Transcript Asthma - University of Arizona Department of Pediatrics

Asthma
Kim Otsuka, MD
Pediatric Pulmonary Fellow
September 21, 2004
UoA PPC 2004 Workshop
Lectures
Objectives
 Overview
of asthma
 Review NHLBI guidelines for asthma
treatment
 Review other management strategies
for asthma
What is Asthma


Disease of chronic
airway inflammation
Characterized by
– Airway inflammation
– Airflow obstruction
– Airway
hyperresponsiveness
Cookson W. Nature 1999; 402S: B5-11
http://health.allrefer.com/health/asthmanormal-versus-asthmatic-bronchiole.html
Pathophysiology

Caused by
– Inflammation and
edema
– Bronchial smooth
muscle spasm and
hypertrophy
– Mucous plugging
Jenkins, HA, et al. Chest 2003; 124:
32-41.
http://www.pathguy.com/histo/087.htm
Asthma in Children
 Asthma
is the most common chronic
disorder of childhood
 Over 9 million children under the age
of 18 in the US have been diagnosed
with asthma
– The disparity between Black and white
non-Hispanic children is increasing
 Asthma
morbidity and mortality is
increasing as well
The Burden of Asthma in
Children
1 million US children <18 y/o experience
some degree of disability due to asthma
– Disabling asthma disproportionately affects
Blacks and Hispanics, single-parents, lower
SES

Disabling asthma lead to ~3 weeks of
restrictive activity per year higher than
other chronic medical conditions
– 9.7 school days/year
– ~9.2 physicians contacts/year
Asthma Etiology

Asthma is a complex trait
– Heritable and environmental factors contribute
to its pathogenesis

Multiple interacting genes
– At least 20 distinct chromosomal regions with
linkage to asthma and asthma related traits
have been identified
 Chromosome
5q – cytokine gene cluster
 ADAM33 – bronchial hyperresponsiveness
 PHF11 – total IgE
Hygiene Hypothesis
 Rapid
rise in atopy and asthma is
greatest in developed countries and
urban areas
– Cannot be explained by change in
genetic background but is thought to be
the result of complex interactions
between genes and the environment
History
“These observations…could be explained if
allergic disease were prevented by infection in
early childhood, transmitted by unhygienic
contact with older siblings, or acquired
prenatally…Over the past century declining
family size, improved household amenities and
higher standards of personal cleanliness have
reduced opportunities for cross-infection in
young families. This may have result in more
widespread clinical expression of atopic
disease.” David Strachan, BMJ, 1989
Allergic Diseases and Autoimmune
Diseases are Rising
Bach JF, N Engl J Med 2002; 347: 911-920
Hygiene Hypothesis

Environmental
impact on asthma
–
–
–
–
Farm exposure
Day care/siblings
Pets
Early infections
Hygiene Hypothesis
Yazdanbakhsh M, et al. Science 2002; 296: 490-494
Etiological Factors – Gene and
Environment
Wills-Karp M, et al. Nature Reviews Immunology; 2001; 1: 69-75
Diagnosing Asthma
 Clinical
diagnosis supported by the
certain historical, physical and
laboratory findings
– History of episodic symptoms of airflow
obstruction
– Physical: wheeze, hyperinflation
– Laboratory: exhaled nitric oxide (eNO),
spirometry
 Exclude
other possibilities
Conditions Mimicking Asthma

Obstruction of
small airways
– Aspiration
– Chronic lung
disease secondary
to prematurity
– Bronchiolitis
– Cystic Fibrosis

Obstruction of
large airways
– Foreign body
– Congenital
malformations
– Cardiac disease
– Endobronchial
tumors
– Extrabronchial
obstruction
– Psychogenic
Natural History of Asthma
Martinez, FD. J Allergy Clin Immunol 1999; 104: S169-74.
Diagnosing Asthma in Young
Children – Asthma Predictive Index

> 4 episodes/yr of
wheezing lasting
more than 1 day
affecting sleep in a
child with one
MAJOR or two
MINOR criteria

Major criteria
– Parent or sibling
with asthma
– Atopic dermatitis
– Aeroallergen
sensitivity

Minor criteria
– Food sensitivity
– Eosinophilia (>4%)
– Wheezing apart
from infection
Adapted from Castro-Rodriquez JA, et al. AJRCCM 2000; 162: 1403
Outcome of Childhood Asthma
Phelan PD, et al. J Allergy Clin Immnol 2002; 109: 189-94.
Asthma Classification
Days with
symptoms
Nights with
symptoms
PEF or
FEV1
PEF
Variability
Mild
Intermittent
<2x/week
<2x/month >80%
<20%
Mild
Persistent
3-6x/week
>2x/month >80%
20-30%
Moderate
Persistent
Daily
>1x/week
>60<80%
>30%
Severe
Persistent
Continuous
Frequent
<60%
>30%
Adapted from Guidelines for the Diagnosis and Management of Asthma-Update
on Selected Topics 2002. NIH Publication No. 02-5075.
Asthma Mortality:
Mild Patients Are Also at Risk
40
30
20
10
0
Severe
Moderate
Patient Assessment
Robertson et al. Pediatr Pulmonol. 1992;13:95-100.
Mild
Rules of TwoTM
 Use
of a quick-relief inhaler more
than: 2 times per week
 Awaken
at night due to asthma
symptoms more than: 2 times per
month
 Refill
of a quick-relief inhaler
prescription more than: 2 times per
year
"Rules of Two" is a trademark of
the Baylor Health Care System
Breaking the “Rules of TwoTM” Results in
Asthma Morbidity
8
7
Total
Age 0-17
6
Relative Risk of
Hospitalization
Inhaled Steroids
ß2-agonists
5
Total
Age 0-17
4
3
2
1
0
None
0-1
1-2
2-3
3-5
5-8
Prescriptions per Person-Year
Adapted from Donahue et al. JAMA. 1997;277:887-891.
8+
Goals of Treatment
SLEEP
 LEARN
 PLAY

Key Components of Asthma
Therapy
 Assessment
and monitoring
 Pharmacologic therapy
 “Trigger” control
 Patient education
Adapted from NAEPP Practical Guide for the Diagnosis and
Management of Asthma. 1997 NIH Pub 97-4053.
Pharmacologic Treatment
“Controller”
Long-term Control
“Rescue”
Short-acting
Mild
Intermittent
None
Β2-agonist
Mild
Persistent
Preferred: low dose inhaled
corticosteroid (ICS)
Β2-agonist
Moderate
Persistent
Preferred: low-medium dose ICS
and long-acting Β2-agonist
Β2-agonist
Severe
Persistent
Preferred: low-medium dose ICS
and long-acting Β2-agonist and
oral corticosteroids if needed
Β2-agonist
Adapted from Guidelines for the Diagnosis and Management of AsthmaUpdate on Selected Topics 2002. NIH Publication No. 02-5075.
Inhaled Corticosteroids
Preferred treatment alone or in
combination for all persistent categories of
asthma
 Safe when use is monitored
 Reduces asthma symptoms, bronchial
hyperreactivity, exacerbations and
hospitalizations, need for rescue
medications
 Improves pulmonary function, quality of
life
 May prevent airway remodeling

ICS Use Lowers Risk of Death
from Asthma
Suissa S et al. N Engl J Med 2000; 343: 332-336
ICS Are More Effective at Decreasing Asthma
Exacerbations Than Anti-leukotriene Agents
Maspero
Baumgartner
Busse
Hughes (BUD)*
Hughes (FP)
Laviolette*
Skalky
Williams
Bleecker
Busse
Kim
Fixed Effects
Pooled Relative Risk
1.6
0.1 -15
-10
-5
0
1
+5
+10
+15
+10
Relative Risk (95% CI)
Favors anti-leukotrienes
Favors inhaled glucocorticoids
Results not affected by type of medication, methods, analysis, publication
status or funding source. Insufficient evidence in children.
* No exacerbations reported
Ducharme FM, BMJ 2003; 326: 621
ICS – Finding the Right Balance
Favorable Benefit:Risk Ratio
Wanted Effects
Response
Unwanted Effects
Dose
The range that the risk:benefit ratio is favorable is that at which the wanted effects in the lungs increases
steeply with dose while the unwanted systemic effects increase gradually. At higher doses, the increase in
risk greatly outweighs the slight remaining increase in benefit. This relationship seems to vary for different
inhaled corticosteroids.
Barnes et al, Am J Respir Crit Care Med Vol 157, 00S1-S53, 1998.
Long Term Effects of Budesonide
or Nedocromil On Growth
Childhood Asthma Management Program Research Group N Engl J
Med 2000; 343: 1054-63.
Adult Height is not Affected by ICS
Use
Agertoft L, Pedersen S. N Engl J Med 2000; 343: 1064-69.
Not All ICS are the Same
 Potency
 Systemic
 Dosing
absorption
Doubling doses of ICS – Twice as
Good?
 FitzGerald
JM, et al.
– No significant difference in exacerbation
outcome when ICS doubled
– Possible explanations
 Not
frequent enough use
 Onset of ICS slower than systemic
corticosteroids
 Airflow limitations affect ICS delivery
 Dose increase insufficient
Adapted from FitzGerald JM, et al. Thorax. 2004; 59:550-556.
Leukotriene Receptor Antagonists
 Alternative
therapy for mildpersistent asthma as well as
alternative combination therapy with
ICS for moderate persistent asthma
 Safe
 Easy to administer
 Improves asthma symptom freedays, but less than ICS
ICS vs. Montelukast
Busse W, et al. J Allergy Clin Immunol 2001; 107: 461-468.
Combination Therapies

Combination therapies work better than
increasing the dose of ICS
Condemi JJ, et al. Ann Allergy Asthma Immunol 1999;82:383–389.
Combination Therapy of ICS and Salmeterol is
Better Than Increasing the ICS dose
Ind
Greening
Woolcock
Kelsen
Murray
Kalberg
Condemi
Van Noord (LD)
Van Noord (HD)
Vermetten
Fixed Effects
Random Effects
-20
-15
-10
-5
0
+5
+10
Treatment Difference (%)
Favors increasing ICS
+20
Favors adding salmeterol
Studies not individually powered to examine exacerbation rates.
Shrewsbury et al. Br Med J. 2000;320:1368-1373.
+15
Montelukast and ICS
Laviolette M, et al. Am J Respir Crit Care Med 1999; 160: 1862-1868
Salmeterol and ICS vs.
Montelukast and ICS
Nelson HS, et al. J Allergy Clin Immunol, 2000; 106: 1088-1095
Pharmacogenetics
 Study
of the role of genetic
determinants in the variable
response to therapy
 The future of asthma treatment
Other Management Issues
 Environmental
– “Safe” room
 Diet
– Infant feeding
– Sodium
– Fatty acids
– Antioxidants
control
Is Environmental Control Helpful?


Single allergen
reduction not effective
“…Treatment by means
of allergen avoidance
requires the definition of
what patients are
allergic to, and
additional measures
beyond the use of
mattress covers and
education” Thomas
Platts-Mills
http://health.allrefer.com/health/asthm
a-common-asthma-triggers.html
Tailored Environmental Intervention
Morgan et al, 2004
 Randomized, controlled trial of
environmental intervention
 Intervention resulted in

– Reduction in asthma symptoms, disruption in
caretakers plans, caretaker’s and child’s sleep,
asthma-related visits to the ER or clinic
– Reduction in asthma symptoms were
correlated to reduction in allergens

No difference in reduction of allergens in
homes with carpets or without carpets
Tailored Environmental Control
Reduces Asthma Symptoms
Morgan WJ, et al. N Engl J Med 2004; 351: 1068-80.
Air Filters and Asthma
McDonald E, et al. Chest 2002; 1535-42.
Diet and Asthma

High sodium diet may result
in adverse effects on airway
reactivity in patients with
asthma
– No recommendation to
implement low salt diets


Potassium and Magnesium
effect unclear
Tartazine exclusion not
helpful except perhaps those
with proven sensitivity
Diet and Asthma

Breast feeding
– Exclusive breast feeding > 4 months





Protective against recurrent wheeze
Higher odds of asthma in children who
are atopic and have a mother with
asthma
Maternal avoidance diets during
pregnancy does not affect
incidence of asthma
Utilization of protein hydrolyzed
formulas have not been shown to
reduce incidence of asthma
Probiotics supplementation has
demonstrated decrease in atopy,
but asthma is unknown
Diet and Asthma

Polyunsaturated fatty acids
– Omega 3’s vs. Omega 6’s


Omega 6 fatty acids, present in animal fat,
metabolized to arachidonic acid generating potent
inflammatory mediators and broncho-constricting
agents
Omega 3 fatty acids, found particularly in fatty fish
are metabolized to eicosapentaenoic acid (EPA) and
docosahexaenoic acid
– May competitively inhibit the use of arachidonic acid as
a substrate for the production of pro-inflammatory
mediators such as prostaglandins and leukotrienes
– Theoretical benefit to lung function, but not
conclusively proven in studies

Trans fatty acids associated with prevalence of
asthma, allergic conjunctivitis, and atopic
eczema
Diet and Asthma

Antioxidants
– Epidemiological evidence suggests
that antioxidants have a role in
asthma
– Randomized trials
 No
current role for Vitamin C in the
treatment of asthma
 Vitamin E supplementation provides
no additional benefit to standard
treatment of asthma
 No substantiated role for Β-carotene
supplementation in asthma
Asthma Education
 Self
management education
associated with:
– Improvements in airflow
– Improvements in self-efficacy scales
– Reductions in school absence
– Reduction in days of restricted activity
– Reduction in emergency room visits
Summary
 Asthma
is a disease of chronic airway
inflammation; thus, inhaled
corticosteroids is the preferred
pharmacologic therapy
 Persistent asthma (those who break
the “rules of two”) need a controller
medication
 Children with asthma should all be
able to sleep, learn, and play