Airway remodeling in childhood asthma: Menace or myth? Paul L.P. Brand

Transcription

1 Airway remodeling in childhood asthma: Menace or myth? Paul L.P. Brand Princess Amalia Children s Clinic Isala klinieken, Zwolle the Netherlands p.l.p.brand@isala.nl

2 Definition Airway remodeling in asthmatic subjects represents a complex multicellular process that leads to structural changes involving the composition, content, and organization of many of the cellular and molecular constituents of the bronchial wall Durrani et al, J Allergy Clin Immunol 2011;128:439-48

3 Remodeling - concepts Originally: Result of long standing inflammation Dysfunctional injury & repair mechanism Relentless progressive loss of lung function Now: Part of inflammation from early age Remodeling present in children, not in infants Associated with loss of lung function

4 Sears et al, N Engl J Med 2003;349: The menace

5 Aims To review the evidence on remodelling in asthma in children, and what we should do about it To focus on remodelling in early life To argue that the presence of remodeling is a fact, its danger a myth

6 Remodeling components (adults) inflammation RBM thickening reduced lung function & persistent BHR These are related J Allergy Clin Immunol 2011;128:439-48

7 Inflammation in childhood asthma we know very little viruses cause episodes, but different viruses cause different cell responses and different symptoms most of the data we base our decisions on are derived from studies in adults Bush, Am J Respir Crit Care Med 2006;173:585-92

8 BAL findings in children with persistent wheeze despite ICS therapy Author + yr Marguet 1999 (n=26) Arnoux 2001 (n=21) Krawiec 2001 (n=20) Najafi 2003 (n=39) Saito 2006 (n=19) Eo (median) range Neutro (median) range % % 0 0% % % % % %?? > 10% in 47%

9 Wildhaber et al, Eur Respir Mon 2006; 37:

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11 Pathology: remodeling RBM thickening consistent finding in children with (troublesome) asthma de Blic, J Allergy Clin Immunol 2005;116:750-4 Jenkins, Chest 2003;124:32-41 Barbato, Am J Respir Crit Care Med 2006;174: Saglani, Am J Respir Crit Care Med 2005;171:722-7 not present in symptomatic infants

12 Children with difficult asthma 6-16 years of age Symptomatic infants with (A) and without (B) airway reversibility vs infants with normal lung function Healthy control children (E) and adults (F) Saglani, Am J Respir Crit Care Med 2005;171:722-7

13 Pathology: remodeling in adults Ongoing disease: structural changes airway wall Airway wall thickening responsible for BHR BHR and PFTs remain abnormal in many patients, even after therapy Remodeling = persistent BHR and PFT abnormalities Current paradigm: remodeling starts in early life Davies et al, J Allergy Clin Immunol 2003;111:215-25

14 Asthma in early life Symptoms start very early in life Early start most likely to persist/recur Reduced lung function: Already present in early life No further decline later on In population studies (Sears), in clinical trials (CAMP) In severe asthma in secondary care (Melbourne) Martinez, N Engl J Med 2003;349:1473-5

15 Remodeling: the current paradigm Davies, JACI 2003 CAMP study, N Engl J Med 2000;343:

16 Remodeling: the current paradigm

17 Remodeling: the current paradigm Payne et al, Eur Respir Mon 2006;37:41-59

18 Remodeling: the current paradigm Ongoing disease ongoing inflammation remodeling Progressive & relentless Loss of lung function ICS don t alter this process

19 Remodeling: problems with the current paradigm Remodeling (RBM thickening) is not fibrosis RBM thickening in children not related to airway wall thickness RBM thickening not related to (loss of) lung function in children Concept of loss of lung function in children is based on historical data

20 The pathology of remodeling in children RBM RBM thickening in childhood asthma is not caused by fibrosis collagen Saglani, Eur Respir J 2006;28:505-12

21 Respir Res 2006;7:46

22 Airway lumen area 17 infants recurrent wheeze 4-21 months of age 14 controls HRCT & infant PFTs Airway wall area No differences in ALA or AWA between cases and controls Cause of reduced PFT?? Collapsible airways? Loss of elastic recoil? Llapur, Eur Respir J 2009;33:107-12

23 Allergy 2008;63:533-41

24 No relationship between RBM thickening and lung function in these studies

25 Remodeling: menace or myth? Remodeling concept based on studies in adults Biopsy studies in children only in severe asthma No correlation between RBM thickening and bronchial wall thickening in children Degree of RBM thickening not/poorly related to severity of disease or level of FEV 1 in children Wildhaber, Sennhauser & Brand, Eur Respir Mon 2006; 37:

26 Remodeling: menace or myth? NZ study: data from way before ICS era CAMP: children had had asthma for 5 yrs prior to use of ICS START: new asthma, but adding ICS was allowed in placebo group (and this happened in >50% of cases) Wildhaber, Sennhauser & Brand, Eur Respir Mon 2006; 37:

27 Merkus et al Payne et al, Eur Respir Mon 2006;37:41-59

28 Do children with asthma have reduced FEV 1 levels? unstable stable Baatenburg de Jong et al, J Allergy Clin Immunol 2006;118:280-2

29 Do children with asthma have persistent BHR? Many of them don t: it s hard to recruit children for trials with poor PFT s and BHR Kamps, Eur Respir J 2001;17:887-91

30 Remodeling in children? Normal FEV 1 is the rule, not the exception in childhood asthma Spahn, Am J Respir Crit Care Med 2004;169:784-6 Decrease in FEV 1 < 1%/yr in childhood Paull, Pediatr Pulmonol 2005;39:311-7 Remodeling occurs in children, but is more likely to be stable than progressive Wildhaber et al, Eur Respir Mon 2006;37:

31 Remodeling in children? Normal lung function can be maintained in children on ICS The early hit may be lack of proper antiinflammatory therapy at early age Remodeling (RBM thickening) in children is real, but its danger is a myth, not a menace

32 Remodeling & phenotypes: conclusions Children are not little adults Asthma pathophysiology in (young) children different from that in adults Remodeling not a big problem provided antiinflammatory therapy is instituted at an early (st)age Treat early!

33 Muchas gracias! Hot pools (water 38 C, air -2 C) Tatio Geysers, San Pedro de Atacama, October 2011