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What does asthma look like for different people? ……Asthma phenotypes

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Presentation on theme: "What does asthma look like for different people? ……Asthma phenotypes"— Presentation transcript:

1 What does asthma look like for different people? ……Asthma phenotypes
Thurs September 19 11.30am-12.00pm

2 What is a phenotype ? The observable characteristics of an individual resulting from the interaction of its genotype with the environment

3 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

4 Phenotypes, why bother ?

5 Asthma deaths Then…….. and now….
Australia, 1979–2006 Figure 4.1: Deaths due to asthma per 100,000 population, 3-year moving average, by sex, all ages and people aged 5–34 years, 1979–2006 Note: Age-standardised to the Australian population as at 30 June Asthma classified according to International Statistical Classification of Diseases, 9th Revision (ICD-9) code 493 and 10th Revision (ICD-10) codes J45 and J46. Deaths coded to ICD-9 (1979–1996) were converted to ICD-10 (1997 onwards) using conversion factors (see Appendix 1 for details). Sources: AIHW National Mortality Database; Australian Bureau of Statistics. Australian Centre for Asthma Monitoring

6 Oral glucocorticosteroid (lowest dose)
Asthma Control Oral glucocorticosteroid (lowest dose) anti-IgE antibodies as needed rapid- acting β2-agonist

7 People vary in how they respond to treatment
responder Are you the average ? Or are you an Individual ? Little response Figure reprinted with permission from Zeiger RS et al. J Allergy Clin Immunol. 2006;117:45–52. Zeiger RS et al. J Allergy Clin Immunol. 2006;117:45–52. 7

8 Clinical phenotypes that don’t fit
Obesity…. 50% Smoking….30% Asthma-COPD Overlap Asthma in the elderly Severe Asthma…10%

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

10 Older person with asthma
Dysfunctional breathing Comorbidity Obesity Anxiety/Depression Inflammation Smoking AFO Exercise limitation Increased inhaler error Cognition Infection Hospitalisation Non adherence Tailored Pharmacotherapy Exercise Rehab Smoking cessation (Individualised education, WAP , Inhaler device assessment ) Vaccinations Assessment and specific management of comorbid conditions Breathing retraining Nutrition/Weight Management LABA Gibson PG, McDonald VM, Marks GM. Lancet 2010; 376:803

11 Airway disease in older people
Multidimensional Assessment 2. Biomarkers drive Pharmacotherapy 3. Case manager Gibson PG, McDonald VM, Marks GM. Lancet 2010; 376:803

12 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

13 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’

14 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

15 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 BMI 22 24.2 HADS A|D 8|10 6|4 4|6

16 Treatment Effects multidimensional assessment and intervention
McDonald VM, Higgins I, Wood L, Gibson PG. Thorax 2013; 68:691 McDonald VM, Gibson PG et al. ERS 2010

17 ‘hidden’ phenotypes genes and environment

18 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.

19 Inflammatory phenotyping
It means: Biomarker + specific treatment = reduced exacerbations + omalizumab Allergen specific IgE Bruselle A, Resp Med 2009

20 Inflammatory phenotyping
It means : Biomarker + specific treatment Anti IL5 mAb = Haldar NEJM 2009; Nair NEJM 2009

21 Exacerbation rate by phenotype
McDonald V, Clin Exp Allergy 2013

22 Inflammatory phenotyping
For Refractory Severe Asthma * ABPA, SAFS

23 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

24 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

25 Managing Asthma in Pregnancy FENO guided treatment reduces attacks
Symptoms Asthma attacks were reduced By Half FeNO Powell et al, Lancet 2011

26 Managing Asthma in Pregnancy What about the babies ?
210 mothers with asthma, 214 beautiful babies What happened to them? Less babies in NICU Fewer attacks bronchiolitis % FeNO Powell et al, Lancet 2011 Mattes J , Thorax 2013, in press

27 Oral Corticosteroids Fewer courses Of steroids Were needed
For wheezing attacks Mattes J , Thorax 2013, in press

28 ‘hidden’ phenotypes, genes and environment
Biomarker is FENO

29 ‘hidden’ phenotypes, genes and environment
‘gene chips’

30 Transcriptomics: Baines K, JACI, 2011
187 genes 24 genes 258 genes 1 2 3 When looking at how EOS NEUT PAUCI

31 Sputum gene expression biomarkers 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. HC Eos Neut

32 Gene signature can predict ICS response
Steroid response trial: n=71 people with asthma treated with 1000ug fluticasone per day, 28 days

33 ‘hidden’ phenotypes, genes and environment
‘gene chips’

34 Phenotypes….Now to next ?
Mortality has reduced Control has improved Overdiagnosis Overtreatment People are still unwell Next: ? Cure Prevention New treatment: breakthroughs Lifestyle

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