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. THE FREQUENT COPD EXACERBATOR PHENOTYPE – LESSONS FROM ECLIPSE Professor Wisia Wedzicha UCL Medical School University College London, UK

3. From Wedzicha, JA, Seemungal T Lancet 2007

4. Days –7 to –1 p < 0.05 TIME COURSE OF AN EXACERBATION Seemungal et al. Am J Respir Crit Care Med 2000

5. DEFINITIONS SYMPTOMATIC (based on Anthonisen et al Ann Intern Med 1987) At least two of: increase in SOB, sputum purulence, sputum volume Or any one above and one of: URTI, Wheeze, Cough, Increase in resp. / pulse rate HEALTH CARE UTILIZATION (Rodriguez-Roisin Chest 2000) Sustained worsening of COPD patient’s condition from stable state necessitating a change in regular medication Used by most studies of therapies in COPD

6. EXACERBATIONS: REPORTED AND UNREPORTED Seemungal et al AJRCCM 1998 50% not reported to study team (UNREPORTED EXACERBATIONS)

7. SGRQ Total < 25% > 75% % Exacerbations Treated IMPORTANCE OF UNREPORTED EXACERBATIONS Wilkinson et all AJRCCM 2004 Rho = -0.22, p = 0.018

8. UK General Practice Database studied in 1992-1993 No lung function data available QJM 1995

9. EXACERBATION FREQUENCY Number of exacerbations per patient Number of patients FREQUENT EXACERBATORS INFREQUENT EXACERBATORS Data from London COPD cohort and Seemungal et al AJRCCM 1998

10. QUALITY OF LIFE AND EXACERBATION FREQUENCY Seemungal et al. Am J Respir Crit Care Med 1998 *p < 0.001 0–2 Exacs/Year 3–8 Exacs/Year * * * *

11. IMPORTANCE OF EXACERBATIONS “Frequent Exacerbator” Poorer Quality of Life Higher Mortality Faster Decline in Lung Function Greater Airway Inflammation

12. FACTORS PREDICTING FREQUENT EXACERBATORS: Number of exacerbations in previous year Daily cough and sputum Poor quality of life Seemungal et al AJRCCM 1998

13. FREQUENT COPD EXACERBATORS AMONG COPD SUBJECTS WITH OR WITHOUT CHRONIC COUGH AND SPUTUM Burgel P. et.al. Chest 2009;135:975-982

14. ISOLDE – oral steroids or antibiotics CCLS – more cough and phlegm European Society Study - Rx RELATIONSHIP OF EXACERBATIONS TO DISEASE SEVERITY Donaldson GC, Wedzicha JA Thorax 2006

15. ECLIPSE EXACERBATION ANALYSIS

16. Agusti et al Resp Res 2010

17. QUESTIONS ADDRESSED IN ECLIPSE EXACERBATION PAPER What is the relationship between exacerbation frequency and disease severity (GOLD stage) in COPD? Does a Frequent Exacerbator phenotype exist independent of FEV 1 ? How stable are exacerbation phenotypes over a 3 year period? 2164 patients across 46 sites in 12 countries 2138 with follow-up data for this analysis 1679 completed 3 years follow up

18. Methodology Recruitment Baseline Assessment

19. Methodology Recruitment Baseline Assessment Number of courses of antibiotics/steroids / hospitalizations for exacerbation in prior year asked and recorded YEAR PRIOR

20. Methodology Recruitment Baseline Assessment Number of courses of antibiotics/steroids / hospitalizations for exacerbation in prior year asked and recorded YEAR PRIOR Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year one COUNTED YEAR 1

21. Methodology Recruitment Baseline Assessment Number of courses of antibiotics/steroids / hospitalizations for exacerbation in prior year asked and recorded YEAR PRIOR Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year one COUNTED YEAR 1 COUNTED in CRFs: data on dates of onset and resolution, and therapy and hospitalization of clinician diagnosed exacerbations

22. Methodology Recruitment Baseline Assessment Number of courses of antibiotics/steroids / hospitalizations for exacerbation in prior year asked and recorded YEAR PRIOR Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year one COUNTED Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year two COUNTED Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year three COUNTED YEAR 1 YEAR 2 YEAR 3

23. Methodology Recruitment Baseline Assessment Number of courses of antibiotics/steroids / hospitalizations for exacerbation in prior year asked and recorded YEAR PRIOR Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year one COUNTED Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year two COUNTED Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year three COUNTED YEAR 1 YEAR 2 YEAR 3 ANALYSIS 1 How do baseline variables relate to observed exacerbations in year 1?

24. Methodology Recruitment Baseline Assessment Number of courses of antibiotics/steroids / hospitalizations for exacerbation in prior year asked and recorded YEAR PRIOR Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year one COUNTED Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year two COUNTED Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year three COUNTED YEAR 1 YEAR 2 YEAR 3 ANALYSIS 1 How do baseline variables relate to observed exacerbations in year 1? ANALYSIS 2 How stable is exacerbation frequency over 3 observed years, and in relation to patient self report?

25. DEFINITION AND CAPTURE OF COPD EXACERBATIONS IN ECLIPSE Definition of exacerbation based on health care utilisation and diagnosed by clinician Definition similar to year before ECLIPSE and during 3 year follow up Exacerbations recorded by CRFs during 7 ECLIPSE visits – data on onset, resolution and management New exacerbation diagnosed at a minimum of 7 days after last exacerbation and recovery monitored by patient Exacerbation therapy at discretion of physician

26. ECLIPSE BASELINE PATIENT CHARACTERSITICS ACCORDING TO COPD SEVERITY Hurst et al NEJM 2011

27. NUMBERS OF EXACERBATIONS IN YEAR PRIOR TO STUDY Agusti et al Resp Res 2010

28. ECLIPSE DATA ASSOCIATION OF DISEASE SEVERITY WITH THE FREQUENCY AND SEVERITY OF EXACERBATIONS Hurst JR et al. N Engl J Med 2010;363:1128-1138

29. ECLIPSE DATA UNIVARIATE ASSOCIATIONS WITH THE OCCURRENCE OF EXACERBATIONS DURING THE FIRST YEAR OF FOLLOW-UP Hurst et al. N Engl J Med 2010;363:1128-1138

30. “Top 10” OR95%CI Exacerbation Last Year4.303.58-5.17 FEV 1 (–100mL)1.111.10-1.14 SGRQ-C Total Score (+4 points)1.101.08-1.12 FEV 1 /FVC ratio (–1 %)1.031.02-1.04 FACIT-F Fatigue Score (-1 unit)1.031.02-1.04 Emphysema LAA% (+5%)1.161.11-1.20 MRC Dyspnoea Score, 2+1.831.54-2.18 6MWD (–50m)1.121.08-1.16 Serum Fibrinogen (+SD)1.351.22-1.49 CES-D Depression score (+1 unit)1.031.02-1.04 ECLIPSE DATA UNIVARIATE ASSOCIATIONS WITH THE OCCURRENCE OF COPD EXACERBATIONS DURING THE FIRST YEAR OF FOLLOW-UP Hurst et al. N Engl J Med 2010;363:1128-1138

31. ECLIPSE DATA FACTORS ASSOCIATED WITH INCREASED EXACERBATION FREQUENCY IN THE STEPWISE MULTIVARIATE MODEL Hurst JR et al. N Engl J Med 2010;363:1128-1138

32. ECLIPSE DATA FACTORS ASSOCIATED WITH INCREASED EXACERBATION FREQUENCY IN PATIENTS WITH MODERATE (GOLD STAGE 2) COPD, ACCORDING TO SEX Hurst JR et al. N Engl J Med 2010;363:1128-1138

33. ECLIPSE - STABILITY OF THE FREQUENT EXACERBATOR PHENOTYPE Year 1 Year 2 Year 3 71% of Frequent Exacerbators in Year 1 and Year 2 were Frequent Exacerbators in Year 3

34. ECLIPSE - STABILITY OF THE FREQUENT EXACERBATOR PHENOTYPE Year 1 Year 2 Year 3 74% of patients having no exacerbations in Years 1 and Year 2 had no exacerbators in Year 3

35. SENSITIVITY AND SPECIFICITY OF REPORTING EXACERBATIONS Sensitivity 43% Specificity 87% Positive predictive value of saying “I’m a frequent exacerbator”: 58% Negative predictive value of saying “I’m not a frequent exacerbator”: 79% Year 1 IEx Year 1 FEx TOTAL Reported Iex 1318 10372811318 Reported Fex 361 150211361 TOTAL11874921679 Hurst et al NEJM 2010

36. STRENGTHS AND LIMITATIONS First large multi-national study with single exacerbation criteria, across GOLD stages, in comprehensively phenotyped patients NOT a population sample No ‘confirmation’ of exacerbation

37. RECALLED AND ACTUAL EXACERBATION FREQUENCY IN LONDON COPD COHORT Quint et al ERJ in press 0 12 34567 No of Patients Exacerbation frequncy

38. PATIENT RECALLED EXACERBATION FREQUENCY AND ACTUAL EXACERATION FREQUENCY infrequent exacerbators frequent exacerbators % Recalling themselves to be IE % Recalling themselves to be FE Classified by diary cards % patients by recall 86.8%87.1% Data from London COPD cohort Quint et al ERJ In press Sensitivity 86.8% Specificity 87.1% Positive predictive value 0.81

39. 0.75 0.80 0.85 0.90 0.95 01234 Years FEV 1 (l) Donaldson et al Thorax 2002 FEV 1 DECLINE OVER 4 YEARS AND EXACERBATION FREQUENCY Frequent exacerbators Infrequent exacerbators

40. EFFECT OF EXACERBATIONS ON DISEASE PROGRESSION Hansel T, Barnes P Lancet 2009

41. LONGITUDINAL CHANGES IN TIME SPENT OUTDOORS AND EXACERBATION FREQUENCY Donaldson et al. AJRCCM 2005

42. DEPRESSION AND COPD EXACERBATION FREQUENCY Quint et al ERJ 2008 p = 0.03

43. EXACERBATION FREQUENCY AND PLASMA FIBRINOGEN Donaldson et al Chest 2005 Frequent Infrequent P<0.04

44. EXACERBATION FREQUENCY AND MYOCARDIAL INFARCTION Donaldson et al Chest 2010 DATA FROM THIN GP DATABASE

45. AIRWAY BACTERIA Rosell, A. et al. Arch Intern Med 2005;165:891-897.

46. EXACERBATION FREQUENCY AND BACTERIAL COLONIZATION Patel et al. Thorax 2002 Exacerbation frequency Proportion of patients with LABC <2.58 per year (n=14) >2.58 per year (n=14) -0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2

47. EXACERBATION RECOVERY Donaldson et al AJRCCM 2005 -14-70714212835 0 1 2 3 30 35 40 45 50 Days Housebound % of patients Symptom count OPEN CIRCLES CLOSED CIRCLES

48. EXACERBATION FREQUENCY AND CRP RECOVERY Perera et al ERJ 2007

49. EXACERBATION CLUSTERING Hurst et al AJRCCM 2009 633 Exacerbations occurred between 3 and 8 weeks, 103 (19.4%) more than that predicted by the exponential function (p=0.040). 2189 Exacerbations 1923 Exacerbation intervals

50. EXACERBATION FREQUENCY IS A SUSCEPTIBILITY PHENOTYPE Susceptible Patient Non-Susceptible Patient Sufficient Trigger EXACERBATION

51. FREQUENT COPD EXACERBATORS Frequent exacerbators can be identified across GOLD stages Frequent exacerbators can be detected by recall by careful/specific questioning Exacerbation frequency is a susceptibility phenotype and is relatively stable Important phenotype for targeting therapies