Bronchial Asthma: Definition,Pathophysiology and Management

Definition and Pathophysiology of Asthma in addition to classification and recent updates in the management of asthma based on GINA-2019 Guidelines, by Dr. Marco Makram.

1. Updates in Asthma Management

2. Asthma is a chronic airway inflammation characterized by: History of Respiratory symptoms that vary in intensity over time, these symptoms include: Wheezing Shortness of breath Chest tightness Cough Definition of Asthma Variable expiratory airflow limitation. FEV1 & PEF variability FEV1 : Forced Expiratory Volume in the 1 st second PEF : Peak expiratory flow

3. Forced Expiratory Volume (FEV1) Spirometry

4. Peak Expiratory Flow (PEF) PEF is the flow (speed) of air coming out of the lung during forced expiration. Peak Flow Meter device

5. Allergic Asthma is the most common form of asthma which results from an inappropriate immune response to common inhaled proteins (or allergens ) ( environmental exposure ) in genetically susceptible individuals. Asthma phenotypes Allergic Asthma (Extrinsic): - Associated with a past family history of Allergic diseases such as: Allergic Rhinitis (AR) Eczema Food/drug allergy

6. Individuals with Allergic asthma are termed atopic asthmatics and exhibit Ig-E reactivity to specific antigens. Allergic Asthma - Examination of the induced sputum in these patients reveals high level of eosinophils. - These patients usually respond well to inhaled corticosteroids (ICS) treatment.

7. The T-cell receptor, or TCR, Molecule found on the surface of T cells , or T lymphocytes,  that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules.

8. The main function of MHC molecules ( major histocompatibility complex) is to bind to  antigens  derived from pathogens and display them on the cell surface for recognition by the appropriate  T-cells .

9. Asthma has been considered a T helper 2 (TH2) cell-associated inflammatory disease , and TH2-type cytokines, such as interleukin-4 (IL-4), IL-5 and IL-13, are thought to drive the disease pathology in patients . Cytokines Attracts & Activates Eosinophils Type 2, T HELPER Cells Involved in : Asthma Atopic Dermatitis Allergic Rhinitis Atopic Triad INTERLEUKIN 5 (IL 5)

10. Asthma phenotypes Non-allergic Asthma (Intrinsic) This type of asthma is not associated with allergic reactions. No relation of intrinsic asthma to inhaled substances or food. ( not driven by a specific allergen). No family history of Allergy. No Urticaria, eczema or other associated allergic manifestations.

11. Neutrophilic Asthma is more severe than Th2/ Eosinophilic. The cellular profile of the sputum of these patients may be Neutrophilic or contains a few inflammatory cells. Patients with non-allergic asthma often respond less well to inhaled corticosteroids (ICS). Non-allergic Asthma (Intrinsic) IL8 Plays key role In Asthma Mechanism of Promoting Asthma is Unknown Neutrophils: Highly inflammatory Phagocytic

12. Medical Department Diagnostic features & Asthma criteria Diagnostic feature Asthma Criteria 1- History of variable respiratory symptoms: Wheezing Shortness of breath Chest tightness Cough More than one type of respiratory symptoms (wheeze, shortness of breath, cough, chest tightness). Isolated cough with no other respiratory symptoms decreases the probability that symptoms are due to asthma. Symptoms occur variably over time and vary in intensity. Symptoms are often worse at night or on waking.

13. Diagnostic features Asthma Criteria 2- Variability in lung functions & documented expiratory airflow limitation according to the following tests: Positive BD (Bronchodilator) reversibility test. Excessive variability in twice daily PEF over 2 weeks. Significant increase & improvement of lung function after 4 weeks of anti-inflammatory treatment The greater the variation, the more confident the diagnosis. Increased in FEV1>12% and >200 ml from baseline after BD indicates asthma (in adults). Average daily diurnal PEF variability > 10% (in adults) Increase in FEV1 by > 12% and 200 ml (or PEF by > 20%) from baseline after 4 weeks of treatment. Diagnostic features & Asthma criteria Medical Department

14. Step 2: Mild Persistent Step 1: Mild intermittent Classification of Asthma Symptoms : Less than or equal 2 times a week & asymptomatic between exacerbations. Night-time symptoms: Not more than 2 times per month Lung functions: FEV1 Or PEF higher than or equal 80% predicted PEF Variability less than 20% Symptoms : Night-time symptoms: Lung functions: More than 2 times a week But Less than daily symptoms More than 2 times per month FEV1 or PEF higher than or equal 80% predicted. PEF Variability from 20% to 30%.

15. Classification of Asthma Step 3: Moderate Persistent Step 4: Severe Persistent Symptoms : Symptoms : Night-time symptoms: Night-time symptoms: Lung functions: Lung functions: Symptoms are daily Daily use of Short-acting Beta2-agonists (SABA) More than once per week FEV1 Or PEF higher than 60% and less than 80% predicted. PEF Variability higher than 30% - Continual daily symptoms - Frequent Exacerbations Frequent Nocturnal symptoms FEV1 Or PEF Less than 60% Predicted PEF Variability higher than 30%

16. Q. What are the differences between controller and reliever medications that used for management of Asthma..?? Controller medication These are used for regular maintenance treatment (Long-term). They reduce airway inflammation, control symptoms, and reduce future risks of exacerbations and decline in lung function. Examples include: Low dose ICS Low dose ICS/LABA Moderate/High dose ICS/LABA Reliever (Rescue) medication These are provided for as-needed relief (Short-term) of breakthrough emerging symptoms during worsening asthma or exacerbations. Examples include: As-needed short-acting beta2-agonist (SABA) as Salbutamol. Formoterol to replace SABA. Low dose ICS/Formoterol as maintenance and reliever therapy .

17. GINA 2018 – main treatment figure

18. GINA 2018 – main treatment figure Step 1 treatment is for patients with symptoms <twice/month and no risk factors for exacerbations Previously, no controller was recommended for Step 1, i.e . SABA-only treatment was ‘preferred’

19. Low, medium & high doses of inhaled Corticosteroids (ICS)(doses in mcg)

20. Recommended Medications by Level of Severity: Level of severity Preferred Daily Controller Medications Other treatment options Step-1: Intermittent Asthma Not necessary Low-dose ICS Step-2: Mild Persistent Asthma Low-dose Inhaled Corticosteroids (ICS) L euko t riene R eceptor A ntagonists ( LTRA ) Theophylline Step-3: Moderate Persistent Asthma Low-dose inhaled ICS\LABA Med/high dose ICS Low dose ICS\LTRA

21. Recommended Medications by Level of Severity: Level of severity Preferred Daily Controller Medications Other treatment options Step-4 Severe Persistent Asthma Med/high dose ICS/LABA High dose ICS Add on: Tiotropium LTRA Step-5 Uncontrolled Asthma Add on: Anti-IgE (SC Omalizumab) Anti-IL5 (For severe Eosinophilic asthma) (SC Mepolizumab) Anti-IL5R (SC Benralizumab) Oral Corticosteroids (OCS)

22. Global Initiative for Asthma (GINA) What’s new in GINA 2019? This slide set is restricted for academic and educational purposes only. No additions or changes may be made to slides. Use of the slide set or of individual slides for commercial or promotional purposes requires approval from GINA.

23. REVIEW RESPONSE ASSESS ADJUST * Off-label; data only with budesonide-formoterol (bud-form ) † Off-label; separate or combination ICS and SABA inhalers PREFERRED CONT R OLLER to prevent exacerbations and control symptoms Other controller options Other reliever option PREFERRED RELIEVER STEP 2 Daily low dose inhaled corticosteroid (ICS), or as-needed low dose ICS-formoterol * STEP 3 Low dose ICS-LABA STEP 4 Medium dose ICS-LABA Leukotriene receptor antagonist (LTRA), or low dose ICS taken whenever SABA taken † As-needed low dose ICS-formoterol * As-needed short-acting β 2 -agonist (SABA) Medium dose ICS, or low dose ICS+LTRA # High dose ICS, add-on tiotropium, or add-on LTRA # Add low dose OCS, but consider side-effects As-needed low dose ICS-formoterol ‡ Box 3-5A Adults & adolescents 12+ years Personalized asthma management: Assess, Adjust, Review response Asthma medication options: Adjust treatment up and down for individual patient needs STEP 5 High dose ICS-LABA Refer for phenotypic assessment ± add-on therapy, e.g.tiotropium, anti-IgE, anti-IL5/5R, anti-IL4R Symptoms Exacerbations Side-effects Lung function Patient satisfaction Confirmation of diagnosis if necessary Symptom control & modifiable risk factors (including lung function) Comorbidities Inhaler technique & adherence Patient goals Treatment of modifiable risk factors & comorbidities Non-pharmacological strategies Education & skills training Asthma medications 1 © Global Initiative for Asthma, www.ginasthma.org STEP 1 As-needed low dose ICS-formoterol * Low dose ICS taken whenever SABA is taken † ‡ Low-dose ICS-form is the reliever for patients prescribed bud-form or BDP-form maintenance and reliever therapy # Consider adding HDM SLIT for sensitized patients with allergic rhinitis and FEV >70% predicted ‘Controller’ treatment means the treatment taken to prevent exacerbations

24. For safety, GINA no longer recommends SABA-only treatment for Step 1 This decision was based on evidence that SABA-only treatment increases the risk of severe exacerbations, and that adding any ICS significantly reduces the risk GINA now recommends that all adults and adolescents with asthma should receive symptom-driven or regular low dose ICS-containing controller treatment, to reduce the risk of serious exacerbations This is a population-level risk reduction strategy, e.g. statins, anti-hypertensives GINA 2019 – landmark changes in asthma management

25. REVIEW RESPONSE ASSESS ADJUST * Off-label; data only with budesonide-formoterol (bud-form ) † Off-label; separate or combination ICS and SABA inhalers STEP 2 Daily low dose inhaled corticosteroid (ICS), or as-needed low dose ICS-formoterol * STEP 3 Low dose ICS-LABA STEP 4 Medium dose ICS-LABA Leukotriene receptor antagonist (LTRA), or low dose ICS taken whenever SABA taken † As-needed low dose ICS-formoterol * As-needed short-acting β 2 -agonist (SABA) Medium dose ICS, or low dose ICS+LTRA # High dose ICS, add-on tiotropium, or add-on LTRA # Add low dose OCS, but consider side-effects As-needed low dose ICS-formoterol ‡ STEP 5 High dose ICS-LABA Refer for phenotypic assessment ± add-on therapy, e.g.tiotropium, anti-IgE, anti-IL5/5R, anti-IL4R Symptoms Exacerbations Side-effects Lung function Patient satisfaction Confirmation of diagnosis if necessary Symptom control & modifiable risk factors (including lung function) Comorbidities Inhaler technique & adherence Patient goals Treatment of modifiable risk factors & comorbidities Non-pharmacological strategies Education & skills training Asthma medications 1 © Global Initiative for Asthma, www.ginasthma.org STEP 1 As-needed low dose ICS-formoterol * Low dose ICS taken whenever SABA is taken † ‡ Low-dose ICS-form is the reliever for patients prescribed bud-form or BDP-form maintenance and reliever therapy # Consider adding HDM SLIT for sensitized patients with allergic rhinitis and FEV >70% predicted PREFERRED CONT R OLLER to prevent exacerbations and control symptoms Other controller options Other reliever option PREFERRED RELIEVER Box 3-5A Adults & adolescents 12+ years Personalized asthma management: Assess, Adjust, Review response Asthma medication options: Adjust treatment up and down for individual patient needs

26. REVIEW RESPONSE ASSESS ADJUST * Off-label; data only with budesonide-formoterol (bud-form ) † Off-label; separate or combination ICS and SABA inhalers STEP 2 Daily low dose inhaled corticosteroid (ICS), or as-needed low dose ICS-formoterol * STEP 3 Low dose ICS-LABA STEP 4 Medium dose ICS-LABA Leukotriene receptor antagonist (LTRA), or low dose ICS taken whenever SABA taken † As-needed low dose ICS-formoterol * As-needed short-acting β 2 -agonist (SABA) Medium dose ICS, or low dose ICS+LTRA # High dose ICS, add-on tiotropium, or add-on LTRA # Add low dose OCS, but consider side-effects As-needed low dose ICS-formoterol ‡ STEP 5 High dose ICS-LABA Refer for phenotypic assessment ± add-on therapy, e.g.tiotropium, anti-IgE, anti-IL5/5R, anti-IL4R Symptoms Exacerbations Side-effects Lung function Patient satisfaction Confirmation of diagnosis if necessary Symptom control & modifiable risk factors (including lung function) Comorbidities Inhaler technique & adherence Patient goals Treatment of modifiable risk factors & comorbidities Non-pharmacological strategies Education & skills training Asthma medications 1 © Global Initiative for Asthma, www.ginasthma.org STEP 1 As-needed low dose ICS-formoterol * Low dose ICS taken whenever SABA is taken † ‡ Low-dose ICS-form is the reliever for patients prescribed bud-form or BDP-form maintenance and reliever therapy # Consider adding HDM SLIT for sensitized patients with allergic rhinitis and FEV >70% predicted PREFERRED CONT R OLLER to prevent exacerbations and control symptoms Other controller options Other reliever option PREFERRED RELIEVER Box 3-5A Adults & adolescents 12+ years Personalized asthma management: Assess, Adjust, Review response Asthma medication options: Adjust treatment up and down for individual patient needs

27. REVIEW RESPONSE ASSESS ADJUST * Off-label; data only with budesonide-formoterol (bud-form ) † Off-label; separate or combination ICS and SABA inhalers STEP 2 Daily low dose inhaled corticosteroid (ICS), or as-needed low dose ICS-formoterol * STEP 3 Low dose ICS-LABA STEP 4 Medium dose ICS-LABA Leukotriene receptor antagonist (LTRA), or low dose ICS taken whenever SABA taken † As-needed low dose ICS-formoterol * As-needed short-acting β 2 -agonist (SABA) Medium dose ICS, or low dose ICS+LTRA # High dose ICS, add-on tiotropium, or add-on LTRA # Add low dose OCS, but consider side-effects As-needed low dose ICS-formoterol ‡ STEP 5 High dose ICS-LABA Refer for phenotypic assessment ± add-on therapy, e.g.tiotropium, anti-IgE, anti-IL5/5R, anti-IL4R Symptoms Exacerbations Side-effects Lung function Patient satisfaction Confirmation of diagnosis if necessary Symptom control & modifiable risk factors (including lung function) Comorbidities Inhaler technique & adherence Patient goals Treatment of modifiable risk factors & comorbidities Non-pharmacological strategies Education & skills training Asthma medications 1 © Global Initiative for Asthma, www.ginasthma.org STEP 1 As-needed low dose ICS-formoterol * Low dose ICS taken whenever SABA is taken † ‡ Low-dose ICS-form is the reliever for patients prescribed bud-form or BDP-form maintenance and reliever therapy # Consider adding HDM SLIT for sensitized patients with allergic rhinitis and FEV >70% predicted PREFERRED CONT R OLLER to prevent exacerbations and control symptoms Other controller options Other reliever option PREFERRED RELIEVER Box 3-5A Adults & adolescents 12+ years Personalized asthma management: Assess, Adjust, Review response Asthma medication options: Adjust treatment up and down for individual patient needs Step 4 treatment is medium dose ICS-LABA; high dose now in Step 5

28. Medical Department