1. Asthma Management What is New? Prof: Samiha Ashmawi Professor of Chest Diseases Ain Shams University

2. Agenda: Asthma Definition. Asthma Prevalence. Asthma Risk Factors. Asthma Pathophysiology. Guidelines. Management.

3. Asthma Definition

4. Asthma Definition: chronic inflammatory disorderAsthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. airway hyperresponsivenessThe chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. Particulary at night or in the early morning. Global Strategy For Asthma Management And Prevention 2011.

5. Asthma Definition: airflow obstruction reversibleThese episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment. Global Strategy For Asthma Management And Prevention 2011.

6. Asthma Definition: Asthma is a disorder defined by its clinical, physiological, and pathological characteristics. The predominant feature of the clinical history is episodic shortness of breath, particularly at night, often accompanied by cough. Wheezing appreciated on auscultation of the chest is the most common physical finding. Global Strategy For Asthma Management And Prevention 2011.

7. Asthma Definition: The main physiological feature of asthma is episodic airway obstruction characterized by expiratory airflow limitation. The dominant pathological feature is airway inflammation, sometimes associated with airway structural changes. Global Strategy For Asthma Management And Prevention 2011.

8. Asthma Prevalence

9. Asthma: Burden Asthma is a problem worldwide, with an estimated 300 million 300 million affected individuals The global prevalence of asthma ranges from 1% to 18% 1% to 18% of the population in different countries 1%The World Health Organization has estimated that asthma represents 1% of the total global disease burden 250,000Annual worldwide deaths from asthma have been estimated at 250,000 Adapted from Global strategy for Asthma management and prevention guidelines 2010.

10. Asthma Risk Factors

11. Asthma Risk Factors: Factors that influence the risk of asthma can be divided into Host Factors: those that cause the development of asthma Environmental Factors: those that trigger asthma symptoms Adapted from Global strategy for Asthma management and prevention guidelines 2010.

12. Risk Factors Host factors predispose people to (or protect them from) asthma Environmental factors influence susceptibility in predisposed people, cause exacerbations, or cause symptoms to persist. Adapted from Global strategy for Asthma management and prevention guidelines 2010.

13. Common Asthma Triggers

14. Asthma Pathophysiology

15. Primary Mechanisms For Asthma Two distinct and interrelated responses are recognized as the primary mechanisms for asthma: airway hyper-responsiveness airway inflammation. Airway hyper-responsiveness: is a defect that causes airways to narrow easily and quickly in response to stimuli that usually have no effect on healthy persons.

16. Primary Mechanisms For Asthma Risk Factors (for development of asthma) Risk Factors (for development of asthma) INFLAMMATIONINFLAMMATION Airway Hyperresponsiveness Airway Hyperresponsiveness Airflow Obstruction Risk Factors (for exacerbations) Risk Factors (for exacerbations) Symptoms

17. Basic Asthma And COPD Medical training -Sci Ops- Medical Division – Mina Aziz

19. Asthma Diagnosis

20. Asthma: Clinical Diagnosis 1.Medical History & Symptoms 2.Physical Examination 3.Tests for diagnosis & monitoring a.Measurement of lung functions: –Spirometer –Peak flow meter b.Measurement of airway responsiveness : –Provocation/ challenge test –Reversibility test c.Allergy test –Skin prick test

21. Asthma: Clinical Diagnosis d.Other Diagnostic tests: –Blood Picture –Sputum cytology –Arterial blood gas tests –Chest radiograph

22. Asthma Medications

23. Reliever Medications SABA (Salbutamol,Albuterol) : Short-acting beta 2 -agonists are the most effective therapy for rapid reversal of airflow obstruction and prompt relief of asthmatic symptoms. Increasing the use of short-acting beta2 agonists or using them more than two days per week for symptom relief generally, indicates inadequate control of asthma and the need to initiate or intensify anti- inflammatory therapy. American Academy of Family Physician. 2010 Nov 15;82(10):1242-51.

24. Reliever Medications

25. Reliever Medications SABA: Tremor, anxiety, heart pounding, and tachycardia (but not hypertension) are common dose-dependent side effects. Some patients are highly sensitive to short-acting beta2 agonists, but most tolerate them well. American Academy of Family Physician. 2010 Nov 15;82(10):1242-51.

26. Controller Medications

27. Controller Medications ICS: Controller medications (inhaled corticosteroids, long-acting beta2 agonists, and leukotriene receptor antagonists) are the foundation of care for persistent asthma and should be taken daily on a long-term basis to achieve and maintain control of symptoms. American Academy of Family Physician. 2010 Nov 15;82(10):1242-51.

28. Controller Medications ICS: Inhaled corticosteroids are the preferred controller medication; studies have demonstrated that when inhaled corticosteroids are used consistently, they improve asthma control more effectively than any other single long-term control medication. American Academy of Family Physician. 2010 Nov 15;82(10):1242-51.

29. Combining long-acting beta2 agonists and inhaled corticosteroids is effective and safe when inhaled corticosteroids alone are insufficient, and such combinations are an alternative to increasing the dosage of inhaled corticosteroids. American Academy of Family Physician. 2010 Nov 15;82(10):1242-51. Controller Medications ICS:

30. Patients with mild to moderate persistent asthma treated with inhaled corticosteroids demonstrate improved symptom scores, lower exacerbation rates, and reduced symptom frequency. They also use fewer supplemental short-acting beta2 agonists, take fewer courses of oral systemic corticosteroids, and have fewer hospitalizations, compared with patients taking other single long-term control medications. American Academy of Family Physician. 2010 Nov 15;82(10):1242-51.

31. Controller Medications ICS: There are clinically significant differences in sensitivity and responsiveness to inhaled corticosteroid therapy. This may be related to high levels of inflammation or reduced corticosteroid sensitivity. Smokers have a decrease responsiveness to steroids, possibly because of persistent irritation and scarring. American Academy of Family Physician. 2010 Nov 15;82(10):1242-51.

32. Controller Medications LABA: Salmeterol and formoterol are bronchodilators that have a duration of action of more than 12 hours. They are very specific for β 2 -adrenergic receptors and, thus, have low rates of tremor and palpitations or tachycardia. Available data strongly suggest that long-acting β 2 agonists should never be used as monotherapy for long-term control of persistent asthma, they should be used only in combination therapy with ICS. American Academy of Family Physician. 2010 Nov 15;82(10):1242-51.

33. NHLBI Guidelines for the Diagnosis and Management of Asthma. NIH Publication 97-4051, 1997; Hall IP, Tattersfield AE.  2 -adrenoceptor agonists. In: Barnes PJ et al., editors. Asthma: Basic Mechanisms and Clinical Management. 3rd ed. Academic Press, 1998 Pharmacological Effects of Long Acting  2 -agonists Relief of bronchoconstriction due to smooth muscle relaxation Reduced vascular permeability and oedema Increased mucociliary clearance due to increased ciliary beat frequency Marked protection against all non-specific bronchoconstrictor stimuli such as histamine and methacholine Reduced inflammation due to inhibition of mediator release from mast cells

34. Controller Medications Leukotriene Receptor Antagonists: Anti-Leukotrienes are appropriate alternative therapies for mild persistent asthma in patients who are unable or unwilling to use inhaled corticosteroids. Leukotriene receptor antagonists have the advantages of ease of use and high rates of compliance. They can provide good control of asthma symptoms in many patients. American Academy of Family Physician. 2010 Nov 15;82(10):1242-51.

35. Controller Medications Leukotriene Receptor Antagonists: Leukotriene receptor antagonists are indicated in exercise-induced bronchospasm and can improve the condition in up to 50 percent of patients. They are the treatment of choice for aspirin-sensitive asthma. American Academy of Family Physician. 2010 Nov 15;82(10):1242-51.

36. Controller Medications: Anti-IgE Treatment:

37. Controller Medications: Anti-IgE Treatment (Omalizumab): Binds to the free serum IgE that plays a role in asthma inflammation. Addition of Anti IgE treatment to other controller medications has been shown to improve control of allergic asthma when control has not been achieved on combinations of other controllers including high-doses of inhaled glucocorticoides. Global Strategy for Asthma management and prevention 2011

38. Asthma exacerbation Omalizumab (Omalizumab) mechanism of action in IgE-mediated asthma Perennial aeroallergens Omalizumab 1- Binds to free IgE, reducing cell-bound IgE 2- Reduces high-affinity receptors 3 -Reduces mediator release 4 -Reduces asthma exacerbations and symptoms Plasma cell B lymphocyte Allergic mediators Release of IgE Mast cells Basophils Allergic inflammation: eosinophils and lymphocytes

39. Fc  RI Allergen C3C3 Allergens and mast cells Binding site IgE Mast cell

40. Omalizumab IgE Omalizumab (Omalizumab) binds to the region of IgE that interact with IgE receptors C  3 region

41. Omalizumab forms small, biologically inert complexes with IgE: Complexes are not bigger than normal IgM (~1000kD)

42. Omalizumab as add-on therapy is indicated to: Adult & Adolescent patients (6 years or above) with severe (uncontrolled) allergic asthma patients who are uncontrolled on ICS (GINA step5) 1. who have the following characteristics 2 : –Positive skin test. –Reducing lung function (FEV1 < 60 % predicted ) –Frequent daytime symptoms –Frequent Nocturnal symptoms –Multiple documented severe asthma exacerbations –Daily high dose of ICS plus LABA ± others 1-Global Strategy For Asthma Management And Prevention 2-Omalizumab Core Data Sheet.

43. Baseline IgE (IU/mL) Body Weight (Kg) > 20 - 25> 25 - 30> 30 - 40> 40 - 50> 50 - 60> 60 - 70> 70 - 80> 80 -90> 90 - 125> 125 - 150> 150 - 200 ≥ 30 -100 75 150 300 225 > 100 - 200150 300 225300375 > 200 - 300150 225300 225 300375525 > 300 - 400225 300225 300 450525 > 400 - 500225300225 300 375 525600 > 500 - 600300 225300 375450 600 > 600 - 700300225 300375450 525 > 700 - 800225 300375450 525600 > 800 - 900225 300375450525600 > 900 - 1000225300375450525600 > 1000 - 1100225300375450600 > 1100 - 1200300 450525600 > 1200 - 1300300375450525 > 1300 - 1500300375525600 Omalizumab Dose is calculated according to the below Table: Dose (mg) to be administered every 4 weeks Dose (mg) to be administered every 2 weeks Omalizumab core data sheet

44. Omalizumab Benefits as add on therapy

45. Omalizumab Significantly Reduces Severe Exacerbation Rate (INNOVATE). Allergy 2005;60:309–16 50%

46. Omalizumab Significantly Reduces Emergency Visits Due to Asthma Worsening (INNOVATE). Allergy 2005;60:309–16 44%

47. Omalizumab Captures IgE and change the lives of patients with uncontrolled allergic asthma (INNOVATE). 51% 49% 55% 40% 49% Improvement In QoL With Omalizumab Copmared With Placebo Improvement in exposure (e.g smoke, dust) with Omalizumab compared with placebo Improvement in Activites (e.g exercising,visiting friends)with Omalizumab compared with placebo Improvement in Symptoms (e.g chest tigtness, shortness of breath) with Omalizumab compared with placebo Improvement in Emotions (e.g fears of attacks, breathlesness) with Omalizumab compared with placebo Results of randomized,double blind,parallel group 28 week trial of 419 patients with severe persistent asthma who were inadequately controlled despite GINA step 4 treatment, In which Omalizumab or placebo was added to Ics and LABA. QoL assessed using Juripor AQLQ at weeks 0,12 and 2 of the treatment phase adapted from Humbert et al (2005)

48. Steroid bursts (mean) Omalizumab (n=2,511) Control (n=1,797) Omalizumab significantly reduces the need for systemic corticosteroid bursts: Pooled Analysis. 0.8 0.6 0.4 0.2 0 Relative risk: –43.0% p<0.001 Maykut R, et al. J Allergy Clin Immunol 2006 (abstract)

49. Omalizumab Shows a Greater Decrease In FeNO Compared With Placebo. Hanania N et al. ERS 2010 Novartis data on file Mean fractional exhaled nitric oxide, ppb n=203 n=191

50. What Is F e NO?

51. Fractional Exhaled Nitric Oxide (FeNO): The ability to assess the inflammatory status of a patient’s airway using a noninvasive method is the ideal situation for clinicians. Owing in part to the relationship between the levels of exhaled nitric oxide to inflammation and the ease of the technique, the measurement of the fraction of exhaled nitric oxide (FeNO) has achieved considerable attention, particularly with respect to asthma. Expert Rev. Respir. Med. 6(1), 105–115 (2012)

52. Pathophysiology Of FeNO: Nitric oxide (NO) is a gaseous molecule expressed in human airways. NO is generated from various resident and inflammatory cells in the human airway when l-arginine undergoes the process of oxidation by one of three NO synthase:  Endothelial NOS.  Inducable NOS.  Neuronal NOS. Expert Rev. Respir. Med. 6(1), 105–115 (2012)

53. Paathophysiology Of FeNO: Once produced, NO diffuses freely into cells and is converted into other substances within seconds. NO appears to act as an inflammatory agent as its production is driven by the stimulation of certain proinflammatory cytokines and its levels are reduced in response to the anti-inflammatory effects of corticosteroids. Expert Rev. Respir. Med. 6(1), 105–115 (2012)

54. Pathophysiology Of FeNO: Although the role of NO in the asthmatic airway is not fully understood, the levels of NO are often increased in asthma. This elevation is thought, in part, to reflect increased inducible NOS activity in the airways. Expert Rev. Respir. Med. 6(1), 105–115 (2012)

55. Measurement Of FeNO: The measurement of exhaled NO in the form of FeNO has become valued for many reasons. First, FeNO has been validated against invasive measurements of eosinophilic inflammation, including bronchoscopic and induced sputum evaluation an consequently is considered to be a surrogate marker of inflammation. Expert Rev. Respir. Med. 6(1), 105–115 (2012)

56. Advantages Of FeNO Measurment: Advantages for the use of FeNO include:  The ease of repeat measurements.  The ability to use this test on children.  Patients who have difficulties with other routine tests, such as spirometry. Expert Rev. Respir. Med. 6(1), 105–115 (2012)