Ian D Pavord

Professor of Respiratory Medicine

University of Oxford

Are Asthma and COPD Two Faces of a Similar Process?Towards a new taxonomy of

airways diseases

Plan

• Asthma and COPD: is the sub-division helpful?

• Is it better to describe rather than categorise?• Eosinophilic airway inflammation in COPD• Development of fixed airflow obstruction

(‘COPD’) in asthma • Could the mechanisms leading to the

development of fixed airflow obstruction in asthma be similar to those resulting in COPD in a smoker?

The various types of airway diseases should not be considered as separate diseases but as one disease, the components of which are influenced by host (genetic) and environmental factors.

Postma DS, Boezen HM. Chest 2004; 126: 96s-109s

Orie, NG

Features of COPD

Features of asthma

Features of COPD

Features of asthma

Why we should all be Dutch

• Community studies have shown that 6% of patients with asthma and 5% of patients with COPD responding to a survey would be eligible for key, opinion forming clinical trials in these conditions1,2

• A common reason for exclusion is presence of features normally associated with the other condition

• Labels suggest exclusivity and inhibit full description• Physiological classification overemphasises this

aspect of the disease • This has inhibited major conceptual advances and

new drug discovery.

1Travers et al. Thorax 2007;62:219-223; 2Travers et al. Resp Med 2007;101:1313-20

Don’t get hung up on the diagnosis

AsthmaCOPD

Cough and sputum

xxxxxxxxxxxxx

Prednisolone xxxxxxxxxxxxxxxxxxxxx Predicted PEF

FENO (ppb) 78 20ppb

The A to E of potential causes for persistent morbidity in patients with

airway disease

• Airway hyperresponsiveness• Bronchitis• Cough reflex hypersensitivity• Damage• Extra-pulmonary factors

Pavord & Wardlaw. Clin Exp Allergy 2010

Airway hyperresponsiveness

• Responsible for many day-to-day symptoms• Exaggerated response to constrictor stimuli,

bronchodilator responsive airflow obstruction, short-term variable airflow obstruction, deep breath-induced bronchodilation

• Most closely linked to mast cell-airway smooth muscle interactions

• Current treatments usually suppresses but not completely

Bronchitis• Eosinophilic or neutrophilic• Bronchodilator unresponsive, corticosteroid

responsive airflow obstruction, less short-term variable airflow obstruction, deep breath-induced bronchoconstriction

• Most closely linked to exacerbations, particularly when associated with acute inflammation in patients with A and D

• Current treatments usually suppress eosinophilic bronchitis effectively; some patients require oral prednisolone

• Neutrophilic bronchitis is corticosteroid resistant

Mechanisms of airflow limitation

Cough and sputum

xxxxxxxxxxxxx

Prednisolone xxxxxxxxxxxxxxxxxxxxx Predicted PEF

FENO (ppb) 78 20ppb

D

A

B

0

0.3

1

3

10

100

30

COPD Normal

Sput

um e

osin

ophi

ls (

%)

Brightling et al. Lancet 2000;356:1480-85; Green et al. Thorax 2002; 57:875-879

Sputum eosinophil counts in COPD

Asthma

Baseline characteristics by tertiles of sputum eosinophil count in patients

with COPD

Eosinophil count <1.3 (22) 1.3-4.5 (23) >4.5 (22)

Male 13 13 15

Age 68 (42-82) 66 (49-83) 64 (47-78)

FEV1 1.16 (0.03) 1.11 (0.09) 0.96 (0.08)

FEV1 BD 1.21 (0.1) 1.15 (0.09) 0.98 (0.08)

Pack years 33 (4.1) 35 (2.5) 37 (4.3)

Atopic 7 7 6

FBC Eo (x109/l) 0.12 (0.02) 0.22 (0.04) 0.17 (0.02)

CRQ Total 3.92 (0.25) 4.04 (0.19) 4.08 (0.25)

Brightling et al. Lancet 2000;356:1480-85

-0.05

0.00

0.05

0.10

0.15

0.20

0.25

D FEV1 (l)

** **p<0.01

<1.3 1.3-4.5 >4.5

Eosinophil countBrightling et al. Lancet 2000;356:1480-85

Response to prednisolone by tertile

Sputum eosinophil directed steroid treatment in asthma and COPD

*p=0.037

Traditional n=20

Sputum n=8*

Ad

mis

sio

ns (

n)

Time (months)

0

10

15

20

5

0 2 4 6 8 12

120

100

80

60

40

20

0

0 1 2 3 54 129 10 116 7 8

Severe

exacerb

ati

on

s (

n)

Time (months)

6 patients admitted

BTS guidelines (n=37)

1 patient admitted

*p=0.01

109*

35

Green et al, Lancet 2002; 360: 1715-21

Asthma

COPD

Sputum guided (n=37)

Siva et al. Eur Respir J 2007; 29:906-913

Mepolizumab (anti-IL-5). Effect on severe exacerbations

Haldar et al. NEJM 2009;360:973-84 Pavord et al. Lancet 2012;380:651-9.

Is there a role for Mepolizumab in eosinophilic

COPD?

• 95 patients in DREAM study would have been eligible for most recent COPD trials if they had smoked for a few more years

• Patients with symptom onset >40 years, a smoking history, a post-bronchodilator FEV1 <80% predicted and FEV1/FVC <0.7 had a 61% reduction in exacerbations, compared to 48% in total population

D FEV1 after salbutamol (ml) Exacerbations/pt/year p-value Mepo Placebo

<50 1.3 3.8 0.0250 to 150 1.7 3.6 0.11>150 2.6 2.4 0.85

Pavord et al. Lancet 2012;380:651-9.

Haldar et al. NEJM 2009;360:973-84

Exacerbation: inflammatory phenotypes

• 145 patients with COPD followed for 1 year; 182 exacerbations characterised

• Three inflammatory patterns: bacterial (55%), viral (29%) and eosinophilic (28%)

• Associated with characteristic and largely predictable sputum and blood cytokine patterns

• A blood eosinophilia is a good marker of eosinophilic exacerbations

• Eosinophilic exacerbations are associated with a more rapid and complete response to steroids

• Bacterial and eosinophilic exacerbations almost never co-exist

• Exacerbation patterns tend to be consistent within patients

Bafadhel et al. Am J Respir Crit Care Med 2011;184:662-71

Eosinophilic exacerbations: bad but treatable

Bafadhel M et al. Am J Respir Crit Care Med 2012;186:48-55

Sp Eos >3% treated with prednisoloneSp Eos <3% treated with placeboSp Eos <3% treated with prednisolone

14 excluded; 11 did not fulfil inclusion criteria, 3 other co-morbidity

13 died, 7 withdrew, 21 other co-morbidity

167 patients screened for eligibility into biomarker intervention study164 entered into biomarker intervention study (94 from biomarker observation

study)

1 treatment failure

3 treatment failures

80 exacerbation events

55 patients randomised to biomarker treatment arm

44 exacerbations received Prednisolone + antibiotics

42 exacerbations received Placebo + antibiotics

86 exacerbation events

156 patients entered biomarker observation study115 patients completed biomarker observation study

170 patients screened for eligibility of biomarker observation study

1 died, 2 withdrew

At exacerbation54 patients randomised to standard treatment arm

≤ 2% > 2%

41 exacerbations received Prednisolone + antibiotics

39 exacerbations received Prednisolone + antibiotics

≤ 2% > 2%

6 treatment failures

4 treatment failures

Phenotype-specific management of COPD exacerbations

Bafadhel et al. Am J Respir Crit Care Med 2012; 186:48-55

• Seen in patients with severe childhood asthma• Also in a subgroup of adult onset disease; association with smoking• Associated with neutrophilic and eosinophilic airway inflammation • Clinical, physiological and radiological evidence of small and large airway damage (remodelling)• Related to frequency of asthma attacks, particularly in untreated disease• One attack/year caused 30 ml excess loss in FEV1/year

Lange et al. NEJM 1998;339:1194-1200

Asthma andSmoking

Early onsetSevere asthma

Asthma -Smoking -

Asthma orSmoking

Age

FE

V1

Bai et al. Eur Resp J 2007;30:452-56

Fixed airflow obstruction in asthma

Why does airway disease become severe?

Mild atopicasthma

Severe COPD

Severe, refractoryasthma

Mild smokers bronchitis

• Large airway inflammation• Homogeneous (eosinophilic, neutrophilic)• Little damage• Responsive to intervention (inhaled steroids, smoking cessation)

• Large and small airway inflammation• Heterogeneous; increased neutrophils• Damage++• Unresponsive to intervention (inhaled steroids, smoking cessation)

Multiple ‘hits’ and the airway

• Amplification of inflammatory response• More distal, neutrophil predominant

response• More airway damage• Corticosteroid resistance• Worse clinical consequences

Pavord et al. ERJ 2006;27:884-888

Multiple ‘hits’ and airway disease: examples

• Enhanced allergen response after viral infection or after exposure to pollutants

• Increased decline in FEV1 in smokers and asthmatics with occupational coal dust exposure

• Increased decline in FEV1 and airway damage in patients sensitised and colonised/infected with aspergillus

• Chronic viral/bacterial infection in COPD and asthma

Multiple ‘hits’ and airway disease

Multiple ‘hits’ and airway disease

• Increased symptoms and exacerbations• Sputum neutrophilia• More rapid decline in FEV1

• Poor response to inhaled and oral corticosteroids

Chalmers et al Thorax 2002;57:226-30

Smoking and asthma

Chaudhuri et al. AJRCCM 2006;174:127-133

Smoking cessation and asthma control

1 3 6Weeks abstinence

• 10 quitters vs 11 continued smokers• Improved FEV1 and ACQ in quitters• Reduced sputum neutrophils (-29% at 6 weeks)• Increased cutaneous vasoconstrictor response to topical steroid

P<0.0001

P<0.05

Positive culture

Negative culture

Logistic regression for Sputum Af culture – Af sensitisation p = 0.004, Age = p= 0.076

Aspergillus sensitisation is associated with impaired lung function

Fairs et al. Am J Respir Crit Care Med 2010;182:1362-68

Denning et al. AJRCCM 2009;179:11-18

Anti-fungal treatment in aspergillus-associated asthma

Macrolides and severe airway disease

Albert et al. NEJM 2011;365:689-98

Simpson et al. AJRCCM 2008;177:148–155

Baseline After treatment Treatment withdrawn

16

14

12

10

8

6

4

2

0

200018001600140012001000

800600400200

0Baseline After treatment Treatment

withdrawn

Clarithromycin

Placebo

Clarithromycin

PlaceboIL

-8 n

g/m

LN

eu

tro

ph

il E

last

ase

ng

/mL

*#

#

#P<0.05

COPD Asthma

Conclusions

• “Asthma” is an important cause of “COPD”• An important number of patients classified as

having COPD are receiving sub-optimal treatment with corticosteroids

• Common features are potentially responsible for evolution of mild to severe disease

• Multiple inflammatory ‘hits’ may be one such factor

• Recognition of potential hits might lead to effective management approaches