Update on COPD & Asthma

1

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 October 09, 2015

Disclosures

•  No Pharma Disclosures •  NHLBI - Asthma Clinical Research Network

•  NHLBI – Severe Asthma Research Program

2

Update on the Management of COPD

3

4

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)

5

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

6

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 Diagnosis 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

7

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

•  Other: –  Proteases/inflammation –  Repetitive bacterial/viral infections –  Genetics, especially α1-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

8

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% predicted

GOLD 3: (Severe COPD) FEV1 30-50% predicted

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

9

2007 Gold Guidelines Not Good Enough

Respir Res 2010; 11:122

Agusti Respir Res 2010; 11:122

Respir Res 2010; 11:122

Agusti Respir Res 2010; 11:122

2007 Gold Guidelines Not Good Enough

10

COPD Assessment: A New Model

Risk

GO

LD C

lass

ific

atio

n of

Air

flow

Lim

itat

ion

(C) (D)

(B) (A)

4

3

2

1

≥2 or

1

0

Risk

Ex

acer

bati

on H

isto

ry

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


≥1 leading to hospital admission

(no hospital admission)

Risk

GO

LD C

lass

ific

atio

n of

Air

flow

Lim

itat

ion

(C) (D)

(B) (A)

4

3

2

1

≥2 or

1

0

Risk

Ex

acer

bati

on H

isto

ry

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


≥1 leading to hospital admission

(no hospital admission)

11

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


Hospitalized Severe AECOPD and Mortality: Severity of AECOPD

1- no AECOPD 2- AECOPD ED

N = 305 men with COPD x 5 years

Soler-Cataluna Thorax 2005

3- AECOPD Hosp 4- AECOPD Readmit

12

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

“Its déjà vu all over again”

13

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

14

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 of a chronic disease”

- Gerard J Criner, MD

Temple University School of Medicine Philadelphia, PA, USA

15

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

16

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

17

Prevention of AECOPD American College of Chest Physicians & Canadian

Thoracic Society Guideline •  PICO (population, intervention, comparator,

outcome)

•  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


Non-Pharmacologic Treatments/Vaccinations:

18

•  LAMA vs PBO (Grade 1A)

•  LABA vs PBO (Grade 1B)

•  LAMA vs LABA (Grade 1C)

•  COMBO Therapy vs MonoTherapy (Grade

1B,C)


Maintenance Inhaled Therapy:


•  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)


Oral Therapy:


19

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

20

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 Med 2012;366:1881-1890

Ray WA et al. NEJM 2012

Macrolides May Increase risk of Cardiovascular Death

21

•  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 reduced 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

22

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

Roflumilast

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

Inhibitor

Articles

www.thelancet.com Vol 385 March 7, 2015 861

The scientifi c oversight of the study was provided by a steering committee responsible for providing scientifi c advice about the study design, execution, interpretation, and publication of results. A major adverse cardiovascular event adjudication committee, comprising independent cardiologists, adjudicated all cardiovascular events in a masked manner (appendix p 6). As sponsor of this study, Takeda (Takeda Development Centre Europe Ltd, London, UK) was responsible for study oversight and overall project management. PPD Global Ltd (Cambridge, UK) managed the administration, coordination, and monitoring of the study, including data management, statistical analysis, and the Interactive Voice Response System–Interactive Web Response System. SAS version 9.1.3 was used for all statistical analyses.

This study is registered with ClinicalTrials.gov, number NCT01329029.

Role of the funding sourceThe study was funded by Takeda. The steering committee, consisting of four academic investigators (PMAC, KFR, LMF, and FJM) and two employees of Takeda (U-MG and MB), developed the design and concept of the studies, approved the statistical plans, had full access to and interpreted the data, wrote the report, and had responsibility for the decision to publish the report. Data collection was coordinated by the two employees of Takeda (U-MG and MB). An academic author (FJM) wrote a draft of the report and an employee of Takeda (MB) did the statistical analysis. All authors vouch for the accuracy and completeness of the data and the analyses. Takeda did not place any restrictions on the academic authors regarding statements made in the fi nal report. The corresponding author had full access to all the data in the study and fi nal responsibility to submit for publication.

ResultsPatient recruitment began on April 3, 2011, and the study ended on May 27, 2014. Of 2708 patients recruited, 1945 were randomly assigned and 1935 actually received treatment (969 in the rofl umilast group and 966 in the placebo group; fi gure 1). Table 1 shows the demographic and baseline characteristics of the randomly assigned patients who received at least one dose of study medication. The mean pre-bronchodilator FEV1 was 1·0 L (SD 0·32) and the mean post-bronchodilator FEV1 was 1·1 L (SD 0·33). As anticipated in view of the inclusion criteria, 1900 (98%) of 1935 patients were using a combination of inhaled corticosteroid–longacting β2 agonist according to the protocol. 1346 (70%) of 1935 patients were also using a longacting muscarinic antagonist during the course of the study, with similar numbers in each study group. Despite the use of these inhaled therapies, study participants had a history of frequent exacerbations and impaired health status.

Figure 1 shows patient disposition throughout the study. The patient withdrawal rate was similar in both treatment

groups (269 [28%] of 969 in the rofl umilast group vs 192 [20%] of 966 in the placebo group). However, more patients withdrew in the fi rst 12 weeks post-randomisation in the rofl umilast group than in the placebo group (appendix p 10). Adherence to treatment was very high (99%) in both groups. 312 (16%) of 1935 participants had protocol violations (appendix p 15), which were mainly failures to meet the spirometric entry criteria.

Figure 2 illustrates and table 2 enumerates the eff ect of rofl umilast versus placebo on the rate of moderate-to-severe exacerbations analysed with Poisson regression and negative binomial regression in the intention-to-treat and per-protocol populations. The numerical reductions were similar in both analyses. In the intention-to-treat population, the frequency of moderate-to-severe exacer-bations was 13·2% lower in the rofl umilast group than in the placebo group in the Poisson regression analysis (rate ratio [RR] 0·868 [95% CI 0·753–1·002], p=0·0529), and was 14·2% lower (0·858 [0·740–0·995], p=0·0424) in the negative binomial regression analysis. The reduction in the moderate-to-severe exacerbation rate was greater in the per-protocol population (analysed with Poisson regression) than in the intention-to-treat population (also analysed with Poisson regression; fi gure 2). Importantly, the eff ect of rofl umilast was similar irrespective of concomitant treatment with a longacting muscarinic antagonist (appendix p 16). Table 2 also shows the eff ects of rofl umilast treatment according to predefi ned, alternative defi nitions for exacerbations.

In view of the small number of anticipated events, we analysed the eff ect of rofl umilast on severe exacerbations and on those necessitating hospital admission using

Figure 2: Mean rate of moderate or severe chronic obstructive pulmonary disease exacerbations per patient per yearRate ratios, 95% CIs, and p values are based on a Poisson regression analysis.

0·921

0·742

Number at riskPatients with at leastone 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

Placebo 369; roflumilast 310

0·806 (0·688–0·943)0·0070

Per protocol0

0·1

0·2

0·3

0·4

0·6

0·8

0·9

1·0

0·5

0·7

Mea

n ra

te o

f chr

onic

obst

ruct

ive p

ulm

onar

y dise

ase

exac

erba

tions

per

pat

ient

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

23

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

Rat

e of

Tre

atm

ent F

ailu

re (%

)

Month 0 1 2 3 4 5 6

60

50

40

20

0

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

24

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 -- appropriate time frame

•  No indication for statins in preventing AECOPD

25

Goals of Treatment For Primary Care Physicians

•  Improve Symptoms

•  Prevent Progressive Loss of Lung Function

•  Prevention of Acute Exacerbations

Question #4: Which of the Following Slows

Loss of Lung Function in COPD?

1.  Smoking Cessation 2. LABA 3. ICS 4. LAMA 5. All of the above 6. 1,2, and 3

26

Question #4: Which of the Following Slows

Loss of Lung Function in COPD?

1.  Smoking Cessation 2. LABA 3. ICS 4. LAMA 5. All of the above 6. 1,2, and 3

Decline in FEV1 in COPD

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

27

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 on 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

Bro

nchd

ilato

r FEV

1 (lit

ers)

28

Effects of a Smoking Cessation Intervention on 14.5-year Mortality

Anthonisen et al Ann Intern Med 2005; 142:233-239

P=0.03

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

Therapy Reduces Lung Decline

(TORCH)

29

Tashkin et al NEJM 359:1543-54, 2008

Tiotropium Reduces Lung Decline

30

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]

31

Definition of Asthma •  Chronic inflammatory disorder; many different cells; BHR; variable/reversible symptoms and obstruction; phenotypes? [GINA, 2011]

•  Heterogeneous; Chronic airway inflammation; variable/reversible symptoms and obstruction; • Different phenotypes or clusters [GINA, 2014]

45M

anaging Asthma Long Term

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

Key: Alphabetical order is used when more than onetreatment option is listed within either preferred oralternative therapy. ICS, inhaled corticosteroid; LABA, long-acting inhaled beta2-agonist; LTRA, leukotriene receptorantagonist; SABA, inhaled short-acting beta2-agonist

Notes:

• The stepwise approach is meant to assist, not replace, theclinical decisionmaking required to meet individual patientneeds.

• If alternative treatment is used and response is inadequate,discontinue it and use the preferred treatment before stepping up.

• Zileuton is a less desirable alternative due to limited studies as adjunctive therapy and the need to monitor liver function. Theophylline requires monitoring of serumconcentration levels.

• In step 6, before oral corticosteroids are introduced, a trialof high-dose ICS + LABA + either LTRA, theophylline, orzileuton may be considered, although this approach hasnot been studied in clinical trials.

• Step 1, 2, and 3 preferred therapies are based on EvidenceA; step 3 alternative therapy is based on Evidence A forLTRA, Evidence B for theophylline, and Evidence D forzileuton. Step 4 preferred therapy is based on Evidence B,and alternative therapy is based on Evidence B for LTRAand theophylline and Evidence D zileuton. Step 5 preferred therapy is based on Evidence B. Step 6 preferredtherapy is based on (EPR—2 1997) and Evidence B for omalizumab.

• Immunotherapy for steps 2–4 is based on Evidence B forhouse-dust mites, animal danders, and pollens; evidence isweak or lacking for molds and cockroaches. Evidence isstrongest for immunotherapy with single allergens. The roleof allergy in asthma is greater in children than in adults.

• Clinicians who administer immunotherapy or omalizumabshould be prepared and equipped to identify and treat anaphylaxis that may occur.

EPR-3, NHLBI, 2011

32

described an early-onset, symptom-predominant group withminimal eosinophilic disease. Cluster 4 described an eosino-philic inflammation–predominant group with few symptoms,late-onset disease, and a greater proportion of males.

Discriminant function modeling identified the majority ofinput parameters used in the cluster analysis of both popula-tions to be significant determinants of cluster membership(Table E1 of the online supplement). The discriminant functionmodel of primary-care and refractory asthma clusters requiredseven of eight input parameters (excluding atopic status) andfive of seven parameters (excluding atopic status and sex),respectively. The accuracy of the discriminant function modelsfor predicting cluster membership was 94.6% (primary care)and 96.8% (refractory asthma).

Cluster analysis was performed from baseline data in 68patients of the prospective study dataset. Three clusters wereidentified (Table E2); all were comparable with clusters ob-served in the larger refractory asthma population. The originalstudy demonstrated a significant reduction in severe exacerba-tion frequency in the sputum arm, with no significant differencein corticosteroid usage between the groups. The present cluster-specific analysis revealed that all of the benefit for preventingexacerbations occurred in the inflammation-predominant co-hort (3.53 [SD, 1.18] vs. 0.38 [SD, 0.13] exacerbation/patient/yr,P 5 0.002) (Table 4). In addition, sputum-guided therapyallowed successful downtitration of corticosteroid therapy inearly symptom-predominant asthma (Table 4; mean difference,1,829 mg beclomethasone equivalent/d [95% confidence interval,307–349 mg]; P 5 0.02), without compromising asthma control.

A univariate ANOVA with the cluster model as a covariateidentified both treatment grouping and the cluster model assignificant determinants for observed differences in exacerba-tion frequency (P 5 0.002, study groups; P 5 0.03, clustermodel), but only the cluster model was a significant determinantfor differences in inhaled corticosteroid dose (P 5 0.07 fortreatment groups and P 5 0.005 for cluster model).

DISCUSSION

The need for classifying asthma heterogeneity has gainedurgency with the parallel development of better tools for mea-suring disease characteristics that highlight disparity in clinical,physiologic, and pathologic markers, together with novel andspecific molecular therapies that are only likely to be efficaciousin particular subgroups of asthma. This study is the first to applyprinciples of cluster analysis for the identification of clinicalasthma phenotypes. We have further shown that phenotypesconstructed in this way exhibit clinically relevant differences inoutcome, with management strategies that use a measure ofeosinophilic inflammation for titrating corticosteroid therapy.

Asthma classification is complicated by the multidimensionalnature of the disease. This prompted our consideration ofcluster analysis techniques for this purpose. We selected the k-means clustering algorithm as it maximizes separation betweenclusters, thereby offering the greatest scope for identifyingdistinct groups within the population. Both familiar and pre-viously uncharacterized asthma subgroups were identified thatare more representative of multidimensionality. The identifica-

Figure 1. Clinical phenotypes of asthma. A summary of phenotypes identified using cluster analysis in primary- and secondary-care asthmapopulations. The clusters are plotted according to their relative expression of symptoms and inflammation because these are the two clinically pertinentand modifiable dimensions of the disease. The plot highlights greater discordance to be a feature of secondary-care asthma. Although reasons forthis dissociation are unclear, the use of measures of airway inflammation in these subgroups is clinically informative. BMI 5 body mass index.

Haldar, Pavord, Shaw, et al.: Clinical Asthma Phenotypes 221

Haldar AJRCCM 2008

Asthma Phenotypes

Fahy, NRI, 2015

33

Not all asthma is the same!!

(Heterogeneity)

(Phenotypes)

34

Question #5 - Asthma

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

1.  True 2.  False

True or False?

Question #5 - Asthma

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

1.  True 2.  False

True or False?

35

Patients (%)

FEV1 Percent Change From Baseline

30

25

20

15

10

5

0 <-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

36

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

37

Th2 Status Predicts Corticosteroid Response

the inflammatory and pathological processes and thus representproximal targets for directed therapy. Second, phenotyping bygene expression identifies the genes that may contribute to thiscomplex disease based on DNA sequence variation and willhelp reduce phenotypic heterogeneity in genetic studies. Third,these gene expression array data facilitate the identification ofsecreted proteins that mark the phenotype and may be de-veloped into diagnostic tests.

One strength of our approach to molecular phenotyping is theuse of multiple sample types to provide a broad view of geneexpression in the airway. Our preparations of epithelial cells andalveolar macrophages are valuable for gene expression profilingbecause they represent relatively homogeneous populations ofcells. On the other hand, bronchial biopsies are valuable becausethe mix of cell types they contain (including inflammatory cells)permits direct measurement of Th1 and Th2 cytokines. However,because of the cell type heterogeneity inherent to bronchialbiopsies, the cellular source of these cytokines remains uncertain.

Finally, these data reveal that a significant percentage ofpatients with asthma have a Th2-low phenotype that manifestsclinical features of asthma, airway obstruction, airway hyper-responsiveness, and bronchodilator reversibility despite a paucityof Th2-driven inflammation. The causes of Th2-low asthma

remain obscure, but possibilities include neutrophilic inflamma-tion, IL-17–driven inflammation, intrinsic defects in barrierfunction and chronic subclinical infection by viruses, and atypicalintracellular bacteria. Whatever the mechanism, our data suggestthat it does not relate to uncontrolled allergic inflammation butrather to alternative mechanisms that are not steroid responsive.Future work should be directed at identifying noninvasive bio-markers that correlate with these molecular phenotypes in theairway and at developing a deeper understanding of the patho-physiologic mechanisms underlying asthma that is not driven byTh2 inflammation.

There are limitations inherent to our study design. First, oursubjects were not treated with inhaled or oral steroids for at least4 weeks before enrollment, and the use of leukotriene antagonistswas excluded. Although these steps facilitated identification ofthis Th2 signature in the absence of the confounding effects ofantiinflammatory medications, these inclusion/exclusion criterialimit the generalizability of the study to patients with more severeasthma. Whether these markers can be used to detect Th2-driveninflammation in patients who are poorly controlled despitecorticosteroid treatment remains to be determined. Second,repeat bronchoscopy was performed 1 week after initiation oftreatment, which was continued for a total of 8 weeks. Thus, thetiming of the second bronchoscopy may underestimate the extentto which inhaled steroids influence inflammation and our molec-ular signature. Third, we excluded healthy control subjects whohad a history of allergic rhinitis. Thus, it is possible that our Th2signature may also be detectable in the upper or lower airway ofatopic nonasthmatic subjects. Finally, our study design does notdefinitively rule out the possibility that the Th2-low phenotype inpart represents patients with well-controlled asthma. However,the majority of our subjects had not been using inhaled steroidsfor a long period before enrollment (i.e., we did not stop the use ofinhaled steroids in recruitment of our subjects but rather soughtpatients who were not using inhaled steroids chronically of theirown accord), minimizing the effect of prior steroid therapy in ouranalyses. Furthermore, patients with Th2-high and Th2-lowasthma did not significantly differ with regard to airway obstruc-tion or reversibility at baseline in this study, which lends furthercredence to the notion that the severity of their disease wascomparable and not due to differences in asthma control.

Conflict of Interest Statement: P.G.W. received more than $100,001 researchgrant to study biomarkers in asthma from Genentech and is the co-inventor ona patent for the development of biomarkers in asthma. B.M. received more than$100,001 in salary from employment by Genentech and has $10,001 to $50,000in stock owernship or options from Genentech. D.F.C. is an employee ofGenentech. G.J. is a full-time employee of Roche/Genentech Inc. A.R.A. doesnot have a financial relationship with a commercial entity that has an interest in

Figure 4. Alveolar macrophage gene expression in Th2-high and Th2-low asthma. Mean (1SEM) expression levels of 15-lipoxygenase(ALOX15) and TNF-a as determined by real-time PCR (*P , 0.03 forsubjects with Th2-high asthma vs. healthy control subjects). n 5 15healthy control subjects (gray bars); n 5 5 patients with Th2-lowasthma (blue bars); and n 5 9 patients with Th2-high asthma (red bars).

Figure 5. Responsiveness ofTh2-high asthma to inhaledsteroids and reproducibilityof phenotypic markers afterplacebo in a randomized con-trolled trial. (A) FEV1 measuredat baseline (week 0), after 4and 8 weeks on daily flutica-sone (500 mg BID), and 1 weekafter the cessation of flutica-sone (week 9). *See Table 2for number of subjects and Pvalues. There was no signifi-cant change in FEV1 in re-

sponse to placebo at any time point in either group. (B) Heatmap depicting unsupervised hierarchical clustering of POSTN, CLCA1, andSERPINB2 as in Figure 1C in bronchial epithelium of patients with asthma 1 week after the initiation of fluticasone or placebo treatment (n 5 19receiving fluticasone; 13 receiving placebo). Cluster at baseline for individual subjects in Figure 1C and treatment are indicated below the heatmap.

394 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 180 2009

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

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

38

39

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)

40

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+?

41

Interim Hx Limited PE Spiro w/IPB MR SI Perios8n eNO Eosinophils Gene8cs Blood Diary Review Review Elig & Compliance Ques8onnaires

EOS-

EOS+

Run-in

Wk 0 3

SI SI

SIENA: Schematic

3-month treatment; 1st mo censored



Consent H&P Spiro w/Alb MR (Mch) CBC, IgE ImmunoCAP SI Perios8n eNO Eosinophils Pregnancy test Ques8onnaires

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

Interim Hx Limited PE Spiro Diary Review Ques8onnaires



6

Randomize Interim Hx Limited PE Spiro (SI) (Perios8n) (eNO) Diary Review Ques8onnaires

12

Phone Visit

Phone Visit



Interim Hx PE Spiro Diary Review Ques8onnaires Pregnancy test

Alb MR = Albuterol Maximum Reversibility SI = Sputum Induc:on IPB MR = Ipratropium Maximum Reversibility ICS = Inhaled Cor:costeroid Mch = Methacholine PC20 LMA = Long-‐ac:ng Muscarinic Antagonist

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 Ques:onnaires)

N = 384

Alternative Treatment?

42

Tiotropium Step-Up for Uncontrolled Asthma

Peters et al. N Engl J Med 363:18, 2010

Eur Respir J; 43:343-73, 2014

43

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 omalizumab

•  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

44

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 occurs for 1 year (Evidence D)”

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

Evidence D = Panel Consensus Judgment

45

Is There Really A Difference

Between Asthma And COPD?

Pathophysiology in COPD versus Asthma

Asthma •  Inflammation

•  Bronchial

hyperresponsiveness

•  Varying airway obstruction

COPD •  Loss of elastic

recoil •  Changes in small

airways •  “Inflammation” •  Fixed airway

obstruction

46

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

n engl j med 373;13 nejm.org September 24, 20151244

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

factor for the development of COPD19 (Fig. 2). The prevalence of bronchial hyperresponsiveness among patients with COPD has been reported to be 60%,20 and it may occur even in patients with mild disease, in whom the baseline level of FEV1should minimally influence the measurement of bronchial hyperresponsiveness.20 One study showed bronchial hyperresponsiveness in 90% of patients with COPD who did not have a his-tory of asthma.21 A recent study showed that more severe bronchial hyperresponsiveness is associ-ated with higher residual volume (a measure of air trapping that is related to small-airway dys-function) in COPD.22 In addition, bronchial hyper-responsiveness is associated with airway inflam-mation — that is, increased levels of neutrophils, macrophages, and lymphocytes in sputum and bronchial-biopsy specimens22 and increased levels of CD8 lymphocytes and eosinophils in periph-

eral lung tissue23 — in patients with COPD. The association of increased eosinophil levels with bronchial hyperresponsiveness was once thought to be limited to patients with asthma.11

What are the clinical implications of bronchial hyperresponsiveness in COPD? Studies have shown that the decline in FEV1 is accelerated in patients with COPD who have bronchial hyper-responsiveness,24,25 and that the decline is even more prominent in smokers.25 Thus, the associa-tion of bronchial hyperresponsiveness with the course of lung-function change and with response to inhaled glucocorticoids differs between COPD and asthma. Bronchial hyperresponsiveness is a risk factor for death from COPD in the general population.26,27 Thus, bronchial hyperresponsive-ness is a marker for more severe disease in both asthma and COPD, but there are not adequate data to indicate whether there is a long-term

Figure 2. Risk Factors for Asthma and COPD and the Influence of Environment and Aging.

There are a large number of established risk factors for asthma and COPD. Although some of these factors are clearly related to one disease and not the other, there is already considerable overlap early in life and early in the develop-ment of either disease. With time and increasing age of patients, cumulative environmental hazards, and the result-ing chronicity of the diseases, the clinical presentations appear more and more similar, making it sometimes impos-sible to clearly differentiate asthma from COPD in a given person. Although a number of characteristics overlap, some features of one or the other underlying disease may still be more prominent. Careful examination of these fac-tors may be helpful to identify the predominant disease phenotype when predicted lung-function values alone are not sufficient. Spirometry (graph) shows limited reversibility of airway obstruction after bronchodilator (BD) use by patients with ACOS. BHR denotes bronchial hyperresponsiveness, BPD bronchopulmonary dysplasia, GERD gastro-esophageal reflux disease, and Th2 type 2 helper T cells.

Asthma

ACOS

COPD

Risks Outcomes

INFLUENCE OF ENVIRONMENT AND AGING ON SEVERITY AND CHRONICITY OF DISEASE

Air f

low

(lite

rs/m

in)

Volume of expired air (liters)

0

4

6

0 1 3 4

The New England Journal of Medicine Downloaded from nejm.org at SAN FRANCISCO (UCSF) on October 7, 2015. For personal use only. No other uses without permission.

Copyright © 2015 Massachusetts Medical Society. All rights reserved.

47

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

Documents

Update on COPD & Asthma