1. Asthma Kim Otsuka, MD Pediatric Pulmonary Fellow September 21, 2004 UoA PPC 2004 Workshop Lectures

2. Objectives  Overview of asthma  Review NHLBI guidelines for asthma treatment  Review other management strategies for asthma

3. What is Asthma  Disease of chronic airway inflammation  Characterized by –Airway inflammation –Airflow obstruction –Airway hyperresponsiveness http://health.allrefer.com/health/asthma- normal-versus-asthmatic-bronchiole.html Cookson W. Nature 1999; 402S: B5-11

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. Allergic Diseases and Autoimmune Diseases are Rising Bach JF, N Engl J Med 2002; 347: 911-920

11. Hygiene Hypothesis  Environmental impact on asthma –Farm exposure –Day care/siblings –Pets –Early infections

12. Hygiene Hypothesis Yazdanbakhsh M, et al. Science 2002; 296: 490-494

13. Etiological Factors – Gene and Environment Wills-Karp M, et al. Nature Reviews Immunology; 2001; 1: 69-75

14. 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

15. 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

16. Natural History of Asthma Martinez, FD. J Allergy Clin Immunol 1999; 104: S169-74.

17. 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

18. Outcome of Childhood Asthma Phelan PD, et al. J Allergy Clin Immnol 2002; 109: 189-94.

19. 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- 60- <80%>30% Severe Persistent ContinuousFrequent <60% >30% Adapted from Guidelines for the Diagnosis and Management of Asthma-Update on Selected Topics 2002. NIH Publication No. 02-5075.

20. Patient Deaths (%) Asthma Mortality: Mild Patients Are Also at Risk Robertson et al. Pediatr Pulmonol. 1992;13:95-100. Patient Assessment 0 10 20 30 SevereModerateMild40

21. "Rules of Two" is a trademark of the Baylor Health Care System Rules of Two TM  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

22. Relative Risk of Hospitalization 876543210 Prescriptions per Person-Year None1-22-33-55-88+0-1 ß 2 -agonists Total Age 0-17 Total Inhaled Steroids Breaking the “Rules of Two TM ” Results in Asthma Morbidity Adapted from Donahue et al. JAMA. 1997;277:887-891.

23. Goals of Treatment  SLEEP  LEARN  PLAY

24. 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.

25. Pharmacologic Treatment “Controller” Long-term Control “Rescue”Short-acting Mild Intermittent None Β 2 -agonist Mild Persistent Preferred: low dose inhaled corticosteroid (ICS) Β 2 -agonist Moderate Persistent Preferred: low-medium dose ICS and long-acting Β 2 -agonist Β 2 -agonist Severe Persistent Preferred: low-medium dose ICS and long-acting Β 2 -agonist and oral corticosteroids if needed Β 2 -agonist Adapted from Guidelines for the Diagnosis and Management of Asthma- Update on Selected Topics 2002. NIH Publication No. 02-5075.

26. 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

27. ICS Use Lowers Risk of Death from Asthma Suissa S et al. N Engl J Med 2000; 343: 332-336

28. ICS Are More Effective at Decreasing Asthma Exacerbations Than Anti-leukotriene Agents Results not affected by type of medication, methods, analysis, publication status or funding source. Insufficient evidence in children. * No exacerbations reported Maspero Baumgartner Busse Hughes (BUD)* Hughes (FP) Laviolette* Skalky Williams Bleecker Busse Fixed Effects Pooled Relative Risk 0.1 -15-10-50+5+10+15+10 Relative Risk (95% CI) Ducharme FM, BMJ 2003; 326: 621 Favors anti-leukotrienesFavors inhaled glucocorticoids 1 Kim 1.6

29. Dose ICS – Finding the Right Balance 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. Response Favorable Benefit:Risk Ratio Wanted Effects Unwanted Effects

30. Long Term Effects of Budesonide or Nedocromil On Growth Childhood Asthma Management Program Research Group N Engl J Med 2000; 343: 1054-63.

31. Adult Height is not Affected by ICS Use Agertoft L, Pedersen S. N Engl J Med 2000; 343: 1064-69.

32. Not All ICS are the Same  Potency  Systemic absorption  Dosing

33. 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.

34. Leukotriene Receptor Antagonists  Alternative therapy for mild- persistent asthma as well as alternative combination therapy with ICS for moderate persistent asthma  Safe  Easy to administer  Improves asthma symptom free- days, but less than ICS

35. ICS vs. Montelukast Busse W, et al. J Allergy Clin Immunol 2001; 107: 461-468.

36. Combination Therapies  Combination therapies work better than increasing the dose of ICS Condemi JJ, et al. Ann Allergy Asthma Immunol 1999;82:383–389.

37. Combination Therapy of ICS and Salmeterol is Better Than Increasing the ICS dose Studies not individually powered to examine exacerbation rates. Ind Greening Woolcock Kelsen Murray Kalberg Condemi Van Noord (LD) Van Noord (HD) Vermetten Fixed Effects Random Effects -20-15-10-50+5+10+15+20 Treatment Difference (%) Shrewsbury et al. Br Med J. 2000;320:1368-1373. Favors increasing ICS Favors adding salmeterol

38. Montelukast and ICS Laviolette M, et al. Am J Respir Crit Care Med 1999; 160: 1862-1868

39. Salmeterol and ICS vs. Montelukast and ICS Nelson HS, et al. J Allergy Clin Immunol, 2000; 106: 1088-1095

40. Pharmacogenetics  Study of the role of genetic determinants in the variable response to therapy  The future of asthma treatment

41. Other Management Issues  Environmental control –“Safe” room  Diet –Infant feeding –Sodium –Fatty acids –Antioxidants

42. 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

43. 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

44. Tailored Environmental Control Reduces Asthma Symptoms Morgan WJ, et al. N Engl J Med 2004; 351: 1068-80.

45. Air Filters and Asthma McDonald E, et al. Chest 2002; 1535-42.

46. 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

47. 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

48. 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

49. 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

50. 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

51. 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