1. Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra. Le ricordiamo che questo materiale è di proprietà dell’autore e fornito come supporto didattico per uso personale.

2. FUNCTIONAL AND CELLULAR EVALUATION OF ASTHMA Pierluigi Paggiaro GINA International Executive Committee, Chairman GINA ITaly Cardio-Thoracic and Vascular Department, University of di Pisa Università degli Studi di Pisa Azienda Ospedaliera Pisana 2011 International Guidelines on Rhinitis, Asthma and COPD Modena, 1-3 march 2011

3. Functional and cellular evaluation of asthma Tradictional assessment of asthma –Symptoms, rescue medication –Baseline pulmonary function –Variability over time –Rate of exacerbations Old and new assessments –Functional »Bronchial hyperresponsiveness »Small airway involvement »Decline in FEV1 over time –Cellular (biomarkers) »Sputum inflammatory cells (eosinophils) »Exhaled NO Are they really useful ?

4. Bronchial hyperresponsiveness a multifactorial manifestation Busse, Chest 2010

5. Koh et al., Chest 2001 Methacholine improvement after ICS depends from the activity of asthma

6. Bronchial reactivity (but not sensitivity) is related to asthma quality of life Cisneros et al, Thorax 2010

7. Small airways involvement is it relevant for asthma management ? Several indices of small airway involvement –Expiratory flows at medium-low expiratory volumes –Closing volume, closing capacity, single breath N2 washout slope –Fractional eNO –Alveolar-arterial differences in O2 and CO2 Related to asthma severity (?) –Difference between severe and non severe asthmatics Target for treatment ? –Oral route vs small inhaled particles May it represent a specific “phenotype” ?

8. In ‘t Ven et al, AJRCCM 2000

9. FEV1%FEF 25-75 Symptom Score ΔPEFSputum Eosinophils % FeNO 50 SBNW, slopeR= -0,424ns CalvNOns D(A-a)O 2 R= -0,494R= -0,624ns D(a-A)CO 2 R= -0,662R= -0,795ns Ventilated Area ns Inhomogen. Index ns In partly controlled asthmatics, indices of small airways poorly correlate with traditional clinical, funtional and biological indices Malagrinò et al, submitted

10. BDP/FF (400/24µg) FP/SALM (500/100µg) # p<0.001 vs baseline Extrafine BDP/FF significantly improves bronchial hyperresponsiveness Scichilone et al., Allergy 2010

11. Decline in FEV1 role of airway remodelling Occurring in a subpopulation of asthmatics –Uncontrolled untreated asthmatics –Related to the rate of exacerbations –Late-onset asthma (?) –Genetic predisposition (?) Detection of rapid decliners –Difference between severe and non severe asthmatics Effect of treatment –On morphologic markers (effect with high ICS doses) –On indirect functional measurement (no effect)

12. Models of the longitudinal changes in FEV1 in the natural history of asthma

13. Relationship between frequent exacerbations and decline in FEV1 Bai et al, ERJ 2007O’Byrne et al, AJRCCM 2009

14. 21 subjects with regular FU BaselineFU N. exacerb./yr1.55 ± 1.910.86 ± 1.23 p=0.04 N. OCS treatments/yr1.45 ± 1.910.62 ± 1.12 p=0.06 12 subjects without regular FU BaselineFU N. exacerb./yr1.25 ± 0.751.75 ± 2.30 p=n.s. N. OCS treatments/yr1.33 ± 0.981.75 ± 2.30 p=n.s. 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200 p=0.01 Non regular FU Regular FU Regular follow-up of severe asthmatics reduces the rate of severe exacerbations and FEV1 decline Dente et al, ERS 2011 (submitted)

16. Cellular evaluation role of different biological phenotypes Eosinophilic vs neutrophilic vs paucigranulocytic –Well characterised »Different pathologic mechanisms and risk factors –Stable over time Different response to treatment –Corticosteroids –Other anti-inflammatory drugs (azitromycin, roflumilast, etc) –New specific targets (anti-IL5, anti-IL13, etc) Different strategies for the management

17. Different asthma phenotypes Haldar et al, AJRCCM 2008

18. Asthma inflammatory phenotypes do not correlate with clinical findings Simpson et al, Respirology 2006

19. Pattern of inflammatory cells in sputum is stable over short-term and long-term period Simpson et al, Respirology 2006

20. 0 10 20 30 40 50 B136B136 nsns Sputum Eosinophils, % LABAICS Noneosinophilic asthma is a fairly stable feature in a subgroup of asthmatics Bacci et al, JACI in press

21. Group B = ICS Group A = LABA Spontaneous changes in sputum eosinophils over 6 months in noneosinophilic asthmatics 0 10 20 40 Basale1 mese3 mesi6 mesi Sputum Eosinophils, %

22. Dente et al, ERS 2010 3% 30% Sputum Eosin % Time Course of sputum eosinophils over 3 yrs 100 10 1 0.1 1 10 100 Sputum eosinophila is a stable characteristic in severe difficult-to-control asthmatics

23. Cellular evaluation role of different biological phenotypes Eosinophilic vs neutrophilic vs paucigranulocytic –Well characterised »Different pathologic mechanisms and risk factors –Stable over time Different response to treatment –Corticosteroids –Other anti-inflammatory drugs (azitromycin, roflumilast, etc) –New specific targets (anti-IL5, anti-IL13, etc) Different strategies for the management

24. Bacci et al, Chest 2006 Absence of sputum eosinophilia in corticosteroid”naive” asthmatics predicts a poor short-term response to ICS

26. Asthmatics with eosinophilic inflammation have a better response to a short period treatment with ICS Cowan et al, Thorax 2010

27. Non-eosinophilic and neutrophilic asthmatics have a good response to tiotropium Iwamoto et al, ERJ 2009

28. Cellular evaluation role of different biological phenotypes Eosinophilic vs neutrophilic vs paucigranulocytic –Well characterised »Different pathologic mechanisms and risk factors –Stable over time Different response to treatment –Corticosteroids –Other anti-inflammatory drugs (azitromycin, roflumilast, etc) –New specific targets (anti-IL5, anti-IL13, etc) Different strategies for the management

29. Green et al, Lancet 2002 The control of sputum eosinophilia is associated with a reduction in asthma exacerbations, but only for eosinophilic exacerbations Jayaram et al, ERJ 2006

30. 0 10 20 30 40 50 60 B123456B123456months Sputum eosinophils, % p<0.05 p<0.05 Group A Group b Strategy to reduce sputum eosinophils in mild-moderate asthmatics does not lead to improvement in BH 1 10 100 1000 10000 PD 20 FEV 1, mcg B123456B123456months p<0.01p<p<0.o0.01

31. Sputum inflammatory cells an important marker for prognosis and treatment Sputum eosinophilia –Associated with more severe asthma –Predictor of future loss of asthma control »In all subjects ? –Possible target of the treatment Sputum neutrophilia –In different asthma models »Smoker asthmatics »Obese asthmatics »Asthma due to pollutants and simple chemicals –Related to chronic asthma (remodelling)

32. Group A Group b 1 10 100 1000 10000 Low sputum eosinophils High sputum eosinophils PD 20 FEV 1, mcg p=0.08 Bacci et al, ATS 2011 Patients with persistent eosinophilia after 1 month ICS treatment tend to have greater BH

33. Eosinophils after ICS < 2%, n=64 Eosinophils after ICS ≥ 2%, n=58 FEV 1, %92±1599±1593±1698±14 PEF, %76±1886±1876±1588±20 PD 20 FEV 1, mcg13043298337 Symptom score1.0 [0.1-3.1]0 [0-2.0]1.5 [0.1-3.6]*0 [0-3.8] Rescue beta2-agonist 0.5 [0.1-3.5]0 [0-1.6]0.8 [0.1-5.0]0 [0-3.0] p < 0.01 for all pre-post comparisons *p < 0.05 between baseline values Bacci et al, ERS 2011 (submitted) 6 months treatment with ICS leaves some patients with sputum eosinophilia, without any relationship with the current asthma control

34. Sputum inflammatory cells an important marker Sputum eosinophilia –Associated with more severe asthma –Predictor of future loss of asthma control »In all subjects ? –Possible target of the treatment Sputum neutrophilia –In different asthma models »Smoker asthmatics »Obese asthmatics »Asthma due to pollutants and simple chemicals –Related to chronic asthma (remodelling)

35. Little et al, AJM 2002 Sputum neutrophilia is related to the decline in FEV1 and asthma duration

36. Persistent sputum neutrophilia is associated with greater remodelling in severe asthmatics Gupta et al, Thorax 2010

38. Severe asthma usefulness of functional and cellular characterization Large heterogeneity (according to WHO 2010 definition) –Severe untreated asthmatics –Difficult to treat asthmatics (comorbididties, compliance) –Treatment resistant asthmatics –Persistent chronic obstruction (?) Different response to treatment –Corticosteroids –Other anti-inflammatory drugs (azitromycin, roflumilast, etc) –New specific targets (anti-IL5, anti-IL13, etc) Different strategies for the management

39. Dente et al. AAAI 2006 Sputum cellular and cytokine pattern in different phenotypes of severe asthma

40. Functional and cellular evaluation which usefulness in asthma Functional evaluation (BH, FEV1 decline, etc) –May select distinct asthma populations »With greater impact on quality of life »With greater remodelling –May be used for targeting treatment (QoL, FU, etc) Cellular evaluation (sputum inflammatory cells) –May distinguish inflammatory phenotypes »With different prognosis and response to treatment –May suggest different treatment strategies More extensive and accurate functional and biological assessment may be useful in asthma management