Long term prognosis of asthma: The impact of treatment

1. Long term prognosisof asthma: The impactof treatment Mina Gaga Athens Chest Hospital

2. What should we measure? Outcomes lung function reduction in symptoms and need for rescue therapy increase in asthma control days prevention of acute exacerbations and nocturnal exacerbations reduction in airway hyper-responsiveness improvement in quality of life. Szefler and Martin, JACI, 2010

3. What should we measure? Exacerbations 311 children –CAMP study-4 years randomized ICS treatment Rogers et al, Pharmacogenomics 2009

4. What should we measure? Lung function Rogers et al, Pharmacogenomics 2009

5. Predictors of poor response during asthma therapy differ with definition of outcome

6. Predictors of poor response during asthma therapy differ with definition of outcome Predictors of recurrent asthma exacerbations are distinct from predictors of poor lung function response. A history of prior asthma exacerbations, younger age and a higher IgE levelare associated with recurrent exacerbations. Lower bronchodilator response to albuterol and specific minor alleles (RS242941 in CRHR1 and T2206C) in FCER2 are associated with poor lung function response. Poor lung function response does not increase the risk of exacerbations and vice versa Rogers et al, Pharmacogenomics 2009

7. Long term prognosis of asthma: The impact of treatment • Which are the relevant outcomes? • What is the natural course and the long term risk of asthma and which are its risk factors? • in adults and in children? • What is the long term impact of treatment both • in terms of effect • in terms of risk ? • in adults and in children? How should we best prevent/manage?

8. Outcomes measured in 159 RCTs, 1998-2007 Disease activity was measured in 99% studies, adverse effects of therapy in 85% functional status in 16% quality of life in 13% health resource utilization in 11% No RCT’s measured the effects of ICS on long-term physical consequences of asthma Sinha et al, PLOS one, 2008

9. Sinha et al, PLOS one, 2008

10. We should measure outcomes in the domains of • disease activity • physical consequence of disease • functional status • social outcomes and quality of life • side effects and long term consequences of therapy • health resource utilization • But RCT’s do not give us such long term data

11. RCTs vs longitudinal cohorts Info regarding risk factors/possible prevention Long term natural history Long term effects of treatment Data difficult to interpret as the effects of environmental factors such as smoking and the treatment regimen are not homogeneous nor clear/measured

12. Cohort studies- risk factorsAustralian cohort Prospective cohort study, 2,602 children enrolled prior to birth Wheezing lower respiratory illness in the first year of life Atopy independently associated with increased risk for current asthma at the age of 6 yrs Children with both factors had far higher risk of developing asthma Oddy et al, ERJ 2002

13. Risk-predicting factorsDutch cohort studies Birth cohort followed 3,963 children for 8 years 11% of children had asthma at 7/8 yrs Eight clinical parameters independently predicted asthma : male sex, post-term delivery, parental education inhaled medication, wheezing frequency, wheeze/dyspnea apart from colds, respiratory infections, eczema. risk score (range, 0-55 points) Symptomatic children with a score of less than 10 points had a 3% risk, whereas children with a score of 30 points or greater had a 42% risk of asthma. Caudri et al, JACI 2009

14. risk factors Tucson cohort Cohort of 1246 healthy children at birth Data at age 22 n=858 Newly diagnosed 49, inactive n=74, chronic=132, no asthma= 594 One fourth of all cases of active asthma at age 22 were newly diagnosed, of which 71% females. Late-onset and persistent wheezing in early life sensitization to Alternaria low airway function and BHR at age 6 were independently associated with chronic asthma at age 22. Stern et al, Lancet 2008

15. lung function evolution Tucson cohort Stern et al, Lancet 2008

16. clinical status -30yrs follow-up Dutch cohort 119 allergic asthmatic children aged 5–14 years at visit 1 (1960’s) 21–33 years at visit 2 (1980’s) 32–42 years at visit 3 (1990’s) at visit 3 22% in complete remission 30% was in clinical remission (total 52%); Complete remission: no asthma symptoms, no use of inhaled corticosteroids, normal lung function, and no BHR. Clinical remission: no asthma symptoms and no use of inhaled corticosteroids Vonk et al, Thorax 2004

18. Lung function decline in asthmaassociation with inhaled corticosteroids, smoking and sex- Dutch cohort Dijkstra et al,Thorax 2006

19. Lung function decline in asthmaassociation with inhaled corticosteroids, smoking and sex Dijkstra et al, Thorax 2006

20. Lung function decline: association with exacerbations Groningen cohort –untreated patients Bai et al, ERJ 2007

21. FEV1 reversibility in the course of asthmaDutch cohort After 21–33 years, 228 adults (aged 13–44 years at baseline) with a history of asthma were re-examined to assess: risk factors for the development of irreversible airway obstruction (IAO) At follow up, 41% did not have airway obstruction (NAO), 43% had reversible airway obstruction (RAO), and 16% had IAO; (FEV1 <80% pred. and reversibility <9% pred. ) 23% had a reduced transfer coefficient. Vonk et al, Thorax 2003

22. FEV1 reversibility in the course of asthmaDutch cohort 80% of patients on anti-inflammatory medication still had airway obstruction, but IAO developed less frequently Vonk et al, Thorax 2003

23. Patients with RAO-asthma-like characteristics (wheezing, asthma attacks, BHR) IAO -COPD-like symptoms (cough, phlegm, dyspnoea) Vonk et al, Thorax 2003

24. Long-term prognosis of asthma is goodGreek cohort to determine the evolution of BA and to investigate possible contributing factors 163 patients 12 year follow up questionnaire skin tests Spirometry methacholine challenge classified into three severity groups according to GINA of 1992 as: Mild, Moderate, and Severe asthma. Porpodis et al, J Asthma. 2009 Aug;46(6):625-31

25. Long-term prognosis of asthma is good-FEV1Greek cohort Porpodis et al, J Asthma. 2009 Aug;46(6):625-31

26. Long-term prognosis of asthma is good-FEV1Greek cohort Long-term prognosis of BA was good The outcome was favorably influenced by male gender, early and mild onset of disease, absence of smoking and presence of rhinitis Inhaled corticosteroid use correlated with improvement in lung function Porpodis et al, J Asthma. 2009 Aug;46(6):625-31

27. impact of ICS treatment on lung functionSTART RCT O’Byrne et al,

28. Impact of treatment-ICSRisk/benefit ratio Benefit was assessed by measuring the improvement in FEV1 and methacholine FEV1 PC20 Risk was assessed by overnight plasma cortisol suppression. Szefler and Martin, JACI, 2010

29. Impact of treatment-ICSRisk/benefit ratio • Maximal FEV1 response occurred with the low and medium dose ICS • not further increased by treatment with high dose ICS. • The same pattern was seen with methacholine FEV1 PC20. • Both BDP-MDI and FP-MDI caused dose-dependent cortisol suppression. Szefler et al, JACI, 2002

30. ICS- impact on growth Skoner et al, pediatrics 2008

31. ICS-Variability of response Good (>15%) FEV1 response vs poor (<5%) FEV1 response associated with high exhaled nitric oxide, high bronchodilator response, and a low FEV1/FVC ratio before treatment. Good (>3 doubling dilutions) improvement in methacholine PC20 vs poor (<1 doubling dilution) improvement, associated with high sputum eosinophil levels older age of onset of asthma. Szefler et al, JACI, 2002

32. Predicting Response to Inhaled Corticosteroid Efficacy (PRICE Trial) improvements on short term inhaled steroid correlate with albuterol reversibility Non-responders: asthma control remained unchanged whether ICS were continued or were substituted with a placebo Responders: maintained asthma control longer term only if maintained on inhaled steroids Martin et al, JACI 2007

33. Predicting Response to Inhaled Corticosteroid Efficacy (PRICE Trial) Martin et al, JACI 2007

34. Predicting Response to Inhaled Corticosteroid Efficacy (PRICE Trial) Martin et al, JACI 2007

35. Impact of other medications? LABA: The RR of death was statistically similar over time between LABA and ICS despite changes in exposure de Vries et al, ERJ 2010 Omalizumab; steroid sparing, small subset of patients Karpel et alAnn Allergy Asthma Immunol. 2010

36. Impact of measures other than medication? Exclusive breastfeeding protects against asthma Diet- fruit, low salt, normal BMI Lifestyle –smoking, exercise Education-support Oddy et al, ERJ 2002, Willers et al, ERJ 2010

37. Impact of better patient/family support 60 preschool children with asthma Intervention : extra information and support to parents in the form of group discussions Results: The burden on the healthcare system was minimal, the intervention group (IG) needed fewer contacts with health care providers and parents had a better quality of life. Hederos et al, Actapaediatrica 2009

38. Outcomes to measure There have been initiatives to standardize the outcomes which are measured in clinical trials. The most notable is the OMERACT collaboration, an international network of clinicians and patients - initially formed in response to the observation that clinical trials of patients with rheumatoid arthritis conducted in the USA measured different outcomes to those conducted in Europe.

39. Outcomes to measure Structured consensus techniques to determine which outcomes should be measured in clinical trials/longitudinal studies increase the likelihood that all important outcome domains are measured reduce the measurement of inappropriate outcomes aid comparison and synthesis of findings between different studies arbitrary or inconsistent outcome selection may lead to clinical trials with unnecessarily large sample sizes and reporting biases

40. Team work and multifaceted approachBest long term studies and outcomes