update on copd & asthma disclosures - · pdf fileupdate on the management of copd what is...

1

Update on COPD & Asthma

Michael C. Peters, M.D. MASDivision of Pulmonary & Critical Care Medicine

Cardiovascular Research InstituteUniversity of California San Francisco

UCSF Primary Care MedicineSan Francisco, CAOctober 13, 2017

Disclosures

• Served on advisory boards for Merck• Given presentations to Genentech/Amgen

• NHLBI - Asthma Clinical Research Network

• NHLBI – Severe Asthma Research Program

Update on the Management of COPD

What is COPD• Disease state characterized by airflow

limitation that is not fully reversible*– Post-Bronchodilator FEV1/FVC <0.7

• Generally caused by cigarette smoke– Biomass fuels (developing world)– α1-antitypsin deficiency– Pollution, chronic infection

• Bronchiectasis, cystic fibrosis are not included in the definition

2

Rate of Deaths per 100,000 in the USA 2005-2011

Heart Disease

Cancer

COPD/Chronic respiratory

Rate

Year2005 2006 2007 2008 2009 2010 2011

Cancer Death by Site

Lung 85,920 (27%)Prostate 26,120 (8%)Colorectal 26,020 (8%)Pancreas 21,450 (7%)Liver 18,280 (6%)

MENLung 72,120 (26%)Breast 40,450 (14%)Colorectal 23,170 (8%)Pancreas 20,330 (7%)Ovary 14,240 (5%)

WOMEN

American Cancer Society 2016

Simel and RennieEvidence-based Clinical DiagnosisMcGraw Hill, 2008

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

Simel and RennieEvidence-based Clinical DiagnosisMcGraw Hill, 2008

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

3

Original Article

Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function

N Engl J MedVolume 374(19):1811-1821

May 12, 2016

Observational study 2734 current and former smokersand controls who never smoked

Examined whether current or former smokers withpreserved lung function had symptoms or suffered COPD exacerbations

Respiratory Symptoms Smokers with Normal Pulmonary Function

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

Symptom Scores

Prevalence of Symptoms and Risk of Respiratory Exacerbations

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

Anthonisen et alJAMA 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

USPTF JAMA 2016

4

GOLD Criteria

Risk

GOLD

Cla

ssif

icat

ion

of A

irfl

ow L

imit

atio

n

(C) (D)

(B)(A)

4

3

2

1

≥2 or

1

0Ri

skEx

acer

bati

on H

isto

ry

mMRC 0-1CAT < 10

mMRC ≥ 2CAT ≥10Symptoms

(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 <10B Low Risk, More Symptoms GOLD 1-2 ≤1 ≥2 ≥10C High Risk, Less Symptoms GOLD 3-4 ≥2 0-1 <10D High Risk, More Symptoms GOLD 3-4 ≥2 ≥2 ≥10

GOLD Guidelines 2017

≥1 leading to hospital admission

(no hospital admission)

Risk

GOLD

Cla

ssif

icat

ion

of A

irfl

ow L

imit

atio

n

(C) (D)

(B)(A)

4

3

2

1

≥2 or

1

0

Risk

Exac

erba

tion

His

tory

mMRC 0-1CAT < 10

mMRC ≥ 2CAT ≥10Symptoms

(mMRC or CAT score)

When assessing risk, choose the highest risk according to GOLD grade or exacerbation history

GOLD Guidelines 2017

≥1 leading to hospital admission

(no hospital admission)

Take HOME

• Treat the patient– Symptoms– Exacerbations

• Spirometry assists with diagnosis• Lung Cancer Screening

Treat The Patient!!!

• Improve Symptoms

• Prevent Progressive Loss of Lung Function

• Prevention of Acute Exacerbations

5

What treatment is the most effective for preventing COPD

exacerbations?

A) RoflumilastB) Pulmonary RehabC) Duel LAMA + LABAD) Azithromycin

Treat The Patient!!!

• Improve Symptoms

• Prevent Progressive Loss of Lung Function

• Prevention of Acute Exacerbations

Hospitalized Severe AECOPD and Mortality:Severity of AECOPD

1- no AECOPD 2- AECOPD ED

N = 305 men with COPDx 5 years

Soler-Cataluna Thorax 2005

3- AECOPD Hosp4- AECOPD Readmit

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

6

Prevention of AECOPDAmerican 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 AECOPDRecommendations

• 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:

Pulmonary Rehab

Effects of interventions

Admission to hospital

Five studies involving 250 patients contributed data on admis-sions to hospital. There was a significant reduction in the odds ofhospital re-admission (OR 0.22; 95% CI 0.08 to 0.58; I2=51%)(Behnke 2000; Eaton 2009; Man 2004; Murphy 2005; Seymour2010; Figure 2) with a NNT of 4 (95% CI 3 to 8) Figure 3. Thefollow-up period for these studies ranged from 3 to 18 months,

with a mean duration of 25 weeks. In one trial (Eaton 2009) therewas a large discrepancy between the intention-to-treat and the per-protocol analysis because only 19 (40%) patients assigned to earlyrehabilitation satisfied the a priori definition of adherence (atten-dance at 75% of rehabilitation sessions). Repeating the meta-anal-ysis using the per-protocol data of that trial did not change theresults of the meta-analysis significantly (OR 0.19; 95% CI 0.09to 0.39, five studies, N = 222) but did reduce heterogeneity (I2=0%).

Figure 2. Forest plot of comparison: 1 Rehabilitation versus control, outcome: 1.1 Hospital admission (to

end of follow-up).

7Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease (Review)

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Puhan Cochrane Database 2011

Pulmonary Rehab






end of follow-up).



Pulmonary Rehab

Control Odds Ratio

Subject 124 126

Total Event 20 51 0.22 (0.08-0.58)

Puhan Cochrane Database 2011

7

Pulmonary Rehab






end of follow-up).



Pulmonary Rehab

Control Odds Ratio

Subject 124 126

Total Event 20 51 0.22 (0.08-0.58)

Number Needed to Treat = 4!!!! CI 3-8Puhan Cochrane Database 2011

• 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:


FLAME TRIAL • LAMA + ICS = Good• LABA + ICS = Good

FLAME TRIAL • LAMA + ICS = Good• LABA + ICS = Good

ICS risk of Pneumonia?

8

FLAME TRIAL • LAMA + ICS = Good• LABA + ICS = Good• LABA + LAMA = ?

ICS risk of Pneumonia?

FLAME TRIAL • LAMA + ICS = Good• LABA + ICS = Good• LABA + LAMA = ?

LABA (indacaterol) + LAMA (glycopyrronium) QDay

LABA (salmeterol) + ICS (fluticasone) BID

VS.

Wedzicha JA et al. N Engl J Med 2016;374:2222-2234 Wedzicha JA et al. N Engl J Med 2016;374:2222-2234

NNT = 9

9

Wedzicha JA et al. N Engl J Med 2016;374:2222-2234

Wedzicha JA et al. N Engl J Med 2016;374:2222-2234

• 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:


NEJM 365:689-98, 2011

• NHLBI – COPD Clinical Research Network

• N = 1130

• Moderately-severe COPDFEV1/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

10

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

NNT=15Ray WA et al. N Engl J Med 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 Med2014; 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 Med2014; 189:1173-1180

11

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

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

Martinez et al. Lancet 2015

• 1 year trial• 40 years old, >20 pack years, +COPD• FEV1% predicted<50%• Symptoms of chronic bronchitis, +cough and sputum• “Exacerbation Prone”• ICS + LABA


Roflumilast


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


Roflumilast


Articles

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

phosphodiesterase 4 inhibition prevents all types of exacerbations in the specifi c group of patients assessed in the present study—ie, those with severe chronic obstructive pulmonary disease and chronic bronchitis at risk of frequent exacerbations that are inadequately controlled with standard inhaled therapy. Rofl umilast did

not change the time to fi rst event but did reduce the total number of events and the time to a second event.

Rofl umilast produced a sustained improvement in post-bronchodilator FEV1 of 56 mL compared with placebo—a change similar to that noted previously in patients receiving less background therapy.17,24,25 The change in lung function, which equated to 5% of the baseline value, is unlikely to have modifi ed the patients’ degree of breathlessness,26 but could have contributed to the reduction in exacerbations. Signifi cant changes in exacerbation frequency have been reported with inhaled corticosteroids without a corresponding change in lung function.7 In view of the diff erent mechanisms of action and the additional spirometric change following rofl umilast treatment versus that due to inhaled corticosteroids, the change in exacerbation rate is likely to have been attributable to an anti-infl ammatory eff ect of rofl umilast. Neither the diary card symptom scores nor the CAT scores diff ered between groups. The CAT score is related to more complex measurements of health status similar to St George’s Respiratory Questionnaire27 and might be expected to improve as exacerbation rates fall.28 A modest decrease in the use of rescue medication was noted, which may refl ect an improvement in symptomatic control or the eff ect of experiencing fewer exacerbations.

Patients who received rofl umilast reported the anticipated range of pharmacologically predictable side-eff ects. The pattern of withdrawal rates was similar to that in previous studies, and the overall adverse event rate was similar to that reported in less severely aff ected patients.24 The magnitude of weight loss was similar to that seen in previous studies. However, bodyweight did not completely return to baseline 3 months after treatment stopped. The mechanism for the weight loss remains to be fully elucidated, although a direct metabolic eff ect has been recorded in patients with diabetes.29 We noted no excess occurrence of pneumonia with rofl umilast treatment. However, the overall rate of pneumonia (in patients taking rofl umilast or placebo) was higher than previously reported, which is indicative of the known risk factors for pneumonia in this population.30

Our study did have limitations. Although patients were recruited according to their past history of exacerbations, the observed exacerbation rate was 25% lower than we anticipated. This fi nding might represent better medical care and treatment adherence than in previous studies, but also draws attention to the diffi culty of using exacerbations as an endpoint in view of their known tendency for temporal clustering.31 Although this study confi rmed that no increase of cardiac side-eff ects occurred in patients treated with rofl umilast,32 we did not observe a reduction of major adverse cardiac events in the current study. The mortality in our patients was low compared with other reports,3,4 especially in view of the high incidence of hospitalisations we saw, which is an established risk factor for mortality.33 We recorded in-treatment mortality but did not follow all participants

Rofl umilast group (n=968)

Placebo group (n=967)

Diff erence between groups (95% CI)

Chronic obstructive pulmonary disease exacerbation

145 (15%) 185 (19%) –4·2% (–5·08 to –3·23)

Diarrhoea 99 (10%) 35 (4%) 6·6% (5·50 to 7·71)

Weight decrease 88 (9%) 27 (3%) 6·3% (5·22 to 7·38)

Nausea 55 (6%) 15 (2%) 4·1% (3·24 to 5·02)

Nasopharyngitis 52 (5%) 52 (5%) 0% (–0·04 to 0·03)

Headache 40 (4%) 21 (2%) 2·0% (1·34 to 2·58)

Pneumonia 39 (4%) 45 (5%) –0·6% (–0·98 to –0·27)

Decreased appetite 36 (4%) 5 (1%) 3·2% (2·42 to 3·99)

Insomnia 29 (3%) 15 (2%) 1·4% (0·91 to 1·98)

Back pain 27 (3%) 14 (1%) 1·3% (0·83 to 1·85)

Upper abdominal pain 25 (3%) 10 (1%) 1·5% (1·00 to 2·10)

Hypertension 24 (3%) 27 (3%) –0·3% (–0·56 to –0·06)

Data are n (%), unless otherwise indicated. Adverse events were reported independently of the investigator causality assessments. Patients might have had more than one adverse event. One patient assigned to rofl umilast accidentally received placebo for the entire duration of the study and was therefore included in the placebo group for the safety analysis.

Table 3: Adverse events occurring in at least 2·5% of patients in either treatment group

Rofl umilast group Placebo group

Mortality (n=969 in rofl umilast group; n=966 in placebo group)

Deaths* 17 (2%) 18 (2%)

Primary cause of death*

Chronic obstructive pulmonary disease exacerbation

7 (1%) 7 (1%)

Adverse event 10 (1%) 11 (1%)

Major adverse cardiovascular events (n=969 in rofl umilast group; n=966 in placebo group)

Composite major adverse cardiovascular events 16 (2%) 16 (2%)

Major adverse cardiovascular event due to cardiovascular death (including death from undetermined cause)

9 (1%) 7 (1%)

Major adverse cardiovascular event due to non-fatal myocardial infarction

3 (<1%) 6 (1%)

Major adverse cardiovascular event due to non-fatal stroke

4 (<1%) 3 (<1%)

Bodyweight changes (n=968 in rofl umilast group; n=967 in placebo group)

Change in bodyweight (kg) during double-blind treatment

–2·65 (4·37); n=938† –0·15 (3·69); n=944†

Change in bodyweight (kg) post-randomisation to end of follow-up‡

Rofl umilast in post-treatment period 0·28 (1·58); n=36† –1·62 (2·49); n=48†

No rofl umilast in post-treatment period 1·10 (2·61); n=612† 0·11 (2·60); n=679†

Data are n (%) or mean (SD). One patient assigned to rofl umilast received placebo for the entire study and was therefore included in the placebo group for the safety analysis. The total numbers of patients for the mortality and major adverse cardiovascular event analyses are based on the full analysis population of patients, whereas bodyweight is based on the safety population. *Analysis includes deaths during the double-blind treatment period only. †The number of patients with bodyweight measurements available. ‡Analysis includes data from the entire observation period.

Table 4: Key safety outcomes

NNT=25 NNH=16

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 (%

)

Month0 1 2 3 4 5 6

60

50

40

20

0

10

308 week2 weekPlacebo

12

Leuppi et alJAMA 2013; 309:2223-2231

• Prednisone, 40 mg/day x 5 daysvs

• Prednisone, 40 mg/day x 14 days

Time to Reexacerbation of COPD

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

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

Summary

• Pulmonary Rehab (NNT=4)• Duel Long Acting Bronchodilator Medications

over ICS + LABA (NNT=9)• Azithromycin prevents COPD Exacerbations

(NNT=15)– Potential Risk of Cardiac Arrhythmias

• Roflumilast offers some benefit in bronchitis patients (NNT=25), (NNH=16)

• 5 days of corticosteroids is the appropriate time frame

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

Therapy Reduces Lung Decline

(TORCH)

Placebo

Salmeterol + Fluticasone

13

Tashkin et alNEJM 359:1543-54, 2008

Tiotropium Reduces Lung Decline

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

2015 Cochrane Review, McCarthy

Update on the Management of Asthma

Definition of Asthma (Clinical)

• Epidemiological: Questionnaires– Diagnosed with asthma by a physician and wheeze

in past 12 months– Diagnosed with asthma by a physician and

currently taking asthma medications• Clinical:

– Intermittent Airflow Obstruction + Symptoms• + Bronchodilator Response (200ml +12%)• + Methacholine Challenge test (PC 20 vs. Resistance)

14

• 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]

Definition of Asthma (Biological)

Epidemiology

• 250-300 million people have asthma globally

• Asthma rates have been increasing in low/middle income countries (caught up)

• Most of the morbidity/mortality from asthma stems from the 5-10% with severe disease

Asthma Prevalence in USA 2001-10 Causes of Asthma• Hygiene Hypothesis (Stein, NEJM 2016)

• Exposure to Antibiotics– Microbiome (Fujimura, Nature 2016)

• Genetics (Moffatt, NEJM 2010)

• Obesity (Sutherland AJRCCM 2007)

• Environmental Influences – Dogs/Cats– Medications

15

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

© Global Initiative for Asthma

Stepwise management - pharmacotherapy

*Not for children <12 years

**For children 6-11 years, the preferred Step 3 treatment is medium dose ICS#For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy

� Tiotropium by mist inhaler is an add-on treatment for patients ≥12 years with a history of exacerbations

GINA 2016, Box 3-5 (2/8) (upper part)

DiagnosisSymptom control & risk factors(including lung function)Inhaler technique & adherencePatient preference

Asthma medicationsNon-pharmacological strategiesTreat modifiable risk factors

SymptomsExacerbationsSide-effectsPatient satisfactionLung function

Other controller

options

RELIEVER

STEP 1 STEP 2STEP 3

STEP 4

STEP 5

Low dose ICS

Consider low dose ICS

Leukotriene receptor antagonists (LTRA)Low dose theophylline*

Med/high dose ICSLow dose ICS+LTRA

(or + theoph*)

As-needed short-acting beta2-agonist (SABA) As-needed SABA or low dose ICS/formoterol#

Low dose ICS/LABA**

Med/high ICS/LABA

PREFERRED CONTROLLER

CHOICE

Add tiotropium*�High dose ICS + LTRA (or + theoph*)

Add low dose OCS

Refer for add-on

treatment e.g.

tiotropium,*�omalizumab,

mepolizumab*

UPDATED!

ICS Formulations• MDI: Metered Dose Inhalers

– Aerosol– Theoretically achieves more distal

distribution (small airways), ciclesonide– Flovent

• DPI: Dry Powder Inhalers– No propellant– Easier to use– Less systemic absorption

ICS Toxicity

1380

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 165 2002

Morning FEV

1

Although this was not an efficacy study, the morning labora-tory FEV

1 was measured at all overnight visits. For each ICS,there was a between 5 and 15% improvement (see online datasupplement) in overall response. At Week 4 the improvementfor FP-CFC MDI and that for FP-DPI were similar.

DISCUSSION

The ACRN set out to develop a workable method to deter-mine whether the available ICS differ in terms of systemic bio-availability on an equivalent microgram basis as measured byeffect on cortisol suppression. An additional goal was to estab-lish equivalent systemic bioavailable doses, so as to use this in-formation in future ACRN trials of the efficacy of ICS prepa-rations. To this end, we found that the most reliable method ofevaluation (i.e., gave the smallest variability within a givendosage, yet demonstrated different mean values across doses)was the 12-hour AUC for the hourly overnight plasma cortisolmeasurements from 8 P.M. to 8 A.M. Although this method in-volves an in-laboratory overnight visit, by far it gave the mostaccurate assessment of ICS effect on cortisol function comparedwith either a 12-hour (8 A.M. to 8 P.M.) “at home” urinary corti-sol collection or a 12-hour (8 P.M. to 8 A.M.) in-laboratory uri-nary cortisol collection. Even combining the two 12-hour timeintervals, the variability was so great as to make urinary corti-sol assays uninterpretable. It should be noted that other inves-tigators have shown that the 24-hour urine cortisol collection

(22) and the overnight collection (23) were sensitive measuresof cortisol suppression. Wilson and Lipworth felt the overnighturinary cortisol collection gave the best signal to noise ratio incomparing two ICS (23).

Although hourly cortisol measurements best met our crite-ria for reliability, every 2 hours measurements were also accu-rate. The concordance correlation between hourly and every 2hours measurements was very strong (r ! 0.96 [95% confi-dence interval 0.96, 0.98]). Blood sampling every 2 hours al-lows for less potential sleep interruption and decreases costfor future studies.

Although 7 A.M. blood osteocalcin values showed signifi-cant dose–responses for four of the six ICS preparations, thecoefficients of variation were large and the results in the pla-cebo group were variable over the time points. However, simi-larities between the osteocalcin and plasma cortisol suppres-sion are evident. Similar differences are found between FP DPIand FP-CFC MDI for osteocalcin and cortisol. TAA-CFC andFP-CFC MDI also demonstrated the same trends in osteocal-cin and cortisol suppression. Other indications of systemic ef-fect such as glaucoma, cataracts, osteoporosis, growth, andskin thinning were not evaluated, as they require both a long du-ration of study and varying age groups. Thus, although our find-ings do document systemic effect, caution needs to be taken ingeneralizing these findings to other organ systems or age groups.

To determine the dose–response of cortisol suppressionfrom ICS, our study used a dose–response design in which thedose of the ICS was progressively escalated. Although we

TABLE 3. INHALED CORTICOSTEROIDS AND AMOUNT DELIVERED PER ACTUATION

ICS BDP-CFC MDI BUD-DPI FLU-CFC MDI FP-DPI FP-CFC MDI TAA-CFC MDI

Labeled dose 84 100 250 50 44 200Emitted dose* MDI 72.7 " 5.1 61.3 " 2.5 219.2 " 13.6 49.4 " 2.8 47.4 " 4.7 78.4 " 8.8

#OptiChamber 25.8 " 7.7 — 78.8 " 10.3 — 27.0 " 5.6 —

Fine particle dose†

MDI 11.7 " 2.8 31.6 " 6.5 64.1 " 8.7 5.4 " 0.7 20.3 " 2.0 25.7 " 4.12#OptiChamber 14.9 " 4.2 — 61.3 " 9.1 — 23.0 " 4.8 —

For definitions of abbreviations, see Table 2.* Micrograms (mean " standard deviation) that are emitted ex-device for the DPI, or from the OptiChamber or tube spacer for the MDI.† Micrograms (mean " standard deviation) that are theoretically delivered to the lung from the inhaler device and with the OptiCham-

ber or tube spacer (TAA).

Figure 2. Dose–response to (A) placebo, beclomethasone-CFC (BDP), budesonide-DPI (BUD), and flunisolide-CFC (FLU), and dose–response to (B)placebo, FP, DPI, FP-CFC MDI, and TAA-CFC. The vertical axis is the percent of baseline for the area under the curve for hourly plasma cortisol con-centrations (8 P.M.–8 A.M.). The horizontal axis represents the ICS or placebo dose: 0 ! baseline; 1$ ! first dose (see Table 2 for both labeled doseand ED) with successive doubling doses represented by 2$, 4$, and 8$. There was a statistically significant dose–response for all three ICS butnot for placebo.

Placebo

Beclomethasone

Budesonide

Flunisolide

Fluticasone MDI

Triamcinolone

Fluticasone DPI

Martin AJRCCM 2002

16

ICS Toxicity

Martin AJRCCM 2002

Martin, Szefler, Chinchilli, et al.: Systemic Effect of Inhaled Corticosteroids 1381

could have proposed a design in which the doses were admin-istered randomly with washout periods, we felt there were sci-entific and practical drawbacks to such a design. A random de-sign would be subject to the possibility of significant carryovereffects when a larger dose of ICS preceded a smaller dose ofICS. To eliminate such carryover effects, we would have to in-troduce a washout period long enough to assure that prior ef-fects of the larger dose had waned and that the responsiveness

of the hypothalamic-pituitary-adrenal axis had recovered. Theappropriate duration of such a washout period has not beenestablished. Using the classic escalating dose–response designminimizes these uncertainties. Further, we considered thateven if a carryover effect did exist from prior use of a lowerdose of ICS, it would be no greater than any effect that wouldoccur when these medications were used as currently pre-scribed, namely for long-term, extended use. We recognize,

TABLE 4. ESTIMATED CORTISOL SUPPRESSIVE DOSES

CS10* CS20* CS30* CS40* CS50*

Labeled doseFLU-CFC 936† 1981 3167

(484, 1387)‡ (1025, 2938) (1639, 4695)TAA-CFC 787 1667 2664 3816 5178

(627, 947) (1329, 2005) (2124, 3204) (3042, 4589) (4128, 6227)BDP-CFC 548 1161

(230, 866) (487, 1835)FP-DPI 445

(0, 918)BUD-DPI 268 567 907 1298

(153, 383) (323, 811) (517, 1297) (740, 1857)FP-CFC 111 234 375 537MDI (67, 154) (142, 327) (227, 522) (326, 748)

Emitted doseFLU-CFC 295 625 998

(153, 437) (323, 926) (516, 1480)TAA-CFC 309 653 1044 1496 2030

(246, 371) (521, 786) (833, 1256) (1192, 1799) (1618, 2441)BDP-CFC 168 356

(71, 266) (149, 564)FP-DPI 440

(0, 907)BUD-DPI 164 348 556 796

(94, 235) (198, 497) (317, 795) (453, 1138)FP-CFC 68 144 230 329MDI (41, 95) (87, 201) (139, 321) (200, 459)

Fine particle doseFLU-CFC 229 486 777

(119, 340) (251, 720) (402, 1151)TAA-CFC 101 214 342 490 665

(81, 122) (171, 258) (273, 412) (391, 590) (530, 800)BDP-CFC 97 206

(41, 154) (86, 325)FP-DPI 48

(0, 99)BUD-DPI 85 179 287 410

(48, 121) (102, 256) (163, 410) (163, 410)FP-MDI 58 123 196 281

(35, 81) (74, 171) (119, 273) (170, 391)

Definition of abbreviations: AUC ! area under the curve; BDP ! beclomethasone dipropionate; BUD ! budesonide; CFC ! chlorofluoro-carbon; CS ! cortisol suppression; DPI ! dry powder inhaler; FLU ! flunisolide; FP ! fluticasone propionate; MDI ! metered dose inhaler.

* Micrograms producing an AUC CS of 10%, 20%, 30%, 40%, and 50%.† Doses in micrograms.‡ Values in parentheses represent 95% confidence intervals.

TABLE 5. MODEL-BASED RATIO OF CORTISOL SUPPRESSIVE DOSES AT A 10% SUPPRESSION

Labeled Dose* Emitted Dose Fine Particle Dose

FLU-CFC MDI 1 1 1TAA-CFC MDI 1.19:1 (0.80, 2.38)† 0.95:1 (0.64, 1.90) 2.27:1 (1:53, 4.54)BDP-CFC MDI 1.69:1 (0.99, 6.25) 1.74:1 (1.02, 6.41) 2.34:1 (1.37, 8.64)FP-DPI 2.08:1 (1.00, 100) 0.67:1 (0.32, 32.0) 4.72:1 (2.27, 227.0)BUD-DPI 3.45:1 (2.17, 9.09) 1.80:1 (1.11, 4.64) 2.68:1 (1.68, 7.05)FP-CFC MDI 8.33:1 (5.26, 20.0) 4.34:1 (2.67, 10.1) 3.91:1 (2.47, 9.38)

Definition of abbreviations: BDP ! beclomethasone dipropionate; BUD ! budesonide; CFC ! chlorofluorocarbon; DPI ! dry powder inhaler;FLU ! flunisolide; FP ! fluticasone propionate; ICS ! inhaled corticosteroid; MDI ! metered dose inhaler; TAA ! triamcinolone acetonide.

* FLU-CFC is assigned the arbitrary numeric order of 1 with progressive ordering of the different ICS for the labeled dose. The ratioschange for the emitted dose and fine particle dose.

† Values in parentheses represent 95% confidence intervals.

Asthma

JAMA 2017

Copyright 2017 American Medical Association. All rights reserved.

Reevaluation of Diagnosis in AdultsWith Physician-Diagnosed AsthmaShawn D. Aaron, MD; Katherine L. Vandemheen, MScN; J. Mark FitzGerald, MD; Martha Ainslie, MD; Samir Gupta, MD; Catherine Lemière, MD;Stephen K. Field, MD; R. Andrew McIvor, MD; Paul Hernandez, MD; Irvin Mayers, MD; Sunita Mulpuru, MD; Gonzalo G. Alvarez, MD;Smita Pakhale, MD; Ranjeeta Mallick, PhD; Louis-Philippe Boulet, MD; for the Canadian Respiratory Research Network

IMPORTANCE Although asthma is a chronic disease, the expected rate of spontaneousremissions of adult asthma and the stability of diagnosis are unknown.

OBJECTIVE To determine whether a diagnosis of current asthma could be ruled out and asthmamedications safely stopped in randomly selected adults with physician-diagnosed asthma.

DESIGN, SETTING, AND PARTICIPANTS A prospective, multicenter cohort study was conductedin 10 Canadian cities from January 2012 to February 2016. Random digit dialing was used torecruit adult participants who reported a history of physician-diagnosed asthma establishedwithin the past 5 years. Participants using long-term oral steroids and participants unable tobe tested using spirometry were excluded. Information from the diagnosing physician wasobtained to determine how the diagnosis of asthma was originally made in the community.Of 1026 potential participants who fulfilled eligibility criteria during telephone screening, 701(68.3%) agreed to enter into the study. All participants were assessed with home peak flowand symptom monitoring, spirometry, and serial bronchial challenge tests, and thoseparticipants using daily asthma medications had their medications gradually tapered off over4 study visits. Participants in whom a diagnosis of current asthma was ultimately ruled outwere followed up clinically with repeated bronchial challenge tests over 1 year.

EXPOSURE Physician-diagnosed asthma established within the past 5 years.

MAIN OUTCOMES AND MEASURES The primary outcome was the proportion of participantsin whom a diagnosis of current asthma was ruled out, defined as participants who exhibitedno evidence of acute worsening of asthma symptoms, reversible airflow obstruction,or bronchial hyperresponsiveness after having all asthma medications tapered off and aftera study pulmonologist established an alternative diagnosis. Secondary outcomes includedthe proportion with asthma ruled out after 12 months and the proportion who underwentan appropriate initial diagnostic workup for asthma in the community.

RESULTS Of 701 participants (mean [SD] age, 51 [16] years; 467 women [67%]), 613completed the study and could be conclusively evaluated for a diagnosis of current asthma.Current asthma was ruled out in 203 of 613 study participants (33.1%; 95% CI, 29.4%-36.8%).Twelve participants (2.0%) were found to have serious cardiorespiratory conditions that hadbeen previously misdiagnosed as asthma in the community. After an additional 12 months offollow-up, 181 participants (29.5%; 95% CI, 25.9%-33.1%) continued to exhibit no clinical orlaboratory evidence of asthma. Participants in whom current asthma was ruled out,compared with those in whom it was confirmed, were less likely to have undergone testingfor airflow limitation in the community at the time of initial diagnosis (43.8% vs 55.6%,respectively; absolute difference, 11.8%; 95% CI, 2.1%-21.5%).

CONCLUSIONS AND RELEVANCE Among adults with physician-diagnosed asthma, a currentdiagnosis of asthma could not be established in 33.1% who were not using daily asthmamedications or had medications weaned. In patients such as these, reassessing the asthmadiagnosis may be warranted.

JAMA. 2017;317(3):269-279. doi:10.1001/jama.2016.19627

Editorial page 262

CME Quiz atjamanetworkcme.com andCME Questions page 314

Author Affiliations: Authoraffiliations are listed at the end of thisarticle.

Group Information: The CanadianRespiratory Research Networkmembers are listed at the endof this article.

Corresponding Author: Shawn D.Aaron, MD, Ottawa Hospital ResearchInstitute, Ottawa Hospital, Universityof Ottawa, 501 Smyth Rd, GeneralCampus, Ottawa, ON K1H 8L6,Canada ([email protected]).

Research

JAMA | Original Investigation

(Reprinted) 269

Copyright 2017 American Medical Association. All rights reserved.

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17

Called patients“Do you have asthma”?


SpirometryPre/Post BD

Positive Asthma Confirmed



Methacholine





Methacholine

Methacholine

Stop All Meds




18



Methacholine

Methacholine

Stop All Meds



MethacholineOr worse symptoms

12 Month Follow up


No Asthma


What percentage of patients had no asthma?

A) 0-10%B) 10-20%C) 30-40%D) 40-50%E) >50%

Black Box Warning

• Data from a large placebo-controlled U.S. study that compared the safety of salmeterol or placebo added to usual asthma therapy showed a small but significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks) versus those on placebo (3 of 13,179)".

Original Article

Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone

NEJM 2016

Adolescent and adult patients >12 years with persistent asthma were randomized to ICS (fluticasone) vs ICS + LABA (salmeterol) for 26 weeks

All patients had a history of a severe asthma exacerbation in the past year

19

Primary Safety End Point (Intention-to-Treat Population).

Stempel DA et al. N Engl J Med 2016;374:1822-1830

Summary of Safety End Points.

Stempel DA et al. N Engl J Med 2016;374:1822-1830

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

20

Not all asthma is the same!!

(Heterogeneity)

(Phenotypes)

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

5030 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

A Large Subgroup of Mild-to-Moderate AsthmaIs Persistently Noneosinophilic (NON Allergic)

• Asthma is a heterogeneous disease• ~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)

21

TH2 Genes Overexpressed in Asthma

Woodruff et alAm J Respir CCM 180:388, 2009

Th2High

Th2High

Th2High

Th2Low

Th2Low

Th2Low

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 alAm J Respir CCM 180:388, 2009

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

22

Type-2 Inhibitors for Severe Asthma• Anti IL-5 Agents

– Mepolizumab (NUCALA)*– Resilizumab (CINQAIR)*

• Anti IL-13 Agents– Lebrikizumab

• Anti IL-4/IL-13– Dupilumab

• Anti TSLP– AMG 157

* FDA Approved

A Large Subgroup of Mild-to-Moderate AsthmaIs Persistently Noneosinophilic (NON Allergic)

• Asthma is a heterogeneous disease• ~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)

23

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

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: Mepolizumab?

• Do not use methotrexate for asthma

• Do not use azithromycin for asthma

24

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 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

Is There Really A Difference

Between Asthma And COPD?

25

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

Inflammation inCOPD versus Asthma

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

COPD AsthmaPredominant Cells

Macrophages EosinophilsNeutrophils Activated Mast Cells

CD-8 T-Lymphocytes CD-4 T Lymphocytes

Predominant CytokinesInterleukin 8 Interleukin 4

Leukotriene B4 Interleukin 5Tumor Necrosis Factor alpha Interleukin 13

COPD Asthma OverlapIN 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

flow

(lite

rs/m

in)

Volume of expired air (liters)

0

4

6

0 1 3 4

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Copyright © 2015 Massachusetts Medical Society. All rights reserved.

Asthma Summary• The “Cause” of asthma remains unknown, but is

unlikely to be fully explained by genetics• Many patients with asthma diagnosis may not have

asthma• LABA are safe to use in asthma patients• Patients respond differently to medications based

upon underlying “endotype/phenotype”• “Th2-High” or Allergic Asthma responds to

corticosteroids• New Medications are on the way for Severe Allergic

Asthma

update on copd & asthma disclosures - · pdf fileupdate on the management of copd what is...

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