Asthma For a better control

1. Asthma For a better control Dr Hatem Al Mubarak, MD, FRCPC, FACCP Pulmonary Specialist Al Jazira and Central Hospital Abu Dhabi, UAE

2. Asthma for a better control • Definition • Epidemiology of asthma • Pathophysiology and asthma evolution • Diagnosis of asthma • Asthma classification • Treatment of asthma • Clinical Scenarios and discussion

3. Definition A chronic inflammatory disorder of the airways in which many cells play a role that causes recurrent episodes of wheezing, breathlessness, chest tightness and cough ic but variable airflow limitation that is at least partly reversible either spontaneously or with treatment. The inflammation also causes. These symptoms associates with widespread and associated increase in airway responsiveness to variety of stimuli.

4. Venn diagram of obstructive lung disease Chronic Bronchitis Emphysema Airflow limitation Asthma

5. Epidemiology and Risk Factors • For all age group : incidence 2.65-4/1000 per year. • Children : 4.3-18/1000 per year • Adult : 2.1/1000 per year • Mortality (1985-1987) between 1.3-9.3 /100,000 of total population • Danish follow-up study showed cigarette smoking, age, presence of blood eosinophilia, impairment of lung function and degree of reversibility contribute to asthma mortality

6. Age and Sex Distribution of Asthma 16 14 12 10 8 6 4 2 0 Individuals per 1000 0 10 20 30 40 50 60 70 80 Female Male

7. Prevalence of self-reported asthma, children aged 13-14 years 12 months prevalence of self-reported asthma with a written questionnaire, for children aged 13-14 years . International Study of Asthma and Allergies in Childhood (ISAAC) including 463,801 children in 56 countries

8. Asthma Evolution Hypothesis Genetic Predis- position + Airway Inflammation Hyper- responsiveness Sensitisation + Asthma Environmental Factors Maternal Smoking Indoor/outdoor Allergens Environmental Factors Smoking, cold air Indoor/outdoor Allergens, viral infection

9. Asthma Evolution Hypothesis Genetic Predis- position Asthma

10. The Genetic of Asthma • 20-25% Increase in prevalence of asthma among first degree relative of asthmatics compare to general population (4%) • Monozygotic twins (50%) dizygotic twins (33%) • Doesn’t follow any medelian pattern • Genetic researches provided evidence of several atopic phenotypes (eosinophil count, skin testing, atopic cytokines)

11. Asthma Evolution Hypothesis Genetic Predis- position + Asthma Environmental Factors Maternal Smoking Indoor/outdoor Allergens

12. Risk factors for development of asthma

13. Atopy • Atopy is characterized by • Elevated IgE level • Detection of IgE against common allergens • Positive skin test against common allergen • Asthmatic are more atopic than non-asthmatic • Increase airway hyperresponsiveness is associated with increase in atopy

14. Atopy in asthma • House dust mite is the most common allergens • Increases in prevalence of asthma in New Guinea when adult exposed to house dust mite. • Association between the level of house dust mite in the bed room of babies during the first year of life and asthma in at 8 years of age. • Cats more than any other animals is a risk for asthma • Children expose to furry cat are at twice the risk for developing asthma • Other allergens including grass, tree pollen, and cockroaches

15. Asthma risk factors • Exercise: occur because of water loss from the airway wall • Occupation: e.g.; wood dust, formaldehyde, latex, animal allergens • Drugs: NSAID, possible biphosphonate, ß-blocker • Premenstrual asthma : associated with late luteal phase

16. Smoking and asthma risk • Passive smoking • It the second major risk after atopy • Parental ,especially maternal, smoking is associated with increase risk of asthma in children • Smoking >10cig/day increase asthma by 2.5 times at 12 years of age • Increase four-fold of the level of IgE from cord blood of newborn of mothers who smoke (even in absence of atopy)

17. Asthma Evolution Hypothesis Genetic Predis- position + Sensitisation Asthma Environmental Factors Maternal Smoking Indoor/outdoor Allergens

18. Th1 and Th2 Balance Bacterial Infection TB, Measles, HepA Rural Environment Widespread use of antibiotics Western lifestyle Diet Sensitisation to allergens Parasitic infection Th1 Th0 Th2 Allergic disease Protective immunity

19. Asthma Evolution Hypothesis Genetic Predis- position + Airway Inflammation Sensitisation Asthma Environmental Factors Maternal Smoking Indoor/outdoor Allergens

20. Mast cell Smooth Muscle PGD2, LTC4/D4 Histamine, Tryptase Eosinophils Cytokines Mast cell Acute Asthma B-cell Chronic Asthma APS TH2

21. Asthma Evolution Hypothesis Genetic Predis- position + Airway Inflammation Hyper- responsiveness Sensitisation + Asthma Environmental Factors Maternal Smoking Indoor/outdoor Allergens Environmental Factors Smoking, cold air Indoor/outdoor Allergens, viral infection

22. Diagnosis of Asthma

23. Case 1 • 22 years old lady came to your office with cough for several weeks with no associated sputum. She deny any other symptoms but remember she use to have similar symptoms when she was young. She also noticed that she get tired slighter sooner that her class mate in sports event. • Examination was normal and her PEF was normal • Does this patient have asthma?

24. Diagnosis of asthma Wheeze Chest tightness Asthma Cough Nocturnal symptoms Difficulty In breathing

25. Canadian Asthma ConsensusDiagnosis and Evaluation of Asthma in Adult • Spirometry: improvement of FEV1 by • 12% and 200ml from the base line after inhalation of short acting ß2 agonist • 20% and 250ml after 10-14 days on inhaled or systemic glucocorticosteroid • 20% and 250 ml with spontaneous variability • Peak Expiratory Flow • 20% or more variability between highest and lowest values ( morning and afternoon, before and after bronchodilator)

28. Spirometry in asthma Normal FVC Normal FEV1 Normal Ratio Normal or mild low FVC low FEV1 low Ratio Normal Asthma

29. Canadian Asthma ConsensusDiagnosis and Evaluation of Asthma in Adult • Airway Hyperresponsiveness • Methacholine neubelizer provocation test to evaluate the airway response • Positive test is there is a drop of more than 20% of FEV1 in a methacholine concentration of less than 8mg/ml • Negative methacholine can exclude asthma

30. Methacholine Provocation Test FEV1 Base line PC20 20% Drop FEV1 Normal Saline 0.25mg/ml 0.5 mg/ml 1mg/ml 2mg/ml 4mg/ml 8mg/ml Methacholine Concentration

31. Asthma Evolution Primary Prevention Secondary Prevention Secondary Prevention Secondary Prevention Genetic Predis- position Regular Anti-inflammatory treatment Avoidance Treatment of exacerbation + Airway Inflammation Hyper- responsiveness Sensitisation + Asthma Environmental Factors Maternal Smoking Indoor/outdoor Allergens Environmental Factors Smoking, cold air Indoor/outdoor Allergens, viral infection

32. Current therapy for asthma

33. ß2 agonist • ß2 receptors are present in all smooth muscles of the airways • Direct effect causing • Smooth muscle relaxation • Reduction in neurotransmitter • Increase ciliary clearance • Decrease the microvascular leakdecrease edema • Salbutamol, terbutaline,fenoterole, metaprotanole • Does not have anti inflammatory effect • Drug of choice in both children and adult for the relief of acute asthma symptoms

34. ß2 agonist • Side effects • Mild tremor (affect on skeletal muscle receptors) • Tachycardia( affect on cardiovascular) • Hypokalemia ( increase K+ entry to skeletal muscle) • No evidence that it increase or induce serious arrhythmias or other cardiac abnormalities

35. ß2 agonist • No evidence that regular four times a day with SAß2 is better than as needed approach in any degree of asthma severity • Regular SAß2 is associated with masking underlying inflammation  increase hyperresponsiveness worsening severity

36. Long acting ß2 • It have more sustained action • It enhance the effect of inhaled steroids • Salmeterol and formoterol • Not recommended for relief of acute symptoms and exacerbation • Does not increase airway hyperresponsiveness and it have some anti-inflammatory effect

37. Theophylline • Phosphodiestterase inhibitors increase in cAMP bronchodilators • Adenosine receptors antagonist CNS stimulation, cardiac arrhythmias,diuresis • Stimulation of adrenaline release • Less effective than ß2 agonist in acute exacerbation and it is more recommended in chronic asthma (especially if nocturnal symptoms present)

38. Anticholiergics • Muscarinic receptors antagonist and inhibit cholinergic receptors that cause bronchoconstrection • Less effective than ß2 but it has additative effect • Are more effective in acute than chronic asthma • More effective in asthmatic who have element of fixed airway • Ipratropium, oxitropium and tiotropium bromide

39. Affect of anticholinergic on smooth muscle Vagus Nerve Anticholinergic Acetylcholine

40. Cromones • It may affect chloride channels that expressed in mast, nerve and some inflammatory cells • Inhibit mediators release from mast cells by membrane stabilization • Effect on sensory nerve ending in the airways • Prophylactic treatment and should be given regularly • Preferred agent in children

41. Antileukotrienes • LTC4,LTE4 and LTD4 are products of inflammatory cells that cause bronchoconstrition • 40 times more potent that histamine or methacholine to cause bronchoconstriction • Blocking leukotriens receptors cause bronchodilatation and decrease eosinophils • Zafirlukast, pranlukast and montelukast • Reduce allergen-exercise-cold induced asthma by 50-70% • Complete response in aspirin-induced asthma

42. Corticosteroids • Action occur through activation of glucocoticosteroid receptors (GCSr) which found in all body cells • When bound to receptors it decreases gene production for many pro and inflammatory cytokines • Systemic (parental/oral) or inhaled are the two major form

43. Systemic corticosteroids • Reserved for moderate to sever cases • Oral bio availability is very high with complete GI absorption. • Parental route reserved if oral rout can’t be tolerated

44. Inhaled corticosteroid • They are as effective as low to moderate dose of systemic steroids with much lesser side effects • Lipophilic: very high binding affinity and fast first pass liver metabolism • five inhaled corticosteroids (ICS) currently available • Fluticasone propionate (Flexotide, Flovent) • Beclomethasone 17,21-dipropionate ( Beclovent, QVAR) • Triamcinolone (Azmacort) • Flunisolide (AeroBid) • Budesonide (Pulmicort)

45. Corticosteroids side effects • Local side effect: • oral candidiasis occur in 10% • Increase risk with poor technique,concomitant use of antibiotics and reduce by use of spacer and rinsing mouth. • Dysphonia (30%) in people who use their voice a lot • Doesn't have any effect on airway mucosa

46. ICS side effects • Hypothalamic-pituitary-adrenal axis • No effect was seen with doses of BDP<1500g/day or budesonide <1600 g/day • Only 2 cases reported with adrenal insufficiency ( very high dose of budesonide of 6400 g/day)

47. ICS side effects • Osteoporosis • ICS shown to have some effect on osteocalcin (bone formation) and hydroxyproline (bone resorption) in doses of budesonide>2000 g/day • Bone densitometry carried out in adult asthmatic on various doses of ICS and it showed no increase bone loss • Does not cause growth retardation in children • Children on ICS were shorter on average than children not on ICS at 2 years of age, but all of them had the same height at 6 years of age

48. ICS side effects • Posterior subcapsular cataract • Usually there is no risk • Risk slightly increase with high doses of ICS and use of MDI • Risk of lung infection • Risk of lung infection is not increased • Does not increase the risk of TB re-activation • Risk of skin bruising increase with height doses of ICS ( from 22% to 47%) in older population

49. Delivery of medication

50. Case 2 • 64 years old gentleman who was known to have asthma for several years on inhaled corticosteroids ( MDI) . • You are seeing him for the first time, his history and exam revealed moderate persistent asthma not will controlled because he claim he can’t use the apparatus. Throat exam showed oral condidiasis and chest exam .