Pediatric Asthma Update

1. Pediatric Asthma Update Thomas Flaim, M.D.

2. Key Differences from 1997 and 2002 Expert Panel Reports • Clearly defined the level of evidence used to support recommendations • Categories A, B, C and D • Strength of recommendation • Severity vs Control • Impairment vs Risk Domains • Stepwise Approach for Managing Asthma • Six treatment steps • Three age categories (0-4 years, 5-11 years, ≥ 12 years) • Inclusion of validated questionnaires • ACT, Childhood Asthma Control Test, ACQ, ATAQ • Peak flow monitoring vs symptom-based monitoring Guidelines for the Diagnosis and Management of Asthma (EPR-3) 2007. NIH, NHLBI. August 2007. NIH publication no. 08-4051.

3. Key Differences from 1997 and 2002 EPRAssessment and Monitoring • Separate but related concepts of severity, control and responsiveness to treatment • Classify severity to initiate therapy • Assess control to monitor and adjust therapy • Both severity and control have 2 domains: • Impairment • Risk Guidelines for the Diagnosis and Management of Asthma (EPR-3) 2007. NIH, NHLBI. August 2007. NIH publication no. 08-4051.

4. Assessment and Monitoring • Impairment • frequency and intensity of symptoms and functional limitations the patient is experiencing or has recently experienced • Risk • likelihood of either asthma exacerbations, progressive decline in lung function or risk of adverse effects from medications Guidelines for the Diagnosis and Management of Asthma (EPR-3) 2007. NIH, NHLBI. August 2007. NIH publication no. 08-4051.

5. Assessment and Monitoring • Severity • The intrinsic intensity of the disease process • Measured most easily and directly in a patient not receiving long-term control therapy • Assessed to guide clinical decisions on appropriate medications and interventions • Control • The degree to which the manifestations of asthma (symptoms, functional impairments and risks of untoward events) are minimized and the goals of therapy are met • Guide decisions to maintain or adjust therapy • Responsiveness • The ease with which asthma control is achieved by therapy Guidelines for the Diagnosis and Management of Asthma (EPR-3) 2007. NIH, NHLBI. August 2007. NIH publication no. 08-4051.

6. Mismatch Between Symptoms, Medication Use, and FEV1Study Design • Objective: To determine if lung function measures in children are consistent with levels of asthma severity as defined by the NAEPP guidelines • Prospective study in 219 children aged 5-18 years attending 2 asthma subspecialty clinics • Parents completed questionnaires regarding their child’s asthma symptom frequency over the last month and medication use over the last week • All children performed spirometry • Differences in lung function were assessed in children of different asthma severities . Bacharier et al. Am J Respir Crit Care Med. 2004;170:426-432

7. FEV1 Values Were Similar Regardless of Asthma Severity FEV180% FEV1 60%–<80% FEV1 <60% 100% 80% 60% 40% 20% 0% % of Patients Mild Intermittent(n=14) Mild Persistent(n=58) Moderate Persistent(n=46) SeverePersistent(n=85) P=0.3, Chi-square test. Bacharier et al. Am J Respir Crit Care Med. 2004;170:426-432.

8. Classifying Asthma Severity and Initiating Treatment in Children 0-4 Years of Age Guidelines for the Diagnosis and Management of Asthma (EPR-3) 2007. NIH, NHLBI. August 2007. NIH publication no. 08-4051.

9. Assessing Asthma Control and Adjusting Therapy in Children 0-4 Years of Age Guidelines for the Diagnosis and Management of Asthma (EPR-3) 2007. NIH, NHLBI. August 2007. NIH publication no. 08-4051.

10. Categories of Evidence Used to Support NAEPP Recommendations

11. Stepwise Approach for Managing Asthma in Children 0-4 Years of Age Intermittent Asthma Persistent Asthma: Daily Medication Consult with asthma specialist if step 3 care or higher is required.Consider consultation at step 2. Step 6 Preferred: High-dose ICS + either LABA or Montelukast Oral systemic corticosteroids Step up if needed (first, check adherence, inhaler technique and environmental control) Step down if possible (and asthma is well controlled at least 3 months) Step 5 Preferred: High-dose ICS + either LABA or Montelukast Step 4 Preferred: Medium-dose ICS + either LABA or Montelukast Step 3 Preferred: Medium-dose ICS Step 2 Preferred: Low-dose ICS Alternative: Cromolyn or Montelukast Step 1 Preferred: SABA PRN Assess control Patient Education and Environmental Control at Each Step • Quick-Relief Medication for All Patients • SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms. • With viral respiratory infection: SABA q 4-6 hours up to 24 hours (longer with physician consult). Consider short course of systemic oral corticosteroids if exacerbation is severe or patient has history of previous severe exacerbations. • Caution: Frequent use of SABA may indicate the need to step up treatment. See text for recommendations on initiating daily long-term-control therapy. Key: ICS, inhaled corticosteroid; LABA, inhaled long-acting beta2-agonist; SABA, inhaled short-acting beta2-agonist Guidelines for the Diagnosis and Management of Asthma (EPR-3) 2007. NIH, NHLBI. August 2007. NIH publication no. 08-4051.

12. Evidence Supporting ICS Use in Children Aged 0 to 4 Years

13. Stepwise Approach for Managing Asthma in Children 5-11 Years of Age Intermittent Asthma Persistent Asthma: Daily Medication Consult with asthma specialist if step 4 care or higher is required.Consider consultation at step 3. Step up if needed (first, check adherence, inhaler technique, environmental control and comorbid conditions) Step down if possible (and asthma is well controlled at least 3 months) Step 6 Preferred:High-dose ICS + LABA + oral corticosteroid Alternative:High-dose ICS + either LTRA or Theophylline + oral systemic corticosteroid Step 5 Preferred:High-dose ICS + LABA Alternative:High-dose ICS + either LTRA or Theophylline Step 4 Preferred: Medium-dose ICS + LABA Alternative:Medium-dose ICS + either LTRA or Theophylline Step 3 Preferred: Low-dose ICS + either LABA, LTRA, or Theophylline OR Medium-dose ICS Step 2 Preferred: Low-dose ICS Alternative:Cromolyn, LTRANedocromil, or Theophylline Step 1 Preferred: SABA PRN Assess control Each step: Patient education, environmental control, and management of comorbidities. Steps 2-4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma. • Quick-Relief Medication for All Patients • SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at 20-minute intervals as needed. Short course of oral systemic corticosteroids may be needed. • Caution: Increasing use of SABA or use >2 days a week for symptom relief (not prevention of EIB) generally indicates inadequate control and the need to step up treatment. Key: ICS, inhaled corticosteroid; LABA, inhaled long-acting beta2-agonist; SABA, inhaled short-acting beta2-agonist Guidelines for the Diagnosis and Management of Asthma (EPR-3) 2007. NIH, NHLBI. August 2007. NIH publication no. 08-4051.

14. Evidence Supporting ICS Use in Children Aged 5 to 11 Years

15. CAMP: Trial Design 0 Experimental Design • Albuterol as needed for symptoms of asthma • Oral prednisone for exacerbations of asthma • Beclomethasone if asthma control was inadequate 1041 mild-to-moderate asthmatic children (5-12 y) 311 312 210 208 Budesonide Nedocromil sodium Matching placebo Matching placebo 200 µg BID 8 mg BID Childhood Asthma Management Research Group. N Engl J Med. 2000;343:1054-1063.

16. Asthma Control in CAMP 0 Continuous daily treatment with inhaled budesonide leads to better control of asthma than symptomatic treatment • 43% lower rate of hospitalizations (P=0.04) • 45% lower urgent care visits (P<0.001) • 43% lower rate and use of prednisone (P<0.001) • Lower airway responsiveness to methacholine • Greater reduction in the need for albuterol for symptoms (P<0.001) • More episode-free days (P=0.01) Childhood Asthma Management Research Group. N Engl J Med. 2000;343:1054-1063.

17. P<0.001 30 P=0.02 Budesonide Nedocromil Placebo 25 22 20 16 P=0.04 No./100 person-years 15 12 10 4.3 4.4 5 2.5 0 Urgent care visits Hospitalizations CAMP: Reduction in Urgent Care Visits and Hospitalizations 0 Greater Reductions in the Need for Emergency Care Childhood Asthma Management Research Group. N Engl J Med. 2000;343:1054-1063.

18. Budesonide Nedocromil Placebo P<0.001 P=0.01 122 125 102 100 70 75 No./100 person-years 50 25 0 Prednisone courses CAMP: Reduction in Prednisone Courses 0 Fewer Courses of Oral Prednisone With Budesonide Childhood Asthma Management Research Group. N Engl J Med. 2000;343:1054-1063.

19. CAMP – Safety Data • Mean increase in height was1.1 cm less in Budesonide group vs. placebo group • No differences in bone density, bone age, projected final height, and Tanner stage between Budesonide and placebo • No posterior subcapsular cataracts • Greater improvement in Children’s Depression Inventory (less depression) in Budesonide vs. placebo group! Childhood Asthma Management Research Group. N Engl J Med. 2000;343:1054-1063.

20. Steroid Response Rate BatesCA, et al. J Allergy Clin Immunol 2003;111:256-62.

21. Viral Infections and Asthma • Rhinovirus accounts for 30-50% of all acute respiratory infections and children are infected several times a year • Viral infection is detected in 85% of reported episodes of a decrease in PEF, upper respiratory symptoms, cough, and wheezing • Atopic asthmatics response to rhinovirus infection is defective ( suboptimal TH1 response ) Johnston SL, et al. BMJ 1995;310:1225-1229. Papadopoulos NG, et al. Thorax 2002;57:328-332.

22. PC20 Restoration with URI • The duration of increased AHR in children after a single cold was 5-11 weeks • An increased rate of symptomatic cold and asthma episodes in atopic children was associated with prolongation of AHR • After multiple colds, AHR remained elevated more than 6 months in some cases Xepapadaki et al. J Allergy Clin Immunol. 2005;116:299-304.

23. PC20 Restoration with URI Xepapadaki et al. J Allergy Clin Immunol 2005;116:299-304.

24. Episodic use of Inhaled Steroid or Leukotriene Receptor Antagonist in Pre-School Children • Methods • Randomized DBPC 12-month trial • 238 children aged 12-69 months with moderate-to-severe intermittent wheezing • Received 7 days of budesonide (1 mg BID), montelukast (4 mg qhs), or placebo in addition to Albuterol with respiratory tract infection (RTI) Bacharier LB, et al. J Allergy Clin Immunol 2008;122:1127-35.

25. Episodic use of Inhaled Steroid or Leukotriene Receptor Antagonist in Pre-School Children • Primary outcome measure • Proportion of episode-free days (EFD) • Results • 3 treatment groups did not differ in proportions of EFDs • 3 groups did not differ in oral corticosteroid use, health care use, quality of life, or linear growth • Modest reductions in symptom severity with RTIs in Budesonide and Montelukast treated groups Bacharier LB, et al. J Allergy Clin Immunol 2008;122:1127-35.

26. Episodic use of Inhaled Steroid or Leukotriene Receptor Antagonist in Pre-School Children Bacharier LB, et al. J Allergy Clin Immunol 2008;122:1127-35.

27. Episodic use of Inhaled Steroid or Leukotriene Receptor Antagonist in Pre-School Children Bacharier LB, et al. J Allergy Clin Immunol 2008;122:1127-35.

28. Episodic use of Inhaled Steroid or Leukotriene Receptor Antagonist in Pre-School Children Bacharier LB, et al. J Allergy Clin Immunol 2008;122:1127-35.

29. Allergy and Asthma • Patients with allergic rhinitis are 3x more likely to develop asthma • 80-90% of patients with asthma have allergy • Allergens are potential triggers for asthma • Presence of allergy is single greatest risk factor for not outgrowing asthma

30. Indirect Exposure to Cat in School Almquist et al. Am J Respir Crit Care Med 2001;163:694-698.

31. RHINITIS Moderate ± conjunctivitis Severe ± conjunctivitis Mild Allergen avoidance when possible Pharmacotherapy Consider immunotherapy ASTHMA Moderate persistent Severe persistent Mild persistent Intermittent Pharmacotherapy Consider immunotherapy When to Consider Immunotherapy

32. Immunotherapy in Asthma • Treats both upper and lower airways simultaneously • long-term immunomodulatory effects (Durham) • May prevent new sensitivities (Des-Roches) • Risk of anaphylaxis, time commitment

33. Allergen Immunotherapy in Asthma • Meta-analysis of 75 randomized controlled trials of allergen-specific immunotherapy (SIT) in asthma involving more than 3,500 patients • decreased symptoms scores • decreased medication requirements • improved allergen and non-specific bronchial hyperresponsivelness Abramson MJ, et al. The Cochrane Library,2003;issue 4.

34. Immunotherapy ( IT ) in Allergic Rhinitis - Effects on Bronchial Hyperresponsiveness • 50% of patients on IT had negative methacholine challenges • 9% of control patients developed asthma vs. 0% in IT group Grembiale RD, et al. Am J Respir Crit Care Med 2000;162:2048-52.

35. Methods ( PAT Study ) • 208 children aged 6-14 years from 6 European pediatric clinics • Clinical history of rhinoconjunctivitis symptoms caused by allergy to birch and/or grass pollen • Positive prick test and conjunctival provocation test results Moller C,et al. J Allergy Clin Immunol 2002;109:251-6.

36. Preventative Asthma Treatment (PAT) Study Moller C,et al. J Allergy Clin Immunol 2002;109:251-6.

37. Vocal Cord Dysfunction • Definition: paradoxical adduction of the vocal cords during inspiration +/- expiration • Etiology: unknown but potential triggers include rhinitis ( post-nasal drip ), GERD, exercise, stress, exposure to strong odors • Oftentimes co-exists with asthma • Female preponderance

38. Vocal Cord Dysfunction – Clinical Cues • Lack of response to asthma medications • Sudden onset and resolution of symptoms • Lack of nocturnal symptoms

39. Vocal Cord Dysfunction • Spirometry • Abnormal inspiratory loop • Normal expiratory loop • Rhinolaryngoscopy demonstrating frequent adduction or “posterior chink” of vocal cords is gold standard

40. Vocal Cord Dysfunction Wood RP, Milgrom H. JACI 1996;98:481-5.

41. Conclusions • NHLBI asthma guidelines stress need to evaluate rate/severity of exacerbations as indicators of severity of disease and control • Inhaled corticosteroids are safe and effective first line therapy • Potential role of allergy in persistent disease should be evaluated