program learning objectives...• smokes 5 cigs per day x 40 years • he adopted a pet dog several...
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Program Learning Objectives
• Apply current management guidelines to diagnose asthma correctly, optimize inhaled therapy, address comorbidities, and recognize when asthma is not well controlled.
• Review evidence related to potential long‐term effects of oral corticosteroids and assess their role in asthma management in the era of biologic therapies.
• Identify key features of moderate to severe asthma that are targets for biologic therapies
• Individualize biologic and non‐biologic therapies for patients based on their inflammatory phenotype, coexisting conditions, and other individual factors.
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The Severe Asthma Roadmap for Navigating Asthma Control will guide the discussion for this activity.
A copy of the Roadmap can be found in your meeting materials.
Overview of Severe Asthma• Affects an estimated 5% to 10% of the asthma population
• Highly heterogeneous disease requiring individualized assessment and management
• Remains poorly controlled despite high‐dose ICS with or without additional controller therapies (ie, LABAs, LAMAs, LTRAs, and/or theophylline)
• Significantly impacts ADLs, morbidity, mortality, QOL, and health care utilization
• Optimal treatment remains challenging despite advances in understanding of the underlying pathophysiology and availability of targeted therapies
Chung KF, et al. Eur Respir J. 2014;43(2):343‐73; Katial R, et al. J Allergy Clin Immunol Pract. 2017;5(2S):S1‐S14; Hossny E, et al. World Allergy Organ J. 2017;10(1):28.
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ATS/ERS (2014): Severe Asthma
• One or more of the following:
• Poor symptom control: ACQ consistently >1.5, ACT <20 (or ‘‘not well controlled’’ by NAEPP/GINA guidelines)
• Frequent severe exacerbations: ≥2 bursts of systemic CS (>3 days each) in the previous year
• Serious exacerbations : ≥1 hospitalization, ICU stay, or mechanical ventilation in the previous year
• Airflow limitation: after appropriate bronchodilator withhold FEV1 <80% predicted (in the face of reduced FEV1/FVC defined as less than the lower limits of normal)
• Controlled asthma that worsens on tapering of high doses of ICS or systemic CS (or additional biologics)
Chung KF, et al. Eur Respir J. 2014;43(2):343‐73
ATS/ERS (2014): Severe Asthma
• Patients ≥ 6 years of age• Requires GINA steps 4 or 5 treatment to prevent it from becoming “uncontrolled” or which remains “uncontrolled” despite this therapy:
ATS, American Thoracic Society; ERS, European Respiratory Society; GINA, Global Initiative on Asthma; CS, corticosteroids.
Chung KF, et al. Eur Respir J. 2014;43(2):343‐73.
High‐dose ICS+LABA or LTRA/theophylline for the previous year
CS for ≥ 50% of the previous year
OR
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Global Initiative for Asthma (GINA) 2019
Global Initiative for Asthma website. https://ginasthma.org/wp‐content/uploads/2019/04/GINA‐Severe‐asthma‐Pocket‐Guide‐v2.0‐wms‐1.pdf Updated 2019. Accessed May 2019.
Step 1 Step 2Step 3
Step 4
Step 5
Preferred Controller Choice
Other Controller Options
Reliever
low dose ICS +/‐ Formoterol
As‐needed SABA or ICS/Formoterol As‐needed SABA or low dose ICS/formoterol
Low Dose ICS or ICS/Formoterol
Low Dose ICS/LABA
MediumDose
ICS/LABA
High dose ICS/LABA
Refer for add‐on treatment
(e.g., tiotropium,
anti‐IgE, anti‐IL‐5/5R, Anti
IL4/13, Bronchial
Thermoplasty)
Leukotriene receptor antagonists (LTRA)
Med/high dose ICS+LTRA
Add low dose OCS
Add tiotropium med/high dose
ICS+LTRA(or + theophylline)
“Severe” Asthma
Difficult‐to‐control asthma
Lack of asthma control is due to factors other than asthma itself (non‐adherence, incorrect inhalation technique, comorbidities)
True refractory asthma
Causes of difficult asthma addressed or excluded, but still have poor asthma control or > 2 exacerbations/year despite high‐intensity treatment & verified adherence
ERS/ATS Guidelines on Definition, Evaluation and Treatment of Severe Asthma Eur Respir J 2014; 43: 343–373Hekking et al J Allergy Clin Immunol. 2015 Apr;135(4):896-902
85-90% 10-15 %
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Confirm diagnosis
Factors to Consider Once Asthma Diagnosis Confirmed
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Patient Case: Greg
• 57 year‐old with lifelong asthma recently discharged from the hospital
• History: allergic rhinitis, gastroesophageal reflux, obesity, obstructive sleep apnea, hypertension, and type 2 diabetes.
• Smokes 5 cigs per day x 40 years
• He adopted a pet dog several years ago
• He has wall‐to‐wall carpeting throughout his home
• Prior allergy testing with sensitivity to cats, dogs, dust mite, cockroach, trees, grass, and weeds.
• Three exacerbations requiring prednisone in the past year including recent ICU admission and intubation.
Patient Case: Greg
• Still feeling poorly: still coughing day and night• Using nebulizer 2‐3 times per day and albuterol MDI 2‐3 times per day with only transient relief of symptoms
• Trouble dressing and showering due to persistent, shortness of breath
• Medications: • Fluticasone / Salmeterol (Diskus device) 500/50 mg one inhalation twice daily
• Albuterol MDI and/or nebulizer solution q 4‐6 hours as needed
• Atenolol 50 mg daily• Metformin 500 mg twice daily• Atorvastatin 40 mg daily
In your office post discharge:
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• PFT’s pre/post albuterol
• Methacholine challenge
• CXR/Chest CT
• Labs: IgE, CBC/diff
• Exhaled NO
• Allergy skin testing
• Sinus CT• Barium swallow / Esophagram
• Esophageal manometry• pH Impedance study• Cystic fibrosis testing• Alpha 1 Antitrypsin level and phenotype
• Cardiac workup• Bronchoscopy
Workup of Refractory Asthma
Factors contributing to Greg’s poor asthma control
• Incomplete controller adherence on review of pharmacy records
• Poor inhaler technique• Comorbidities (e.g. GERD)• Environmental factors
(e.g. smoking, allergens in home environment)• Possibly medications
(i.e. beta blocker use)
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Evaluating Adherence and Inhaler Technique
Check inhaler technique and adherence
• Acknowledge likelihood of incomplete adherence (no judgments!)
• Review asthma obstacles, attitudes, knowledge (OAK)• Do they understand how medications work• Do they have a routine?• What do friends/family tell them about their medications?• Are they having/are they worried about adverse effects?• Can they afford their medications?
• Check adherence and technique (CAT)-Inhaler counters -Call pharmacies-Observe technique (again and again!)
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Greg: Follow Up Visit
• It has been six weeks since you last saw Greg • Review of EMR confirms refills of inhalers• You review his inhaler technique and it is perfect• He has been working to quit smoking • Atenolol has been changed to Amlodipine• Dog adopted by his son• GERD treated with lifestyle modification and PPI• You are meeting with him today to review his pulmonary function test results and to discuss his current asthma symptoms.
• Asthma Control Test Score now 20.
Patient Case: Theresa
• 54‐year old w/ uncontrolled asthma & chronic rhinosinusitis w/ nasal polyposis
• No asthma as a child, but onset of severe symptoms over the past three years
• Hospitalized for asthma several times, 5 courses of oral corticosteroids in the past year
• Recently placed on 10 mg prednisone daily by her pulmonologist
• Gained 10 lbs, + new hypertension diabetes, anxiety and poor sleep
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• Theresa’s CBC and differential come back with a peripheral blood absolute eosinophil count of 60/uL. She had a measurement of 420/uL eight months prior to being on oral steroids.
• Induced sputum cell differential count• 4% eosinophils• 76% macrophages• 10% lymphocytes• 10% polymorphonuclear cells
Evaluation: Theresa
Next Steps on the Severe Asthma Roadmap
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Adverse effects of chronic corticosteroid use
Cardiovascular (edema, dyslipidemia, premature CAD, arrhythmias) Skin (Striae, Skin thinning/bruising, acne) Skeletal (AVN, Osteoporosis, myopathy)Hypertension, HPA suppression, Hematologic (leukocytosis)Immunosuppression leading to infections
Neuropsychiatric (depression, mood changes, insomnia, akathisia, mania, psychosis, euphoria)Glucose Intolerance (steroid associated diabetes)Osteoporosis, Obesity, Ocular (cataracts, glaucoma)Impaired wound healing
Next Steps on the Severe Asthma Roadmap
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Asthma Phenotype vs Endotype
PhenotypeThe set of observable characteristics of an individual resulting
from the interaction of its genotype with the
environment
EndotypeA specific biologic mechanism that
explains observable properties of an organism
Different asthma phenotypes and endotypes may respond differently to targeted therapies
Type 2IL‐4, IL‐5, IL‐13 or IgE mediatedInflammation with high eosinophils or FENO
Non‐Type 2Neutrophilic airway inflammation or Paucigranulocytic
Biomarker: Blood Eosinophils
• Eosinophilic airway inflammation is often found in patients with asthma
• Blood eosinophils can be a surrogate marker for eosinophilic inflammation in the airway
• Studies suggest blood eosinophil counts as low as 150 cells/μL may predict positive treatment response with certain targeted therapies
Douwes J, et al. Thorax. 2002;57(7):643‐648; Eltboli O, Brightling C. Expert Rev Respir Med. 2013;7(1):33‐42 Ortega HG, et al. Lancet Respir Med. 2016;4(7):549‐556 Wagener A, et al. Thorax. 2015;70(2):115‐120
Eosinophildifferentiation
Eosinophiltraffickingto tissues
Th2 cellIL-5 IL-4
IL-5
IL-13
ILC2 cell
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Biomarker: Fraction of exhaled nitric oxide (FeNO)
• Nitric oxide is produced by the lung and present in exhaled breath
• Patients with asthma can have high FeNO in their exhaled breath
Alving K, et al. Eur Respir J. 1993;6(9):1368‐1370; Dweik RA, et al. Am J Respir Crit Care Med. 2011;184(5):602‐615 Kharitonov SA, et al. Lancet. 1994;343(8890):133‐135
FeNO Levels Clinical Implications
High>50 ppb in adults>35 ppb in children
Likely eosinophilicinflammation and corticosteroid responsiveness
Medium20‐50 ppb in adults20‐35 ppb in children
Cautious interpretation necessary
Low<25 ppb in adults<20 ppb in children
Less likely eosinophilicinflammation or cortico‐steroid responsiveness
Biomarker: Immunoglobulin E
• Elevated IgE levels can predict asthma diagnosis in some patients
• IgE levels are associated with higher blood eosinophil counts and FeNO concentrations
• IgE levels are tested to determine eligibility for certain severe asthma therapies—eg, anti‐IgE biologic agents
• Anti‐IgE therapy may be more effective in patients with high levels of biomarkers associated with type 2 inflammation
Ahmad Al Obaidi AH, et al. J Asthma. 2008;45(8):654‐663; Matsui EC, et al. Allergy. 2010;65(11):1414‐1422; Hanania NA, et al. Am J Respir Crit Care Med. 2013;187(8):804‐811
IgE
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Severe Asthma Phenotype Biomarkers: Strengths and Limitations
BAL, bronchoalveolar lavage; CBC, complete blood count, IgE Menzella F, et al. Ther Clin Risk Management. 2016;12:907‐916; Mathur SK, et al. Ann Allergy Asthma Immunol. 2016;117(5):551‐553
Procedure/Type of Sample
Strengths Limitations
Allergy SPT +/‐ specific and total IgE • Atopy linked to type 2 inflammation • Do not predict response to biological therapies (anti‐IgE and anti‐IL‐5)
Sputum eosinophils• Specific biomarker of airway inflammation
• Requires specialized expertise to obtain and interpret sample
Blood eosinophils
• Easy blood sample collection; standard inclusion in CBC; predictive for efficacy with anti IgE, anti IL‐5 and IL4/13 therapies
• Variability of estimates• Suppressed by oral corticosteroids
FeNO• Easily measurable with available device• Predictive of response to anti IgE anti
IL4/13 therapies
• Interpretation of results still controversial
Serum periostin• Easy blood sample collection; induced by IL‐4 and IL‐13
• Data still controversial
Bronchoscopy with biopsies and BAL • Cell count and differential
• Present gold standard• Invasive procedure
Biologic Therapies: Anti‐IgE
Treatment of refractory allergic asthma: Omalizumab (anti‐IgE)
Binds free IgE & inhibits its binding to mast cells
Reduces early & late allergic responses
Eligibility: IgE in dosing range (35‐700) and + perennial allergen
Reduces exacerbations (~50%)
Non‐responders
Pelaia et al Journal of Asthma and Allergy 4:49‐59 2011
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Biologic Therapies: Anti–IL‐5 and Anti–IL‐5 Receptor
• Mepolizumab & Reslizumab - anti-IL-5 monoclonal antibodies
• Benralizumab - antibody
to the alpha subunit of
the IL-5 receptor
Varricchi et al Front. Immunol. 2017; Farne et al‐IL5 therapies for asthma. Cochrane Database of Systematic Reviews 2017, Issue 9
• Reduction of asthma exacerbations by ~ 50%• Reduction in steroid dose in oral corticosteroid dependent patients (~ 50% reduction)
Vatrella et all J Asthma Allergy 2014Castro et al NEJM vol 378 # 26 June 2018Rabe et al NEJM vol 378 # 26 June 2018
Biologic Therapies: Anti–IL‐4 Receptor‐α
• Phase 3 studies reduced exacerbation, improved lung function and asthma control
• Greater benefit in patients with higher FeNO and eosinophilia, but benefit still present at AEC < 300/uL
• Approved by the FDA in October of 2018
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FDA Approved Biologic Therapy for Severe Asthma
Biologic Therapy Target Approval Date
Omalizumab IgE 2003
Mepolizumab IL‐5 2015
Reslizumab IL‐5 2016
Benralizumab IL‐5Rα 2017
Dupilumab IL‐4Rα/IL‐13 2018
Non‐Type 2 Asthma Therapies
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Type 2 Asthma Therapies
Theresa: Follow Up Visit
• Four months have passed since Theresa began biologic therapy for asthma.
• You are seeing her today and she is still taking 10 mg prednisone daily.
• She had one exacerbation requiring a boost of her chronic OCS dose.
• You are meeting with her today to discuss her asthma and its management.
• Asthma Control Test score now 19
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• Establish that dose of OCS being currently used is truly needed (optimization)
• Taper at a rate that will prevent destabilization of underlying disease and avoid HPA axis suppression
• Increased risk of HPA axis suppression • > 20 mg for more than 3 weeks• Evening dose of > 5 mg daily for > few weeks• Cushingoid appearance
General principles for tapering oral corticosteroids
Relative corticosteroid‐sparing effects of biologic therapies
Outcome MepolizumabN=69
PlaceboN=66
BenralizumabN=145 (pooled)
PlaceboN=75
DupilumabN‐103
PlaceboN=107
Median % dose reduction (IQ range)
‐50 (20‐75) 0 (‐20‐33) ‐75 (‐100‐100) 25 (‐150‐100)
‐100 (‐100 to ‐62.5)
‐50 (‐100‐0)
Dose at screening (med mg)
12.5 (5‐35) 15 (5‐35) 10 (7.5‐40) 10 (7.5‐40) 10 (5‐35) 10 (5‐35)
100% reduction (%)
14 8 30 10 52 29
Exacerbation reduction vs. placebo (%)
32 55‐75 59.3
Mepolizumab (SIRIUS) Bel et al N Engl J Med 2014; 371: 1189‐9; Benralizumab (ZONDA) Nair et al N Engl J Med 2017; 376: 2448‐58; Dupilumab (LIBERTY ASTHMA VENTURE) Rabe et al N Engl J Med 2018; 378: 2475‐85
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Steroid reduction schemes in corticosteroid‐sparing biological clinical trials
Key points• Reduction by 10 mg every 4 weeks for those taking 20 mg or more (SIRIUS, VENTURE), then by 5 mg from 10‐15 mg down to 5 mg, then by 2.5 mg
• 5 mg every 4 weeks until 10 mg then by 2.5 mg increments (ZONDA)
• Only those on 12.5‐20 mg tapered to 0 (SIRIUS, ZONDA) vs. as high as 30 mg (VENTURE)
Mepolizumab (SIRIUS) Bel et al N Engl J Med 2014; 371: 1189‐9; Benralizumab (ZONDA) Nair et al N Engl J Med 2017; 376: 2448‐58; Dupilumab (LIBERTY ASTHMA VENTURE) Rabe et al N Engl J Med 2018; 378: 2475‐85
Criteria to use for stopping taper (either optimization or during active treatment)
1. Symptom score (ACQ)‐increase > 0.5 (MCID)
2. FEV1 or AM PEF < 70‐80 % of baseline
3. Level of SABA use (increase of 4 puffs per day over baseline, < 12 puffs daily
4. > 50% increase in nocturnal symptoms
5. Exacerbation, requires OCS
6. Symptoms of adrenal insufficiency or steroid withdrawal
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Inflammation, Phenotypes, Endotypes, and in Severe Asthma are Heterogeneous
Eosinophilia (eosinophilic asthma)
Severe Asthma
Type 2‐high Type 2‐low IL‐4, IL‐13, IL‐5‐ mediated IL‐6, IL‐17, TNF mediated
Allergic sensitization
Neutrophilia
Paucigranulocytic
Disease burden: Exacerbations, symptoms, airflow obstruction/FEV1 impairment
Early age of onset Later age of onset
Elevated FeNO
Chronic rhinosinusitis ± nasal polyps
Atopic dermatitis
Elevated IgE
gType 2 inflammation is prevalent in patients with uncontrolled persistent asthma, and these patients have
the highest disease burden
Endotype
Phenotype
Comorbidities
Biomarker
Obesity, infections, smokers
Type 2 Asthma Treatment Approaches
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Bronchial Thermoplasty
• FDA approved for asthma not controlled on standard therapy
• Most safety data in patients with moderate lung function impairment (FEV1 > 60%)
• Ongoing controversy about its role• Reimbursement limitations • Who is the ideal target population?• We don’t know but maybe…….
– Severe BHR despite maximal medical therapy
– Pauci‐inflammatory forms of asthma (obesity?) with poor response to ICS and BHR Image source: www.btforasthma.com
Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma
• Uncontrolled on ICS/LABA, age > 18 (n=420)
• No hearing impairment or prolonged corrected QT
• Azithromycin 500 mg vs placebo 3x per week x 48 weeks
• Reduced annualized exacerbations and proportion of participants with an exacerbations
Gibson et al Lancet 2017; 390: 659‐68
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When to select a biologic
• Frequent exacerbations?•Chronic OCS use?•Persistent symptoms despite current therapy?
How to choose a biologic based on biomarkers
• Convenience of administration
• Frequency of adminsitration
• Presence of Type 2 comorbidities as determinants• Atopic dermatitis
• Nasal polyposis
• Chronic rhinosinusitis
IgEBlood EOSFeNO
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In Summary
• Common causes of poorly controlled asthma are non‐adherence, poor inhaler technique, environmental triggers, and comorbidities
• In true refractory patients, biomarkers can be useful in classifying asthma phenotypes and predicting treatment responses
• Targeted Type 2 biologic therapies, including anti‐IgE, anti‐IL‐5, anti‐IL‐5Ranti‐IL‐4Rand anti‐IL‐13 can improve symptoms, decrease exacerbation risks, and improve QoL
Conclusions
• Asthma is a spectrum of diseases, with different pathologic and clinical phenotypes
• There has been an increased understanding of the immunology of asthma, leading to new therapeutic options
• Defining phenotypes and endotypes in asthma is a young field, but it is making progress
• Tailoring treatment to phenotypes and endotypes is the ultimate goal
• Patients with severe asthma may require additional evaluation and referral to specialty centers
• Patients with allergic asthma not well controlled with high‐dose ICS and an additional controller can be considered for treatment with omalizumab
• Patients with severe eosinophilic asthma not controlled with ICS/LABA may benefit from an inhibitor of IL‐5 (mepolizumab, reslizumab, or benralizumab)
• Consider Dupilumab with eosinophilic or type 2moderate severe asthma or on systemic steroids