1. Pediatric Asthma Evaluation & ManagementTM
Prepared for your next patient.
Pediatric Asthma Evaluation & Management
Bradley E. Chipps, MD, FAAP
Capital Allergy & Respiratory Disease Center
Sacramento, CA
Welcome slide for use during audience walk-in.

2. Disclaimers
Statements and opinions expressed are those of the authors and not necessarily those of the American Academy of Pediatrics.
Mead Johnson sponsors programs such as this to give healthcare professionals access to scientific and educational information provided by experts. The presenter has complete and independent control over the planning and content of the presentation, and is not receiving any compensation from Mead Johnson for this presentation. The presenter’s comments and opinions are not necessarily those of Mead Johnson. In the event that the presentation contains statements about uses of drugs that are not within the drugs' approved indications, Mead Johnson does not promote the use of any drug for indications outside the FDA-approved product label.
Session agenda

3. Definition of Asthma
A chronic inflammatory disease of the airways with the following clinical features:
Episodic and/or chronic symptoms of airway obstruction
Bronchial hyperresponsiveness to triggers
Evidence of at least partial reversibility of the airway obstruction
Alternative diagnoses are excluded
Asthma is defined as a chronic inflammatory disease of the airways with
• Episodic and/or chronic symptoms of airway obstruction (eg, cough, wheeze, shortness of breath, tachypnea).
• Bronchial hyperresponsiveness to triggers. Triggers may be specific, such as airborne allergens in sensitized patients, (the most common of which are pets, mold, dust mites, and pollen), or nonspecific, such as irritants (eg, cigarette or wood smoke).
• Evidence of at least partial reversibility of the airway obstruction. This concept will be expanded later in this presentation, but is classically defined as a 12% increase in forced expiratory volume in 1 second (FEV1) after bronchodilators or a course of oral corticosteroids.
The diagnosis of asthma involves fulfilling these diagnostic criteria and excluding alternative diagnoses. 3

4. Diagnosis History Pulmonary function tests (PFTs) Challenge studies
Session agenda 4

5. All that wheezes is not asthma.
Wheezing—Asthma?
Wheezing with upper respiratory infections is very common in small children, but:
Many of these children will not develop asthma.
Asthma medications may benefit patients who wheeze whether or not they have asthma.
There are important pitfalls in the diagnosis of asthma. For example, wheezing with upper respiratory infections (URIs) is very common in small children but not all of these children will develop asthma. On the other hand, asthma is commonly under-diagnosed in children and asthma medication may benefit small children who wheeze with URIs, whether they eventually develop asthma. Related observations are that wheezing does not always mean asthma and many patients with asthma do not wheeze.
All that wheezes is not asthma. 5

6. Cough may be the only symptom present in patients with asthma.
Cough—Asthma?
Consider asthma in children with:
Recurrent episodes of cough with or without wheezing
Nocturnal awakening because of cough
Cough that is associated with exercise/play
Cough without wheeze is often not asthma
The clinical presentation of asthma may be subtle. Recurrent cough or nocturnal awakening because of cough are usually associated with asthma, even if other typical asthma symptoms, such as wheeze or shortness of breath, are not present.
Cough may be the only symptom present in patients with asthma.
Goldsobel AB, Chipps BE. Cough in the pediatric population. J Pediatr. 2010;156(3):352–358 6

7. Asthma Predictive Index
Identify high risk children (2 and 3 years of age):
≥4 wheezing episodes in the past year (at least one must be MD diagnosed)
PLUS OR
One major criterion
Parent with asthma
Atopic dermatitis
Aero-allergen sensitivity
Two minor criteria
Food sensitivity
Peripheral eosinophilia (≥4%)
Wheezing not related to infection
We identified high risk children based on a modified asthma predictive index developed by Castro-Rodriguez using data from the Tucson CRS study.
Modified from: Castro-Rodriguez JA, Holberg CJ, Wright AL, et al. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med. 2000;162(4 Pt 1):1403–1406 7

8. Objective Evaluation of Asthma
Physical examination
Pulmonary function
Bronchoprovocation
Validated control tools
The objective evaluation for asthma includes the physical examination, objective monitoring of pulmonary function (ideally with spirometry initially), and, in some cases, evaluating the response to bronchoconstrictive tests or agents. 8

9. Defining Asthma Severity and Control
0–4 years
5–11 years
12 years and older
Session agenda 9

10. How Can Asthma Control Be Measured?
Lung function?
Inflammation?
Direct or indirect?
Daytime symptoms?
Utilization of healthcare resources?
Nighttime awakenings?
Asthma
Control
Use of “quick relief” inhaler and/or nebulizer?
Functional status?
Session agenda
Missed work and/or school?
Patient self-report of control?
Asthma control test is a trademark of QualityMetric Incorporated. 10

11. Asthma Control Cannot be Assessed at a Single Time Point35 30 25 20
% of Patients 15 10 5
This slide shows data from Chipps et al and Calhoun et al.
It illustrates that asthma control cannot be adequately assessed in many patients by using discrete point-in-time assessments
Approximately one-third of patients in both age groups had 15 or more changes in their asthma severity as assessed by PEF during a 12-week study.
Potential consequences of asthma variability include:
Underestimation of disease severity
Inadequate therapy
Asthma morbidity.
Refs: Chipps B, Murphy KR. Assessment and treatment of acute asthma in children. J Pediatr. 2005;147:
Calhoun W, Sutton LB, Emmett A, et al. Asthma variability in patients previously treated with beta2-agonists alone. J Allergy Clin Immunol. 2003;112: 1 2 3 4 5 6 7 8 9 10 11 12 13 14
15-19
20-24
25+
Number of Changes Over Weeks 1–12
Approximately one-third of both adult and pediatric subjects had 15 or more changes in their asthma severity classification based upon peak expiratory flow (PEF) during the 12-week studies.
Chipps BE, Span JD, Sorkness CA, et al. Variability in asthma severity in pediatric subjects with asthma previously receiving short-acting beta2-agonists. J Pediatr. 2006;148(4):517–521; Calhoun WJ, Sutton LB, Emmett A, et al. Asthma variability in patients previously treated with beta2-agonists alone. J Allergy Clin Immunol. 2003;112(6):1088–1094 11

12. Classifying Asthma Severity and Initiating Treatment in Children 0 to 4 Years of Age
Session agenda
Adapted from: National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma. US Department of Health and Human Services. Available at: Accessed July 5, 2012 12

13. Assessing Asthma Control and Adjusting Therapy in Children 0 to 4 Years of Age
Session agenda
Adapted from: National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma. US Department of Health and Human Services. Available at: Accessed July 5, 2012 13

14. Test for Respiratory and Asthma Control in Kids (TRACK)
Session agenda 14

15. Stepwise Approach for Managing Asthma in Children 0 to 4 Years of Age
Session agenda
Adapted from: National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma. US Department of Health and Human Services. Available at: Accessed July 5, 2012 15

16. Classifying Asthma Severity and Initiating Treatment in Children 5 to 11 Years of Age
Session agenda 16

17. Assessing Asthma Control and Adjusting Therapy in Children 5 to 11 Years of Age
Session agenda 17

18. Childhood Asthma Control Test™
Session agenda 18

19. Stepwise Approach for Managing Asthma in Children 5 to 11 Years of Age
Session agenda
Adapted from: National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma. US Department of Health and Human Services. Available at: Accessed July 5, 2012 19

20. Classifying Asthma Severity and Initiating Treatment in Youth ≥12 Years of Age and Adults
Session agenda 20

21. Assessing Asthma Control in Children ≥12 Years of Age and Adults
Session agenda 21

22. Asthma Control Test™ (ACT)
Session agenda 22

23. Stepwise Approach for Managing Asthma in Children 12 Years of Age and Adults
Session agenda 23

24. Infants and Young Children— When to Start Controllers
>3 episodes of wheezing in the last year, and
Parental history of asthma or physician diagnosis of eczema
Or 2 of the following:
Physician diagnosis of allergic rhinitis, wheezing apart from colds, peripheral eosinophilia
Courses of oral steroids more often than every 6 weeks
Symptoms >2 times per week, nocturnal symptoms >2 times per month
Based on observational studies, it is the opinion of the Expert Panel 2 that the initiation of long-term control therapy should be considered in infants and young children who have had more than 3 episodes of wheezing in the past year that have lasted more than 1 day and affected sleep, and who have risk factors for the development of asthma (parental history of asthma or physician-diagnosed atopic dermatitis or 2 of the following: physician-diagnosed allergic rhinitis, wheezing apart from cold, peripheral blood eosinophilia). This is in addition to previously recommended indications for starting long-term control therapy—ie, in infants and young children requiring symptomatic treatment more than 2 times per week or experiencing severe exacerbations less than 6 weeks apart. 24

25. Step-down Therapy Step down once control is achieved:
After 2–3 months
25% reduction over 2–3 months
Follow-up monitoring:
Every 1–6 months
Assess symptoms.
Review medication use.
Objective monitoring (PEF or spirometry)
Review medication.
Once asthma is brought under control, consideration should be given to stepping down therapy by either decreasing dosage (eg, of an inhaled corticosteroid) or eliminating part of the combination therapy. An adequate period should be given for the maintenance of asthma control before considering stepping down, however. This is somewhat arbitrary, but it is generally recommended that symptomatic control for at least (in milder asthma) 2 to 3 months after initial therapy should be maintained prior to consideration of stepping down. Stepping down may include the possibility of decreasing the frequency of medication as a way to enhance adherence and decrease dosage at the same time.
Asthma is a dynamic and often fluctuating disorder that may require step-up and step-down therapy periodically. The entire step-up and step-down process implies the need for regular monitoring of patients, the frequency of which is dictated by the stability of asthma and degree of asthma control possible. Reassessment includes carefully eliciting evidence of symptomatic control and measuring airflow objectively. Although symptoms can reflect lung functions, it is important to emphasize the imperfect relationship between airflow limitation and symptoms, with a wide range among the patient population of perceived degree of airflow limitation. Review of adherence, the ability to use medication properly, and other aspects of therapy are also important on a repeated basis.
PEFR = peak expiratory flow rate 25

26. Step-up Therapy
Indications: Symptoms, need for quick-relief medication, exercise intolerance, decreased lung function
May need a short course of oral steroids.
Continue to monitor.
Follow and reassess every 1–6 months
Step down when appropriate.
Consider stepping up therapy when goals of therapy are not being achieved. This may require short-term aggressive therapy to obtain or regain control, after which it may be possible to step down therapy to the previous or a new maintenance level. 26

27. Phenotypic Expressions of Childhood Wheezing Disorders
Viral induced wheezing
Severe intermittent wheezing
Exercise bronchospasm/asthma
Persistent asthma
Severe asthma
Session agenda 27

28. Viral Induced Wheezing
Triggered by viral infections
Non-atopic
Remission in childhood
Session agenda 28

29. Infants
Session agenda 29

30. Intermittent Inhaled Corticosteroids (ICS) in Infants with Episodic Wheezing
Single randomized double-blind study
N=411 infants with a 3-day history of wheezing
Infants treated with budesonide 400 µg/d or placebo for 2 weeks
Primary outcome variables were:
Number of symptom free days
Number of days free from rescue medication use
Number of episodes
Number of treatments with open label budesonide
Session agenda
Bigaard H, Hermansen MN, Loland L, et al. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Eng J Med. 2006;354(19):1998–2005 30

31. Intermittent ICS in Infants: Withdrawal Due to Persistent Wheezing50 40 30 20 10
Budesonide
Percentage of Children Withdrawn
Because of Persistent Wheezing
Placebo
P=0.41
Session agenda
100
200
300
400
600
700
500
800
900
Days after Randomization
No. at Risk
Budesonide
149
115 78 27
Placebo
145
114 92
Progression from episodic to persistent wheezing. Results were not significant.
Bigaard H, Hermansen MN, Loland L, et al. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Eng J Med. 2006;354(19):1998–2005 31

32. Role of Viral Infections
Session agenda 32

33. Rhinovirus (RV) Wheezing versus Respiratory Syncytial Virus (RSV) Wheezing in First 3 Years of Life and Asthma at 6 Years of Age
Session agenda
Jackson DJ, Gangnon RE, Evans MD, et al. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am J Respir Crit Care Med. 2008; 178(7):667–672 33

34. Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted
Session agenda 34

35. RV Infections and the Development of Asthma
RV infections can produce more than upper airway illnesses during infancy.
Children who develop asthma by 6 years of age have a significantly increased burden of viral wheezing illnesses in early life.
Pulmonary function abnormalities at 6 years of age are most significantly associated with early childhood wheezing illnesses due to RV (not RSV).
Of all outpatient wheezing viral illnesses in early life, those due to RV are most significant.
Session agenda 35

36. Oral Prednisolone for Preschool Children with Acute Virus-induced Wheezing
Randomized, double-blind, placebo-controlled trial comparing a 5-day course of oral prednisolone (10 mg daily for children 10–24 months and 20 mg daily for older children) versus placebo in 700 children between the ages of 10 and 60 months.
No difference in 7-day symptom scores, albuterol use, or readmission
Primarily non-atopic and 60% first time wheezers
Session agenda
Panickar J, Lakhanpaul M, Lambert PC, et al. Oral prednisolone for preschool children with acute virus-induced wheezing. N Engl J Med. 2009;360(4):329–338 36

37. Severe Intermittent Wheezing
Session agenda 37

38. Acute Intermittent Management Strategies (AIMS)—Primary Hypothesis
In young children with recurrent severe wheezing, intervention with an ICS or leukotriene receptor antagonist (LTRA) at the onset of respiratory tract illness (RTI)-associated symptoms will increase the proportion of episode-free days over a 12-month period compared with conventional therapy.*
Session agenda
*Conventional therapy—inhaled bronchodilator followed by the sequential addition of systemic corticosteroids 38

39. At first sign of RTI symptoms x 7 days
Episodic Use of an ICS or LTRA in Preschool Children with Moderate-to-Severe Intermittent Wheezing
Acute Intermittent Management Strategies (AIMS)
Montelukast 4 mg daily + Placebo ICS + b-agonist
At first sign of RTI symptoms x 7 days
Study Overview
Budesonide 1 mg bid + Placebo LTRA + b-agonist
Randomization
Run in
Placebo LTRA + Placebo ICS + b-agonist
Randomized, multicenter, double-blind, placebo-controlled 1 year trial
238 children, 12–59 months, with recurrent episodes of intermittent wheezing
2 episodes in the previous year
2 urgent care visits, 2 oral steroid courses, or 1 of each
Primary outcome = episode free days
Secondary outcomes = symptoms scores during illnesses and oral corticosteroids (OCS) use
Session agenda
Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122(6):1127–1135 39

40. 1° Outcome—Mean Proportion of Episode Free Days
The primary outcome measure was the mean proportion of episode free days over the 12 month study period, here shown on the y-axis. The three groups experienced comparable proportions of EFDs, with the montelukast group experiencing 73% EFD, the budesonide group 76%, and the conv therapy group 74%. There was no significant differnce between the 3 groups.
Proportion of episode free days adjusted for age group, API status, center 40

41. Maintenance versus Intermittent Inhaled Steroids in Wheezing Toddlers (MIST) Study
12 month R, DB, active control: 278 children (12–53 months)
4 episodes of wheezing last year: Positive mAPI
1 episode: OCS, emergency department, urgent care or hospital
Primary outcome: Exacerbation with OCS
Session agenda 41

42. Treatment Phase: 52 weeks
Run-in: 2 weeks
Treatment Phase: 52 weeks
Pbo run-in nightly +
Albuterol PRN
Randomized
Treatment Group
Nightly, except during RTI
During RTIs only for 7 days
Daily low dose budesonide
0.5 mg PM
Pbo AM
Intermittent high dose budesonide
Pbo PM
1.0 mg AM
1.0 mg PM
Session agenda 42

43. MIST Study Exacerbations 0.95/patient year; p=0.6
Similar time to first exacerbation; p=0.87
No difference in treatment failures or episode free days
Height=0.26 cm average difference; weight=0.16 Kg average difference
Session agenda 43

44. Diagnosis of Exercise-induced Bronchospasm (EIB) / Exercise-induced Asthma (EIA)
Session agenda 44

45. EIA Therapy—General Principles
EIA may reflect suboptimally controlled asthma, which may require adjustment of overall therapy of asthma.
Goal: Facilitate normal activity levels, including competitive sports.
Individualize therapy.
Child needs to understand and be a partner in therapy.
It is important to recognize that exercise-induced asthma is a physiologic test for bronchial hyperresponsiveness and may reflect suboptimally controlled asthma that requires adjustment of overall therapy. The goal of therapy is to facilitate normal activity levels, including competitive sports, at least to the point that there is no interference with normal physical activity and what the child wishes to be able to do. At the same time it is important to recognize that many children with exercise-induced asthma will decrease their activity levels and choose not to be more active because of the discomfort they personally experienced from these activities.
There are general rules of therapy but much individualization of therapy is needed, as in asthma overall. The child needs to understand and be a partner in therapy to accomplish the goals of therapy. This, of course, is true also of the caregivers. Appropriately therapy should be immediately available for preventing or treating exercise-induced asthma. 45

46. Diagnosis of EIB Normal PFT at rest No other stimulus for bronchospasm
Most common in allergic rhinitis patients
Dx: 10% decrease FEV1 after 8 minutes of exercise at 90% maximum predicted heart rate
Rx: B-agonist before exercise, LTRA daily
Session agenda 46

47. Diagnosis of EIA Normal or obstructive PFT at rest
Patient has other stimuli for asthma symptoms.
Patient has both inflammatory and bronchospasm component.
Dx: Same criteria
Rx: ICS, LTRA, ICS/long-acting beta antagonist (LABA) daily, B-agonist before exercise
Session agenda 47

48. Persistent Asthma
Session agenda 48

49. Multicentre Allergy Study (MAS)
Birth cohort: 1314
13-year follow up: 441 (33.6% all visits)
No wheeze 1st year: 315 (74%)
Early wheezers: 126
No wheeze (4–13 years): 79 (68%)
Initial wheeze: 43 (34%)
Persistent wheeze: 4 (3%)
Wheeze 3–6 years: 40 (13%)
Wheeze 6–13 years: 42 (13%)
Session agenda
Matricardi PM, Illi S, Grüber C, et al. Wheezing in childhood: incidence, longitudinal patterns and factors predicting persistence. Eur Respir J. 2008;32(3):585–392 49

50. The Prevalence of Wheezing Varies Depending on Age and Atopic Status
Session agenda
Illi S, von Mutius E, Lau S, et al. Perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study. Lancet. 2006;368(9537):763–770 50

51. Time of Sensitization and Degree of Exposure to Indoor Allergens and Lung Function Impairment at 7 Years of Age
Session agenda
Illi S, von Mutius E, Lau S, et al. Perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study. Lancet. 2006;368(9537):763–770 51

52. Melbourne Epidemiological Study
Session agenda
Phelan PD, Robertson CF, Olinsky A. The Melbourne Asthma Study: J Allergy Clin Immunol. 2002;109(2):189–194 52

53. A Longitudinal, Population-based, Cohort Study of Childhood Asthma Followed to Adulthood
Session agenda
Sears MR, Greene JM, Willan AR, et al. A longitudinal population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med. 2003;349(15):1414–1422 53

54. ICS Therapy in Preschool Children
Multicenter, double-blind, randomized placebo controlled study designed to determine if ICS therapy can modify the subsequent development of asthma in high risk children
Children with a positive asthma predictive index (2–3 years of age, N=285) treated with either fluticasone 88 µg BID or placebo for 2 years followed by a year of observation
Primary outcome variable: Proportion of episode free days
Session agenda
Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006; 354(19):1985–1997 54

55. Fluticasone Had No Carryover Effect During the Observation Period
1.00
0.95
0.90
0.85
0.80
0.75
0.00
Fluticasone
Placebo
Proportion of Episode-free Days
Session agenda
Months
Treatment Period
Observation Period
The increase in symptom free days in the fluticasone cohort during the treatment period was lost in the 12 months subsequent during the observation period.
Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006;354(19):1985–1997 55

56. The Need for Oral Corticosteroids
Children Not Receiving Supplementary Medication
All Children
Observation
Treatment
Observation 25 50 75
100 25 50 75
100
Fluticasone
Placebo
No Need for a First course of Prednisolone (% of children)
Fluticasone
Placebo
Session agenda 6 12 30 18 24 36 24 26 28 30 32 34 36
Months
Months
No. at Risk
Fluticasone
143
102 80 66 57 42
Placebo
142 87 62 50 41
No. at Risk
Fluticasone
132 88
Placebo
130 85 56

57. The Need for Supplementary Controller Meds: No Difference at 36 months25 50 75
100 25 50 75
100
Fluticasone
Fluticasone
Placebo
No Need for Supplementary Asthma-Controller Medication
(% of children)
Placebo 6 12 30 18 24 36 24 26 28 30 32 34 36
Session agenda
Months
Months
No. at Risk
Fluticasone
132
111
Placebo
130
105
No. at Risk
Fluticasone
143
131
118
116
113 99
Placebo
142
125
103 93 86
The fluticasone group had less of a need for supplementary medications during the treatment period (p<0.01). By the end of the observation period (36 months), the groups were indistinguishable (P=0.99)
Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006; 354(19):1985–1997 57

58. Changes in Height from Baseline and Between Groups5 10 15 20
-1.5
-1.0
-0.5
Difference in Height Change
between Fluticasone and Placebo Groups (cm)
Change in Height from Baseline (cm) 10 20 30 10 20 30
Session agenda
Months
Month
P value
0.81
0.07
0.0001
<0.001
<0.001
0.003
<0.001
<0.001
<0.001
0.008
Change in height from baseline represented by the panel on the left. The difference between groups with associated p-values represented on the right. At the end of 24 months the fluticasone group averaged 1.1 cm less than the placebo group. At the end of the observation period (36 months) the difference between groups was 0.7 cm.
Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006; 354(19):1985–1997 58

59. Summary and Clinical Implications
Based on the results of the Prevention of Early Asthma in Kids (PEAK) study:
ICS are effective in improving asthma-like symptom burden, exacerbations, and lung function in high risk toddlers.
Continuous ICS therapy for 2 years once discontinued does not modify the natural history of asthma in early childhood.
Our findings suggest that ICS modulate airway inflammation in this age group similar to adults, but the mechanisms that determine the natural progression of the disease may be different from those that generate the symptoms associated with acute and persistent asthma. Finally, our results strongly support the continued evaluation of other immunotherapeutic interventions to determine if abrogation of disease progression is indeed achievable during early childhood. 59

60. The World’s Largest Study
START Inhaled Steroid Treatment As Regular Therapy in Early Asthma
The World’s Largest Study
in Asthma Therapy
Session agenda
Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet. 2003;361(9363):1071–1076 60

61. Primary Study Objective and Primary Variables
Examines effect of early intervention with ICS on evolution of newly diagnosed asthma
Primary outcome:
Time to first severe asthma-related event (SARE) during first 3 years of study
A severe event requiring hospitalization or emergency treatment due to worsening of asthma or death due to asthma
Secondary outcome:
Change in postbronchodilator FEV1
Intent to treat analysis
Session agenda
Pauwels RA, Busse WW, O’Byrne PM, et al. The inhaled Steroid Treatment as Regular Therapy in early asthma (START) study: rationale and design. Control Clin Trials. 2001;22(4):405–419 61

62. Double-blind (Part A) and Open-label (Part B) Design
Part A – Pulmicort therapy
Adults
Pulmicort 400 g once daily + usual asthma therapy
Part B: Open-label
Adults
Children (6–10 y of age)
Pulmicort 200 g once daily
+ usual asthma therapy
Pulmicort 400 g once daily + usual asthma therapy
Part A – Reference therapy
Children (6–10 y of age)
Adults and Children
Pulmicort 200 g once daily
+ usual asthma therapy
Session agenda
Placebo once daily + usual asthma therapy
Year 1 2 3 4 5
Visit 62

63. Time to First SARE 44% (95% CI, 29–55%) reduced risk of first SARE*
0.10
Reference therapy
Budesonide therapy
0.08
0.06
Cumulative Probability
0.04
0.02
Session agenda
0.00 1 2 3
*Hazard ratio = 0.56; P<.0001.
Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet. 2003;361(9363):1071–1076 63

64. Patients Requiring Additional Corticosteroids*
Session agenda
*Inhaled, oral, or systemic
Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet. 2003;361(9363):1071–1076 64

65. Changes in Postbronchodilator FEV1 Over 3 Years
Session agenda
Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet. 2003;361(9363):1071–1076 65

66. Early Intervention with Budesonide in Mild Persistent Asthma
Session agenda
Sullivan SD. Early intervention with budesonide in mild persistent asthma—the START study. Presented at the European Respiratory Society (ERS). Stockholm, Sweden, 2002 66

67. Early Intervention with Budesonide in Mild Persistent Asthma
Budesonide therapy reduces the risk of a severe asthma exacerbation by 44% in patients with mild persistent asthma.
Daily treatment with low dose budesonide decreases the need for oral corticosteroids in mild persistent asthma.
Budesonide daily improves asthma control
More symptom free days
Less additional asthma medication
Session agenda
Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet. 2003;361(9363):1071–1076 67

68. BADGER Trial
Session agenda 68

69. BADGER Trial
182 children (6–17 years of age), uncontrolled asthma, FP 100 µg BID, triple crossover design, 16-week period
FP 250 µg BID FP 100 µg + SALM 50 µg BID FP 100 µg BID + MTL 5 or 10 mg daily
3 outcomes
Exacerbations
Symptom free days
FEV1 (Pre)
Session agenda
Lemanske RF, Mauger DT, Sorkness CA, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med. 2010;362:975–985 69

70. Primary Predictors of a Differential Response to Step-up Therapy
Session agenda
Lemanske RF, Mauger DT, Sorkness CA, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med. 2010;362:975–985 70

71. Primary Predictors of a Differential Response to Step-up Therapy
Session agenda
Lemanske RF, Mauger DT, Sorkness CA, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med. 2010;362:975–985 71

72. Secondary Predictors of a Differential Response to Step-up Therapy
Session agenda
Lemanske RF, Mauger DT, Sorkness CA, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med. 2010;362:975–985 72

73. Enrollment, Outcomes, and Schedule of Evaluations
Session agenda
Lemanske RF, Mauger DT, Sorkness CA, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med. 2010;362:975–985 73

74. Pairwise Comparisons Session agenda 74
Lemanske RF, Mauger DT, Sorkness CA, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med. 2010;362:975–985 74

75. Probability of Best Response
Session agenda
Lemanske RF, Mauger DT, Sorkness CA, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med. 2010;362:975–985 75

76. Severe Asthma
Session agenda 76

77. Severe Asthma Refractory Difficult to control asthma
Uncontrolled asthma refractory to conventional treatment
Frequent exacerbations
? Distinct phenotype or subgroup
Session agenda 77

78. Reasons for Failure to Achieve Control
Compliance
Asthma heterogeneity
Wrong diagnosis
Wrong target
Failure to deliver drug to the target site
Session agenda 78

79. Demographic and clinical characteristics of children and adolescents with severe or difficult-to-treat asthma
Session agenda 79

80. TENOR Study Design 3-year, multi-center, observational study
Patients continued to receive medications and treatments administered for their asthma as indicated by their physician.
4,756 patients enrolled between January and October 2001
6 years of age or older
283 sites across the US
The TENOR trial is a multicenter observational study of nearly 5000 patients with severe or difficult-to-control asthma receiving care from a pulmonologist or allergist.
Dolan CM, Fraher KE, Bleecker ER, et al. Design and baseline characteristics of The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma. Ann Allergy Asthma Immunol. 2004; 92(1):32–39 80

81. Objectives Primary objective Secondary objectives
Describe the natural history of patients considered by physicians to have “severe” or “difficult-to-treat” asthma.
Secondary objectives
Examine relationship between features of asthma, treatments, and outcomes.
Observe frequency of comorbid conditions.
Examine the relationship between immunoglobulin and disease.
Session agenda 81

82. Methods Cross-sectional baseline data analyzed
TENOR patients between 6 and 17 years of age included (N=1,261)
Patients categorized into 4 age groups by gender:
Age group (years)
Males
(N=791)
n (%)
Females
(N=470)
Total
(N=1,261)
6-8
145 (18)
88 (19)
233 (18)
9-11
282 (36)
120 (26)
402 (32)
12-14
240 (30)
171 (36)
411 (33)
15-17
124 (16)
91 (19)
215 (17)
Session agenda
Chipps BE, Szefler SJ, Simons FE, et al. Demographic and clinical characteristics of children and adolescents with severe or difficult-to-treat asthma. J Allergy Clin Immunol. 2007;119(5):1156–1163 82

83. Spirometry by Age and Gender
Session agenda
Chipps BE, Szefler SJ, Simons FE, et al. Demographic and clinical characteristics of children and adolescents with severe or difficult-to-treat asthma. J Allergy Clin Immunol. 2007;119(5):1156–1163 83

84. Medication Use by Age Session agenda 84
*Based on test for linear trend, a statistically significant age trend (P <.05) was seen for methylxanthines and long-acting -agonists.
Chipps BE, Szefler SJ, Simons FE, et al. Demographic and clinical characteristics of children and adolescents with severe or difficult-to-treat asthma. J Allergy Clin Immunol. 2007;119(5):1156–1163 84

85. Healthcare Utilization by Long-term Controller Use: 6–11 and 12–17 Years of Age
Session agenda
Chipps BE, Szefler SJ, Simons FE, et al. Demographic and clinical characteristics of children and adolescents with severe or difficult-to-treat asthma. J Allergy Clin Immunol. 2007;119(5):1156–1163 85

86. Summary―Predicting Persistence of Wheezing
Family history of asthma
Recurrent lower airway symptoms in infancy
Absence of nasal symptoms at 1 year
Atopic sensitization before 4 years and early exposure
Eczema
Exposure to ETS
Females
Acetaminophen ?
Vitamin D ?
Session agenda 86

87. Thank You
Session agenda 87

88. For more information…
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