1. COPD EXACERBATIONS Francesco Blasi Dipartimento Toraco-Polmonare e Cardiocircolatorio University of Milan, Italy

2. COPD OUTCOMES
Cazzola M et al. ERJ 2008 2

3. Decline in FEV1 over 12 months in patients with COPD
FEV1, forced expiratory volume in 1 second
Pauwels et al. Am J Respir Crit Care Med 2001;163:1256–76 3

4. COPD exacerbations: health status 613 moderate-to-severe COPD patients followed for ≤3 years*
*p<0.0001
(Worse) †
3.0
†p<0.004
n=235
n=285
2.0
SGRQ slope (units/year)
n=91
1.0
None in 3 years
Infrequent <1.65/year
Frequent >1.65/year
Exacerbation category
SGRQ, St George’s Respiratory Questionnaire
Spencer et al. Eur Respir J 2004;23:698–702 4

5. COPD Exacerbations: mortality60
1016 pts with severe COPD exacerbation
(PaCO2 > 50 mm Hg)
49% 50
43% 40
33%
Mortality (%) 30
20% 20
11% 10
Hospital
stay
60 days
180 days
1 year
2 years
Connors AF Jr et al. Am J Respir Crit Care Med. 1996;154:959-67 5

6. Probability of survival
COPD Exacerbations: survival
1.0
0.8
No exacerbation
p<0.001
0.6
Probability of survival
1–2 exacerbations
p<0.0001
0.4
p=0.07
0.2
3–4 exacerbations
0.0 10 20 30 40 50 60
Time (months)
Soler-Cataluña et al. Thorax 2005;64:925–31 6

7. Probability of survival
COPD Exacerbations: survival
1.0
0.8
No exacerbation NS
0.6
ER visits
p<0.0001
Probability of survival
p<0.01
0.4
1 hospitalisation NS
0.2
Readmission
p<0.0001
0.0 10 20 30 40 50 60
Time (months)
Soler-Cataluña et al. Thorax 2005;64:925–31 7

9. COPD and cardiovascular disease
Cumulative incidence of first MI
Cumulative incidence of first CVA
600
2000
No COPD
COPD
No COPD
COPD
1500
400
Cumulative events
Cumulative events
1000
200
500
200
400
600
800
1000
200
400
600
800
1000
Follow-up time in days
Follow-up time in days
Thorax 2010;65: doi: /thx

10. Plasma fibrinogen at exacerbation
Increased fibrinogen with colds P = 0.024
Increased fibrinogen with sputum purulence P = 0.033
Rise 0.56 g/l during viral Exs
Rise in 0.27 g/l during non-viral Exs
p=0.056
N = 120 Exacerbations
P<0.001
P<0.001
4.3
4.2
4.1 4
Fibrinogen g/l
3.9
3.8
3.7
3.6
3.5
3.4
Stable
Exacerbation
Convalescence
Mean ± SEM
Wedzicha, et al. Thromb Haem 2000. 10

11. Exacerbation frequency and myocardial infarction5 4
Myocardial Infarction
(per 100 patient per year) 3 2 1 1 2 3 4
>=5
Exacerbations (Prescriptions of Antibiotics and Steroids per year)
Donaldson, et al. Chest 2010.
DATA FROM THIN GP DATABASE

12. Exacerbation frequency
FREQUENT
EXACERBATORS
INFREQUENT
Number of patients 1 2 3 4 5 6 7 8 9 10 11
Number of exacerbations per patient
Data from London COPD cohort and Seemungal TAR, et al. AJRCCM 1998;157:

13. FACTORS PREDICTING FREQUENT EXACERBATORS:
Number of exacerbations in previous year
Daily cough and sputum
Poor quality of life
Seemungal, et al. AJRCCM 1998. 13

14. Exacerbation frequency is a susceptibility phenotype
Susceptible Patient
Non-Susceptible Patient
Sufficient Trigger
EXACERBATION

17. Exacerbation stability: eclipse
Year 3
Exacerbation stability: eclipse
Year 2
Year 1
n = 1679
ECLIPSE 3 year data
Reproduced with permission Massachusetts Medical Society (MMS), Copyright © MMS
Hurst JR, et al. N Engl J Med. 2010;363:

18. SEVERE
MODERATE
Blasi F. submitted

19. SEVERE
MODERATE
Blasi F. submitted

20. SEVERE
MODERATE
Blasi F. submitted

21. Blasi F. submitted

22. Patient recalled exacerbation frequency and actual exaceration frequency
100
87.1%
86.8% 90 80 70 60
% patients by recall
% Recalling themselves to be IE
% Recalling themselves to be FE 50 40 30
Sensitivity 86.8%
Specificity 87.1%
Positive predictive value 0.81 20 10
Infrequent exacerbators
Frequent exacerbators
Classified by diary cards
Quint, et al. ERJ 2011.
Data from London COPD Cohort 22

23. Exacerbations: reported and unreported
50% not reported to
study team (UNREPORTED EXACERBATIONS)
Total
Reported
Unreported
Seemungal, et al. AJRCCM 1998.

24. Exacerbation clustering
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 6
rho=0.810 p<0.001
Recurrent exacerbations per year 3 5 10
Total exacerbations per year
Hurst, et al. AJRCCM 2009.

25. Exacerbation recovery50 3
CLOSED CIRCLES
OPEN CIRCLES 45 2
Symptom count 40
Housebound
% of patients 1 35 30
-14 -7 7 14 21 28 35
Days
Donaldson GC, et al. AJRCCM 2005;171:

26. Onset and resolution of COPD exacerbations - data from london COPD cohort
Intensity
FAST ONSET AND RESOLUTION
SLOW ONSET AND
RESOLUTION
Time
Aaron et al Thorax 2011

27. Results from the European COPD audit: outcomes
ERS 2011
Results from the European COPD audit: outcomes
In-hospital deaths
EU: 4.9%

28. Patient-related factors associated to in-hospital mortality
ERS 2011
Results from the European COPD audit: outcomes
Patient-related factors associated to in-hospital mortality
Variables
Crude OR
Age
1.06 (1.05 – 1.07)
Gender female
1.17 (1.01 – 1.36)
Current smoker
0.52 (0.43 – 0.63)
Sputum colour change
0.84 (0.72 – 0.98)
Pack-years
1.004 (1.001 – 1.007)
Previous admissions 12 months
1.07 (1.03 – 1.10)
FEV1
0.978 (0.972 – 0.985)
BMI
0.95 (0.93 – 0.96) pH
0.003 (0.001 – 0.007)
PaCO2
1.001 (1 – 1.002)

29. Organisational factors associated to in-hospital mortality
ERS 2011
Organisational factors associated to in-hospital mortality
Variables
Crude OR
Number of respiratory specialists
0.98 (0.97 – 0.99)
Number of respiratory trainees
Number of physiotherapists
0.96 (0.93 – 0.99)
% seen by respiratory specialist
0.996 (0.994 – 0.999)
University hospital
0.80 (0.69 – 0.92)
Hospital with ICU
1.86 (1.24 – 2.7)
Respiratory Specialist on call everyday
0.76 (0.65 – 0.88)
Outpatient clinic
0.60 (0.41 – 0.89)
With HDU
1.40 (1.21 – 1.62)
Respiratory ward
0.67 (0.58 – 0.77)

30. Triggers of COPD exacerbations and associated pathophysiological changes leading to increased exacerbation symptoms
Wedzicha JA et al Lancet 2007 30

31. Acute exacerbation of chronic bronchitis (AECB): aetiology
Papi et al. Am J Respir Crit Care Med 2006;173:1114–21 31

32. COPD exacerbations: early therapy and recovery24
0.42 d/d-delay
(p<0.001) 18
Symptom recovery time (days) 12 6 7 14
Delay between onset and treatment (days)
Wilkinson et al. Am J Respir Crit Care Med 2004;169:1298–303 32

33. No influenza vaccination: 28% No rehabilitation program: 86%
Modifiable risk factors in patients with COPD exacerbation (EFRAM study)
No influenza vaccination: 28%
No rehabilitation program: 86%
No home O2 in pts with PaO2 < 55 mm Hg: 28%
Failed in inhaler maneuvers: 43%
Current smokers: 26%
García Aymerich J et al. ERJ 2000; 16: 33

34. Dunican EM, et al. Thorax 2011 66(4)358-9

35. Multivariate analysis identified:
Hospitalisation in the previous year (p<0.03, OR 2.26, CI 1.1 to 4.8) AND Borg score > 3 (p<0.04, OR 2.15, CI 1.0 to 4.6) Predicted readmission by day 14 in 75% of cases.
Longterm oxygen therapy (p<0.001, OR 3.28, CI 1.6 to 6.5), pack-year history >50 (p<0.008, OR 3.13, CI 1.4 to 7.3) AND Borg score > 3 (p<0.001, OR 3.31, CI 1.6 to 6.8) Predicted 6 week admission in 68.9%.

36. 36

37. 37

39. Steroids + Antibiotic
Steroids 39

41. Bacterial community profiles for explanted lung from patients with severe COPD

43. Rothberg MB et al. JAMA 2010

45. 45

46. Randomized, double-blind, placebo-controlled study of erythromycin administered at 250 mg twice daily to patients with COPD over 12 months 46

49. Exacerbations/colonization in COPD
Impaired host defences:
respiratory virus
new strains of bacteria
environmental irritants
Smoking/irritants
Chronic bacterial colonisation
Chronic
cycle
Acute
cycle
Damaged respiratory epithelium
Acute on chronic inflammation
(bacterial + host-mediated inflammatory factors)
Chronic inflammation
(bacterial + host-mediated inflammatory factors)
Progressive loss of lung function and deteriorating quality of life

50. A new perspective on ‘optimal care’ for patients with COPD
The terminologies introduced in this concept paper are – ‘optimal COPD care’, ‘best current control’, and ‘future risk reduction’ reflecting the concept that , to a COPD patient, prevention of future risk is of equal importance to the immediate impact of treating symptoms.
The impact an intervention may have on long-term disease progression is sometimes independent of any effect it may have on current symptoms.
Clinicians already apply this broader approach to risk factors such as hypertension and hypercholesterolaemia. Treatments that reduce high blood pressure and serum cholesterol are nowadays prescribed independently of any acute effects on current symptoms. It has now been suggested that this approach should also be considered in COPD.
Title: Patient experiences of exacerbations in a real world setting:
global results from the Hidden Depths Survey
Authors: Barnes N,1 Calverley P,2 Kaplan A,3 Rabe KF 4
(First names required; presenting author first)
Affiliations: (to be entered)
Body text:
Background: There are many clinical trials in which COPD exacerbations have been studied but less is known about the real life patient impact.
Aim: To establish patient reported exacerbation frequency in a real world, global setting & investigate the emotional & physical impact of these events.
Method: A cross-sectional online survey of clinician diagnosed COPD patients from 14 countries conducted from 09/07 to 02/ Patients were recruited from opt-in research panels with >18,000,000 members. 255,710 people were invited to participate in the survey. 75,233 respondents were screened. Patients self-classified their COPD severity using the MRC dyspnoea scale.
Results: 2,000 patients were interviewed (1231=MRC1&2 (M1-2) & 769=MRC3,4&5 (M3-5) & mean age of 53 years). 73% of M1-2 & 64% of M3-5 patients thought they controlled their COPD but reported 10 (M1-2) to 18 (M3-5) days in a 30 day month as negatively affected by COPD. Regardless of severity or treatment, the percentage of patients reporting exacerbations in the preceding year was high:
0 events
1 or more event
2 or more events
M1-2
471(38%)
760(62%)
558(45%)
M3-5
152(20%)
617(80%)
514(67%)
27% of M1-2 & 52% of M3-5 patients who experienced exacerbations reported a hospitalisation & 6% of these M3-5 patients reported never recovering to their prior state of health. Patients also reported significant effects on their personal lives with 71%, 58% & 77% respectively. reporting an effect on their sex life, relationship with partner & ability to socialise freely.
Conclusions: Despite recruiting a relatively young patient cohort on treatment, exacerbation frequency in the real world setting is high & the burden on patients is substantial.
Postma D, Anzueto A, Calverley P, et al. Prim Care Respir J 2011; 20: 50

51. Make every exacerbation count - THORAX May 2011 EDITORIALS
“We suspect that the generally accepted view of exacerbation is that it is like the exasperation of falling over on an icy road temporarily inconvenient, but reversible by dusting oneself down and taking paracetamol and whisky”
“A lung attack is not a temporary inconvenience, it can be associated with permanent damage and is a sign of a worse outlook unless something is done
In the case of an acute myocardial infarction initial management is much more aggressive, risk stratification is routine and patients are usually discharged on a medication bundle. In addition standard of care involves patients being enrolled in well-funded cardiac rehabilitation programs.
LUNG ATTACK?
Speaker notes
This definition of COPD comes from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. This document is widely accepted as the most up-to-date guidance on COPD management.1
The major symptoms of exacerbations are increased breathlessness, increased cough and/or sputum, and changes in colour and/or tenacity of sputum.2
Exacerbations may be classified based on symptoms or on the type of medication used to treat the exacerbation.3 Patients may take several weeks to recover from severe exacerbations.4
Exacerbations are commonly associated with bacterial and/or viral infections of the airways and worsening air pollution.1
Exacerbations are associated with increased levels of inflammatory markers, such as IL-6, in the airways and systemic circulation.5-8
References
Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of COPD
Donaldson GC and Wedzicha JA. COPD exacerbations: Epidemiology. Thorax 2006;61:164–168.
Pauwels R, Calverley P, Buist AS, et al. COPD exacerbations: the importance of a standard definition. Respir Med 2004;98:99–107.
Seemungal TA, Donaldson GC, Bhowmik A, et al. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1608–1613.
Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation in Chronic Obstructive Pulmonary Disease severe exacerbations. Am J Respir Crit Care Med 2006;173:1114–1121.
Hurst JR, Perera WR, Wilkinson TM, et al. Systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;173:71–78.
Wedzicha JA and Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370:786–796.
Perera W, Hurst JR, Wilkinson TM, et al. Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur Respir J 2007;29:527–534.
Bush A & Pavord I. Thorax 2011;66:367 FitzGerald JM. Thorax 2011;66:365-66 51

52. A new perspective on ‘optimal care’ for patients with COPD
PATIENT CHARACTERISTICS
MANAGEMENT PLAN
FUTURE RISK REDUCTION
BEST CURRENT CONTROL
Exacerbations
Postma D, et al. Prim Care Respir J 2011; 20: 52

53. Conclusions
COPD phenotypes can be identified across COPD stages and will need different therapeutic approaches
Frequent exacerbators are more likely to have chronic bronchitis
Frequent exacerbations contribute to disease progression in COPD
Important phenotype for targeting therapies