Severe Asthma

Robert S. Hutcheson, Jr., M.D. Lectureship

Venkat K Kollipara, M.D Pulmonary and Critical care Physician 4/22/2021 • No conflict of interest Objectives

Clinical scenario of asthma presentation

Asthma phenotypes, endotypes and biomarkers

Changes in new GINA guidelines 2019 and EPR-3 2020 update

Management for severe asthma Case

• Beth is a 25-yo-old schoolteacher with history of asthma, allergic rhinitis presented with chief complaint of worsening shortness of breath and cough. • She was diagnosed with asthma a kid and has been using inhalers since then. • She recently needed to use her albuterol about 3 x wk and is waking up nightly for cough. • She also states that she notes that at times she gets winded when climbing up the stairs to her classroom.

Case

• Currently she is taking Symbicort 160/4.5 bid, Singulair, OTC Allegra and Albuterol prn • Further pertinent history: o She had allergy shots while living in NC as a teenager for about 4-5 years, which she states did help o Lives in a house with mainly wood floors/linoleum. Central air and central heat. She has one indoor cat for the past 6 years. No other pets

Exam

• BP 125/77, Pulse 89, Temp 98.8 °F, Resp 15, BMI 31.2 kg/m2, SpO2 98% • ENT: no nasal polyps • Chest: clear to auscultation. No wheezes and no crackles • ACT 19, NIOX 45

What questions do you ask her next? Assess inhaler technique Types of inhaler devices

• Metered dose inhalers, MDIs • Dry powder inhalers • Soft mist inhalers • Nebulizers • Spacers Mitigation Strategies

• Allergen mitigation interventions are recommended only in individuals with asthma who are both exposed to and either sensitized to or develop symptoms on exposure to specific allergens • Multicomponent Allergen Mitigation Strategies • Dust mite–impermeable pillow and mattress covers • HEPA vacuums, carpet removal • Mold mitigation • Integrated pest management (rodents and/or cockroaches)- block infestation (eg, filling holes in walls, reducing standing water) and abatement (eg, traps, fumigation) Asthma

• Asthma is a chronic inflammatory disorder of the airways characterized by bronchial hyperresponsiveness and variable airflow limitation • Affects > 300 million people worldwide • Majority of patients with asthma can achieve disease control with standard controller therapy • Approximately 5-10% have severe asthma that remains inadequately controlled despite adherence to standard treatment with a high-dose ICS plus LABA/LAMA Prevalence and burden of asthma

The direct costs of uncontrolled asthma in adolescents and adults in the United States over the next 20 years is likely to be a staggering $1.5 trillion

National Center for Environmental Health, CDC, 2017 Contributing Factors to Asthma

Genetic Factors Environmental Factors Triggers Viral infections Exposure to allergens Occupational exposure Tobacco smoke Aspirin Indoor and outdoor pollutants Factors Influencing the Development of Atopy and Allergic Inflammation Mediated by Th2 Cells

A.B. Kay, M.D, N Engl J Med 2001; 344:30-37 Asthma characteristics

• Variable and recurrent symptoms • Reversible Airflow obstruction • Bronchial hyperresponsiveness • Airway inflammation Case cont..

Next clinic visit, patient stated she is using inhalers as prescribed and demonstrated good technique

Still complaining of shortness of breath and episodic wheezing

What further workup do you need? Terminology

• Phenotype: The observable characteristics of a disease, such as morphology, development, biochemical or physiological properties, or behaviors. • Examples: allergic asthma, aspirin-exacerbated respiratory disease, severe eosinophilic asthma

• Endotype: A subtype of disease, defined functionally and pathologically by a distinct molecular mechanism or by distinct treatment responses (Anderson, Lancet 2008) • Examples: emphysema due to alpha1-antitrypsin deficiency

• Biomarker: A defined characteristic measured as an indicator of normal biologic processes, pathogenic processes or response to an intervention • Potential examples: FeNO, blood eosinophils – but these may not meet quality criteria for biomarkers

Anderson, Lancet 2008; Reddel, ERJ Open Res 2019 © Global Initiative for Asthma, www.ginasthma.org Asthma endotypes

• Heterogeneous disease with multiple phenotypes that are caused by a variety of pathophysiologic mechanisms, or endotypes • There are two specific endotypes, • Type 2 (T2) high • T2 low • These endotypes are defined based on their level of expression of cytokines such as IL-4, IL-5, and IL-13 that may be secreted by the classic T-helper cell type 2 (Th2)-type cells, such as the CD4 lymphocytes, or nonclassic immune cells, such as the innate lymphoid cells–type 2 (ILC-2)

Mary Clare McGregor et al, Am J Respir Crit Care Med, Feb 15, 2019 Major biomarkers in Asthma

• Blood eosinophils • Sputum eosinophils • FeNO • Periotin • Serum IgE Eosinophil as an Inflammatory Biomarker

• Variable numbers of blood and airway eosinophils are present in patients with type 2 cytokine profiles • Likely relates to level of type 2 activation • Eosinophils in blood and airway are correlated with: • Frequency of asthma exacerbations • Degree of airflow limitation • Presence and severity of chronic rhinosinusitis/nasal polyposis Sputum Eosinophil Count

• Sputum is induced with hypertonic saline (subject inhales aerosol of hypertonic saline for 15-minute periods and then is encouraged to cough up a sample of sputum) • Normal sputum eosinophils is 3% in adults

Sputum Eosinophils

• Sputum eosinophils appear to correlate well with disease severity, lung function, and BHR • Asthmatics treated with ICS show a decrease in sputum eosinophils NITRIC OXIDE

• In asthma, there is some evidence that this enzyme is up-regulated, and elevated levels of NO have been detected in the exhaled air of asthmatic subjects • Potent vasodilator and bronchodilator • Utility of exhaled NO may be in monitoring asthma control, guiding therapy and providing an indication of corticosteroid sensitivity

Source of exhaled nitric oxide

• Current thinking is that exhaled NO is derived from the upper and lower respiratory tract (airway & alveolar) and diffuses by gaseous diffusion down a concentration gradient, thus conditioning exhaled air • Exhaled NO is produced by NO synthase in respiratory epithelium under direct control of IL-13 and possibly other factors • often, but no always correlated with sputum/blood eosinophil numbers • is a moderately reproducible marker of Th2 phenotype

Periostin

• Up-regulated by type 2 cytokines IL-4 and IL-13 • Serum periostin can predict the efficacy of anti-IL 13 antibodies (lebrikizumab) and anti-IgE antibodies (omalizumab) • Periostin-high asthma patients have several unique characteristics, including eosinophilia, high fraction of nitric oxide, aspirin intolerance, nasal disorders, and late onset

Asthma Control Test (ACT) Case cont..

. Component Value o Alternaria Alternata <0.10 kU/L o Cat Dander (E1) IgE 31.00 kU/L o Cladosporium Herbarum IGE <0.10 kU/L • Right now, using ICS/LABA and o American Cockroach (I206) IGE <0.10 kU/L PRN SABA o Common Ragweed IGE 1.04 kU/L • ACT 18, NIOX 45 o Dust Mite(D.Farinae) (D2) IGE <0.10 kU/L o Dust Mite(D.Pterno.) (D1) IGE <0.10 kU/L o Dog Dander (E5) 1.26 kU/L o Elm (T8) IGE 0.44 kU/L • What is your next step? o IgE 164 kU/L

WBC 11,300, 3.6% eosinophils = 396 eosinophils Goals of asthma treatment

• Few asthma symptoms • No sleep disturbance Symptom control • No exercise limitation • Maintain normal lung function • Prevent flare-ups (exacerbations) • Prevent asthma deaths Risk reduction • Avoid medication side-effects

• The patient’s goals may be different from these • Symptoms and risk may be discordant – need to assess both

The best predictor of future exacerbations was a history of previous exacerbation

• Consider and treat comorbidities • Exclude other diagnosis • Poor asthma control due to inadequate understanding of disease management by the patients must be excluded

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. European Respiratory Journal . 2014 43: 343-373.

SMART (Single Maintenance And Reliever Therapy)

• SMART is recommended in adolescents (aged 12-17 years) and adults (aged 18 years or older) with moderate persistent asthma as the preferred therapy for steps 3 and 4 (strong recommendation, high certainty of evidence). • SMART has been reported only with formoterol as the LABA, which is why the recommendation is specific to formoterol therapy. • Regular daily use in SMART is defined as 1 to 2 puffs once to twice daily. • As-needed use in SMART is defined as 1 to 2 puffs (4.5 μg of formoterol per puff) every 4 hours as needed for asthma symptoms, up to a maximum of 12 total puffs per day for individuals aged 12 years or older.

2020 Asthma Guideline Update From the National Asthma Education and Prevention Program 2020 Asthma Guideline Update From the National Asthma Education and Prevention Program Case cont..

• You get all the labs results (+RAST, IgE- 164, blood eosinophils 396, FeNO 54, ACT 17) • Follow up clinic visit, patient is compliant with her inhalers, good tech, no triggers, well controlled allergies • Patient still symptomatic and recently admitted to hospital for asthma exacerbation

• What treatment options do you have to better control her asthma?

How to investigate uncontrolled asthma

• Severe asthma is asthma that requires Step 5 treatment o Morbidity, mortality, o Increased hospitalizations, o Detrimental side effects of oral corticosteroids (OCS), o Poor quality of life (QOL), and o Impaired lifestyle as compared with patients with well-controlled disease • Referral for expert advice should be considered for patients who have been hospitalized for asthma, or who re-present for acute asthma care or had >1-2 exacerbations/year despite Step 4-5 treatment

Type 2 High and T2 Low Airway Inflammation

• In T2-high asthma, inhaled allergens, microbes, and pollutants interact with the airway epithelium, which subsequently leads to activation of mediators such as thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 • This process leads to activation of IL-4, IL-5, and IL-13, which can result in attraction and activation of basophils, eosinophils, and mast cells; secretion of IgE by B cells; and activation of innate cells such as the airway epithelium and smooth muscle, resulting in bronchoconstriction, airway hyperresponsiveness, mucus production, and airway remodeling Characterization of Inflammatory Pathways and Biomarkers

Type 2 (T2)—50% to 70% T2 low—30% to 50% Main cytokines = IL-4, IL-5, IL-13 Cytokines and cells not well-characterized; may involve IL-17, GM-CSF Cell sources = Th2 cells, IL-C2 cells, mast Frequently related to bronchial infection cells Variable airway, tissue and blood No increase in eosinophils, eNO; may have eosinophilia and eNO; leukotrienes in AERD increase in sputum PMNs Large portion have elevated total IgE and Typically, do not have elevated IgE or specific IgE relevant specific IgE eNO, exhaled nitric oxide; GM-CSF, Granulocyte-macrophage colony-stimulating factor; IgE, Immunoglobulin E; PMN, polymorphonuclear; Th2, T helper 2 Cytokines Mechanism of action IgE Stimulate mast cells IL-4 Stimulate B cells to proliferate and class switch IL-5 Differentiation, survival, migration, and activation of eosinophils IL-13 Bronchial enlargement, basement mem thickening, goblet cell hyperplasia/mucous production, smooth ms contractility TSLP Stimulate dendritic cells and differentiation IL-17 Potent proinflammatory cytokines, stimulate neutrophil CRTh2 Th2 and ILC-2 cell differentiation

Allergic & eosinophilic T2-high severe asthma

ERJ Open Res 2018; 4: 00125-2017

Monoclonal antibodies Anti-eosinophilic drugs in Asthma

Elisabeth H. Bel et al, CHEST 2017; 152(6):1276-1282 Anti-IgE- Omalizumab (Xolair)

Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma

Placebo

✔ Phase III RCT 525 patients with severe Primary outcome: ✔ Double blinded allergic asthma and daily ✔ Asthma exacerbations ✔ Placebo controlled ICS ✔ Decrease in ICS dose

Omalizumab sc q 2 or 4 wks based on body wt and serum IgE levels

Busse W et al, J Allergy Clin Immunol. 2001 Aug;108(2):184-90 Results

Busse W et al, J Allergy Clin Immunol. 2001 Aug;108(2):184-90 Omalizumab (Xolair)

Mechanism of Indication Dose Side effects Monitoring action • Binds to free • Moderate- • Based on • Black box • None IgE severe pre- warning- uncontrolled treatment anaphylaxis asthma IgE level and • Close • Positive body weight observation allergy test, for at least IgE- 30 to 30 mins in 700 clinic Anti-IL-5 > Mepolizumab (Nucala) Reslizumab (Cinqair)

Anti-IL-5 rec > Benralizumab (Fasenra)

Elisabeth H. Bel, N Engl J Med 2014; 371:1189-1197 Hector G. Ortega et al, N Engl J Med 2014; 371:1198-1207 Ian D Pavord et al, LANCET 2012, doi.org/10.1016/S0140-6736(12)60988-X Chupp at al, April 05, 2017 doi.org/10.1016/S2213-2600(17)30125-X Sumita Khatri et al, J Allergy Clin Immunol 2019;143:1742-51 Mepolizumb (Nucala)

Indications Dose Side effects Monitoring

• Moderate- • 100 mg SC q • No life • None severe 4 weeks thretening uncontrolled side effects, asthma rare • Peripheral anaphylactic eosinophils- reaction 150 to 300 Benralizumab (Fasenra)

Bleecker ER et al, Lancet. 2016;388(10056):2115-2127 (SIROCOO) FitzGerald JM et al, Lancet. 2016;388(10056):2128-2141 (CALIMA)

Anti-IL-5 therapies in Asthma

JAMA. 2018;319(14):1501-1502. doi:10.1001/jama.2018.3609 Anti-IL-4- Dupilumab (Dupixent)

Mario Castro at el, N Engl J Med 2018; 378:2486-2496 Change in the Prebronchodilator FEV1 from Baseline over the 52-Week

Mario Castro at el, N Engl J Med 2018; 378:2486-2496 WENZEL S AT EL, LANCET, JULY 02, 2016 Mario Castro at el, N Engl J Med 2018; 378:2486-2496

Biologics Mech Clinical criteria Lab criteria Dose Other uses Side effects (Add on therapy) Omalizumab Anti-IgE Severe asthma on +RAST SC q 2/4 Chronic Anaphylaxis (Xolair) high dose ICS + IgE >30 idiopathic (0.3%) LABA/LAMA urticaria Mepolizumab Anti-IL 5 Above w at least 1 PEC >150 SC 100 q 4 EGPA- 300 q Auto (Nucala) exacerb in last 1 within 6 wks 4 injection year or >300 in available last 1 yr Benralizumab Anti-IL 5 rec Above w at least 1 PEC >300 SC 30 mg q Auto (Fasenra) alpha exacerb in last 1 4 > q 8 injection year available Reslizumab Anti-IL 5 Above w at least 1 PEC >400 IV 3 mg/kg Anaphylaxis (Cinqair) exacerb in last 1 with in 4 wks q 4 (0.3%) year Dupilumab Anti-IL 4 Above w at least PEC >150 SC 400/600 Atopic Auto (Dupixent) 1 exacerb in last +/- FeNO > mg > dermatitis, injection 1 year 50 200/300 mg chronic available q 2 rhinosinusitis w nasal polyposis European Respiratory Journal 2016 47: 304-319 Under investigation Biologics Mech Clinical trials

Lebrikizumab Anti-IL 13 Failed to show benefit in 2 trials Tralokinumab Anti-IL 13 On going

Tezepelumab TSLP On going

Fevipiprant DP2/CRTh2 rec antagonist 3 phase III trials (NCTO2563067, NCTO3052517, NCTO2555683) Bronchial thermoplasty

• Delivers controlled thermal energy to the airway wall during a series of bronchoscopy procedures, resulting in a prolonged reduction in airway smooth muscle (ASM) mass. • Increased mass and contractility of ASM augments asthma morbidity by causing greater bronchoconstriction and airflow obstruction. • Decreasing the amount and/or contractility of ASM may provide a means to ameliorate the symptoms of asthma.

AIR2 trial

Mario Castro et al, Am J Respir Crit Care Med 2010 Jan 15 Long-term outcomes of bronchial thermoplasty in subjects with severe asthma: a comparison of 3-year follow-up results from two prospective multicenter studies

Severe exacerbation rates ED visit rates Hospitalization rate

Geoffrey Chupp et al, European Respiratory Journal 2017 50: 1700017 ERJ Open Res 2018; 4: 00125-2017 • The treatment of asthma is moving toward a personalized treatment strategy that is based on patient-specific characteristics and underlying endotype rather than disease severity alone.

Back to our patient, Beth

• Given her +RAST and IgE, you decided to start on Anti-IgE medication > Omalizumab

• On next clinic visit > her breathing is better, and she no longer needed ED visits or hospital admissions for asthma exacerbation and haven’t used her PRN inhalers What triggers and risk factors did we find on Beth?

• Cat allergy • Triggers for asthma Allergic phenotype • Inhaler technique • Excluded mimics of asthma • Allergy panel (+RAST) • Elevated serum eosinophils Th2 high endotype • Elevated serum IgE levels

Thank you!

Questions??