2. Childhood Asthma 上海交通大学医学院附属新华医院 鲍一笑

3. 1953-1995 （ 42 岁） Died in Thailand due to acute asthma exacerbation 邓丽君

4. Died in Vienna because there is no effective treatment for asthma 1770-1827 （ 57 岁） 贝多芬

5. Introduction

6. Definition Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements plays a role. The chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment.

7. Asthma is an inflammation indduced by allergy Allergy Eosinophils cell infiltrate Corticosteroids as anti-inflammatory therapy Infection Neutrophils cell infiltrate Red swelling, hot and pain Antibiotics therapy

8. The Role of Th2 Cytokines in Allergic Cascade

9. The balance of Th1 and Th2

10. Epidemiology Prevalence↑ Death rates↑ (per 10,0000 population) China 0.5-3.3% 36.7 worldwide 0.1-32% 1.3 Shanghai 90 ： 1.79% 00 ： 4.52% The prevalence of asthma has been increasing since the early 1980s for all age, sex, and racial groups. Europe and north America10% Asia 5%

11. The death rate1979-2000

12. The current asthma prevalence 2003 in USA

13. Etiology

14. Genetic Factor Epidemiology Atopy is the strongest identifiable predisposing factor. An elevated IgE level is often found in the serum of allergic patients, because IgE is the primary antibody associated with allergic reactions. In asthma children, 30-40% have a family history of asthma, 50-60% have a family history of allergic disease.

15. Related gene of Asthma More than 22 loci on 15 autosomal chromosomes have been linked to asthma. Gene associated with IgE Genetic variation in receptors for different asthma medications (polymorphisms in the β2-adrenergic receptor).

16. Environmental Factor Respiratory Tract Infections （ viral, bacterial, mycoplasma ） Inhalant Allergen Others About 40% of infants and young children who have wheezing with viral infections in the first few years of life will have continuing asthma through childhood.

17. Inhalant Allergens Sensitization to inhalant allergens increases over time and is found in the majority of children with asthma. Animal danderEnvironmental tobacco smoke Indoor allergensAir pollutants Dust mitesCold air, dry air CockroachesExercise MoldsStrong or noxious odors or fumes Pollens (trees, grasses, weeds)Crying, laughter, hyperventilation

18. Pollen

19. Mite

20. House Pet

21. Smoke Exposure to tobacco smoke, especially from the mother, is also a risk factor for asthma.

22. Food Allergen Animal Protein Fishery,product,milk,meat,egg Oil Crop and Nuts Peanuts Fruit and Greengrocery Grain Food additive

23. Drug Allergen Benzylpenicillin Sulfonamides Antipyretic analgesic Anesthetic agent Biological products Aspirin sensitivity is uncommon in children.

24. Contactant allergen Para-phenylenediamine Nickel sulphate Mercurial Plastics products Rubber goods Essence

25. Pathogenesis Genetic factors Immunity factors Psychological factors Endocrine factors

26. allergen DC 、 MC 、 B cell Th 2 Eos IgE B cell Airwayinflammation,Hyperresponsiveness,Airway contraction, bronchoconstriction, airway wall edema, mucus plug formation Wheezing, Cough, Dyspnea, IL-4 LAR Mast cell Excise 、 Wether Harmful gas ECF histamine,LT,PG,PAF PAF,LT,MBP,ECP IL-5 EAR Airway remodeling Allergic inflammation

28. Pathologic features Shedding of airway epithelium Edema Mucus plug formation Mast cell activation Collagen deposition beneath the basement membrane

29. Bronchospasmmucosal edema mucus plug formation Pathologic features

30. Asthma Normal Changes of Airway Epithelium shedding of airway epithelium

31. Specimen of Bronchial Mucosa In the subject without asthma, the epithelium is intact; there is no thickening of the sub- basement membrane, and there is no cellular infiltrate. BA In the patient with mild asthma, there is evidence of goblet-cell hyperplasia in the epithelial-cell lining. The sub-basement membrane is thickened, with collagen deposition in the submucosal area, and there is a cellular infiltrate.

32. Clinical Manifestation

33. Symptoms Precursory symptoms:  Rhinocnesmus  Sneezing  Nasal obstruction  Nasal discharge  Itching of eye  Dry cough

34. Wheezing is the most characteristic sign of asthma. Patients may also have cough and shortness of breath. Symptoms

35. Physical signs General signs: Cyanosis, Agitation and lethargy Chest auscultation: Prolongation of the expiratory phase and wheezing. As the obstruction becomes more severe, wheezes become more high pitched and breath sounds diminished. Chest Radiograph: Bilateral hyperinflation Others: Tachycardia and pulsus paradoxus severe obstruction: Flaring of nostrils, intercostal and suprasternal retractions, and use of accessory muscles of respiration

36. Laboratory Examination Clumps of eosinophils on sputum smear and blood Chest radiograph: Bilateral hyperinflation Immunologic test (1) Allergen skin testing (2) Elevated total serum IgE levels (3) Abnormality of cytokines （ IL-3 、 IL-4 、 IL-5 ）

37. Pulmonary Function Test Spirometry (in clinic) Airflow limitation Low FEV1 (relative to percentage of predicted norms) FEV1/FVC ratio <0.80 Bronchodilator response (to inhaled β-agonist) Improvement in FEV1 ≥12% or ≥200 mL Exercise challenge Worsening in FEV1 ≥15% Daily peak flow or FEV 1 monitoring: Day to day and/or AM-to-PM variation ≥20% Lung Function Abnormalities in Asthma FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity.

38. Diagnosis

39. Diagnostic Criteria of Childhood Asthma Children older than 3 years, reccurent wheezing Prolongation of the expiratory phase and expiratory wheezing Improved after the use of inhaled bronchodilators Exclusion of other diseases which can also cause wheezing, dyspnea, and cough

40. Diagnostic Criteria of Infant’s Asthma 1. Children younger than 3 years, more than three episodes of wheezing （ 2 score ） 2. Acute asthma exacerbation （ 1 score ） 3. Prolongation of the expiratory phase and wheezing can be heard on chest auscultation. （ 2 score ） 4. Allergic disease, such as allergic rhinitis and atopic dermatitis. （ 1 score ） 5. A family history of allergic disease （ 1 score ） ≥5 score to diagnose asthma 。 ≤4 score or just two episodes of wheezing, to diagnose suspicious asthma or asthmatic bronchitis Wheezing decrease or disappear after use bronchodilators 2 score

41. Classification of Asthma Severity The presence of one of the features of severity is sufficient to place a patient in the category. An individual should be assigned to the most severe grade in which any features occurs. symptomsNighttime symptoms Lung function FEV1/PEF % predicted PEF variability Step1 Mild intermittent ≤2 times a week≤2 times a month ≥80%<20% Step2 Mild persistent >2 times a week>2 times a month ≥80%20%-30% Step3 Moderate persistent Daily symptoms>1 times a week60%-80%>30% Step4 Severe persistent Continual symptoms Limited physical activity Frequent≤60%>30%

42. Differential diagnosis Viral bronchiolitis Foreign body Congenital laryngeal stridor Tuberculosis of trachebronchial lymph nodes Vascular malformation Gastroesophageal Reflux

43. Treatment To control airway inflammation. To prevent asthmatic attack.

44. General Measures Avoid exposure to sensitive allergens Give inactivated influenza vaccine Cure respiratory tract infections Avoid trigger factors Self-management education Regular follow-up PEFR monitoring physical exercise

45. Glucocorticosteroid ICS therapy is recommended daily as the treatment of choice for all patients with persistent asthma. ICS therapy has been shown to reduce asthma symptoms, improve lung function, reduce AHR, reduce “rescue” medication use and, most important, reduce urgent care visits, hospitalizations. ICS therapy may lower the risk of death due to asthma.

46. The role of Glucocorticosteroid

47. Inhaled corticosteroids versus systemic corticosteroids :  The drug nonstop to bellows  Low doses  Rapid onset of action  High security  Effectiveness Inhalation therapy

48. Distribution of inhalation in lungs

49. Metabolic pathway of Inhaled corticosteroids circulation adverse effect biological activity 80 - 90% swallow 10 - 20 % To both lungs Intestinal Absorption Inactivation due to first pass effect

50. Inhaler

51. Nebulizing therapy an infants

52. 180 170 160 150 140 130 120 110 Adult height (cm) patients use inhaled corticosteroids unimpaired child 6岁6岁 8岁8岁 10 岁 12 岁 14 岁 16 岁 Pedersen,1999 Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. Children with asthma who have received long-term treatment with budesonide attain normal adult height.

53. Bronchodilators Short-acting inhaledβ-agonist (SABA) Give their rapid onset of action, effectiveness, and 4–6 hr duration of action. (albuterol, levalbuterol, terbutaline, pirbuterol) Long-acting inhaledβ-agonist (LABA) have a prolonged duration of effect of at least 12 hr. (salmeterol, formoterol)

54. Adverse effect of long-term use of β-agonists Induce down regulation of the β2-receptor function. Aggravate airway inflammation and airway hyperreactivity. Overuse of β-agonists is associated with an increased risk of death or near-death episodes from asthma.

55. β2-receptor Corticosteroids may enhance Expression of β2-receptor Hormone receptor Glucocorticoids Anti-inflammatory effect of β2-agonists may enhance Anti-inflammatory effect of Corticosteroids β2-agonists Bronchiectasis effect ++ ++ Interaction between corticosteroids and β2-agonists The addition of LABA to ICS to is superior to doubling the dose of ICS

56. Other drugs Leukotriene receptor antagonists (LTRA). Aminophylline Sodium Cromoglicate

57. Specific immunotherapy —— hyposensitization therapy Nonspecific immunotherapy —— immunoloregulation therapy Immunotherapy

58. WHO issued Global initiative for asthma (GINA) in 1994. The aims were to set up standardization of asthmatic treatment. It works with health care professionals and public health officials around the world to reduce asthma prevalence, morbidity, and mortality. GINA

59. Stepwise Approach

60. Summary Asthma is a chronic inflammatory condition of the lung airways resulting in episodic airflow obstruction. The inflammatory cell infiltrate is the main pathologic features includes eosinophils, lymphocytes, and neutrophils. Airway hyperresponsiveness to nonspecific stimuli is a hallmark of asthma. Wheezing, dry cough, and shortness of breath is the characteristic sign of asthma.

61. Asthma medications include long-term control medications combined with quick-relief medications. Anti- inflammatory therapy is the core of modern treatment of asthma. Corticosteroids is the most effective anti- inflammatory agent. Inhalation therapy is the main medication for asthma. Up to now, there is no radical treatment Summary

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64. Thanks ！