are asthma and copd two faces of a similar process? towards a new taxonomy of airways diseases
DESCRIPTION
Barcelona-Boston Lung ConferenceTRANSCRIPT
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