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

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 Australian Centre for Asthma Monitoring

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

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

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. 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 Older person with asthma Increased inhaler error Non adherence Hospitalisation Smoking Exercise limitation Infection Inflammation Comorbidity AFO Cognition Obesity Dysfunctional breathing Anxiety/Depression 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’s perspective Ester, 87years, ♀, Asthma • ‘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

15. Outcomes

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

17. ‘hidden’ phenotypesgenes 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. 3 1 2 258 genes 24 genes 187 genes Transcriptomics: Baines K, JACI, 2011 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 ? Now: Mortality has reduced Control has improved Overdiagnosis Overtreatment People are still unwell Next: ? Cure Prevention New treatment: breakthroughs Lifestyle