What does asthma look like
for different people?
……Asthma phenotypes
Thurs September 19
11.30am-12.00pm
What is a phenotype ?
The observable characteristics of an
individual resulting from the interaction of its
genotype with the environment
What is a phenotype ?

Phenotype: observable qualities of an individual
= gene X environment

Clinical Phenotype: Clinically important
observable qualities of an organism


Han MLK etal, AJRCCM 2010;182:598
Endotype: endogenous mechanism that
underlies a phenotype

Anderson GP, Lancet 2008; 372:1107
Phenotypes, why bother ?
Asthma deaths
Then…….. and now….
Australia, 1979–2006
Australian Centre for Asthma Monitoring
Asthma Control
as needed rapidacting β2-agonist
Oral
glucocorticosteroid
(lowest dose)
anti-IgE
antibodies
People vary in how they respond to
treatment
responder
Are you the
average ?
Or are you an
Little response
Individual ?
Zeiger RS et al. J Allergy Clin Immunol. 2006;117:45–52.
Clinical phenotypes that don’t fit

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Obesity…. 50%
Smoking….30%
Asthma-COPD Overlap
Asthma in the elderly
Severe Asthma…10%
Older people with airway disease:
age >55, multiple problems, irrespective of the diagnosis
Health Related quality of life impairment was associated
with the number of management problems identified by
the MDA
Health Status (SGRQ) by Diagnosis
100
HRQOL (SGRQ)
SGRQ units
100
p=0.74
p=0.03
p=0.003
50
75
r=0.59
p<0.0001
50
25
0
0
0
COPD
Asthma
Ov erlap OAD
McDonald VM et al, Age Ageing 2011:40;42-9
5
10
15
20
number of clinical management problems
Gibson PG, McDonald VM, Marks GM. Lancet 2010; 376:803
Airway disease in older people
1. Multidimensional
Assessment
2. Biomarkers drive
Pharmacotherapy
3. Case manager
Gibson PG, McDonald VM, Marks GM. Lancet 2010; 376:803
Ester, 87 years, ♀, Asthma



Presents to clinic following admission
Exacerbation of asthma and worsening
depressive symptoms
Background –




Asthma since age 7
Depression, AF, HT, heart failure, TIAs, Cataracts,
GORD: CCI= 7
Never Smoker
Exacerbation history – 4 courses of
antibiotics in the past 12 months
Ester, 87years, ♀, Asthma
Ester’s perspective

‘I get puffed so easily, I can’t walk up hills. I stop
doing things because my breathing gets worse, my
biggest problem is getting puffed’

‘I feel useless’

‘No I don’t think rehab is for me, I don’t want that.
It’s too much effort, I would rather just do exercise at
home. I don’t want to do the group stuff’
Ester, 87years, ♀, Asthma
Body Composition
BMD -T scores = total body 0, hip -0.8 =
normal
ASMMI 5.9km/m2 = normal
Slow gait speed & unable to do 5 chair
rises
Pulmonary Rehab + home based
resistance training 3 X week
Airway Inflammation= normal
No sputum, FENO 17.5ppb
Maintenance ICS/LABA
Systemic Inflammation= YES
CRP mg/mL 18.1
Simvastatin 20mg
Breathing dysfunction = YES
Nijmegen 37
Breath retraining
Anxiety/Depression = YES
HADS (A) 8 (D) 10
Depression management – Paroxetine
20mg + counselling
Frequent Infections
Self Management Education with
WAP
Outcomes
Baseline
3 months
6 months
FEV1
1.27 (77)
1.3 (81)
1.12 (66)
SGRQ
56.3
24.3
27.4
Exacerbations
4 past 12/12
0 past 3/12
0 past 6/12
6MWD
257.2
333.8
359.1
FENO
17.5
16.2
18
CRP
18.1
4.2
Nijmegen
37
41
29
ASMMI
5.9kg/m2
6kg/m2
6kg/m2
BMI
22
24.2
24.3
HADS A|D
8|10
6|4
4|6
Treatment Effects
multidimensional
assessment
and intervention
Change in SGRQ
0
-2
-4
-6
-8
-10
-12
M
B
IP
R
C
A
SU
A
L
FT
PL
I
IP
B
M
U
U
E
)
FC
(S
H
C
TO
R
(T
IO
)
x
M
Se
lf
R
eh
ab
-14
McDonald VM, Higgins
Gibson PG
I, Wood
et al. L,
ERS
Gibson
2010 PG. Thorax 2013; 68:691
‘hidden’ phenotypes
genes and environment
Phenotype = gene X environment
Gene = DNA
How do you tell
when it is relevant?
The gene has to be doing something,
And you tell that from….
RNA
Protein
We call that a biomarker.
Inflammatory phenotyping
It means: Biomarker +
specific treatment
= reduced exacerbations
Annual severe exacerbation rate

+
3
2.69
2.5
2
1.5
0.90
1
0.5
0
Before omalizumab
Allergen specific IgE
Week 52 after omalizumab
omalizumab
Bruselle A, Resp Med 2009
Inflammatory phenotyping

It means : Biomarker + specific treatment
Anti IL5
mAb =
Haldar NEJM 2009; Nair NEJM 2009
5
4.5
Exacerbation rate by phenotype
4
3.5
3
2.5
Exac/yr
2
1.5
1
0.5
0
Nonsevere
Allergic
severe
Eosinophilic Early onset
severe
allergic
McDonald V, Clin Exp Allergy 2013
Inflammatory phenotyping
For
Refractory
Severe Asthma
Severe
Asthma
Raised IgE
Omalizumab
Itraconazole*
Anti IL-13 Mab
* ABPA, SAFS
Eosinophilic
Oral/IMI
Corticosteroid
Anti IL5 Mab
Noneosinophilic
Macrolides
Managing Asthma in Pregnancy
Biomarker:
The Protein: an enzyme, iNOS.
When active it produces a gas,
called Nitric oxide, or FENO
That is measured in your breath
Managing Asthma in Pregnancy
Treatment guided
By symptoms
Treatment guided
by FeNO + symptoms
OR
106 women
With asthma
104 women
With asthma
Powell et al, Lancet 2011
Managing Asthma in Pregnancy
FENO guided treatment reduces attacks
Symptoms
Asthma attacks
were reduced
By Half
FeNO
Powell et al, Lancet 2011
Managing Asthma in Pregnancy
What about the babies ?
210 mothers with asthma,
214 beautiful babies
Less babies in NICU
Fewer attacks bronchiolitis
What happened to them?
18
%
16
14
12
10
8
6
4
2
FeNO
0
NICU
Powell et al, Lancet 2011
Mattes J , Thorax 2013, in press
Oral Corticosteroids
Fewer courses
Of steroids
Were needed
For wheezing
attacks
Mattes J , Thorax 2013, in press
‘hidden’ phenotypes,
genes and environment
Biomarker is FENO
‘hidden’ phenotypes,
genes and environment
‘gene chips’
Transcriptomics: Baines K, JACI, 2011
3
1
2
258 genes
24 genes
187 genes
EOS
NEUT
PAUCI
Sputum gene expression biomarkers for asthma
phenotype

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Microarray screening approach to identify sputum biomarkers for eosinophilic,
neutrophilic and paucigranulocytic asthma.
Candidate biomarkers (n=35) were tested and 27 validated using qPCR in 3
studies (discovery, clinical validation, ICS response). A combination of 6 genes
including CLC, CPA3, DNASE1L3, IL1B, ALPL, CXCR2, can predict asthma
inflammatory phenotypes from each other and healthy controls.
HC
Eos
Neut
Gene signature can predict ICS response
•
Steroid response trial: n=71 people with asthma treated
with 1000ug fluticasone per day, 28 days
‘hidden’ phenotypes,
genes and environment
‘gene chips’
Phenotypes….Now to next ?
Now:
 Mortality has reduced
 Control has improved
 Overdiagnosis
 Overtreatment
 People are still unwell
Next: ?


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Cure
Prevention
New treatment:
breakthroughs
Lifestyle