COPD and Severe Asthma Update Updates in Internal Medicine March 8 - - PowerPoint PPT Presentation

Beth Israel Deaconess Medical Center

COPD and Severe Asthma Update Updates in Internal Medicine March 8th, 2019

Douglas Beach, MD, MPH BIDMC Pulmonary, Critical Care, and Sleep Medicine

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Overview

• Identification and management of COPD
• How to think about “Asthma/COPD” overlap
• New monoclonal antibodies in treating severe asthma

(and COPD?)

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Outpatient Case

• 66 year old man comes to clinic for shortness of

breath

• Diagnosed with “asthma” 8-10 years ago
• Former smoker, 20 pk year, quit 30 years ago
• Has been on 2 courses of prednisone and

antibiotics for exacerbations in the past 3 months

• No PFTs are available, yet…

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Global initiative for chronic Obstructive Lung Disease (GOLD)

• 1998: Created by the U.S. NHLBI and WHO
• Goal of increasing awareness of COPD to improve

prevention and management

• Updated recommendations 2018
• www.goldcopd.org

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Definition of COPD (GOLD report 2009)

Chronic Obstructive Pulmonary Disease (COPD) is a preventable and treatable disease… Characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases.

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Burden of COPD

• 10% of general population and 50% of heavy smokers
• Excess health expenditures: $6,000 per year/patient (6%
• f total healthcare expenditures U.S.)
• COPD is the 4th leading cause of death
• The number of deaths from COPD is increasing in

women.

• History of asthma increases risk of developing COPD 12-

fold

• 20% of patients with asthma will develop irreversible

airway obstruction

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Consider COPD Diagnosis if patients:

– Symptoms

• Dyspnea
• Chronic cough
• Chronic sputum production

– Have a history of exposure to risk factors (smoking/tobacco, biomass cooking, occupational and environmental exposures to dusts, chemicals, pollution)

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The “GOLD” Standard

• “Spirometry should be performed on individuals over age

40 with symptoms or history suggestive of COPD”

• Remember, it is a preventable and treatable disease!

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Spirometry is necessary for diagnosis

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mMRC score 0-1 CAT < 10 mMRC score ≥ 2 CAT ≥ 10 ≥ 2 exacerbations

• r ≥ 1 hospital

admission

C D

0 or 1 exacerbations and no hospitalization

A B

GOLD 2018: Assessment of symptoms/risk of exacerbations (Group A, B, C, D)

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Back to our patient

• 66 year old with “asthma”, former smoker
• FEV1/FVC ratio 0.54 (73% predicted)
• FEV1 58% predicted (moderately severe)
• Two exacerbations not requiring hospitalization
• mMRC score 1
• CAT: Less than 10

GOLD Grade 2, Group C !!

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www.goldcopd.org

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Recommended initiation treatment of COPD by GOLD Group

Group A: – Short acting bronchodilator when needed Group B:

• One or more long-acting bronchodilators (LABA /LAMA)

Group C: – LAMA – LABA/LAMA or LABA plus Inhaled corticosteroids if repeated exacerbations occur Group D:

• LABA/LAMA/ICS (“triple therapy”)

– Consider macrolide therapy for non-smokers – Consider Roflumilast (Daliresp) if FEV1 less than 50% and recurrent exacerbations

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Beth Israel Deaconess Medical Center

COPD Therapy Goals

– Symptom control (dyspnea, exercise limitation, cough, wheezing) – Reduce exacerbation frequency – Reduce need for hospitalizations – Reduce mortality

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Reducing Mortality

• Smoking cessation should be first and foremost focus of treatment

as it is the only proven method of reducing mortality and rate of lung function decline

• Oxygen therapy for patients with resting hypoxemia has been shown

to reduce mortality – ≤ 88 % (PaO2 55 mmHg) oxygen should be prescribed for 15-18 hours a day to keep PaO2 > 60mmHg and SaO2 > 90%** – ≤ 89% with presence of cor pulmonale

1. **Niewoehner DE. NEJM 2010;362:1407-16. 2.

• NOTT. Ann Intern Med 1980;93:391-8.

3.

• MRCWP. Lancet 1981;1:681-6.

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Smoking Cessation 5 Step Program

US Public Health Service

1. ASK 2. ADVISE 3. ASSESS 4. ASSIST 5. ARRANGE

JAMA 2000; 28:3244-54 NEJM 2011;365:1222-31

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Smoking Cessation Fiore M, et al. NEJM 2011

• For patients who are not ready to quit…
• Motivational Interviewing to discuss the “5 R’s”

– personally relevant reasons to quit – risks associated with continued smoking – rewards for quitting – roadblocks to successful quitting – repetition of the counseling at subsequent clinic visits

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Acute Exacerbations of COPD

• Typically defined by 2 or more cardinal features:

– Change in baseline shortness of breath – Change in sputum volume – Change in sputum purulence Exacerbations are “a natural event in the course

• f the disease…” treated with systemic steroids,

antibiotics, and bronchodilators.

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AECOPD (Hurst JR, et al, 2010)

• Rates of exacerbation increase with:

– decrease in FEV1 (and GOLD stage) – prior history of exacerbations – GERD – Elevated WBC (new data also note eosinophilia associated with exacerbations)

GOLD stage Rate of AE per year (per person) % with 2+ AE/year 2 0.85 22% 3 1.34 33% 4 2.0 47%

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Azithromycin for Prevention of AECOPD

(NEJM 2011;365:689-98.)

• 1142 patients, RCT of azithromycin 250 mg/day vs. placebo
• 1 year f/u ~90% both groups
• Frequency of exacerbations lower in azithromycin group

Group Rate of AECOPD per patient-year P Azithromycin 1.48 0.01 Placebo 1.83

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Advanced therapies for Severe COPD

– Nutrition Therapy – Surgical Options: endoscopic lung volume reduction, Lung Volume Reduction Surgery, Lung Transplant Evaluation. – Referral to pulmonary medicine or other specialist:

• Persistent symptoms and exacerbations.
• Consider alternative diagnosis: severe asthma,

bronchiectasis, alpha-1 antitrypsin deficiency.

• Significant comorbidities: cardiac, sleep disorders,
• r immune deficiency.
• Discussion of goals of care and palliation of

symptoms.

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Outpatient Case

• 66 year old man comes to clinic for shortness of

breath

• Diagnosed with “asthma” 8-10 years ago
• Former smoker, 20 pk year, quit 30 years ago
• Has been on 2 courses of prednisone and

antibiotics for exacerbations in the past 3 months

• Does he have ACOS?

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ACOS (Asthma/COPD Overlap Syndrome)

• COPD: Caused primarily by smoking, pollution,
• ccupational exposures. Occurs after age 40-45

– Inflammation caused by neutrophilic inflammation and CD8 lymphocytes

• ASTHMA:
• Primarily eosinophilic inflammation driven by TH2

lymphocytes

• typically in childhood with allergies. However, asthma

develops in adulthood in a sub-group of patients

• Typically associated with bronchial hyper-

responsiveness

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ACOS (Asthma/COPD Overlap Syndrome)

• Think about ASTHMA
• Triggers?
• Allergies? Allergy testing? IgE?
• PFTs normalize (or near normal)?
• Remember: Severe, persistent asthma that is

UNCONTROLLED looks like COPD

• Patients with ASTHMA component

– Trigger avoidance, Trigger avoidance, Trigger avoidance – Leukotriene modifier – LAMA add on therapy – Immunotherapy?

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Principles of treatment ACOS

• Patient Education
• Trigger avoidance!

– Vaccination – Irritants (allergens, irritants, smoking) – GERD

• “Rescue” inhalers
• Controller medications
• Compliance/Adherence
• Monitoring/follow up

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Biologic Therapies for Asthma

• Omalizumab: Anti-IgE Mab (FDA 2003)
• Mepolizumab: Anti-IL5 Mab (FDA 2015)
• Reslizumab: Anti-IL5 Mab (FDA 2016)
• Benralizumab: Anti-IL5R Mab (FDA 2017)
• Dupilumab: Anti-IL4/IL13 Mab (FDA 2018)

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Omazilumab

• FDA approved 2003
• 200,000 patients treated from 2003-2016
• Moderate to severe persistent allergic asthma on high

dose ICS

• Positive skin/specific IgE tests with IgE 30 to 700 IU/mL
• Binds IgE to prevent activation of mast cells and

basophils which leads to further release of inflammatory mediators (histamine, leukotrienes, tryptase, inflammatory cytokines)

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Omalizumab

• Hanania NA, et al. Ann Int Medicine. 2011
• 850 pts severe asthma on ICS and LABA, IgE 30-700

IU/mL, weight 30kg-150kg

• “poorly controlled asthma”
• 25% reduction in exacerbations

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Targeting Eosinophilic Asthma/COPD

Adapted from: Wills-Karp and Karp,Science, 2004 TH2-High Targets: IL-4 IL-13 Eosinophil Targets: IL-5 Surface Targets (i.e. Siglec-8, EMR-1)

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Anti-IL5 Therapy

• Mepolizumab
• 2 studies NEJM 2009
• N=61 and N=20
• Severe asthma and recurrent exacerbations
• Mepolizumab 750mg IV monthly vs. placebo for 50

weeks

• Results:

– Significant decrease in severe exacerbations

• 2.0 vs. 3.4 (p=0.02)

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Anti-IL-5 Therapy (mepolizumab) in Eosinophilic Asthma

Haldar et al, NEJM, 2009

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Anti-IL-5 Therapy (mepolizumab) in Eosinophilic Asthma

Nair et al, NEJM, 2009

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Mepolizumab: “DREAM” Study

Pavord et al, Lancet, 2012

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Mepolizumab SC randomized trials “MENSA” Ortega HG, et al. NEJM 2014.

• N=576 severe asthma
• Eosinophils > 150/ul during run-in phase or 300/uL in

past year

• Monthly Mepolizumab 100mg sc vs. 75mg IV vs.

placebo

• 32 weeks
• RESULTS:

– Significant reduction in asthma exacerbations requiring hospitalization or ED visits

• Decrease 61% in SC group vs. 32% in IV group vs. Placebo

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Mepolizumab SC randomized trials “SIRIUS”. Bel EH, et al. NEJM 2014

• N=135 patients severe eosinophilic asthma (greater than

150/uL past 3 months or 300/uL 12 months) on chronic steroids

• Mepolizumab 100mg sc once monthly vs. placebo for 20

weeks

• Results

– Significant reduction in annualized rate of exacerbations (32% relative reduction) – 50% reduction in steroid dose compared with placebo

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Reslizumab anti-IL5 MAB (IV route)

• Fewer studies of exacerbation outcomes
• Castro M, et al. Lancet Respir Med. 2015.
• n=953 with poorly controlled asthma on ICS/LABA and

Eos > 400 and one or more exacerbations/12 months

• 12 months
• 50-59% reduction in rate of exacerbations

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Benralizumab (Anti-IL5 receptor MAB)

• FDA approval 11/2017
• Studies have shown a similar response in patients with

severe eosinophilic asthma

• Still EXPENSIVE! ($28-30k/year)
• Given once per month for 3 months, then every other

month

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Benralizumab (Anti-IL5R MAB) in severe persistent asthma with eosinophilia

• NEJM 2017; 376: 2448-2458 (ZONDA)
• Severe asthma on chronic steroids with Eos > 150 past

12 months

• 28 week RCT (Benra 30mg sc once a month x 3 months

then every other month vs. monthly vs. PLACEBO)

• N=220
• RESULTS!

– Steroid dose reduced by 75% vs. 25% for placebo (both doses) – BENRA exacerbation rate reduced: BENRA (8 weeks) 70% reduction vs. BENRA (4 weeks) 55% reduction vs. placebo

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Targeting Eosinophilic Asthma/COPD

Adapted from: Wills-Karp and Karp,Science, 2004 TH2-High Targets: IL-4 IL-13 Eosinophil Targets: IL-5 Surface Targets (i.e. Siglec-8, EMR-1)

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Dupilumab (anti-IL4/IL13 MAB) in OCS dependent severe asthma

• NEJM 2018; 378: 2475-2485)
• 210 patients assigned to DUPILUMAB vs. PLACEBO for

24 weeks

• Steroid dose decreased 70% vs. 42%
• Steroid discontinued in 48% vs. 25%
• Exacerbation rate 59% lower than placebo
• FEV1 increased by 0.22 liters (95% CI 0.09-0.34)
• Transient blood eosinophilia observed in Treatment vs.

Placebo 14% vs. 1%

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Mepo in COPD

• NEJM 377;17: 2017 Pavord ID.
• Two RCT METREO and METREX
• METREX mepo 100mg sc vs. placebo
• METREO mepo 300mg sc vs. 100mg sc vs. placebo
• COPD and asthmatic smokers with chronic obstruction

included

• 52 weeks
• Eos >300 previous year or >150 in 3 months

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MEPOLIZUMAB for COPD with Eosinophilia

• Combined results showed 18-20% reduction

in exacerbations vs. placebo

• No evidence higher doses was effective

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Cost-effectiveness?

Biologic Cost

Omalizumab $10k/year Mepolizumab $30k/year Reslizumab ? Benralizumab $28-30k/year Dupilimab $38k/year

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Take Home Points

• COPD remains underdiagnosed and has high burden of

morbidity and mortality.

• Classification of COPD based on PFTs, symptoms and

risk of exacerbation may help guide therapy.

• Asthma/COPD overlap syndrome (ACOS) is a hot topic

in pulmonary medicine and new trials targeting these patients are underway.

• New monoclonal antibody therapies for patients with

eosinophilia and COPD/severe asthma have shown significant reductions in exacerbations of both.

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Thank you!

• Questions:
• dbeach@bidmc.harvard.edu