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Impact of treatment on the natural course of asthma

Impact of treatment on the natural course of asthma. Prof Dr Elif Dağlı Marmara University Pediatric Pulmonology. What do we expect to change?. What needs to be changed in the naural course? What are the clinical and experimental effects of the drugs?

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Impact of treatment on the natural course of asthma

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  1. Impact of treatment on the natural course of asthma Prof Dr ElifDağlı Marmara University Pediatric Pulmonology

  2. What do we expect to change? • What needs to be changed in the naural course? • What are the clinical and experimental effects of the drugs? • Do the cohort studies reflect the experimental effects? • Why is there a difference between experimental effects of treatment and cohort studies ?

  3. Question 1 What needs to be changed in the naural course?

  4. What do we want to prevent? • Loss of lung fuctions • Remodelling • Inflammation • Asthma attacks • Low quality of life

  5. Natural course of asthma Initiation and chronicity factors Initiation Chronicity factors Initiation factors Remission factors Fernando D Martinez www.thelancet.com Vol 368 , 2006

  6. FD Martinez Lancet , 2006 • Persistent asthma starts early in life • Children with persistent asthma have low lung functions • Low lunfctions are settled in early childhood and does not deteroriate further

  7. Remodelling Severe asthma Thickened BM Normal bronchus Severe asthma Thickened BM Collagen stain Normal bronchus Collagen stain M.L.K. Tang et al. / Pharmacology & Therapeutics 112 (2006) 474–488

  8. Does Remodelling Start before Asthma Symptoms ? Bronchus of a 4 year old child who died of asthma PAEDIATRIC RESPIRATORY REVIEWS (2002) 3, 315±320

  9. Does Remodelling Start before Asthma Symptoms ? • Histological changes in bronchi of children who died of asthma attack, that resembles changes seen in adults • Bronchial biopsy findings in children who later develop asthma • Development of remodelling in children who are unresponsive to inhaled steroid treatment • Correlation of lung functions and remodelling • Early wheezers should be treated before established asthma symptoms Pohunek P, Eur Respir J 1997; Martinez FD N Engl J Med 1995; 332: 133±138. Merkus PJFM. Am Rev Respir Dis 1993; 148: 1484±1489. 35.

  10. Soru 2 • What are the clinical and experimental effects of the drugs?

  11. Effects of Inhale steroids on the consequences of asthma

  12. İnhale steroid reduces BAL Bronchial mucosa Sputum • Barnes PJ, Adcock IM: Ann Intern Med 2003, 139(5 Pt 1):359-370.

  13. Glococorticoids INHIBIT • Barnes PJ, Adcock IM: Ann Intern Med 2003, 139(5 Pt 1):359-370.

  14. glucocortikoids Barnes PJ, Chung KF, Page CP: Inflammatory mediators of asthma: an update. Pharmacol Rev 1998, 50(4):515-596. 32

  15. Fluticasone İnhibits • IL-13 • IL-5 In peripheral blood CD4+ T cell cultures Increases synthesis of • IL-10 Peek EJ, et al Am J Respir Cell Mol Biol 2005, 33(1):105-111

  16. Beclametasone and Fluticasone Inhibit • T cell proliferation • IL-5 • GM-CSF expression Powell N, Till SJ, Kay AB, Corrigan CJ: Clin Exp Allergy 2001, 31(1):69-76

  17. Flunisolide • In cultured sputum cells • Inhibit TGFβ release • Increase MMP-9 (Profita et al., 2004).

  18. Inhaled steroids Can stop and even reverse structural changes Decreases reticular basal membrane thickness and fibroblast activity. Hoshino, M.et al. J Allergy Clin Immunol 102, 783–788. Hoshino, M.,et al . Clin Exp Allergy 28, 568–577. Hoshino M et al. Clin Rev Allergy Immunol 27, 59–64.

  19. Inhaled steroids inhibits microvascular angiogenic remodelling • Pla Placebo IKS Placebo IKS VEGF VEGFR Vascular endothelial growth factor inhibition Plasebo IKS B N Feltis Thorax 2007;62:314–319.

  20. Inhaled steroids • Anti-mitogenic for airway smooth muscle • Anti-mitogenic on normal basement membrane • Can not exhibit the same effect on collagen • Can not be effective after fibrosis development. Bonacci, et al Clin Exp Pharmacol Physiol 30, 324–328. Bonacciet al Br J Pharmacol 138, 1203–1206.

  21. Steroids in effective in the presence of collagen Basal membrane Airway smooth muscle cells After 48 hrs Inhibits cell proliferation Collagen deposition Airway smooth muscle cells After 48 hrs Collagen deposition Airway smooth muscle cells After 7 days Bonacci JV British Journal of Pharmacology (2006) 149, 365–373.

  22. Ekshale Sistenil Lökotrienler ile Bazal Membran ilişkisi Montelukast (-) Montelukast (+) Lex C et al. Respiratory Research 2006, 7:63

  23. Question 3 • Do the cohort studies reflect the experimental effects?

  24. No evidence that inhale steroids reduces asthma at 10 Devulapalli C,Carlsen K et al

  25. 7241 5-66 aged Mild persistent asthma Busse et al J Allergy Clin Immunol 2008 START Budesonide 200 or 400 mcg/day +regular asthma treatment Budesonide 200 or 400 mcg/day +regular asthma treatment Placebo +regular treatment 0 1 2 3 4 5 Double blind phase Open phase

  26. (Busse et J Allergy Clin Immunol 2008;121:1167-74.) In mild persistent asthma early intervention with inhaled budesonide was associated with improved asthma control and less additional asthma medication use.

  27. Question 4 • Why is there a difference between experimental effects of treatment and cohort studies ?

  28. Why are cohorts different? • Early treatment----- how early? • Are the dose and duration of medication adequate ? • Are all the cohorts have standardised methods?

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