Disclosures Update on COPD & Asthma No Pharma Disclosures - - PDF document

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Update on COPD & Asthma

Michael C. Peters, M.D. MAS Division of Pulmonary & Critical Care Medicine Cardiovascular Research Institute University of California San Francisco

UCSF Primary Care Medicine San Francisco, CA May 27, 2016

Disclosures

• No Pharma Disclosures
• NHLBI - Asthma Clinical Research Network
• NHLBI – Severe Asthma Research Program
• Parker B. Francis Foundation

Update on the Management of COPD

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To review COPD

• COPD is a leading cause of death worldwide, and

mortality is increasing

• Exacerbations are the major complication of COPD
• Associated with increased loss of lung function
• And Mortality
• There are effective strategies for decreasing

exacerbations

• COPD = Inflammatory Disease
• O2 therapy
• Pharmacologic Therapy:

(“it’s not just for symptoms anymore”)

• Decreasing exacerbations
• Change natural history?
• Pulmonary Rehab: reduces symptoms, depression,

health care utilization; improves Q of L, exercise

COPD

• Smoking Cessation modifies natural history

(lung function, mortality)

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Question #1: Which of the following is NOT true?

1. COPD mortality has plateaued

• 2. Hospitalization for

exacerbation predicts mortality

• 3. Most exacerbations are

caused by infection

• 4. There are effective

strategies for decreasing exacerbations

Question #1: Which of the following is NOT true?

• 1. COPD mortality has

plateaued

• 2. Hospitalization for

exacerbation predicts mortality

• 3. Most exacerbations are

caused by infection

• 4. There are effective

strategies for decreasing exacerbations

Percent Change in Age-Adjusted Death Rates (US, 1965–1998)

Proportion of 1965 Rate

0.0 0.5 1.0 1.5 2.0 2.5 3.0 1965 – 1998 1965 – 1998 1965 – 1998 1965 – 1998 1965 – 1998 –59% –64% –35% +163% –7% CHD Stroke Other CVD COPD All other causes

Hey Doc, Do I Have COPD????

Simel and Rennie Evidence-based Clinical Diagnos is McGraw Hill, 2008

• CHRONIC Obstructive Pulmonary Disease
• NEED SPIROMETRY: FEV1/FVC < 0.70
• Physical Exam:

>90% Specificity Poor Sensitivity

• > 55 Pack Years
• Wheezing on Auscultation
• Self-reported wheezing

Likelihood Ratio: 156 High Probability For COPD

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Hey Doc, Do I Have COPD????

Simel and Rennie Evidence-based Clinical Diagnos is McGraw Hill, 2008

• CHRONIC Obstructive Pulmonary Disease
• NEED SPIROMETRY: FEV1/FVC < 0.70
• Physical Exam:

>90% Specificity Poor Sensitivity

• > 55 Pack Years
• Wheezing on Auscultation
• Self-reported wheezing

Likelihood Ratio: 156 High Probability For COPD Respiratory Symptoms Smokers with Normal Pulmonary Function

Woodruff PG et al. N Engl J M ed 2016;374:1811-1821

Symptom Scores

Prevalence of Symptoms and Risk of Respiratory Exacerbations

Woodruff PG et al. N Engl J M ed 2016;374:1811-1821

20%

Anthonisen et al JAMA 272:1497-505, 1994

• No benefit of screening adults with no symptoms
• No evidence that treating asymptomatic individuals

prevents future symptoms, or reduces the subsequent decline in lung function.

Qaseen, Ann Int Med 155:179-91, 2011

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• Other:

– Proteases/inflammation – Repetitive bacterial/viral infections – Genetics, especially a 1-antitrypsin deficiency

NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. April 2001; (Updated 2003). American Thoracic Society Statement Statement. Am J Respir Crit Care Med. 1995;152(suppl 5):S77-S120.

Risk Factors for COPD Give it to me Straight. Is it BAD?

GOLD Guidelines 2007

GOLD 1: (Mild COPD) FEV1 > 80% predicted FEV1/FVC < 0.70 GOLD 2: (Moderate COPD) FEV1 50-80% predicte d GOLD 3: (Severe COPD) FEV1 30-50% predicte d GOLD 4: (Very Severe COPD) FEV1 <30% predicted

GOLD 2007

N = 2164 stable COPD N = 337 “Healthy Smokers” N = 245 Never Smokers Characterized Extensively at: Baseline 3, 6, 12, 18, 24, 30, 36 months

Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points (ECLIPSE)

Eur Respir J 2008; 31:869-73

2007 Gold Guidelines Not Good Enough

Respir Res 2010; 11:122 Agusti Respir Res 2010; 11:122 Symptom Scores

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Respir Res 2010; 11:122 Agusti Respir Res 2010; 11:122

2007 Gold Guidelines Not Good Enough COPD Assessment: A New Model

Risk GOLD Classification

• f Airflow Limitation

(C) (D) (B) (A)

4 3 2 1 ≥2 or 1

Risk Exacerbation History

mMRC 0-1 CAT < 10 mMRC ≥ 2 CAT ≥10 Symptoms (mMRC or CAT score) When assessing risk, choose the highest risk according to GOLD grade or exacerbation history Patient Category Characteristics Spirometric Classification Exacerbations per year mMRC CAT A Low Risk, Less Symptoms GOLD 1-2 ≤1 0-1 <10 B Low Risk, More Symptoms GOLD 1-2 ≤1 ≥2 ≥10 C High Risk, Less Symptoms GOLD 3-4 ≥2 0-1 <10 D High Risk, More Symptoms GOLD 3-4 ≥2 ≥2 ≥10

GOLD Guidelines 2015

≥1 leading to hospital admission (no hospital admission)

Risk GOLD Classification

• f Airflow Limitation

(C) (D) (B) (A)

4 3 2 1 ≥2 or 1

Risk Exacerbation History

mMRC 0-1 CAT < 10 mMRC ≥ 2 CAT ≥10 Symptoms (mMRC or CAT score) When assessing risk, choose the highest risk according to GOLD grade or exacerbation history

GOLD Guidelines 2015

≥1 leading to hospital admission (no hospital admission)

Patient Category Characteristics Spirometric Classification Exacerbations per year mMRC CAT A Low Risk, Less Symptoms GOLD 1-2 ≤1 0-1 <10 B Low Risk, More Symptoms GOLD 1-2 ≤1 ≥2 ≥10 C High Risk, Less Symptoms GOLD 3-4 ≥2 0-1 <10 D High Risk, More Symptoms GOLD 3-4 ≥2 ≥2 ≥10

GOLD Guidelines 2015

7 Hospitalized Severe AECOPD and Mortality: Severity of AECOPD

1- no AECOPD 2- AECOPD ED N = 305 men w ith COPD x 5 years Soler-Cataluna Thorax 2005 3- AECOPD Hosp 4- AECOPD Readmit

Question #2: Which of the Following Is the Best Predictor of a Future Acute Exacerbations of COPD?

• 1. Spirometry
• 2. Symptoms
• 3. Smoking Status
• 4. Socio-Economic Status
• 5. Prior Exacerbation History

Predictors of Acute Exacerbations of COPD

Number of Exacerbations ≥2 vs. 0 1 vs. 0 Odds Ratio (95% CI) Odds Ratio (95% CI) Exacerbation in Prior Year 5.7 (4.5-7.3) 2.2 (1.8-2.8) FEV1 per 100ml decrease 1.1 (1.08-1.1) 1.1 (1.0-1.1) SGRC (symptom score) per 4 points 1.1 (1.0-1.1) 1.1 (1.0 – 1.1) GERD 2.1 (1.6-2.7) 1.6 (1.2-2.1) WBC Count 1.1 (1-1.1) 1.1 (1.0-1.1)

Hurst NEJM 2010

Acute Exacerbations of COPD

• Some patients seldom exacerbate
• Some patients exacerbate frequently
• Best predictor of ≥2 AECOPD/year

(“Frequent Exacerbator”) = previous frequent exacerbations

• Spirometry does not correlate well with

clinical features of disease

• “Frequent Exacerbator” is a stable phenotype

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COPD Exacerbations

• “Exacerbations are to COPD what myocardial

infarctions are to coronary artery disease”

• “They are the acute, often trajectory-

changing, and sometimes deadly manifestations

• f a chronic disease”
• Gerard J Criner, MD

Temple University School of Medicine Philadelphia, PA, USA

The Battle Plan.

• Improve Symptoms
• Prevent Progressive Loss of Lung Function
• Prevent Acute Exacerbations

COPD Exacerbations (AECOPD): The Major Complication of COPD

• Characterized by episodic increases in

dyspnea, sputum production and cough

• 16 million office visits/year
• 500,000 hospitalizations/year
• 110,000 deaths/year
• $18 billion in direct health care costs

Mannino et al. MMWR Surveill Summ 2002; 51:1-16 NHLBI: http://www.nhlbi.gov/resources/docs/02_chtbk.pdf

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Question #3: Which of the Following DOES NOT Reduce Acute Exacerbations of COPD?

• 1. Inhaled Corticosteroids
• 2. Long Acting Beta Agonist
• 3. Long Acting Muscarinic Agonists
• 4. Azithromycin
• 5. EMR training

Question #3: Which of the Following DOES NOT Reduce Acute Exacerbations of COPD?

• 1. Inhaled Corticosteroids
• 2. Long Acting Beta Agonist
• 3. Long Acting Muscarinic Agonists
• 4. Azithromycin
• 5. EMR training

Prevention of AECOPD

American College of Chest Physicians & Canadian Thoracic Society Guideline

• PICO (population, intervention, comparator,
• utcome)
• Literature Search
• Quality Assessment (AGREE II, DART)
• Grading Evidence (GRADEpro)
• Recommendations (CHEST)

Criner et al. CHEST 147:894-942, 2015

Prevention of AECOPD

Recommendations

• Influenza Vaccine (Grade 1B)
• Pulmonary Rehab (Grade 1C)
• Smoking Cessation (Grade 2C)
• Pneumococcal Vaccine (Grade 2C)

Mod-severe-very severe; recent AECOPD<4 weeks

Criner et al. CHEST 147:894-942, 2015

Non-Pharmacologic Treatments/Vaccinations:

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• LAMA vs PBO (Grade 1A)
• LABA vs PBO (Grade 1B)
• LAMA vs LABA (Grade 1C)
• COMBO Therapy vs MonoTherapy (Grade

1B,C)

Criner et al. CHEST 147:894-942, 2015

Maintenance Inhaled Therapy:

Prevention of AECOPD

Recommendations

• Macrolide (Grade 2A)

(Frequent AECOPD despite Tx)

• Systemic Corticosteroids (Grade 2B)

(For AECOPD – prevent next 30 days)

• Roflumilast (Grade 2A)

(Chr Bronchitis, ≥1 AECOPD in year)

• Do not use statins for AECOPD (Grade 1B)

Criner et al. CHEST 147:894-942, 2015

Oral Therapy:

Prevention of AECOPD

Recommendations

NEJM 365:689-98, 2011

• NHLBI – COPD Clinical Research Network
• N = 1130
• Moderately-severe COPD

FEV1/FVC < 70%; FEV1 <80%

• “Exacerbation Prone”
• Primary Outcome: Time to first AECOPD

The MACRO Study

(Azithromycin 250mg/day x 1 year)

NEJM 365:689-98, 2011

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Rates of Acute Exacerbations of Chronic Obstructive Pulmonary Disease per Person-Year, According to Study Group.

Albert RK et al. NEJM 2011

Macrolides Decrease AECOPD

Ray WA et al. N Engl J M ed 2012;366:1881-1890

Ray WA et al. NEJM 2012

Macrolides May Increase risk of Cardiovascular Death

• Macrolides can prolong QT and QTc leading to

arrhythmias, including torsades de pointes

• Most arrhythmias with macrolides occur in

patients with underlying risk factors

• Incidence of arrhythmias in absence of additional

risk factors is very low, perhaps 1 in 100,000.

Mosholder, NEJM 2013

Am J Respir Crit Care Med 2014; 189:1173-1180

“Macrolide-associated arrhythmias can be reduce d by not prescribing to patients with comorbidities of concern…the majority of which can be discovered by:

• History
• ECG before initiating therapy
• ECG a short time after initiating therapy”

Am J Respir Crit Care Med 2014; 189:1173-1180

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Ray WA et al. N Engl J M ed 2012;366:1881-1890

Roflumilast

• Oral Tablet
• 500 ug Once Daily
• Phosphodiesterase-4

Inhibitor

a c interpretation, cardiovascular independent a study, td, and ambridge, and management, esponse version number , , d

Figure 2: Mean rate of moderate or severe chronic obstructive pulmo Number at risk Patients with at least

• ne exacerbation (n)

Rate ratio (95% CI) Two-sided p value Intention to treat Placebo 432; roflumilast 380 0·868 (0·753–1·002) 0·0529 0·1 0·2 0·3 0·4 0·6 0·8 0·9 1·0 0·5 0·7 Mean rate of chronic obstructive pulmonary disease exacerbations per patient per year Placebo group Roflumilast group 0·927 0·805

Martinez et al. Lancet 2015

Side Effects, GI Diarrhea Weight Loss Nausea

N Engl J Med. 2014 Jun 5;370(23):2201-10

Effect of Corticosteroids on Treatment Failure Rates after AE COPD

Niewoehner et al., NEJM 340:1941, 1999

2 week = Solumedrol 125mg q6hr x 3d, Prednisone 60mg qd x 4d, 40mg qd x 4d, 20mg qd x 4d 8 week = additional 10mg qd x 5 week, then 5 mg qd x 1 week

Rate of Treatment Failure (%) Month

1 2 3 4 5 6 60 50 40 20 10 30

8 week 2 week Placebo Leuppi et al JAMA 2013; 309:2223-2231

• Randomized, noninferiority multicenter trial
• N = 314, ED with AECOPD
• Prednisone, 40 mg/day x 5 days

vs

• Prednisone, 40 mg/day x 14 days

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Time to Reexacerbation of COPD

(Intention-to-treat) (Per-Protocol)

Leuppi et al. JAMA 2013;309(21):2223-2231

Summary

• Azithromycin prevents COPD Exacerbations

– Potential Risk of Cardiac Arrhythmias

• Roflumilast offers some benefit in bronchitis

patients

• 5 days of corticosteroids is the appropriate

time frame

• No indication for statins in preventing

AECOPD

Goals of Treatment For Primary Care Physicians

• Improve Symptoms
• Prevent Progressive Loss of Lung Function
• Prevention of Acute Exacerbations

Decline in FEV1 in COPD

Fletcher and Peto BMJ, 1977;1:1645-1648

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Smoking Cessation: the Lung Health Study

Anthonisen et al. JAMA 272:1497 (1994)

Research Question: Does smoking intervention, ± ipratropium change the course of “mild” COPD

n = 5887 smokers; ages 35-60 (mean 48); FEV1 = 63%

Effect of Smoking Cessation

• n FEV1

JAMA 272:1497,1994.

Sustained Quitters 2.9 2.8 2.7 2.6 2.5 2.4 Continuing Smokers

Follow-up in years

1 2 3 4 5 Screen 2

Post Bronchdilator FEV1(liters)

Effects of a Smoking Cessation Intervention on 14.5-year Mortality

Anthonisen et al Ann Intern Med 2005; 142:233-239 P=0.03 Smoking Cessation Usual Care

Celli et al Am J Respir Crit Care Med 178:332-38, 2008

Therapy Reduces Lung Decline (TORCH)

Placebo Salmeterol + Fluticasone

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Tashkin et al NEJM 359:1543-54, 2008

Tiotropium Reduces Lung Decline

Goals of Treatment For Primary Care Physicians

• Improve Symptoms
• Prevent Progressive Loss of Lung Function
• Prevention of Acute Exacerbations

Goals of Treatment For Primary Care Physicians

• Improve Symptoms

– LABA – LAMA – ICS

• Prevent Progressive Loss of Lung Function
• Prevention of Acute Exacerbations

Downward Spiral In Function Associated With COPD

Disease Dyspnea Inactivity Deconditioning

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Pulmonary Rehabilitation

• Benefits all levels of disease severity
• Reduces respiratory symptoms
• Reduces anxiety and depression
• Reduces medical and hospital usage
• Improves exercise performance
• Improves quality of life
• Is typically provided as outpatient
• Can be initiated as an inpatient until functional

ability has improved

Update on the Management of Asthma

Definition of Asthma

• Obstruction that is reversible either

spontaneously or with treatment; [NAEPP-EPR, 1991]

• Chronic inflammatory disorder (MCs, Eos,

Tcells, Macs, PMNs, Epi); variable obstruction; [NAEPP-EPR2, 1997]

• Variable symptoms, obstruction, BHR;

inflammation; interaction [NAEPP-EPR3, 2007]

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Definition of Asthma

• Chronic inflammatory disorder; many different

cells; BHR; variable/reversible symptoms and

• bstruction; phenotypes? [GINA, 2011]
• Heterogeneous; Chronic airway inflammation;

variable/reversible symptoms and obstruction;

• Different phenotypes or clusters [GINA, 2014]

FIGURE 16. STEPWISE APPROACH FOR MANAGING ASTHMA IN YOUTHS ≥12 YEARS OF AGE AND ADULTS

Ke treatment alternative acting anta Notes:

• EPR-3, NHLBI, 2011

Haldar AJRCCM 2008

Asthma Phenotypes

Fahy, NRI, 2015

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Not all asthma is the same!! (Heterogeneity) (Phenotypes)

Question #4 - Asthma

Inhaled Corticosteroids are effective (at some dose) in all asthmatics.

• 1. True
• 2. False

True or False?

Question #4 - Asthma

Inhaled Corticosteroids are effective (at some dose) in all asthmatics.

• 1. True
• 2. False

True or False?

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Patients (%) FEV1 Percent Change From Baseline

30 25 20 15 10 5 <-30

• 30 to

<-20

• 20 to

<-10

• 10 to

<0 0 to <10 10 to <20 20 to <30 40 to <50 50 30 to <40

Beclomethasone (n=246) Montelukast (n=375)

Patients (≥15 Years) Not Controlled on PRN Beta-Agonists FEV1: Distribution of Individual Patient Responses

Malmstrom et al. Ann Intern Med. 130:487-495, 1999

Eosinophils Charcot-Leyden Crystals

A Large Subgroup of Mild-to-Moderate Asthma Is Persistently Noneosinophilic

• Asthma is a heterogeneous disease
• Prior ACRN data (n=995; 2.7 SI; ≥2% eos):
• ~50% of asthmatics – poor response to steroids
• Eosinophilic airway inflammation not ubiquitous

McGrath et al (ACRN) Am J Respir Crit Care Med 185:612–619, 2012

Sputum Eosinophil Percentage (No ICS)

TH2 Genes Overexpressed in Asthma

Woodruff et al Am J Respir CCM 180:388, 2009 Th2 High Th2 High Th2 High Th2 Low Th2 Low Th2 Low

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Th2 Status Predicts Corticosteroid Response

Woodruff et al Am J Respir CCM 180:388, 2009

• N=135, prednisone x ≥6 months, eosinophils >300

21 A Large Subgroup of Mild-to-Moderate Asthma Is Persistently Noneosinophilic

• Asthma is a heterogeneous disease
• Prior ACRN data (n=995; 2.7 SI; ≥2% eos):
• ~50% of asthmatics – poor response to steroids
• Eosinophilic airway inflammation not ubiquitous

McGrath et al (ACRN) Am J Respir Crit Care Med 185:612–619, 2012

Sputum Eosinophil Percentage (No ICS)

Steroids in Eosinophil Negative Asthma (SIENA)

• 1. Does the response to ICS differ between

subjects who are persistently EOS– and those who are EOS+?

Co-Primary Research Questions:

• 2. Does the response to LMA differ between

subjects who are persistently EOS– and those who are EOS+?

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Inte rim Hx Limite d PE Spiro w/IPB MR SI Pe riostin e NO E

• sinophils

Ge ne tics Blood Diary Re vie w Re vie w E lig & Compliance Que stionnaire s

EOS- EOS+ Run-in Wk 3 SI SI

SIENA: Schematic

3-month trea tment; 1

st mo c ens

• red

3-month trea tment; 1

st mo c ens

• red

3-month trea tment; 1

st mo c ens

• red

Conse nt H&P Spiro w/Alb MR (Mch) CBC, IgE ImmunoCAP SI Pe riostin e NO E

• sinophils

Pre gnancy te st Que stionnaire s LMA + Int ICS LMA + Int ICS LMA + Int ICS PBO + Int ICS PBO + Int ICS PBO + Int ICS PBO + Int ICS PBO + Int ICS PBO + Int ICS LMA + Int ICS LMA + Int ICS LMA + Int ICS

Phone Visit 18 30 42 24 36 Phone Visit Phone Visit Phone Visit Phone Visit

Inte rim Hx Limite d PE Spiro Diary Re vie w Que stionnaire s Inte rim Hx Limite d PE Spiro Diary Re vie w Que stionnaire s Inte rim Hx Limite d PE Spiro Diary Re vie w Que stionnaire s

6

Randomize Inte rim Hx Limite d PE Spiro (SI) (Pe riostin) (e NO) Diary Re vie w Que stionnaire s

12 Phone Visit Phone Visit

Inte rim Hx Limite d PE Spiro Diary Re vie w Que stionnaire s Inte rim Hx Limite d PE Spiro Diary Re vie w Que stionnaire s Inte rim Hx PE Spiro Diary Re vie w Que stionnaire s Pre gnancy te st Alb MR = Alb u tero l Ma ximu m Reversib ility SI = Sp u tu m In d u ctio n IPB MR = Ip ra tro p iu m Ma ximu m Reversib ility ICS = In h a led C

• rtico stero id

Mch = Meth a ch o lin e P C2 0 LMA = Lo n g -a ctin g Mu sca rin ic An ta g o n ist ICS + Int ICS ICS + Int ICS ICS + Int ICS ICS + Int ICS ICS + Int ICS ICS + Int ICS

Single-blind Placebo (SI) Phone Visit V 1 2 3 4 5 6 7 8 9

(See Appendix A for list of Questionnaires)

N = 384

Alternative Treatment? Tiotropium Step-Up for Uncontrolled Asthma

Peters et al. N Engl J Med 363:18, 2010 Eur Respir J; 43:343-73, 2014

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Eur Respir J; 43:343-73, 2014

Recommendations:

• In adults with severe asthma – use sputum eos in

experienced centers

• In severe allergic asthma – therapeutic trial of
• malizumab
• Do not use methotrexate for asthma
• Do not use azithromycin for asthma

Eur Respir J; 43:343-73, 2014

Recommendations:

• Use anti-fungals for ABPA
• Do not use anti-fungals without ABPA
• Consider bronchial thermoplasty only as part of a

study

NAEPP GUIDELINES

“If there is a clear and positive response for at least 3 months, a careful step down in therapy should be attempted to identify the lowest dose required to maintain control. (Evidence D)” Evidence D = Panel Consensus Judgment

Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. National Asthma Education and Prevention Program. J Allergy Clin Immunol. 2007 Nov;120(5 Suppl):S94-138.

GINA GUIDELINES

“Controller treatment may be stopped if the patient’s asthma remains controlled on the lowest dose of controller and no recurrence of symptoms

• ccurs for 1 year (Evidence

D)”

Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J. 2008 J an;31(1):143-78.

Evidence D = Panel Consensus Judgment

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Is There Really A Difference Between Asthma And COPD? Pathophysiology in COPD versus Asthma

Asthma

• Inflammation
• Bronchial

hyperresponsiveness

• Varying airway
• bstruction

COPD

• Loss of elastic

recoil

• Changes in small

airways

• “Inflammation”
• Fixed airway
• bstruction

Inflammation in COPD versus Asthma

Calverley, Barnes. AJRCCM 2000; 161:341-344

COPD Asthma Predominant Cells Macrophages Eosinophils Neutrophils Activated Mast Cells CD-8 T-Lymphocytes CD-4 T Lymphocytes Predominant Cytokines Interleukin 8 Interleukin 4 Leukotriene B4 Interleukin 5 Tumor Necrosis Factor alpha Interleukin 13

COPD Asthma Overlap IN COPD

Postma DS, Rabe KF . N Engl J Med 2015; 373: 1241-1249

Asthma

• ACOS

COPD Risks Outcomes

INFLUENCE OF ENVIRONMENT AND AGING ON SEVERITY AND CHRONICITY OF DISEASE

Air flow (liters/min) Volume of expired air (liters)

• 4

6

• 1

3 4

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Asthma Summary

• Asthma not a single disease but a

heterogeneous group of diseases

• Patients respond differently to medications

based upon underlying “endotype/phenotype”

• “Th2-High” or Allergic Asthma responds to

corticosteroids

• Treatments for “Th2-Low” or Non-Allergic

Asthma remain unclear