Asthma Part 1 - Definition, Epidemiology and Pathophysiology_Khurana.pptx

Asthma

1. Asthma - Part 1 Definition, Epidemiology and pathophysiology Sandhya Khurana, MD, FCCP Professor, Pulmonary & Critical Care Medicine Director, Mary Parkes Center for Asthma, Allergy & Pulmonary Care University of Rochester, NY

2. Pathophysiology and diagnosis of asthma Genetics, Epidemiology, Biology Evaluation Severity and stepped care Mild, moderate, Severe Asthma in pregnancy Perioperative care Complications of care  Special types and phenotypes of asthma Aspirin-sensitive asthma E x e r cise-indu c ed a s t h m a Eosinophilic TH2-high asthma Cough variant asthma and other special types Asthma mimics Vocal cord dysfunction Genetic (cystic fibrosis, alpha-1 antitrypsin disease, primary ciliary dyskinesia) and nongenetic Hypereosinophilic Löffler's syndrome and other parasitic infections Infiltrative airway processes (granulomatous, amyloidosis, and other processes) Heart failure Central airway obstruction Exacerbation Status asthmaticus Viral infections, allergens, and other causes Allergic bronchopulmonary aspergillosis and fungosis Eosinophilic granulomatosis with polyangiitis ABIM Blueprint – Asthma (9%)

3. Review definition of asthma and burden on the disease Discuss asthma pathophysiology and immunology List cytokines involved in type-2 asthma Learning Objectives

4. Research funding – GSK, Sanofi Royalties – Springer Disclosures

5. Heterogeneous disease Usually chronic airway inflammation Symptoms that vary in intensity and over time Variable expiratory airflow limitation The term ‘asthma’ originates from the Greek word ‘aazein’ that means ‘short-drawn breath’ or ‘panting’ Asthma - definition GINA report 2020. ginaasthma.org

6. Most prevalent chronic respiratory disease worldwide Estimated global prevalence of 358 million (2015) 25 million Americans have current asthma; US prevalence 7.8% (2019) U.S. population with asthma has increased over time (7.3% in 2001 to 7.8% in 2019) Asthma - burden of disease 10 9 8 7 6 5 2001 2003 2005 2007 2009 Year 2011 2013 2015 2017 Percent U S A st h m a P r e v a l en c e b y Y ea r T o t a l Adu lt Children GBD2015 chronic respiratory disease collaborators. Lancet Respir Med 2017;5:691 CDC data; accessed June, 2021 from https:// www.cdc.gov

7. Asthma prevalence in the US 6 . 4 5 . 4 9 . 5 9 . 3 9 . 8 7 . 3 10 9 8 7 6 5 4 3 2 1 T o t a l C h i l d P r e v a l en c e ( % ) Asthma Prevalence by Sex, 2017 M a l e Adult F e m a l e 8.1 8.1 7.7 10.1 9.2 12.6 6.4 5.8 7.7 12.8 13.5 1 1 . 3 5.1 4.5 6.2 2 4 6 8 10 12 14 Child M e x i c a n Prevalence (%) Asthma Prevalence by race/ethnicity, 2017 T o t a l Adu lt Wh ite NH Black NH Hispanic Pue r t o R i c an data from https:// www.cdc.gov

8. Early life determinants of asthma A lle r g e n s - C ock r oach Dust Mites - Mold Pets Mice Air Pollution - Industrial - Vehicle Emissions - Environmental T obacco s m oke Ot h e r s - Diet - Obesity - Socioeconomics - Psychosocial stress Genetic Predisposition Microbiome - Vaginal v. caesarian delivery - Formula v. breastfeeding Farm/Endotoxin Pre/Post-natal Antibiotics Protective vaginal birth microbial diversity more siblings & later birth order Farm/endotoxin exposure Pr o m ote A s th m a Antibiotics respiratory infection (RSV, RV) allergen exposure air pollution Modified from Burbank et al. JACI 2017;140:1

9. Estimates of heritability range from 35-70% Heritability is higher for early-onset asthma Chromosome 17q21 - genes GSDMB and ORMDL3 - specific to childhood onset disease Polymorphism in: IL-4, IL-13 genes - allergies, IgE CD14 and TLR genes - farming and endotoxin exposure TGF-β1, MCP-1 – fibrosis/remodeling Gene for the β chain of the high-affinity receptor for IgE ( FCER 1 -β) - allergies  -receptor (Arg/Arg) and glucocorticoid polymorphism determine heterogeneity in treatment response Genetics and A sthma

10. Asthma pathophysiology Israel E, et al. N Engl J Med. 2017; 377(10) :965 Airway Hyperresponsiveness Smooth muscle hypertrophy Airway Remodeling Mucus hypersecretion

11. Biologics: Targets and Therapy 2013:199 Airway inflammation in asthma Neu t r o phi l i c Mixed Granulocytic Pauci-Granulocytic Eosinophilic Non-Type 2 Type 2

12. Type-2 immune responses in asthma Khurana S et al. Breathe June 2020, 16 (2) 200058

13. Type-2 immune responses in asthma Khurana S et al. Breathe June 2020, 16 (2) 200058

14. Type-2 immune responses in asthma Khurana S et al. Breathe June 2020, 16 (2) 200058

15. Type-2 immune responses in asthma Eosinophilic inflammation may be allergic or non-allergic Khurana S et al. Breathe June 2020, 16 (2) 200058

16. Cytokines in Type 2 Asthma Epithelial cytokines (alarmins) – TSLP , IL-33, IL-25 IL-4, IL-5, IL-13 are produced by helper T cells, basophils, mast cells & eosinophils IL-5: differentiation and maturation of eosinophils IL-13: recruitment of eosinophils into the airway, mucus hypersecretion, airway hyperresponsiveness IL-4: IgE production by B-cells (class switching) IgE: activates mast cells & basophils to produce leukotrienes that recruit and activate eosinophils

17. Mechanisms of non - T2 or T2 low asthma Sze & Nair. Allergy 2019 Neutrophilic asthma Persistent inflammation Increased disease severity Airway remodeling C or t i c o s t e r o id refractoriness Paucigranulocytic asthma Most common phenotype in stable asthma 20% of PGA can be severe/refractory T S LP IL-33 IL-25

18. Asthma - Part 2 Diagnosis, Evaluation, Phenotypes, Occupational Asthma Sandhya Khurana, MD, FCCP Professor, Pulmonary & Critical Care Medicine Director, Mary Parkes Center for Asthma, Allergy & Pulmonary Care University of Rochester, NY

19. Describe approach to Asthma Diagnosis List available biomarkers of T2 high asthma Discuss evaluation and management of Occupational Asthma Learning Objectives

20. Research funding – GSK, Sanofi Royalties – Springer Disclosures

21. COPD = chronic obstructive pulmonary disease. Aaron SD, et al. JAMA. 2017; 317(3):269 2020 GINA report, global strategy for asthma management and prevention Misdiagnoses of Asthma is Common Age 6 – 11 years 12 – 39 years 40+ years Conditions Chronic upper airway cough syndrome Inhaled foreign body Bronchiectasis Primary ciliary dyskinesia Congenital heart disease Bronchopulmonary dysplasia Cystic fibrosis Chronic upper airway cough syndrome Inducible laryngeal obstruction Hyperventilation, dysfunctional breathing Bronchiectasis Cystic fibrosis Congenital heart disease Alpha 1 –antitrypsin deficiency Inhaled foreign body Inducible laryngeal obstruction Hyperventilation, dysfunctional breathing COPD Br on c hie ct a s i s Cardiac failure Medication-related cough Parenchymal lung disease Pulmonary embolism Central airway obstruction ≈ 30% of adults with ‘physician diagnosed asthma’ may not have asthma

22. Diagnosis of Asthma Pattern of Symptoms Wheeze, shortness of breath, cough and/or chest tightness More than one symptom Worse at night or early morning Vary over time and in intensity Identifiable triggers Relevant History Childhoo d asthma or atopy Family history of asthma or allergy Occupational or environmental exposures Physical Exam Is often normal Expiratory wheeze (may only be heard on forced exhalation) Wheeze may be absent in acute severe asthma – ‘silent chest’ Nasal polyps/rhinitis Testing PEFR variability Airflow limitation on spirometry Bronchodilator reversibility Variability in FEV1 between visits or after treatment Airway hyper- responsiveness FeNO

23. Document airflow limitation - reduced FEV1/FVC Confirm bronchodilator reversibility - Improvement in FEV1 > 200 ml AND 12% Look for between-visit FEV1 variability - FEV1 change >200 ml AND 12% Diurnal PEFR variability, >10% in adults, performed twice daily over 2 weeks Bronchoprovocation testing Exercise challenge – fall in FEV1 >10% and 200 ml from baseline Methacholine or histamine challenge – fall in FEV1 > 20% Mannitol or Eucapnic hyperventilation – fall in FEV1 > 15% PEFR= Peak Expiratory Flow Rate Confirmation of variable airflow obstruction

24. Measuring Airway Responsiveness © Global Initiative for Asthma

25. Procedures and devices for nebulizing methacholine are not standardized PD20 compares better than PC20 between devices Methacholine Challenge Test 2017 ERS update Severity PD20 (micrograms) PC20 (mg/mL) Normal >400 >16 Borderline 100-400 4-16 Mild 25-100 1-4 Moderate 6-25 0.25-1 Marked <6 <0.25 Coates AL et al. ERJ 2017;49:1601526

26. Exercise testing Isocapneic hyperpnea Hypertonic saline Mannitol Adenosine 5'-monophosphate (AMP) Sulfur dioxide Bradykinin Allergens Indirect Bronchial Challenge Testing Direct stimulation of airway sensory nerve endings Increase in the osmolarity of the airway surface results in mediator released from mast cells or basophils Activation of A 2b receptors on mast cells Joos et al. ERJ 2003;21:1050

27. More specific though less sensitive than direct challenge tests for identifying patients with active asthma Correlate better with airway inflammation and are more predictive of a response to anti-inflammatory treatments The best choice when exercise bronchospasm is the question (eg, certification for international athletic competition, armed forces, scuba diving). Indirect Bronchial Challenge Testing

28. 2020 Focused Updates to the Asthma Management Guidelines J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270.

29. 2020 Focused Updates to the Asthma Management Guidelines J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270 Ludviksdottir et al. Clin Respir J. 2012 Oct;6(4):193-207

30. Phenotype – observable characteristics that result from a combination of hereditary and environmental influences Endotype – Distinct mechanistic/molecular pathway leading to a certain phenotype Biomarker – A measurable indicator of presence or severity of a disease state Definitions

31. Comparison of Type-2 Biomarkers in Asthma Biomarker Levels Limitations Low Medium High Total IgE (IU) < 30 31 – 149 > 150 Affected by age; poor predictor of response to biologic therapy Blood eosinophils (cells/μL) < 150 151 - 399 > 400 Affected by weight, allergen exposure, steroids, and infection; optimal cut off value varies per therapy Sputum eosinophils - - ≥ 3% Semi-invasive; confined to research settings FeNO (ppb) < 25 26 – 49 > 50 Affected by age, weight, sex, smoking, and respiratory infections Serum periostin (ng/mL) - - ≥ 50 Unknown competing causes of systemic increases; unclear differences between asthma and healthy subjects; studied only in context of anti-IL-13 and anti-IgE therapy ppb = parts per billion Peters MC, et al. Curr Allergy Asthma Rep. 2016;16(10):71

32. Wenzel Nature Medicine 2012 Phenotypes & Endotypes in Asthma

33. Holgate Nat. Rev. Dis. Primers 2015 Phenotypes & Endotypes in Asthma

34. Aspirin exacerbated respiratory disease (AERD) Asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP) Bronchospasm that occurs (typically 20min to 3 hours) after ingestion of aspirin/NSAIDs Non-IgE mediated – ”pseudo-allergic” Prevalence 7% of adults with asthma; more common in women Can take years for all three components to develop - CRS usually the first manifestation Asthma has a severe and protracted course Angioedema and GI symptoms may occur Elevated blood eosinophils Strong association with HLADPB1*0301

35. Aspirin exacerbated respiratory disease (AERD) Diagnosis usually by history. Aspirin challenge for definitive diagnosis Treatment is same as for asthma without AERD, except consider early use of LTMs and avoidance of NSAIDs Emerging role of biologics ASA desensitization indicated if worsening sinonasal symptoms despite maximal therapy or treatment of other condition requiring ASA or NSAIDs Patients must continue daily aspirin therapy after completing desensitization ASA therapy after desensitization Improved nasal symptoms and decreased regrowth of NP Improved asthma control

36. Exercise Induced Bronchoconstriction (EIB) Triggered by inhalation of large volumes of relatively cool dry air during vigorous exercise Symptoms occur after the end of exercise or during prolonged exercise Initial bronchodilation followed by bronchoconstriction that peaks 10-15 minutes after exercise Diagnosis by exercise challenge test (15% decrease in FEV1 suggests EIA) Treatment Pre-treatment with short-acting bronchodilators (alone or combination) Chromoglycates, ICS + LABA, leukotriene modifiers

37. Obesity & A sthma Obesity is associated with Worse asthma control Higher health care utilization Poor response to standard controller therapy Weight loss – dietary or surgical – is effective Recent studies support a role for exercise Diet quality – high protein/low glycemic index, plant-based, Mediterranean Inflammation High fat/low fiber diet Adipose tissue & adipokines Innate & adaptive immune function Gut microbiome Mechanical factors Increased peripheral airway closure In c r ea s e d im p e d a n c e Mass loading Decreased ERV Comorbidities Anxiety/Depression GE R D OSA D i x o n A E . A J R CC M 201 6

38. Asthma due to causes and conditions attributable to a particular occupational environment and not to stimuli encountered outside the workplace Two types of OA: Immunological (sensitizing) or non-immunological Needs to be distinguished from workplace exacerbated asthma When to suspect OA? Any new adult-onset asthma (OA accounts for 10-25%) Worsening asthma control in a previously well-controlled asthmatic Symptoms worse at work; improve over weekend and holidays Latency period from exposure to onset of symptoms is highly variable Occupational Asthma (OA)

39. Occupational Asthma (OA) - Etiologies High Molecular Weight Flour: Bakers, pastry, cook Animals: Handlers, pet shop Crab: crab processing Psyllium: Nurses, pharma Latex: Healthcare workers Antibiotics, enzymes: Nurses, pharma Low Molecular Weight Di-isocyanates: Auto-body shops, insulation, electronics Woods (red cedar, exotic): Carpentry, sawmills, doors/windows Meth/cyanoacrylates: dental hygienist, orthotist, glues Phthalic anhydrides: plastic industry, glues, epoxy Colophony: Electric soldering

40. Rhinitis is a frequent feature for both HMW and LMW agents but more severe with HMW Wheezing, nasal and ocular itching at work positively associated with OA to HMW agents Rash sometimes associated with OA, particularly with HMW agents Symptoms and questionnaires are not specific Diagnosis must be confirmed objectively Skin tests and serology Monitoring PEFR, FEV1, AHR at and off work Specific inhalation challenge (the gold standard) Occupational Asthma (OA)

41. Suspect OA in all adult-onset asthma Treat as for non-OA Objectively confirm diagnosis Early diagnosis and removal from exposure for best outcomes Absolute avoidance for patients with sensitizer induced OA For irritant induced workplace exacerbated asthma Reduce exposure Respiratory protective equipment, appropriate ventilation Optimize treatment Occupational Asthma (OA) - Management

42. Asthma - Part 3 Guidelines-Based Management & Role of Comorbidities Sandhya Khurana, MD, FCCP Professor, Pulmonary & Critical Care Medicine Director, Mary Parkes Center for Asthma, Allergy & Pulmonary Care University of Rochester, NY

43. Review goals of asthma management Understand the difference between asthma control and severity Discuss the key updates from GINA and NAEPP asthma guidelines Learning Objectives

44. Research funding – GSK, Sanofi Royalties – Springer Disclosures

45. GI N A and N AEP P - EPR 4

46. 2020 GINA report, global strategy for asthma management and prevention Goals of Asthma Management Reduce Current Impairment and Future Risk Effective asthma management requires a partnership between patient and healthcare provider to define and achieve treatment goals Improve Symptom control Management of comorbidities Lung function Reduce Exacerbations Rescue medication Treatment related AEs Emergency visits

47. Classifying Asthma Severity - NAEPP EPR3 2007 NH L B I . NAEP P EP R 3 : G u i de li ne s f o r t h e Diagnosis and Management of Asthma R i s k

48. Asthma Control and Severity Khurana & Jarjour. Clin Chest Med. 2019 Mar;40(1):59 Severity Asthma severity can be estimated by minimum level of treatment required to achieve good control Control Level of asthma control is the degree to which therapeutic interventions minimize the manifestations of asthma in terms of impairment and risk.

49. 201 9 G I N A re p o r t , gl o ba l st r a t e g y f o r a st h m a m ana g e m e n t an d p reve n ti o n S t eppe d A pproac h t o As t hm a T herapy GINA 2019 – As-needed ICS/formoterol

50. Rationale & Evidence for as-needed ICS/formoterol Patients use their inhaler when they have symptoms Adherence to scheduled ICS is poor SABA overuse is associated with increased risk of death Even people with mild asthma have exacerbations SYGMA 1&2, Novel START, PRACTICAL Four 12-month studies, ~10000 patients As-needed ICS/formoterol decreased severe exacerbations vs SABA As-needed ICS/formoterol similar to scheduled ICS Much lower steroid exposure O’Byrne et al. NEJM 2018 Bateman et al. NEJM 2018 Beasley et al. NEJM 2019 Hardy et al. Lancet 2019

51. © Global Initiative for Asthma, www.ginasthma.org GINA 2021, Box 3-5A: Personalized asthma management, adults and adolescents GIN A 2021

52. 202 1 G I N A re p o r t , gl o ba l st r a t e g y f o r a st h m a m ana g e m e n t an d p reve n ti o n Asthma management Assess – Adjust – Review response

53. NAEPP EPR-4 Update 2020

54. FeNO Allergen mitigation ICS LAMA Immunotherapy Bronchial Thermoplasty NAEPP EPR4 Focused Update 2020 Focused Updates to the Asthma Management Guidelines J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270.

55. Inhaled Corticosteroids (ICS) for Persistent Asthma Large body of evidence shows that ICS use in asthma Reduces risk of severe exacerbations and hospitalization Reduces mortality Improves symptoms and quality of life Reduces exercise induced bronchoconstriction Improves lung function Slow the deterioration of lung function May prevent airway remodeling

56. Adding LABA to low dose ICS (in a combination inhaler) provides Additional improvement in symptoms Additional improvement in lung function Decrease in risk of exacerbations Small reduction in reliever use Addition of LABA to low dose ICS was more effective than increase in ICS dose alone LABA should NEVER be used as monotherapy in asthma ICS + Long-acting β2-agonists (LABA) for Asthma

57. Tiotropium soft mist inhaler is the only LAMA that is FDA approved for Asthma As add-on therapy to ICS* Improved lung function; Reduced exacerbations *LABA still preferred over LAMA for add-on therapy to ICS As add-on therapy to ICS + LABA Improved lung function Improved asthma control Increased time to first exacerbation Not recommended as monotherapy Long-acting muscarinic antagonist (LAMA) in Asthma

58. Efficacy (v. placebo) Reduce risk of exacerbations Improve lung function Improve symptoms and QOL Reduce need for rescue SABA Effects are variable and generally less than with ICS Less effective than LABA as add-on therapy to ICS in improving exacerbations and lung function Greater response in AERD and EIB Leukotriene modifiers in asthma Figure from © 2020 UpToDate, Inc.

59. © Global Initiative for Asthma, www.ginasthma.org GINA 2021, Box 3-4Bii: Starting asthma treatment in adults and adolescents

60. Association, prevalence and treatment outcomes of comorbidities in difficult asthma A dap te d f r o m Ra d h a k r i s h n a N . J o u r n a l o f A s th ma . 201 6 Comorbidity Associated with asthma? Prevalence in asthma Does treatment improve asthma? Sino-nasal disease AR Yes 80 % # Yes Sino-nasal disease CRS Yes 70-74 % * Yes GERD Yes 59 % # Inconsistent OSA Yes 75-95 % * Yes VCD/ILO Yes 75 % * Inconsistent Dysfunctional Breathing Yes 29 % # Yes Anxiety/Depression Yes 49 % * Yes * D i f f i c u lt a s t h m a # A l l a s t h m a

61. GERD & Asthma Prevalence 32-84% by esophageal pH-monitoring studies; about half are asymptomatic Carefully review symptoms: Heartburn, Regurgitation, Water brash, Dysphagia, Sore throat, Choking, Hoarseness, Dental erosions, Chest pain, Cervical pain, Worsened asthma symptoms with Eating, Alcohol, Supine position, Theophylline Proposed mechanisms – ‘Reflux’ vs ‘Reflex’ Likely a bi-directional relationship Studies demonstrate some benefit in symptomatic GERD and uncontrolled asthma Improvement in peak flow, quality of life, exacerbations AJRCCM 2006 May 15;173(10):1091-7 A J RCC M 201 M a y 15 ; 181 ( 10 ) : 1042 - 8. Chest 2005 Sep;128(3):1128-35 N E n g l J M e d 2009; 360 : 1 48 7 - 1499

62. CRS & A s t hm a Symptomatic inflammation of the paranasal sinuses and the nasal cavity Chronic Rhino-Sinusitis = lasting > 12 weeks With or without nasal polyps (CRSwNP or CRSsNP) The unified airway model Links the upper and lower airway as a single functional group Shared systemic inflammatory pathways Prevalence of CRS 10-12% general population 23.4-74% in all asthma 84% in severe asthma Associated with decreased lung function, QOL, severe exacerbations Ear Nose Throat J 2007; 86: 409. J Allergy Clin Immunol 2001;107:73. J Allergy Clin Immunol 2002;109:621 . Otolaryngol Head Neck Surg. 2007;136:S75-S106. Otolaryngol Clin N Am. 2008;48:297-309. 2015 NHIS data.

63. PVFM & Asthma VCD/ILO/PVFM Laryngeal hypersensitivity Occurs commonly as asthma mimic and comorbidity Prevalence 19% in all asthma 32% in difficult asthma Clinical suspicion and detailed history Triggers, rapid onset/offset, phase of respiration affected, other laryngeal symptoms Objective confirmation often elusive - Questionnaire screening, Laryngoscopy, Challenge tests Respiratory retraining, laryngeal hygiene, treat LPRD

64. Obesity & A sthma Obesity is associated with Worse asthma control Higher health care utilization Poor response to standard controller therapy Weight loss – dietary or surgical – is effective Recent studies support a role for exercise Diet quality – high protein/low glycemic index, plant-based, Mediterranean Inflammation High fat/low fiber diet Adipose tissue & adipokines Innate & adaptive immune function Gut microbiome Mechanical factors Increased peripheral airway closure In c r ea s e d im p e d a n c e Mass loading Decreased ERV Comorbidities Anxiety/Depression GE R D OSA D i x o n AE . A J R CC M 2 1 6

65. Asthma- Part 4 Advanced Therapies in Severe Asthma Sandhya Khurana, MD, FCCP Professor, Pulmonary & Critical Care Medicine Director, Mary Parkes Center for Asthma, Allergy & Pulmonary Care University of Rochester, NY

66. Define severe asthma and prevalence Review available biologic therapies and mechanism of action Discuss management of non-T2 asthma Learning Objectives

67. Research funding – GSK, Sanofi Royalties – Springer Disclosures

68. Asthma that requires treatment at GINA steps 4–5 or systemic CS for > 50% of the previous year to prevent it from becoming ‘‘uncontrolled’’ or remains ‘‘uncontrolled‘‘ despite this therapy Or Controlled asthma that worsens on tapering of these high doses of ICS or systemic CS (or additional biologics) Severe Asthma - Definition Chung et al. Eur Respir J 2014; 43: 343–373

69. © Global Initiative for Asthma, www.ginasthma.org What proportion of asthma in adults is severe? GINA 2021, Box 3-15: What proportion of adults with asthma have severe asthma?

70. Available Biologics in Asthma Drug Mechanism Route Setting Omalizumab Anti-IgE Subcutaneous Home/Clinic Mepolizumab Anti-IL5 Subcutaneous Home/Clinic Reslizumab Anti-IL5 Intravenous Clinic Benralizumab Anti-IL5Ra Subcutaneous Home/Clinic Dupilumab Anti-IL4Ra Subcutaneous Home Omalizumab Dupilumab Mepolizumab Reslizumab B en r a liz u m a b

71. Anti-IgE humanized recombinant monoclonal antibody Binds to free circulating IgE at the same site as high-affinity IgE receptor Indication Moderate-Severe allergic asthma Serum IgE 30-700 IU/ml with sensitivity to >1 perennial allergen AEs: Small risk of delayed anaphylactic reactions (0.2%) Administration: Subcutaneous injection every 2-4 weeks Anti-IgE Monoclonal Antibody (Omalizumab)

72. Anti-IL5 monoclonal antibodies (mepolizumab, reslizumab) Anti-IL5 receptor monoclonal antibody (benralizumab) Indication: Add-on maintenance therapy for patients with severe asthma with an eosinophilic phenotype Administration: Mepolizumab: 100 mg subcutaneous injection every 4 weeks Reslizumab: Weight-based intravenous infusion every 4 weeks Benralizumab: 30 mg subcutaneous every 4 weeks x 3, then every 8 weeks Anti-IL5 Therapy IL -5 IL -5 R 

73. Fully human monoclonal antibody Binds to alpha subunit of IL-4 receptor Inhibits the activity of both Il-4 and IL-13 Indication: moderate-to-severe, eosinophilic asthma and OCS-dependent asthma Dose: 400 mg or 600 mg initial loading dose, then 200mg or 300 mg every 2 weeks subcutaneously Higher dose in OCS-dependent asthma or comorbid atopic dermatitis Anti-IL4R  antibody (dupilumab)

74. Biologics for Type 2 Asthma ICER 2018 6

75. Biologics for Type 2 Asthma: Efficacy Drug Asthma Exacerba t ions Rate Ratio OCS % dose reduc t ion % Off OCS FEV1 (L) ACQ Omalizumab 0.52 - - 0.06 - (0.37-0.73) (0.02-0.10) Mepolizumab 0.45 -50% vs 0% 14% vs 8% 0.10 -0.42 (0.36-0.55) (0.01-0.18) (-0.56 to -0.28) Reslizumab 0.43 - - 0.12 -0.27 (0.33-0.55) (0.08-0.16) (-0.36 to -0.19) Benralizumab 0.59 -75% vs -25% 52% vs 19% 0.13 -0.23 (0.51-0.68) (0.08-0.19) (-0.34 to -0.12) Dupilumab 200mg 0.52 (0.41-0.66) - - 0.14 (0.08-0.19) -0.39 (-0.53 to -0.25) Dupilumab 300mg 0.54 (0.43-0.68) -70% vs -42% 52% vs 29% 0.13 (0.08-0.18) -0.22 (-0.36 to -0.08)

76. Treatment of Type 2 Low Asthma 40 - 50% of asthma patients do not have Type 2 inflammation Severe, uncontrolled asthma without evidence for Type 2 inflammation referred to as ‘Type 2 low asthma’ Potential targets for Type 2 low asthma: Macrolide antibiotics Bronchial Thermoplasty

77. N=420 Symptomatic asthma despite ICS/LABA Azithromycin 500 mg thrice weekly vs placebo for 48 weeks Azithromycin in asthma AMAZES Gibson, Peter G et al. The Lancet 2017

78. Bronchial Thermoplasty AIR2 Trial  Improvement in Asthma Quality of Life Reduction in Health Care Utilization Castro M, et al, Am J Respir Crit Care Med 2010; 81 : 116

79. Tezepelumab – anti-TSLP ab Menzies-Gow et al. Respir Res 2020 Menzies-Gow et al. NEJM 2021

80. Thank you!