Download Optimal Asthma Management - Dartmouth

WOODSTOCK 2004
What’s New in Allergy and Asthma?
Robert B. Klein, MD
Director, Asthma and Allergy Center
Professor of Pediatrics, Brown Medical School
Discussion Topics
The Future of Allergy/Asthma
Atopic condition is important
Disparity – one size doesn’t fit all
Hygiene Hypothesis
Phamacogenetics - introduction
Optimal Asthma Management
Severity vrs. Control
Multiple controllers – low dose ICS
Therapies
Omalizumab (anti-IgE) - Xolair
Theophylline and Allergy Shots – a new look
Leukotrienes place in therapy
Discussion Topics
The Future of Allergy/Asthma
Atopic condition is important
Disparity – one size doesn’t fit all
Hygiene Hypothesis
Phamacogenetics - introduction
The Future of Allergy/Asthma
Pediatric respiratory/asthma inpatient admissions by month
200
180
160
140
120
100
80
60
40
20
0
Pediatric ED respiratory/asthma visits by month
350
300
250
200
150
100
50
0
Oct- Nov- Dec- Jan01
01
01
02
Feb- Mar02
02
Apr- May- Jun02
02
02
Jul02
Aug- Sep- Oct02
02
02
Nov- Dec- Jan- Feb- Mar- Apr- May- Jun02
02
03
03
03
03
03
03
BRONCHIOLITIS 2003-4
Modern definition: Lower airway obstruction associated with a viral
respiratory infection during infancy (<12 months)
With regard to subsequent wheezing, longitudinal studies have
associated bronchiolitis with 3 eventual phenotypes (Martinez:
Pediatrics 109: 362, 2002):
•Transient early wheezing: prematurity; low expiratory flow at
birth; day care; pre- or postnatal maternal smoking
•Non-atopic asthma: normal expiratory flow at birth
•Atopic asthma: normal expiratory flow at birth; IgE; maternal
asthma; eczema; clear rhinorrhea between VRIs; Hispanic
origin
Question 1
Dr. Patricia Nolan
Immune System Balance
in Asthma Development
Immune System
Development and the
Hygiene Hypothesis
Birth:TH2
Older siblings:
Many infections
[TH1 stimuli]
TH1
No allergies
Allergen
Exposure
Only child:
Few infections
Still TH2
Allergies
Source: Busse WW, Lemanske RF. N Engl J Med 2001.
Role of “Western” Lifestyle
• Increase in indoor furnishings
• Humidity and indoor temperature
• Decreased ventilation
• Increased time indoors
• Reduction in physical activity
• Can Result in allergic sensitization and
“priming” for asthma development
Factors Influencing Atopy
Newest Version of Hygiene
Hypothesis
Persistent challenges to the immune
system enhance the production of
regulatory cells that inhibit both TH1
and TH2 responses.
Pharmacogenetics
LOWER BRONCHODLATOR
RESPONSIVENESS IN PR THAN
MEXICANS SUBJECTS WITH ASTHMA
In USA PR and Mexicans have the highest &
lowest asthma prevalence, morbidity and mortality
respectively
684 subjects in SF, NYC, PR and Mexico City
PR had 7.3% lower bronchodilator responsiveness
to B2-adrenergics in asthma during ER visits
Subgroup analysis shows more severe disease in PR
subjects
Burchard , Rodriguez-Santana et. al. AJRCCM 2004
Genetics
Asthma is a complex genetic disorder
with variable phenotypes.
Current state of knowledge is
inadequate.
Many polymorphisms.
Many inconclusive results.
Small select samples.
Potential Chromosomes
Linkage, association studies, and
genome-wide screening suggest many
genes located on several chromosomes
are involved.
Susceptibility loci have been located for
the cytokine gene cluster, the IL-4
receptor, and the high affinity IgE
receptor.
B2AR Gene
Efforts to explain individual differences in
response to B-agonist and tachyphylaxis have
focused on the B2AR gene.
The coding variants within B2AR gene
(chromosome 5q31-32, position 16) have
been shown to be functionally important.
CAMP program looked at 707 and 8 SNPs
(single nucleotide polymorphisms)
Silverman et.al. JACI Vol. 112, Nov 2003
Palmer, Weiss et.al.2002 AJRCCM
ALOX5 Gene
ALOX5 is the enzyme required for the
production of LTC4, LTD4, LTE4, and
LTB4.
Patients with variable nucleotide
tandem repeat other than the wild type
have diminished transcription of the
ALOX5 gene and produce fewer
leukotrienes.
Drazen et.al. Nat Genet 1999
Discussion Topics
The Future of Allergy/Asthma
Atopic condition is important
Disparity – one size doesn’t fit all
Hygiene Hypothesis
Phamacogenetics - introduction
Optimal Asthma Management
Severity vrs. Control
Multiple controllers – low dose ICS
How Do We Define Asthma Severity
and Disease Control?
Mild Persistent Asthma
(NAEPP)
Clinical features before treatment or
adequate control1
Symptoms >2 per week but <1 per day1
Nighttime symptoms >2 nights per month1,2
FEV1 or PEF 80%1,2
PEF variability 20%–30%1,2
Exacerbations may affect activity2
1. Guidelines for the Diagnosis and Management of Asthma—Update on Selected Topics
2002. NIH, NHLBI. 2002. NIH publication 02-5075.
2. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. NIH,
NHLBI. 1997. NIH publication 97-4051.
Questions to Consider:
Asthma Care Based on
Disease Severity Classification
Is it possible to assess asthma severity
based on “clinical features before
treatment”?
Does the variable nature of asthma
affect severity classification?
Are patients with mild persistent asthma
at risk for bad outcomes?
Does airway inflammation correlate with
asthma severity classification?
Asthma Control Protocol for
Selecting Controller Treatment
“Control” is defined as the achievement of the
goals of asthma therapy
Prevent day and nighttime troublesome symptoms
Minimal or no need for rescue medications
Maintain normal activity level
Maintain near “normal” pulmonary function
Prevent recurrent exacerbations
The ultimate goal of asthma therapy is the
same for all levels of disease severity: disease
control
Cockcroft & Swystun. J Allergy Clin Immunol. 1996;98:1016-1018.
Measures of Asthma Control
Symptoms: day and night
Physical/social limitations
Rescue albuterol use
Exacerbations: ED, hospital, OCS
Physiologic measures: FEV1, PEFR,
PC20 methacholine
Inflammatory markers: direct and
surrogate measures
“RULES OF TWO”*
Patients Are Candidates for Maintenance
Therapy If …
• Use a quick-relief inhaler >2 times /week
• Awaken due to asthma >2 times/month
• More than 2 times/year:
- Refill a quick-relief inhaler
- Receive a “burst” of oral steroid
- Unscheduled acute asthma care
*“RULE S OF TWO
TWO” is a tr ademark of the Ba ylor Health Ca re S ystem.
FEV1 vs Age
4.0
Females
FEV1
(L)
3.0
2.0
Caucasians
African-Americans
Mexican-Americans
1.0
5
15
25
35
45
Age (y)
Hankinson et al. A m J Respir Cr it Care Med 19 99;1 59:179-87.
55
65
75
85
Inhaled Corticosteroids
Most potent and effective long-term
anti-inflammatory medication
MDI, DPI, suspension for nebulization
Management of persistent asthma, all
levels of severity
Broad action on inflammatory processes
Improve symptoms and pulmonary
function
Reduce need for quick-relief medications
Early Use of Inhaled Corticosteroids
Annual change in percent predicted FEV1
12
10
8
6
4
2
0
<2
2-3
3-5
>5
Asthma duration at start of ICS therapy (years)
Agertoft and Pedersen. Respir Med 1994;88:373-381.
Benefit of Combination
Therapy
Combination therapy (long acting beta
2 agonist and inhaled steroid) improves
lung function, decreases symptoms, and
lessens the use of rescue therapy.
May also allow a lower dose of inhaled
steroid and thereby lessen steroid side
effects.
Discussion Topics
The Future of Allergy/Asthma
Atopic condition is important
Disparity – one size doesn’t fit all
Hygiene Hypothesis
Phamacogenetics - introduction
Optimal Asthma Management
Severity vrs. Control
Multiple controllers – low dose ICS
Therapies
Omalizumab (anti-IgE) - Xolair
Theophylline and Allergy Shots – a new look
Leukotrienes place in therapy
New Treatments
IgE monoclonal antibody.
Regular treatment diminishes early and
late phase responses to allergen
challenge.
Also diminishes the need for
corticosteroid and beta agonist.
Tolerability is excellent; there has been
no evidence of anti-IgE antibodies.
Asthma Studies Protocol
Randomized, double-blind, placebo-controlled,
multicenter, parallel-group
Omalizumab versus placebo, administered
subcutaneously
Study population of adults and adolescents with
moderate to severe symptomatic asthma treated with
inhaled corticosteroids
Omalizumab dosing tailored to baseline body weight
and serum free IgE level
150-300 mg at 4-week intervals (1-2 injections every month)
225-375 mg at 2-week intervals (2-3 injections every 2
weeks)
Busse W, et al. J Allergy Clin Immunol. 2001;108:184-190; Soler M, et al. Eur Respir J. 2001;18(2):254-261.
Key Inclusion Criteria
Diagnosis of asthma
Diagnosed 1 year; stable 1 month
FEV1 reversible 12% at screening
Positive skin test to 1 perennial allergen
IgE levels
30 to 700 IU/mL (BW between 30 to 150 kg)
Level of disease control
Residual symptoms (symptom score > 3)
FEV1 40 to 80% predicted
Inhaled corticosteroids
420 to 840 µg/day Beclomethasone (Busse)
500 to 1,200 µg/day Beclomethasone (Soler)
No oral steroids, LABAs, LRTAs, or theophyline
Busse W, et al. J Allergy Clin Immunol. 2001;108:184-190; Soler M, et al. Eur Respir J. 2001;18(2):254-261.
Study Design
BDP
conversion
R
A
N
D
O
M
I
Z
E
Run-in
phase
4 - 6 wk
Pivotal Studies Busse, Soler
Omalizumab
or
placebo
+
stable
BDP/2
Omalizumab
or
placebo
+
stepwise BDP
reduction/2
Stable steroid Steroid-reduction
phase
phase
16 wk
12 wk
Omalizumab or
placebo
+
free treatment
Extension
phase
24 wk
Core
28 wk
Total
52 wk, double blind, placebo-controlled
BDP = Beclomethasone dipropionate; 2 = Rescue albuterol.
T
R
E
A
T
M
E
N
T
E
N
D
Follow-up
12 wk
Exacerbations
0.8
P < .001†
0.7
0.66
0.6
0.5
0.4
0.3
P = .006†
0.54
 48%
0.28
 58%
0.28
0.2
0.1
0
Study 008
Study 009
Xolair™
†van Elteren test; protocol-defined analysis with imputation.
0.8
Mean exacerbations per patient
Mean exacerbations per patient
Stable steroid phase
16 wk
Steroid-reduction phase
12 wk
P < .001†
0.66
0.7
0.6
0.5
0.4
0.75
P = .003†
 41%
0.39
 52%
0.36
0.3
0.2
0.1
0
Study 008
Placebo
Study 009
Efficacy Conclusions
Both pivotal studies show that Omalizumab
reduces asthma exacerbations requiring steroid
interventions
These reductions are statistically significant,
robust to alternate analyses, and clinically
relevant to patients with moderate to severe
asthma
All other endpoints are positive, including
daytime and nightime asthma symptom scores,
and pulmonary function
Omalizumab
Overall Safety Conclusions
Omalizumab comparable with placebo
AEs and SAEs
Laboratory and platelet measurements
Causal relationship between Omalizumab and
cancer unlikely
Immune responses
Type I and III hypersensitivity
Infection/inflammation
Omalizumab is safe and well tolerated
Summary of Anaphylaxis
Cases
Clinical course not consistent with medical
definition of anaphylaxis
Occurred with first dose in 2 of 3 cases
History of previous allergic reactions in 2 of 3
cases
Intravenous administration in 1 case
Overall very low incidence in study population
Data does not support more specific
recommendations for monitoring beyond
statement in PI
New Treatments
Phosphodiesterase inhibitors (increase cyclic
AMP)
Phosphodiesterase IV is the predominant
isoenzyme in neutrophils and eosinophils and is
found in mast cells and airway epithelium.
Selective PDE IV inhibitors are bronchodilators and
inhibit lymphocyte proliferation and cytokine
release.
PDE IV inhibitors may prove to be more effective
and safer than theophylline.
Long-Term Study on
Children
Source: Johnstone DE, Dutton A. Pediatrics 1968

14-year study on
preventive effects of
immunotherapy published
in Pediatrics

Allergy shots reduced
number of children who
developed asthma
Shift from TH2 to TH1-like
Response After Immunotherapy
70
60
50
40
30
20
10
0
Before SIT
After 3 Months
TH2
After 12 Months
TH1
Source: Ebner et al. Clin Exp Allergy 1997
Leukotriene Modifiers
Block LTD4 receptors
Available as tablets
Position of leukotriene modifiers in
overall therapy not fully established now also approved for AR
Maybe considered alternative therapy to
low doses of ICSs for mild persistent
asthma
Improved symptoms, pulmonary function
Reduced need for quick-relief medications
MONTELUKAST
DOSAGE AND
ADMINISTRATION
Taken once daily
Seasonal Rhinitis - time may be individualized
to suit needs
Asthma taken in evening (both conditions use
evening dosage)
Adults and adolescents: 15 years and older=
10 mg
Children 6-14: 5 mg
Children 1-5: 4mg
New Treatments
Cytokine modulation therapy.
IL-4 receptor antagonist have shown
clinical benefit in moderate
asthmatics requiring daily inhaled
corticosteroids.
Monoclonal antibodies to IL-5 block
eosinophil recruitment but ineffective
in symptomatic asthma.
The Present:
We Can Make A Difference
Improve provider and patient
understanding of asthma.
Improve recognition, earlier diagnosis,
and greater utilization of current
effective treatments.
Raise provider and patient expectations
regarding goals of therapy.
The Future
Better genetic knowledge and
improved environmental controls will
reduce the prevalence of asthma.
Newer, genetically appropriate and
mediator-specific therapies will lessen
morbidity and may influence longterm prognosis.
Question 2
One Disease & one Rx
Optimal Asthma Management
Expect beautiful results
Conclusions
ASTHMA IS A
DISEASE OF
COMMUNICATION
NOT OF
INFLAMMATION
Randall Brown M.D. 1999
Yogi Berra
“If you ask me a question I don’t know,
I’m not going to answer.”
Asthma at 14 year follow-up, %
Prevention of Asthma 14 Years
Later
80
70
60
50
40
30
20
10
0
No Asthma
Mild
Control
Source: Johnston & Dutton 1968
Moderate
SIT
Severe
Asthma at 14 year follow-up, %
Prevention of Asthma 14 Years
Later
80
70
60
50
40
30
20
10
0
No Asthma
Mild
Control
Source: Johnston & Dutton 1968
Moderate
SIT
Severe
Mechanisms Underlying the
Definition of Asthma
Risk Factors
(for development of asthma)
Airway
Hyperresponsiveness
Risk Factors
(for exacerbation)
Airflow
Limitation
Symptoms
Growth and Decline of
FEV1
There are three
ways to reach a low
level:
1) Decreased
maximal
growth
2) Premature
decline
3) Accelerated
decline
Rijken B. Bronchial responsiveness and COPD
risk: an epidemiologic study (postdoctoral
dissertation, 1991).
The Burden of Asthma
In 2000, the national prevalence rate
for asthma was 5.6%.
In Rhode Island, the adult asthma
prevalence was 8.5%, the fifth highest
among the 50 states.
The Burden of Asthma
The highest rates were seen in young
males, women over 65 years, and
people of especially low income.
Asthma mortality rates decreased from
1989-1997.
NHLBI Guidelines June 2002
Gaps in the Application of
Asthma Treatment Guidelines
The guidelines are not followed because of:
Lack of awareness or familiarity with details.
Lack of agreement with guidelines.
Lack of self-efficacy to carry it out properly.
Lack of confidence in outcomes.
Inertia of previous practice.
Source: Cabana and Lewis. Improving Physician Adherence to
Asthma Guidelines. JCOM. 8(3), March 2001.
Consequences of Improper
Assessment of Asthma Severity
• Inadequate utilization of controller therapy
–
–
High usage of short-acting beta2-agonists
alone
Underutilization of ICS in persistent asthma
• Inadequate patient monitoring
• Unnecessary morbidity and mortality
Education for a Partnership in
Asthma Care
Key educational messages to teach and
reinforce at every opportunity
Basic facts about asthma
Environmental control measures
Role of medications
Medication skills and self monitoring
Asthma action plan
Work With The Patient To
Develop Treatment Goals
Determine patient’s own treatment
goals
Agree upon the goals of treatment
Share the general goals of asthma
treatment with patient and family
Action Plans Versus Medical
Management: Monitoring Answer #1

Data are insufficient to support or refute the
use of written action plans

In a Cochrane review, self-management
education with a written action plan had the
greatest benefits for improving lung function
and reducing emergency department visits
and hospitalizations
NIH/NHLBI Guideline Update. June 2002. NIH Publication No. 02-5075.
Modern View of
Asthma
Allergen
Macrophage/
dendritic cell
Mast cell
Th2 cell
Mucus plug
Neutrophil
Eosinophil
Epithelial shedding
Nerve activation
Plasma leak
Oedema
Vasodilatation
Mucus
New vessels
hypersecretion s
Hyperplasia
Barnes PJ
Subepithelial
fibrosis
Sensory nerve
activation
Cholinergic
reflex
Bronchoconstriction
Hypertrophy/hyperplasia
Chronic Care Model
(http://www.improvingchroniccare.org)
Community and Health System
Resources
Informed Activated Patients
Prepared Practice Teams
Improved Outcome
Chronic Care Model
Community and Health Care System
Self Management Support
Delivery System Design
Decision Support
Clinical Information Systems
Self Management Support
Emphasis on patient role
Standardized assessment
Effective intervention
Care planning and problem solving
Clinical Information Systems
Care planning
Care reminders
Feedback
Individual treatment plan
Airway Inflammation
Other Important Players
Airway smooth muscle can also secrete
cytokines, chemokines and express cell
adhesion molecules that modify
submucosal inflammation.
Vascular permeability may result from
the excess production of nitric oxide.
Development of the Immune
System
Conclusions
Hygiene Hypothesis
Less asthma in rural America.
Endotoxins and microbial heat shock
proteins (HSP) are found in high
concentrations in rural areas especially
farm environments.
These allergens have been found to
trigger the release of IL-12, favoring the
TH1 response.
Hygiene Hypothesis
The hygiene hypothesis states that
infants in modern industrial societies
(improved sanitation, widespread use of
vaccines and broad spectrum
antibiotics) are exposed to fewer
viruses and bacteria and thus exhibit
greater TH2 cell activity.
Determinants of TH1 vs. TH2
Viruses and bacteria (endotoxins) can
stimulate macrophage secretion of IFNalpha and IL-12, favoring TH1 response.
Reasons for More Asthma
Indoor Air Pollution (dust mites)
Outdoor Air Pollution (diesel exhaust)
Hygiene Hypothesis