1. Mark A. Brown, MD Arizona Respiratory Center mabrown@arc.arizona.edu
Asthma
Mark A. Brown, MD
Arizona Respiratory Center
Tucson Pediatric Pulmonary Center

2. Definition
Intermittent lower-airway obstruction that is reversible either spontaneously or as the result of treatment
Inflammation and edema
Bronchial smooth-muscle spasm
Mucous plugging
Primary immune mechanism of asthma: antigen with immunoglobulin E bound to the cell surfaces which triggers the release of histamine and a variety of other factors that promote both bronchospasm and local inflammation
Inflammation:
--Lymphocytic and eosiophilic submucosal infiltrates seen on tracheal
and bronchial biopsy specimens correlate with severity of disease
--Mast cells, epithelial cells and T lymphocytes are activated and
produce proinflammatory cytokines
--Mediators such as histamine, leukotrienes, platelet-activating factor
and others are found locally as well as systemically in increased conc
Histamine: increases leakage of protein and fluid from venules
increases airway secretions,can stimulate irritant receptors in the airway walls
This leads to relex vagal release of acetylcholine near smooth muscles
leading to further bronchoconstriction
Antihistamines are not helpful in asthma
Other factors besides histamine:
--lipoxygenage products of arachidonate--leukotrienes--other bronshospasm mediators: platelet activating factor, bradykinin, substance P, oxidants
Cholinergic nerves that travel in the vagus nerve may release acetylcholine Stimulation of these receptors is also responsible for cough
Epithelial Destruction renders airways hyperirritable
The hyperirritable and chronically inflamed airway is susceptible to acute
obstruction triggered by such factor as allergen exposure, URI, environmental
irritants, exercise, second hand smoke, emotional stress, GER, and drugs.

3. Definitions
Asthma exacerbation: symptoms that require a change in medication from baseline
Status asthmaticus: increasingly severe asthma that is not responsive to drugs that are usually effective
Review Article in Chest Status Asthmaticus in Children. A Review. Heinrich A Werner, MD

4. Epidemiology
10% of children in the US: 5 million children under the age of 18
Prevalence is increasing
Asthma morbidity and mortality is increasing
50% have family history of asthma, rhinitis, eczematous dermatitis, or urticaria
10 % of children in the US: the most common chronic illness of childhood in the US Reference: Pediatric Asthma:Promoting Best Practices. Guide for managing asthma in child, 1999
Prevalence is increasing—especially among children less than 12: Source: NCHS, national health interview survey,
Diagnostic shift (use of “asthma” for conditions classified differently)
cannot fully account for this development—asthma prevalence is increasing
world-wide
Asthma morbidity is also on increase—rates have doubled for kids aged 1-4
About 50% of children with asthma improve or become symptom free on reaching early adulthood but a very early onset of disease is associated with a less favorable prognosis

5. Onset of Symptoms in Children With Asthma
20%
30%
1-2 years
<1 year
20%
2-3 years
30%
Slide 7. Onset of Symptoms in Children With Asthma
Most children who experience wheezing before age 5 years are likely to receive an asthma diagnosis in childhood.
Approximately 10% of young children are affected by asthma. Of these children, 30% will have an onset of symptoms within the first year of life.
Approximately 50% of children with asthma experience symptom onset by age 2 years and 70% do by age 3 years.
Dodge R, Martinez FD, Cline MG, Lebowitz MD, Burrows B. Early childhood respiratory symptoms and the
subsequent diagnosis of asthma. J Allergy Clin Immunol 1996;98:48-54.
Wainwright C, Isles AF, Francis PW. Asthma in children. Med J Aust 1997;167:
McNicol KN,Williams HB. Spectrum of asthma in children. I. Clinical and physiological components. BMJ
1973;4:7-11.
>3 years
McNicol and Williams. BMJ 1973;4:7-11; Wainwright et al. Med J Aust 1997;167:

6. Natural History of Childhood Asthma
Transient early wheezers
Non-atopic wheezers
IgE-associated wheeze/asthma
Wheezing Prevalence
Slide 8. Natural History of Childhood Asthma
Childhood asthma often persists or recurs in adulthood, with approximately one third of children with asthma experiencing symptoms as adults.The occurrence of wheezing and other respiratory symptoms in children aged 3 to 4 years is significantly associated with future asthma.
Most infants who wheeze have no increased risk of asthma or allergies later in life. However, for a minority of infants, early wheezing episodes may be related to future asthma.These children have elevated immunoglobulin E (IgE) levels during the first months of life and have lung function deficits by 6 years of age.
Development of asthma may also be related to allergen sensitivity. Children who wheeze at age 6 years and who are skin-test positive to asthma-related allergens are more likely to have persistent symptoms and show hyperresponsiveness to methacholine beyond that age (and up to age 11 years). In contrast, children who wheeze at age 6 years and who are skin-test negative to allergens are much less likely to show persistent wheezing beyond the early school years.
Oswald H, Phelan PD, Lanigan A, Hibbert M, Bowes G. Olinsky A. Outcome of childhood asthma in mid-adult
life. BMJ 1994;309:95-96.
Dodge R, Martinez FD, Cline MG, Lebowitz MD, Burrows B. Early childhood respiratory symptoms and the
subsequent diagnosis of asthma. J Allergy Clin Immunol 1996;98:48-54.
Martinez FD,Wright AL,Taussig LM, et al. Asthma and wheezing in the first six years of life. N Engl J Med
1995;332:
Martinez FD. Present and future treatment of asthma in infants and young children. J Allergy Clin Immunol
1999;104:S169-S174.
Age (Years)
Martinez. J Allergy Clin Immunol 1999;104:S169-S174.

7. Asthma Prevalence in US Children
SOURCE: US EPA (NCHS, ).

8. Asthma Ambulatory Visits
Akinbami LJ, et al. Pediatrics, 2009; 123:S131-S145

9. Childhood Asthma Deaths
Akinbami LJ, et al. Pediatrics, 2009; 123:S131-S145

10. Arizona vs. US Asthma Age-Adjusted Mortality Rate 1991-98
Deaths/100,000 population

11. Risk Factors Previous attack with:
Severe unexpected or rapid deterioration
Respiratory Failure (ICU/Intubation)
Seizure or loss of consciousness
Recent use of oral steroids or decrease in ICS
Frequent use of short acting -agonist
Risk Factors for potentially fatal asthma
Although several contributors to the mortality risk have been described—as many as one third of children who die from asthma may have only had mild asthma before and were not previously classified as high risk by any available criteria
In the US : nonwhite children with poor access to health care have the highest risk for near-fatal and fatal asthma

12. Risk Factors Two or more hospitalizations in the last year
Hospitalization or ED in the last month
3 or more ED visits in the last year

13. Risk Factors Psychosocial Denial or failure to perceive severity
Depression
Nonadherence
Dysfunctional family
Inner-city resident

14. Inflammation in Mild Asthma
Slide 11. Inflammation in Mild AsthmaBusse and Lemanske N Engl J Med 2001/figure 1
Inflammation in asthma leads to structural airway changes, even in patients with mild to moderate disease.Busse 2001/350/2/1
This photograph, which appeared in a New England Journal of Medicine review, shows a specimen of bronchial mucosa from a subject without asthma and a patient with mild asthma.
The epithelium is intact in the subject without asthma. Neither thickening of the sub-basement membrane nor cellular infiltrate is evident.
In the patient with mild asthma, there is evidence of goblet-cell hyperplasia in the epithelial cell lining, sub-basement membrane thickening, collagen deposition in the submucosal area, and a cellular infiltrate.Busse 2001/351/Figure 1
Busse WW, Lemanske RF. Asthma. N Engl J Med. 2001;344:
Subject Without Asthma
Patient With Mild Asthma
Busse and Lemanske. N Engl J Med. 2001;344:

15. CXR
Heart has been shifted medially and inferiorly by the hyperexpansion of the lungs. Also can see this hyperexpansion with anterior air on lateral film

16. Airway Remodeling 30 P<.003 20 P<.01 10
P<.003
P<.01
Subepithelial Layer Thickness (µm) *
Slide 29. Airway Remodeling Occurs Even in Patients With Mild AsthmaChetta
1997/855/figure 1 and 854/2/2
Airway remodeling, as determined by subepithelial layer thickness, is a characteristic pathologic finding in patients with asthma.Chetta 1997/853/1/3, 852/Abstract
Airway biopsies were taken from 34 patients with asthma (aged 15–55 y) controlled only with inhaled 2-adrenergic agonists and 8 healthy volunteers.Chetta 1997/853/2/2 Patients with asthma were excluded if they required theophylline, corticosteroids, or sodium cromoglycate.
Asthma severity was assigned based on symptoms, bronchodilator use, and peak expiratory flow variability, each of which was rated on a 0 to 4 scale.Chetta 1997/853/1/4
Differences in subepithelial layer thickness were computed for each biopsy. Differences were significant among the groups of asthma patients identified by disease severity (P<.003 for severe vs mild asthma; P<.01 for severe vs moderate asthma) and between all patients with asthma versus healthy controls (P<.001).Chetta 1997/854/2/2
In the figure shown, bars indicate the mean and circles indicate the individual values for subepithelial layer thickness in each group of patients with asthma and the group of healthy controls.Chetta 1997/855/1/ Figure 1
Chetta A, Forest A, Del Donno M, Bertorelli G, Pesci A, Olivieri D. Airways remodeling is a distinctive
feature of asthma and is related to severity of disease. Chest. 1997;111:852-7.
Severe Moderate Mild Healthy (n=6) (n=14) (n=14) (n=8)
*P<.001, healthy subjects vs patients with asthma.
Chetta et al. Chest. 1997;111:852-7.

17. Frequent Use of B2 Agonists Increased Likelihood of Asthma-related Hospitalizations8 7 6 5 4 3 2 1
ß2-agonists
Inhaled Steroids
Total
Age 0-17
Total
Age 0-17
Relative Risk of
Hospitalization
Overuse of rescue beta agonists may indicate worsening asthma.
In this study by Donahue et al,
The relative risk for hospitalization increased as the number of beta2-agonist prescriptions increased above approximately 3 prescriptions per person-year among non-recipients of inhaled corticosteroids.
Regardless of the number of beta2-agonist prescriptions per person-year, the relative risk for hospitalization did not increase among recipients of inhaled corticosteroids.
Inhaled corticosteroids were associated with a 50% reduction in the relative risk of hospitalization compared with people who were not dispensed an inhaled corticosteroid.
None
0-1
1-2
2-3
3-5
5-8 8+
Prescriptions per Person-Year
Adapted from Donahue et al. JAMA. 1997;277:

18. Effects of Corticosteroids on Inflammatory Cells
B cell
IgE
dendritic
cell
ICAM-1/3
IL-1
CD4
antigen presentation
IL-12
CD8
mast
MCP-3
IL-5
IL-6
NCF
MIP-1
LTB-4
SCF
IL-3
IL-14
tryptase
GM-CSF
LTC-4
RANTES
TNF-
IL-8
eotaxin
IL-13
LTE-4
IFN-
PGD2
histamine
PAF
chemokines
LTD-4
IL-4
neurone
neurokinins
myofibroblast
C-kit
Th-2
IL-1
IL-10
Th-1
TNF-
IL-2
Th-0
basophil
cytokines
PGS
protease
neutrophil
TGF-1
TXA2
IL-1
MPO
O species
BIP
endothelial cell
adhesion molecules
ICAM-1
L-selectin
ET-2
ET-1
G-CSF
fibroblast
TGF-
PDGF
MIP-1
COLLAGEN I, II, V
MCP-1
PGE2
collagenase
IL-11
VCAM-1
eosinophil O2
PDGF-B
ECP
HB-EGF
TGF
TXB-2
EDP
MBP
15-HETE
0 species
CR-3
EDN
MCP-2
macrophage
IL-
iNOS
EAF
epithelial cell
15-LD
SLPI
NEP
COX2
15-LT5
PGF2
IGF-I
CGRP
FGF
IL-16
CPLA2
GRO- NO
VIP
9/13 HODE
IL-17
smooth
muscle cell
Mediator release
modified
monocyte
There are a multitude of cells, each capable of releasing a variety of mediators that participate in the inflammatory process of asthma. However, as can be seen from this slide, corticosteroids affect a significant number of the key inflammatory cells, and the release of their pro-inflammatory mediators.

19. ICS May Prevent Death From Asthma
0.0
0.5
1.0
1.5
2.0
2.5 2 4 6 8 10 12
Rate Ratio for Death From Asthma
Slide 28. Low-Dose Inhaled Corticosteroids May Prevent Death From
AsthmaSuissa 2000/335/figure 1
A study of 30,569 members (aged 5–44 y) of the Canadian Saskatchewan Health database examined whether the use of inhaled corticosteroids (ICS) could prevent deaths from asthma.Suissa 2000/332/1/3, 333/1/1 Those who received at least 3 prescriptions for an asthma medication in any 1-year period from 1975 to 1991 were included.
A nested–case control design was used to match patients who died of asthma (n=66) with cohort controls (n=2681) according to the length of follow-up at death of the case patient (index date), date of study entry, and asthma severity.Suissa 2000/332/1/abstract; 333/results
The figure shows the fitted rate ratio for death from asthma as a function of the number of canisters of ICS used during the year before the index date. The rate ratio was adjusted for the patient’s age and sex; the number of prescriptions for theophylline, nebulized and oral 2-adrenergic agonists, and oral corticosteroids in the year before the index date; the number of canisters of inhaled 2-adrenergic agonists dispensed in the year before the index date; and the number of hospitalizations for asthma during the 2 years before the index date.Suissa 2001/335/15/Figure 1
The rate of death from asthma among ICS users was reduced by 50% with the use of at least 6 canisters per year. Higher rates of death from asthma may be associated with sporadic ICS use (<4 canisters/y).Suissa 2000/335/1/1 For each additional canister of ICS used in the previous year, the rate of death decreased by 21% (adjusted rate ratio, 0.79; 95% confidence interval, 0.65–0.97).Suissa 2000/332/abstract, 334/table 1
Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. Low-dose inhaled corticosteroids and the prevention of
death from asthma. N Engl J Med. 2000;343:332-6.
Number of Canisters of Inhaled Corticosteroids Used in the Year Before Death From Asthma
Suissa et al. N Engl J Med. 2000;343:332-6.

20. Effects of Inhaled Corticosteroids on Inflammation
Laitinen Study
- Numerous studies in patients with asthma including the one above from Laitinen et al, have demonstrated that inhaled corticosteroids reduce airway inflammation.
- Randomized, double-blind, parallel-group trial in 14 newly diagnosed mild asthmatics (mean duration of asthma was 7.4 months)
- Subjects entered a 6-week baseline period, treated with terbutaline 375 mcg (three puffs) bid
- Prior to randomization to either budesonide via MDI with spacer (600 mcg bid) or terbutaline (375 mcg bid) via MDI with spacer, subjects had a baseline bronchial biopsy
- Bronchial biopsy was repeated after three months of (blinded) treatment
- In the Figure are shown lymphocytes (arrow heads), eosinophils (thick arrows) and mast cells (thin arrow)
- The histologic changes were associated with an improvement in lung function, asthma symptom scores, and bronchial responsiveness to inhaled histamine
Pre- and post- 3 month treatment with budesonide (BUD) 600 mcg BID; E = epithelium, BM = basement membrane
Laitinen. J Allergy Clin Immunol.1992;90:32-42.

21. Health Resource Utilization
Greater reductions in the need for emergency care
Budesonide Nedocromil Placebo
P<.001 30
P=.02 22
No./100 Person-Year 20 16
P=.04 12
Slide 52. Health Resource UtilizationCAMP 2002/1057/table 2
Compared with the placebo group, the budesonide group had a 45% lower rate of urgent care visits (P<.001). The nedocromil group had a 27% lower rate versus the placebo group (P=.02).CAMP 2000/1057/1/2
The hospitalization rate for the budesonide group was 43% lower (P=.04) than that for the placebo group. The rate of hospitalization with nedocromil treatment was similar to that with placebo.CAMP 2000/1057/1/2
The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or
nedocromil in children with asthma. N Engl J Med. 2000;343: 10
4.3
4.4
2.5
Urgent Care Visits
Hospitalizations
Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343:

22. CAMP: ICS Reduced Oral Prednisone Use
First Course of Prednisone
1.00
Budesonide
Nedocromil
0.75
Placebo
Cumulative Probability
0.50
P<.001 budesonide vs placebo P=.32 nedocromil vs placebo
0.25
Slide 73. CAMP: Inhaled Corticosteroid Use Reduced Oral Prednisone UseCAMP
2000/1060/figure 2
The Childhood Asthma Management Program (CAMP) Research Group study compared the long-term effectiveness of budesonide and nedocromil versus placebo in 1041 children aged 5–12 years with mild to moderate persistent asthma.CAMP 2000/1054/abstract
Children were randomized to treatment with 200 g budesonide (n=311), 8 mg nedocromil (n=312), or placebo (n=418), twice daily, for 4–6 years.CAMP 2000/1555/1/2
Asthma control was best in children treated with budesonide. Time to the first course of oral prednisone was significantly longer for the budesonide group versus the placebo group (P.001), but not for the nedocromil group versus the placebo group (P=.32).CAMP 2000/1057/2/2, 1060/figure 2
Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in
children with asthma. N Engl J Med. 2000;343:
0.00 1 2 3 4
Time (y)
CAMP = Childhood Asthma Management Program.
Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343:

23. Prednisone Use Budesonide Nedocromil Placebo P<.001 P=.01 122 125
102
100
No./100 Person-Year 70 75
Slide 53. Prednisone UseCAMP 2002/1057/table 2
The rate of use of prednisone courses was lowest in the budesonide group, with a 43% lower rate compared with that of the placebo group (P<.001).CAMP 2000/1057/1/2
The rate of use in the nedocromil group was 16% lower than that in the placebo group (P=.01).CAMP 2000/1057/1/2
The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or
nedocromil in children with asthma. N Engl J Med. 2000;343: 50 25
Prednisone Courses
Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343:

24. Corticosteroid Dose Response Curves for Various Outcomes
100 80 60
Symptoms (reduction)
% of Maximum
FEV1 (increase)
Exercise (FEV1) (increase) 40
Nitric oxide (reduction)
FEF25-75% (increase) 20
Slide 20: Corticosteroid Dose Response Curves for Various
Outcome ParametersBarnes 1998/S12/figure 8
This figure displays dose-response relationships for several asthma outcome parameters after treatment with inhaled budesonide.
Desired effects on outcomes measuring asthma symptoms, lung function, and exhaled nitric oxide (a surrogate marker of inflammation), increase steeply with increasing doses of budesonide in the subclinical dose range, and plateau within the clinical dose range.Barnes1998/S12/Figure 8/peer group
Barnes PJ, Pedersen S, Busse WW. Efficacy and safety of inhaled corticosteroids: new developments. Am J
Respir Crit Care Med. 1998;157:S1-S53.
200
400
600
800
Daily Dose of Budesonide (g)
Barnes et al. Am J Respir Crit Care Med. 1998;157:S1-S53.

25. Lower Doses Are Associated With Fewer Risks
Favorable
Benefit:Risk
Ratio
Therapeutic Effects
Response
Undesirable Effects
Slide 19: Lower Inhaled Corticosteroid Doses Are Associated
With Fewer RisksPedersen 1997/28/figure 14
Unwanted systemic effects of inhaled corticosteroids (ICS) in the most commonly used dose range are only rarely of clinical significance.Pedersen 1997/27/2/4
Although lower ICS doses may be associated with systemic effects in some patients, unwanted effects in most patients occur at higher doses where the therapeutic dose-response curve has already plateaued.Pedersen 1997/27/2/5
In the figure shown, the dose range at which the benefit to risk ratio for an ICS is favorable is that at which the therapeutic effects “increase steeply with dose while the unwanted systemic effects increase only gradually.”Pedersen 1997/28/Figure 14
Pedersen S, O’Byrne P. A comparison of the efficacy and safety of inhaled corticosteroids in asthma. Allergy.
1997;52(suppl 39):1-34.
Dose
Pedersen et al. Allergy. 1997;52:1-34.

26. Long Term Effects of Budesonide and Nedocromil On Growth
Standing Height
Standing-Height Velocity
160
6.5
155
6.0
150
145
5.5
140
5.0
135 cm
cm/yr
4.5
130 1 2 3 4 1 2 3 4
Time (yr)
Time (yr)
Number of Patients Remaining in the Study
Number of Patients Remaining in the Study
Budesonide
Nedocromil
Placebo
The difference between the BUD and placebo groups in the rate of growth was evident primarily during the first year of treatment and did not increase later. All groups had similar rates of growth by the end of the treatment period. The difference between in height for the BUD and Placebo groups was 1.1cm. This difference did not increase over time. Calculations of projected final adult height suggest that the children in this study will reach similar adult heights. Some catch up growth may also occur during puberty.
Budesonide
Nedocromil
Placebo
Childhood Asthma Management Program Research Group. N Engl J Med 2000;343:

27. Predicted and Measured Adult Height
= Girls
 = Boys
Agertoft L & Pedersen S. NEJM 343:1064, 2000

28. Important Additional Steps
Asthma education
Triggers, Adherence, Follow-up
Identify and treat comorbidities
Allergies, Sinus Disease, Reflux
Address Barriers to Care

29. Childhood Asthma Serious, common disease Inflammation
Inhaled steroids are effective
Environmental and social factors are very important

30. He who knows and knows that he knows is conceited; avoid him.
He who knows not and knows not that he knows not is a fool; instruct him. He who knows and knows not that he knows is asleep; awaken him. But he who knows not and knows that he knows not is a wise man; follow him. — Arab proverb