Defining and diagnosing
severe asthma
SY9
WAO – WISC2010
Dubai December 2010
Eric D. Bateman
MD, MBChB, FRCP, DCH
Professor of Respiratory Medicine, University of Cape Town
Director of University of Cape Town Lung Institute
Head, Division of Pulmonology, Cape Town
Presenter Disclosures
Eric D Bateman
Lecture Fees: AstraZeneca, Alk Abello, Boehringer
Ingelheim, Chiesi, GlaxoSmithKline, Nycomed, Pfizer, TEVA
Consultancy or Advisory Boards: Almirall, AlkAbello, Amgen,
AstraZeneca, Boehringer Ingelheim, Chiesi, Forest,
Hoffmann la Roche, GlaxoSmithKline, Merck, Morria
Biopharmaceuticals, Novartis, Nycomed, Pfizer,
ScheringPlough
Industry-sponsored grants (Institution): Aeras, Almirall,
Altana, AstraZeneca, Boehringer Ingelheim, Chiesi,
Hoffmann la Roche, GlaxoSmithKline, Merck, Morria
Biopharmaceuticals, Novartis, Nycomed, Pfizer.
Defining and diagnosing severe asthma
Learning objectives
To review new definitions of severe asthma
WHO
ATS/ERS Task Force on Severity and Control
ATS/ERS Task Force on Severe Asthma
Consider the clinical implications of these
definitions
Asthma is not a single disease!
Asthma phenotypes
“The characteristics of an organism which develop as a
consequence of interactions of the genetic background
with the environment...”
Genotype
Pathobiology
(marker/s)
Environment
Clinical features
Treatment
responsiveness
Natural history
ATS/ERS Task Force on Severe Asthma 2009:
Co-Chairs: Sally Wenzel & Fan Chung
Conceptual framework asthma and its management
(ATS/ERS Task Force)
ASTHMA CONTROL
Current control
Future risk
ASTHMA SEVERITY
TREATMENT
(“difficulty in treating”
treating”)
DISEASE ACTIVITY
Genetic and
environmental
factors
ASTHMA PHENOTYPES
Taylor DR et al, ERJ 2008; 32:54532:545-554
Severity Classification: Cockcroft
Severity
Level of
control
Treatment
None or rare ß2-agonist
Mild infrequent Well
controlled
Severe
High- to very high-dose ICS
+ occasional OCS
Well controlled
Very severe
Very high dose ICS + Oral
CS + additional therapies
Not well controlled
Very mild
Mild
Moderate
s
s
Rare ß2-agonist +/- Low- ne
e
Well controlled
v
i
dose ICS
s
n
o
Moderate
to high dose ICS
p
s
Well controlled
e
+
occasional
OCS
R
Cockcroft DW, Swystun VA. JACI 1996; 98: 1016-8.
Stoloff SW, Boushey HA. JACI 2006
SARP: Assessment of Asthma Phenotypes
628 variables from 726
patients
353 questionnaire
data
Demographics
1 Sex
2 Race
3 BMI
4 Age
5 Onset of asthma
6 Asthma duration
COMPOSITE VARIABLES:
14-17 medication use
18-19 Health care utilization
20-21 Symptoms
26-29 Asthma triggers
30 Co-morbidities
31-32 Family history
33 Tobacco exposure
34 Women/hormones
197
Lung function
19
Atopy
59
Biomarkers
Lung function
13 Skin tests
7-9 pre b.d.
afo
Composite
variables
22, 23 Perennial
allergens
24, 25 Seasonal
allergens
IgE
FeNO
Sputum
BAL
10-12 post
b.d. response
to albuterol
PC20 Meth
34 variables in
cluster analysis
11 variables in discriminant
analysis
3 variables in tree
analysis
Moore , WC et al, AJRCCM 2009: epub
Severe Asthma Research Program (SARP)
Severe Asthma Research Programme:
Phenotyping by Cluster Analysis
628 variables
34 core variables
726 patients
Cluster 2
Cluster 3
Cluster 1
Branch based on treatment
responsiveness
Cluster 4
Cluster 5
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0.175
0.200
0.225
0.250
0.275
0.300
0.325
0.350
Semi-Partial R-squared
Moore , WC et al, AJRCCM 2009: epub
Severe Asthma Research Program (SARP)
SARP: Tree Performance
Mild Atopic
Asthma
Mild-Moderate
Atopic Asthma
Late-onset
Non-atopic
Asthma
Severe
Atopic
Asthma
Using only prepre- and postpost-bronchodilator FEV1% predicted and age of onset, 80%
correctly assigned
% = percentage of patients from that cluster correctly assigned
assigned
N = 728
Severe
Asthma with
Fixed Airflow
were
Moore , WC et al, AJRCCM 2009: epub
Severe Asthma Research Program (SARP)
Severe asthma requiring high intensity treatment
ATS / ERS Task Force Asthma Control and Exacerbations
Standardizing Endpoints for Clinical Asthma Trials and Clinical Practice
“Severe asthma is defined as the requirement for high intensity
treatment after modifiable factors and comorbidites have been
appropriately managed”
Good control on high
intensity treatment
Treatment
responsive, but
with persistent
problems e.g. poor
adherence,
smoking
Poor control despite high
intensity treatment
Persistent comorbidities e.g.
GE reflux, obesity
Treatment
resistant/
refractory asthma
Reddel H, et al, Amer J Resp Crit Care Med 2009;180:59-99
WHO: Definition of Severe or Difficult to
Manage Asthma
•
•
•
All severe asthma requires confirmed diagnosis of asthma,
compliance/adherence and co-morbidities addressed
All severe asthma requires treatment with “gold standard
medication” (for that age group) for 3 months by asthma
specialist* to prevent patient from becoming uncontrolled or
which remains uncontrolled.
*Asthma specialist can vary from country to country and from children to adults.
In adults, this is traditionally an allergist or pulmonologist/respirologist with
advanced training and experience in asthma. In pediatric populations this may
also include pediatricians with additional training and experience in severe
asthma
Bousquet J et al, JACI 2010
Definition of Severe or Difficult to Manage Asthma:
Gold Standard Therapy
High dose inhaled CS and LABA (or LT modifier) and /
or systemic CS for >50% of the previous year.
High dose ICS is fluticasone >1000 mcg/day (or equivalent)
Bousquet J et al, JACI 2010
Failed
Step 3
Levels of CONTROL achieved in GOAL
Total or Well Controlled* at 52 weeks
% of patients CONTROLLED
100
80
Salm/FP 500
Salm/FP 250
Fluticasone 100
Salm/FP 100
Severe asthma
50%
62%
60
47%
Fluticasone 500
Fluticasone 250
50%
40
20
0
Previously uncontrolled on
moderate doses of ICS
*GOAL definitions of control
n = 1155
Bateman ED et al. Am J Respir Crit Care Med 2004; 170: 836–844
Patients (% per week) achieving GINA Controlled or Partly
Controlled weeks during Bud/Form M&R studies
Bud/Form M&R vs
Same-dose
ICS/LABA
+ SABA1,3
Bud/Form M&R vs
High-dose ICS
+ SABA1,2
60
50
40
30
20
10
0
Controlled and Partly
Controlled (%)
60
Controlled and Partly
Controlled (%)
Controlled and Partly
Controlled (%)
60
Bud/Form M&R vs
High-dose
ICS/LABA
+ SABA4,5
50
40
30
20
10
40
30
20
10
0
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56
Week
Week
Bateman ED et al, JACI 2010
50
0
4
8 12 16 20 24 28
Week
1. O’Byrne PM, et al. Am J Respir Crit Care Med 2005;171:129–136
2. Scicchitano R, et al. Curr Med Res Opin 2004;20:1403–141
3. Rabe KF, et al. Lancet 2006;368:744–753
4. Kuna P, et al. Int J Clin Pract 2007;61:725–736
5. Bousquet J, et al. Respir Med 2007;101:2437–2446
Definition of Severe or Difficult to Manage Asthma
Definition of Uncontrolled Asthma
Any one of the following:
•
•
•
•
Poor symptom control: ACQ consistently >1.5 (or “not well
controlled” by NAEPP guidelines)
Frequent exacerbations: 2 or more bursts of systemic CSs (>3
days each) in the previous year
Severe exacerbations: at least one hospitalization, ICU stay or
mechanical ventilation in the previous year
Persistent airflow limitation: pre-short and long acting bronchodilator
FEV1< 80% predicted (in the face of reduced FEV1/FVC)
Bousquet J et al, JACI 2010
Future risk of exacerbations… in relation FEV1
(pre-bronchodilator)
Incidence of asthma exacerbations
over next 3 years
70
Netherlands
60
United States
50
40
30
20
10
0
>100
90-100
80-89
70-79
60-69
50-59
<50
FEV1 % predicted
Kitch BT et al, Chest 2004;126:1875-82.
Fuhlbrigge AL et al, JACI 2001;107:61-7.
Definition of Severe or Difficult to Manage
Asthma
• Controlled asthma on these high doses of inhaled corticosteroids or
systemic CS (or additional biologics) places a patient at high future risk
for side effects from medications
Bousquet J et al, JACI 2010
Exacerbation rate in maintenance phase
(according to control status achieved in phase I)
Mean exacerbation rate
per patient per year
Historical = 0.70
Fluticasone
Salm-FP
0.8
Historical = 0.40
0.6
0.4
0.42
0.28
0.2
0.13
0
0.17
0.09
0.05
Not TC or
Well
WC
controlled
0.01
0.23
0.19
0.02
Total
control
Not TC or
Well
WC
controlled
0.07
0.13
Total
control
Stratum 1: ICS-naive
Stratum 3: Moderate ICS
*Requiring either oral steroids or hospitalisation / emergency visit
Bateman ED, et al Am J Resp Crit Care 2004
Patients (% per week) experiencing exacerbations requiring
medical intervention
3.6
3.2
2.8
2.4
2.0
1.6
1.2
0.8
0.4
0.0
3.6
3.2
2.8
2.4
2.0
1.6
1.2
0.8
0.4
0.0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56
Week
Week
60
40
30
20
10
0
2.8
2.4
2.0
1.6
1.2
0.8
0.4
0.0
0
4
8 12 16 20 24 28
Week
50
40
30
20
10
40
30
20
10
0
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56
Week
Week
Bateman ED et al, JACI 2010
3.2
Controlled and Partly
Controlled (%)
50
3.6
60 the dose of ICS
Increasing
in the combination
inhaler
50
60
Controlled and Partly
Controlled (%)
Controlled and Partly
Controlled (%)
HigherHigher-dose ICS/LABA
+ SABA vs Bud/Form M&R
Exacerbations in week (%)
SameSame-dose ICS/LABA
+ SABA vs Bud/Form M&R
Exacerbations in week (%)
Exacerbations in week (%)
HighHigh-dose ICS
+ SABA vs Bud/Form M&R
0
4
8 12 16 20 24 28
Week
Severe and difficult to manage asthma
Disease factors:
Wrong diagnosis: Functional upper airway problems,
heart disease
Unrecognised trigger factors: drugs, occupational
agents
Associated disease: GORD, sinusitis, thyrotoxicosis
Corticosteroid refractoriness or resistance
Health system factors:
Inadequate or inappropropriate treatment
Failed patient / physician partnership
Patient factors:
Poor adherence
Psychological / personality
Socio-behavioural
Corticosteroid refractoriness is not absolute
‘normal’
Improved
asthma
control
Mild asthma
steroid-responsive
Reduced
airway
inflammation
(%)
Severe asthma
‘steroid-dependent’
Steroid resistant
Dose of corticosteroid
Severe and difficult to manage asthma
Disease factors:
Wrong diagnosis: Functional upper airway problems,
heart disease
Unrecognised trigger factors: drugs, occupational
agents
Associated disease: GORD, sinusitis, thyrotoxicosis
Corticosteroid refractoriness or resistance
Health system factors:
Inadequate or inappropropriate treatment
Failed patient / physician partnership
Patient factors:
Poor adherence
Psychological / personality
Socio-behavioural / economic considerations
Severe /Difficult to
manage asthma
Patients are not all the same !
Revised NEO Personality Inventory
Costa PT & McCrae RR, 1992
Asthma Management and Prevention Programme
Component 1: Develop a doctor /
patient partnership
Doctor-directed patient self-management
Written self-management plans are associated with
improved asthma outcomes
Alexithymia
Alexithymia
= difficulty in perceiving and expressing
emotions and body sensations
Prevalence: 8 - 19% of males in general population
Toronto Alexithymia Score
Correlates with neuroticism
Negative correlation with Extraversion and Openness
Alexithymia more common in patients with near-fatal
asthma episodes (36 versus 13%)
More severe asthma, and very severe near-fatal episodes
Bagby RM et al, J Pschosom Res 1994; 38: 23
Serrano J et al, ERJ 2006; 28: 296
Luminet O et al, J Pers Assess 1999; 73:345
Plaza V et al, J Asthma 2006; 43: 639
Severe and Difficult to Manage Asthma
Take home messages
Severe asthma is common !
Definition is clinical
Consider domains to establish cause
In real life practice, patient factors are most common
Resistance to treatment is relative and seldom complete
New second/third line (targeted) controllers are needed