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 ?

Australia, 1979–2006

Asthma deaths Then…….. and now….

Australian Centre for Asthma Monitoring

Asthma Control Asthma Control

Oral glucocorticosteroid

(lowest dose)

anti-IgE antibodies

as needed rapid-acting β2-agonist

People vary in how they respond to treatment

Are you the

average ?

Or are you an

Individual ?

Zeiger RS et al. J Allergy Clin Immunol. 2006;117:45–52.

responder

Little response

Clinical phenotypes that don’t fit 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

COPD Asthma Overlap OAD0

50

100 p=0.003 p=0.03

p=0.74

SG

RQ

un

its

Health Status (SGRQ) by Diagnosis

0 5 10 15 200

25

50

75

100

r=0.59p<0.0001

number of clinical management problems

HR

QO

L (

SG

RQ

)

Health Related quality of life impairment was associated with the number of management problems identified by the MDA

McDonald VM et al, Age Ageing 2011:40;42-9

Older person with asthma

Older person with asthma

Gibson PG, McDonald VM, Marks GM. Lancet 2010; 376:803

Airway disease in older people

Gibson PG, McDonald VM, Marks GM. Lancet 2010; 376:803

1. Multidimensional Assessment

2. Biomarkers drive Pharmacotherapy

3. Case manager

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’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

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

OutcomesBaseline 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

McDonald VM, Gibson PG et al. ERS 2010McDonald VM, Higgins I, Wood L, Gibson PG. Thorax 2013; 68:691

Rehab

Self M

x

TORCH (SFC)

UPLIFT (T

IO)

IPBM

USUAL C

AREIP

BM

-14

-12

-10

-8

-6

-4

-2

0

Ch

ang

e in

SG

RQ

‘hidden’ phenotypesgenes 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….RNAProtein

We call that a biomarker.

Inflammatory phenotyping

It means: Biomarker + specific treatment

+

2.69

0.90

0

0.5

1

1.5

2

2.5

3

Before omalizumab Week 52 after omalizumab

An

nu

al s

eve

re e

xace

rba

tion

rate

= reduced exacerbations

Bruselle A, Resp Med 2009

omalizumabAllergen specific IgE

Inflammatory phenotyping It means : Biomarker + specific treatment

Anti IL5mAb =

Haldar NEJM 2009; Nair NEJM 2009

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Nonsevere Allergicsevere

Eosinophilicsevere

Early onsetallergic

Exac/yr

Exacerbation rate by phenotype

McDonald V, Clin Exp Allergy 2013

Severe Asthma

Raised IgEOmalizumabItraconazole*

Anti IL-13 Mab

EosinophilicOral/IMI

CorticosteroidAnti IL5 Mab

NoneosinophilicMacrolides

* ABPA, SAFS

Inflammatory phenotyping For Refractory SevereAsthma

Managing Asthma in Pregnancy

Biomarker:The Protein: an enzyme, iNOS.When active it produces a gas, called Nitric oxide, or FENOThat is measured in your breath

Powell et al, Lancet 2011

Treatment guided By symptoms

Treatment guided by FeNO + symptoms

106 women With asthma

104 women With asthma

Managing Asthma in Pregnancy

OR

Powell et al, Lancet 2011

Asthma attacks were reducedBy Half

Managing Asthma in PregnancyFENO guided treatment reduces attacks

FeNO

Symptoms

Powell et al, Lancet 2011

210 mothers with asthma,

214 beautiful babies

What happened to them?

0

2

4

6

8

10

12

14

16

18

NICU

Less babies in NICUFewer attacks bronchiolitis

Managing Asthma in PregnancyWhat about the babies ?

FeNO

%

Mattes J , Thorax 2013, in press

Fewer courses Of steroidsWere neededFor wheezing attacks

Oral Corticosteroids

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

187 genes

24 genes 258 genes

ASTHMA

Non-GranulocyticGranulocytic

Eosinophilenriched

Neutrophilenriched

1 2

3

EOS NEUT PAUCI

Sputum gene expression Sputum gene expression biomarkers for asthma phenotypebiomarkers for asthma phenotype

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.

Eos NeutHC

Gene signature can predict ICS Gene signature can predict ICS responseresponse

• 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: ? Cure Prevention New treatment:

breakthroughs Lifestyle