MS, et al. Ann Allergy Asthma Immunol. 1998;81:478-518.
Squillance SP. Otolaryngol Head Neck Surg. 1992;107:831-834.
Urval KR. Primary Care. 1998;25:649-662.
Adapted from American Academy of Allergy, Asthma, and Immunology. The Allergy Report. Vol 1. Milwaukee, Wis: 2000.
How Do We Make The Diagnosis ?
History
Chronic cough, esp. at night & on exertion
Role of infection: esp. important in children
Night time symptoms
Limitation of activities
Response to bronchodilator ?
Diagnosis
The Physical Exam
Growth and development
Evidence for allergic diathesis
Evidence for expiratory respiratory difficulty
Wheezing
Diagnosis
Pulmonary Function Tests-Baseline
• Spirometry - Preferred Method of Evaluation
– Airflow obstruction: FEV1 & FEV1/FVC
– Bronchodilator response: 12 - 15 % represent significant
reversibility
• Peak Expiratory Flow (PEF) Monitoring
– Daily to weekly monitoring as the situation dictates
– Helps assess disease severity
– Helps patient & family better understand asthma
Diagnosis
• Allergy Evaluation
– Goal is to identify and avoid environmental triggers,
e.g.:
• Dust mites; cockroach
• Mold/mildew
• Food (in conjunction with the patient’s history)
– All children over the age of 4 with persistent asthma
symptoms
– Test with a limited number of allergens: skin testing;
RAST
Classification and Clinical Features of
Asthma
Symptoms/Day
Symptoms/Night
PEF or FEV1
PEF Variability
Step 4
Severe Persistent
Continual
Frequent
≤60%
>30%
Step 3
Moderate
Persistent
Daily
>1 night/week
>60 – <80%
>30%
Step 2
Mild Persistent
>2/week but < 1x/day
>2 nights/month
≥80%
20 – 30%
Step 1
Mild Intermittent
≤2 days/week
≤2 nights/month
≥80%
<20%
Adapted from National Heart, Lung and Blood Institute, NIH Publication No 02-5074, 2003.
Is It Time for a New Classification?
• Asthma is a complex, immunologic,
variable, & heterogeneous disease.
• Mild asthma is not well defined.
• Patients with asthma do not remain
consistently in “one category.”
Why Is Proper Classification of the
Disease Important ?
• Asthma severity is inconstant.
• Inhaled corticosteroids are the only
drugs recommended as the treatment of
chronic persistent asthma.
• Mild, moderate, and severe chronic
persistent asthma have the same
mortality.
Pediatric / Adolescent Asthma Deaths:
Mild Patients Are Also at Risk
40
35
30
Patient
Deaths
(%)
25
20
15
10
5
0
Severe
Moderate
Mild
Patient Assessment
Findings from a cohort study reviewing all pediatric / adolescent asthma-related deaths
(n=51) in the Australian state of Victoria from 1986 to 1989.
Robertson et al. Pediatr Pulmonol. 1992;13:95-100.
Accuracy of Perception of Severity
• Patients (n=255) in 11
general practices
70
Patients (%)
60
60%
50
40%
40
30
20
10
0
Poor
Discriminators
Good
Discriminators
Kendrick et al. BMJ. 1993;307:422-424.
– Recorded asthma severity
on a visual analog scale
– Measured PEF up to 4 times
daily
• In 60% of patients, there
was no correlation
between asthma
symptom scores and
PEF
– The lack of correlation was
not related to sex, age, or
particular practices
Misclassification of Mild Intermittent
Asthma
# of patients
1200
n = 4,362
70
1000
60
800
50
600
Mild
Intermittent
60%
40
953
patients
400
Mild
Persistent
22%
30
20
200
10
0
0
Mild Intermittent Asthma
based on symptoms and
FEV1 alone
Moderate
Persistent
15%
Severe
Persistent
3%
Classification of the same group but
now based on symptoms, FEV1 and
medication use
Adapted from Liard. Eur Resp J. 2000;16:615-620.
An Hypothesis
One Airway, One Disease???
United Airways Disease???
Asthma and Allergic Rhinitis: Two Related
Conditions Linked by One Common Airway
• Frequently overlapping
conditions
• Involvement of the same tissues
• Common inflammatory
processes
– Common inflammatory cells
– Common inflammatory mediators
Adapted from Phillip G et al Curr Med Res Opin 2004;20(10):1549–1558.
Allergic Rhinitis and Asthma Have
Common Triggers
• Outdoor allergens
– Pollens
– Molds
• Indoor allergens
– House-dust mites
– Animal dander
– Insects (e.g., cockroach allergen)
Adapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and
Prevention: A Pocket Guide for Physicians and Nurses. Publication No. 95-3659B. Bethesda, MD: National Institutes of
Health, 1998; Workshop Expert Panel Management of Allergic Rhinitis and its Impact on Asthma (ARIA) Pocket Guide. A
Pocket Guide for Physicians and Nurses, 2001.
Many Patients with Asthma Have
Allergic Rhinitis
At least 80%
of all asthmatic patients have allergic rhinitis.
All asthmatic patients
Adapted from Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S147–S334;
Sibbald B, Rink E Thorax 1991;46:895–901; Leynaert B
et al J Allergy Clin Immunol 1999;104:301–304; Brydon MJ Asthma J 1996:29–32.
Allergic Rhinitis Is a Risk Factor for Asthma
Allergic rhinitis increased the risk of asthma about
threefold. 12
p<0.002
10
% of
patients who
developed
asthma
10.5
8
6
4
2
0
3.6
No allergic rhinitis
at baseline
(n=528)
Allergic rhinitis
at baseline
(n=162)
23-year follow-up of first-year college students undergoing allergy testing; data based on 738 individuals (69% male)
with average age of 40 years
Adapted from Settipane RJ et al Allergy Proc 1994;15:21–25.
Allergic Rhinitis Increased the Risk
of Asthma Attacks
25
p=0.046
20
% of
patients
15
21.3
17.1
10
0
Patients
with asthma
(n=597)
Patients with asthma
+ allergic rhinitis
(n=893)
Post hoc analysis of medical resource use/asthma attacks in asthmatic patients with and without concomitant allergic
rhinitis over 52 weeks
Adapted from Bousquet J et al. Poster presented at the European Academy of Allergology and Clinical Immunology
(EAACI), June 12–16, 2004, Amsterdam. Poster 141.
Allergic Rhinitis Doubled the Risk
of ED Visits in Patients with Asthma
4.0
p=0.029
3.5
3.6
3.0
2.5
% of
patients
2.0
1.5
1.7
1.0
0.5
0
Patients
with asthma
(n=597)
Patients with asthma
+ allergic rhinitis
(n=893)
Post hoc analysis of medical resource use/asthma attacks in asthmatic patients with and without concomitant allergic
rhinitis over 52 weeks
ER=emergency room
Adapted from Bousquet J et al. Poster presented at the European Academy of Allergology and Clinical Immunology
(EAACI), June 12–16, 2004, Amsterdam. Poster 141.
Allergic Rhinitis Increased the Odds
of Hospitalization for Asthma by 50%
p<0.006
0.8
0.7
0.76
0.6
% of
0.5
patients
hospitalized 0.4
annually
0.3
0.45
0.2
0.1
0
Patients
with asthma
(n=22,692)
Patients with asthma
+ allergic rhinitis
(n=4611)
Analysis of health-care resource use in adults 16 to 55 years of age with asthma and allergic rhinitis in a general
practice in the UK
Adapted from Price D et al Clin Exp Allergy 2005, in press.
Allergic Rhinitis Increased the Number of
Prescriptions for Rescue Therapy (SABA)
in Patients with Asthma
3.3
3.2
3.1
3.0
Annual
2.9
prescriptions 2.8
per patient 2.7
2.6
2.5
2.4
0
p<0.0001
3.2
2.7
Patients with asthma
(n=22,692)
Patients with asthma
+ allergic rhinitis
(n=4611)
Analysis of health-care resource use in adults 16 to 55 years of age with asthma and allergic rhinitis in a general practice
in the UK
SABA=short-acting beta2-agonists
Adapted from Price D et al Clin Exp Allergy 2005, in press.
Both Asthma and Allergic Rhinitis Are
Inflammatory Conditions
• Asthma is fundamentally a disease of
inflammation
– Inflammation of the lower airways causes
bronchoconstriction and airway hyperresponsiveness,
resulting in asthma symptoms
• Allergic rhinitis is an IgE-mediated inflammatory
disorder
– Inflammation of the nasal membranes in response to
allergen exposure results in nasal symptoms
IgE=immunoglobulin E
Adapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention: A Pocket Guide for
Physicians and Nurses. Publication No. 95-3659B. Bethesda, MD: National Institutes of Health, 1998; Bousquet J et al J Allergy Clin Immunol
2001;108(suppl 5):S148–S149.
Allergic Rhinitis and Asthma Share a Common
Inflammatory Process and Occur in the Same
Mucosa
Allergic rhinitis
Asthma
Bronchial Mucosa
Nasal Mucosa
Eosinophil infiltration
Eos=eosinophils; neut=neutrophils; MC=mast cells; Ly=lymphocytes; MP=macrophages
Adapted from Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S148–S149.
Symptoms Correlate with the Early- and Late-Phase
Responses in Allergic Rhinitis and Asthma
Upper
Airways
(Allergic
rhinitis)
Score for nasal
symptoms
Sneezing
Nasal pruritus
Congestion
Rhinorrhea
Antigen
challenge
Lower
Airways
(Asthma)
Late phase
Early phase
1
3–4
8–12
24
Time postchallenge (hours)
100
FEV1
(% change)
50
0
0
1
2
3
4
5
6
7
8
9
10
24
Time (hours)
Adapted from Varner AE, Lemanske RF Jr. In: Asthma and Rhinitis. 2nd ed. Oxford: Blackwell Science, 2000:1172–1185;
Togias A J Allergy Clin Immunol 2000;105(6 pt 2):S599–S604.
Patients with Allergic Rhinitis Experience
Increased Bronchial Hyperresponsiveness
Prevalence of bronchial hyperresponsiveness*
60
(n=27)
p<0.02
50
48
40
% of
patients
30
20
10
0
11
Out of
season
In season
Study of bronchial hyperreactivity in patients (mean age 20 years) with hay fever; challenges were performed in the fall
of one year and approximately six months later.
*PD20 <1 mg after carbachol challenge
PD=provocation dose
Adapted from Madonini E et al J Allergy Clin Immunol 1987;79:358–363.
Allergen Challenge to the Nose Increases
Bronchial Hyperresponsiveness
Change from baseline in PC20*
3
Geometric
mean PC20
(methacholine,
mg/ml)
Placebo (n=5)
Allergen (n=5)
p=0.0009
p=0.011
2
0
Baseline
0.5 hr
4.5 hr
postchallenge postchallenge
Randomized, crossover two-day investigation of the relationship between allergic rhinitis and lower airway dysfunction in
patients with allergic rhinitis and asthma (mean age 31.4 years)
PC=postchallenge
*Lower PC20 values indicate greater hyperresponsiveness
Adapted from Corren J et al J Allergy Clin Immunol 1992;89:611–618.
Many Patients with Asthma Have Nasal Inflammation
Eosinophil counts in the nasal mucosa
18
(n=9)
(n=8)
(n=10)
16
14
12
Eosinophils/
field of
nasal biopsy
10
8
6
4
2
p<0.001
p<0.001
0
Rhinitis
No rhinitis
Control
Asthmatic
Study of whether nasal mucosal inflammation exists in asthma regardless of the presence of allergic rhinitis in atopic
subjects 20 to 66 years of age
Bars represent median values.
Adapted from Gaga M et al Clin Exp Allergy 2000;20:663–669.
Inflammatory Changes in the Nasal and
Bronchial Mucosa Are Correlated
40
(n=17)
35
30
Asthmatic
nasal
mucosa
eosinophils
25
20
15
10
5
r=0.851, p<0.001
0
0
5
10
15
20
25
30
Asthmatic bronchial mucosa eosinophils
Study of whether nasal mucosal inflammation exists in asthma regardless of the presence of allergic rhinitis in
atopic subjects 20 to 66 years of age
Adapted from Gaga M et al Clin Exp Allergy 2000;20:663–669.
Shared Pathophysiology of Allergic Rhinitis and
Asthma
• Allergic rhinitis and asthma share several
pathophysiologic characteristics
– Common triggers
– Similar inflammatory cascade on exposure to
allergen
– Similar pattern of early- and late-phase responses
– Infiltration by the same inflammatory cells (e.g.,
eosinophils)
– Several potential connecting pathways, including
systemic transmission of inflammatory mediators
Adapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention: A Pocket Guide
for Physicians and Nurses. Publication No. 95-3659B. Bethesda, MD: National Institutes of Health, 1998; Casale TB, Amin BV Clin Rev Allergy
Immunol 2001;21(1):27–49; Workshop Expert Panel Management of Allergic Rhinitis and its Impact on Asthma (ARIA) Pocket Guide. A Pocket
Guide for Physicians and Nurses. 2001; Kay AB N Engl J Med 2001;344:30–37; Varner AE, Lemanske RF Jr. In: Asthma and Rhinitis. 2nd ed.
Oxford, UK: Blackwell Science, 2000:1172–1185; Togias A J Allergy Clin Immunol 2000;105(6 pt 2):S599–S604; Togias A Allergy 1999;
54(suppl 57):94–105.
ARIA Guidelines Recommend a Combined
Approach to Managing Asthma and
Allergic Rhinitis
• Patients with allergic rhinitis should be
evaluated for asthma
• Patients with asthma should be evaluated
for allergic rhinitis
• A strategy should combine the treatment
of upper and lower airways in terms of
efficacy and tolerability
Adapted from Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S147–S334.
Treatment of Asthma
• Environmental and Trigger Control
– Allergens
– Smoking
– Infection
– Pollutants
– Emotional upset/anxiety/depression/laughter,
etc.
• Medical Therapy
Goals of Asthma Therapy = Control
•
•
•
•
•
Minimal or no chronic symptoms day or night
Minimal or no exacerbations
No limitations on activities; no school/work missed
Maintain (near) normal pulmonary function
Minimal use of inhaled short-acting
beta2-agonist
• Minimal or no adverse effects from medications
NAEPP Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma—Update on
Selected Topics 2002. NIH, NHLBI. May 2003 (reprint). NIH publication 02-5075.
Pharmacologic Therapy
Reliever Medications:

Rapid-acting inhaled β2-agonists

Systemic glucocorticosteroids

Anticholinergics

Methylxanthines

Short-acting oral β2-agonists
Pharmacologic Therapy
Controller Medications:
Inhaled glucocorticosteroids
 Systemic glucocorticosteroids
 Cromones
 Methylxanthines
 Long-acting inhaled β2-agonists
 Long-acting oral β2-agonists
 Leukotriene modifiers

COMBINATION THERAPY
Single Device Maintenance Delivery
System
– Highly effective
– Convenient and easy to use
– Quick patient benefit
– Ability to use a lower steroid dose
– Raises no new safety issues
Complementary Modes of Action
LABA

 

 
•
•
•
•
Smooth
muscle
dysfunction
Bronchoconstriction
Bronchial hyperreactivity
Hyperplasia/hypertrophy
Inflammatory mediator
release
Airway
inflammation
• Inflammatory cell
infiltration/activation
• Mucosal edema
• Cellular proliferation
• Epithelial damage
• Basement membrane
thickening
ICS

 



Symptoms
Adapted from Bousquet et al. Am J Respir Crit Care Med. 2000;161:1720-1745.
Mean Change from Baseline
in Morning PEF
Steroid-Sparing Effect of
FP/Salmeterol Combination: Morning PEF
Busse W et al. J Allergy Clin Immunol 2003;111:57-65 with permission from Mosby, Inc..
FP/
Salmeterol
FP
Mean Change from Baseline
in Number of Puffs/Day Albuterol
Steroid-Sparing Effect of
FP/Salmeterol Combination: Albuterol Use
Busse W et al. J Allergy Clin Immunol 2003;111:57-65 with permission from Mosby, Inc.
Evolution of Asthma Paradigms
Symptoms
Relieve Symptoms
After William Calhoun, 2004
Bronchial
Hyperreactivity
Prevent Symptoms
Prevent Attacks
Fixed
Obstruction
Prevent Symptoms
Prevent Attacks
Prevent Remodeling
Time Course of Achieving Control
(Which Marker is Best?)
No night symptoms
100
AM PEF
% Improvement
FEV1
No “rescue” SABA use
AHR
FENO???
Days
Weeks
Months
Years
For illustrative purposes only.
Woolcock et al. Presented at: 10th Annual ERS Congress; Florence, Italy; August 30-September 3, 2000.
What Does the Evidence Say?
Guidelines/Analysis
Preferred Treatment
• NAEPP, 2002 Update
• Inhaled corticosteroids
• Global Initiative for
Asthma (GINA), 2003
• Inhaled corticosteroids
• Inhaled corticosteroids
• Cochrane analysis
Ducharme FM. BMJ. 2003;326:621-625.
Global Initiative for Asthma. NIH Publication
(No. 02-3659A). 2003.
NAEPP Expert Panel. NIH Publication (No.
02-5075). 2002.
Asthma Pathophysiology
Smooth
muscle
dysfunction
Airway
inflammation
Airway
remodeling
Integrative Model of the Components
of Airway Remodeling
Lazaar AL. Am J Med. 2003;115:652- 659.
Inflammation in Asthma
Acute
inflammation
“Acute on chronic inflammation”
Steroid
response
Chronic inflammation
Structural changes
Time
After PJ Barnes
Height-adjusted FEV1 (litres)
Increased loss of FEV1 in asthma
Male non-smokers
P <0.001
No asthma (n= 5480)
Asthma (n= 314)
Age (years)
Lange P et al, NEJM 1998
“RULES OF TWO”™* Dictate
Maintenance Anti-Inflammatory
Controller Therapy
• They are using a quick-relief inhaler more
than 2 times per week
• They awaken at night due to asthma more
than 2 times per month
• They refill a quick-relief inhaler
prescription more than 2 times per year©
*“RULES OF TWO”™ is a trademark of the Baylor Health Care System.
Principles of Treatment
Allergen immunotherapy &/or
monoclonal anti-IgE ABs
Immunologic intervention
Bronchodilators
Anti-inflammatories, rhinitis meds
Pharmacological intervention
Avoidance of allergic triggers
Environmental intervention
Summary
• Appropriate assessment, diagnosis, and
management play critical roles in asthma
control
• Asthma control/severity may change over
time
– A snapshot assessment taken on one day may
not predict subsequent disease activity
• Long-term periodic assessment and
continued well asthma care may improve
clinical outcomes
Summary (cont.)
• Lung function impairment and other factors in
childhood may influence the occurrence of
asthma in adults
• Asthma is a complex disease with two main
components: inflammation and
bronchoconstriction
• Both ICS and LABA have important effects on
the underlying pathophysiology of asthma
• Complementary modes of action
– LABA: long-lasting effects on airway smooth muscle
– ICS: potent topical anti-inflammatory effects