Pediatric Asthma Evaluation & Management Bradley E. Chipps , MD, FAAP Capital Allergy & Respiratory Disease C

1. TM Prepared for your next patient. Pediatric Asthma Evaluation & Management Bradley E. Chipps, MD, FAAP Capital Allergy & Respiratory Disease Center Sacramento, CA

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.

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

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

5. Wheezing—Asthma? All that wheezes is not 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.

6. Cough—Asthma? Cough may be the only symptompresent in patients with asthma. Goldsobel AB, Chipps BE. Cough in the pediatric population. J Pediatr. 2010;156(3):352–358 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

7. Asthma Predictive Index • Two minor criteria • Food sensitivity • Peripheral eosinophilia (≥4%) • Wheezing not related to infection • One major criterion • Parent with asthma • Atopic dermatitis • Aero-allergen sensitivity 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 • 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

8. Objective Evaluation of Asthma • Physical examination • Pulmonary function • Bronchoprovocation • Validated control tools

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

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? Missed work and/or school? Patient self-report of control? Asthma control test is a trademark of QualityMetric Incorporated.

11. Asthma Control Cannot be Assessedat a Single Time Point 35 30 25 20 % of Patients 15 10 5 0 0 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. JAllergy ClinImmunol. 2003;112(6):1088–1094

12. Classifying Asthma Severity and InitiatingTreatment in Children 0 to 4 Years of Age 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: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed July 5, 2012

13. Assessing Asthma Control and AdjustingTherapy in Children 0 to 4 Years of Age 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: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed July 5, 2012

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

15. Stepwise Approach for Managing Asthma in Children 0 to 4 Years of Age 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: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed July 5, 2012

16. Classifying Asthma Severity and InitiatingTreatment in Children 5 to 11 Years of Age

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

18. Childhood Asthma Control Test™

19. Stepwise Approach for Managing Asthmain Children 5 to 11 Years of Age Adapted from: National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis andManagement of Asthma. US Department of Health and Human Services. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed July 5, 2012

20. Classifying Asthma Severity and InitiatingTreatment in Youth ≥12 Years of Age and Adults

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

22. Asthma Control Test™ (ACT)

23. Stepwise Approach for Managing Asthmain Children 12 Years of Age and Adults

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

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.

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.

27. Phenotypic Expressions of ChildhoodWheezing Disorders Viral induced wheezing Severe intermittent wheezing Exercise bronchospasm/asthma Persistent asthma Severe asthma

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

29. Infants

30. Intermittent Inhaled Corticosteroids (ICS)in Infants with Episodic Wheezing 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 • 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

31. Intermittent ICS in Infants:Withdrawal Due to Persistent Wheezing 0 100 200 300 400 500 600 700 50 40 30 20 10 0 Budesonide Percentage of Children Withdrawn Because of Persistent Wheezing Placebo P=0.41 800 900 Days after Randomization 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

32. Role of Viral Infections

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

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

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.

36. Oral Prednisolone for Preschool Childrenwith 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 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

37. Severe IntermittentWheezing

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.* *Conventional therapy—inhaled bronchodilator followed by the sequential addition of systemiccorticosteroids

39. Episodic Use of an ICS or LTRA in Preschool Childrenwith Moderate-to-Severe Intermittent Wheezing Acute IntermittentManagement Strategies (AIMS) Study Overview At first sign of RTI symptoms x 7 days Budesonide 1 mg bid+ Placebo LTRA + b-agonist Montelukast 4 mg daily + Placebo ICS + b-agonist Run in Randomization 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 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 ClinImmunol. 2008;122(6):1127–1135

40. 1° Outcome—Mean Proportion ofEpisode Free Days Proportion of episode free days adjusted for age group, API status, center

41. Maintenance versus Intermittent InhaledSteroids 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

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

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

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.

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

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

48. Persistent Asthma

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%) Matricardi PM, Illi S, Grüber C, et al. Wheezing in childhood: incidence, longitudinal patterns and factors predicting persistence. EurRespir J. 2008;32(3):585–392

50. The Prevalence of Wheezing VariesDepending on Age and Atopic Status 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