1. Ruolo delle riacutizzazioni della BPCO1

2. Le riacutizzazioni della BPCO
Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines an exacerbation as:
“an event in the natural course of the disease characterized by a change in the patient’s baseline dyspnea, cough, and/or sputum that is beyond normal day-to-day variations, is acute in onset and may warrant a change in regular medication”1
May be mild, moderate or severe in nature. Severe exacerbations require hospitalisation and are associated with a prolonged recovery period2
Commonly caused by bacterial/viral infections of the lungs and airways1
Associated with increases in markers of inflammation3,4
Distressing for patients and their loved ones
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.
1. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive
Lung Disease (GOLD) Available from Seemungal TA, Donaldson GC, Bhowmik A, et al. Am J Respir Crit Care Med 2000;161:
3. Perera W, Hurst JR, Wilkinson TM, et al. Eur Respir J 2007;29: Papi A, Bellettato CM, Braccioni F, et al. Am J Respir Crit Care Med 2006;173:1114–1121. 2

3. Riacutizzazioni e aumento delle cellule infiammatorie
This study shows that the numbers of neutrophils was significantly increased during exacerbations (P<0.01).
Riacutizzazioni e aumento delle cellule infiammatorie
* p<0.01 versus stable disease
300 * *
250
200
Neutrophils/mm2
150
100
Speaker notes
A small study in patients with COPD and symptoms of chronic bronchitis provided clear evidence that exacerbations are associated with increases in inflammation.
Bronchial biopsies and sputum samples were obtained from 11 subjects with chronic bronchitis examined during an exacerbation, and from 12 subjects with chronic bronchitis examined under baseline conditions.
Lobar bronchial biopsies were assessed using histochemical and immunohistochemical techniques, and sputum was examined for differential cell counts of leukocytes.
The number of neutrophils was significantly increased during exacerbations compared with during the stable state (p<0.01). The number of other inflammatory cells also increased during exacerbations, providing clear evidence that exacerbations are associated with an increased inflammatory response.
Reference
Saetta M, Di Stefano A, Maestrelli P, et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med. 1994;150:1646–1652.
Acute Exacerbation, Neutrophil 50
Stable disease
Exacerbations
Adapted from Saetta M, Di Stefano A, Maestrelli P, et al. Am J Respir Crit Care Med 1994;150: 3

4. Number of exacerbations in previous year
Marker dell’infiammazione: aumento al basale nei frequenti riacutizzatori
20,000
n=23
IL-8 (pg/mL)
10,000
n=21
Speaker notes
In addition to increases in inflammation during exacerbations, patient who experience frequent exacerbations also have a higher level of chronic inflammation in the stable state, i.e. between exacerbations, compared with patients with less frequent exacerbations.
In this study, sputum samples from 57 patients with moderate to severe COPD were taken during a stable period.
Patients who had experienced ≥3 exacerbations during the previous year had higher levels of inflammatory cytokines (IL-8 and IL-6) in sputum samples, compared with patients who had experienced ≤2 exacerbations.
Cytokine levels increased further during exacerbations.
Reference
Bhowmilk A, Seemungal TA, Sapsford RJ, et al. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax 2000;55: ≤2 ≥3
Number of exacerbations in previous year
Bhowmilk A, Seemungal TA, Sapsford RJ, et al. Thorax 2000;55: 4

5. Le riacutizzazioni frequenti e la progressione della BPCO
Patients with frequent exacerbations
Lower quality of life
Increased mortality rate
Increased
inflammation
Increased risk of recurrent exacerbations
Speaker notes
Some patients with COPD are susceptible to frequent exacerbations.1,2 Cohort studies have reported evidence of a phenotypic exacerbator,3 and other studies have reported differences in exacerbation rate despite similar FEV1 levels.4
While exacerbation frequency is linked to disease severity, it is important to consider that not only patients with severe COPD are frequent exacerbators.2
Exacerbations are associated with increased inflammation, which persists after the attack and affects the length of recovery period.5 In addition, patients who suffer from frequent exacerbations have increased airway inflammation in the stable state.6
Frequent exacerbators display worse quality of life,1,7 faster decline in lung function,1,2,7 and higher mortality rates than patients with less frequent exacerbations.1,2,8,9
Managing exacerbations, including reducing their frequency and severity, is a major goal of COPD disease management in the GOLD Global strategy for the diagnosis, management, and prevention of COPD.10
References
Wedzicha JA and Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet 2007;370:786–796.
Donaldson GC and Wedzicha JA. COPD exacerbations: Epidemiology. Thorax 2006;61:164–168.
Seemungal TAR, Hurst JR and Wedzicha JA. Exacerbation rate, health status and mortality in COPD – a review of potential interventions. Int J COPD 2009;4:203–223.
Kim V, Han MK, Vance GB, et al. Chronic bronchitic symptoms are associated with worse symptoms and greater exacerbation frequency in COPD. Am J Respir Crit Care Med 2010;181:A1533.
Perera W, Hurst JR, Wilkinson TM, et al. Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur Respir J 2007;29:527–534.
Bhowmik A, Seemungal TA, Sapsford RJ, et al. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax 2000;55:114–120.
Decramer M, Celli B, Kesten S et al. Frequency of exacerbations adversely impacts the course of COPD. Am J Respir Crit Care Med 2010;181:A1526.
Soler-Cataluna JJ, Martinez-Garcia MÁ, Román Sánchez P, et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax 2005;60:925–931.
Groenewegen KH, Schols AMWJ, Wouters EFM. Mortality and mortality-related factors after hospitalization for acute exacerbation of COPD. Chest 2003;124:459–467.
Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of COPD
Faster disease progression
Increased likelihood of hospitalisation
Adapted from Wedzicha JA and Seemungal TA. Lancet 2007;370: ; and Donaldson GC and Wedzicha JA. Thorax 2006;61: 5

6. Sopravvivenza per limitazione del flusso aereo in base a bronchite cronica, fumo ed età
Kaplan–Meier survival curves for incident airflow limitation. (A) Survival curves for the four groups generated by the combination of smoking status (ever smoked at least 1 pack-year vs never smoked 1 pack-year) and chronic bronchitis (C. Bronchitis) at enrolment. (B) Survival curves for the four groups generated by the combination of age (<50 years vs ⩾50 years) and chronic bronchitis at enrolment.
Guerra S, et al. Thorax 2009;64: 6

7. Declino del FEV1 nei frequenti riacutizzatori
0.95
Frequent exacerbators
Infrequent exacerbators
0.90
25% of FEV1 DECLINE ATTRIBUTED TO EFFECT OF EXACERBATIONS
0.85
FEV1 (l)
0.80
0.75 1 2 3 4
Years
Donaldson, et al. Thorax

8. Effetti delle riacutizzazioni sulla progressione della BPCO
Hansel T, Barnes P. Lancet 2009;374:

9. Le riacutizzazioni in cluster
2189 Exacerbations
1923 Exacerbation intervals
633 Exacerbations occurred between 3 and 8 weeks, 103 (19.4%) more than that predicted by the exponential function (p=0.040). 6
rho=0.810 p<0.001
Recurrent exacerbations per year 3 5 10
Total exacerbations per year
Hurst, et al. AJRCCM 2009.

10. Risoluzione delle riacutizzazioni50
CLOSED
CIRCLES
OPEN
CIRCLES 3 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:

11. Probability of survival
Frequenza, gravità delle riacutizzazioni e aumento del rischio di mortalità
Probability of survival
1.0
0.8
0.6
0.4
0.2
0.0 10 20 30 40 50 60
Time (months)
Patients with no acute exacerbations
Patients with 1–2 acute exacerbations requiring hospital management
Patients with ≥3 acute exacerbations
p <
p<
p = 0.069
Speaker notes
This study investigated whether severe acute exacerbations of COPD affect mortality.
A cohort of 304 men with stable COPD were recruited and followed for 5 years.
Severe acute exacerbations were defined as symptomatic changes requiring modification of regular medication and hospital treatment (either a visit to the emergency room or admission). Patients were divided into 3 groups based on the number of severe acute exacerbations experienced during the 5-year observation period.
During the study, 53.6% of patients experienced no exacerbations, while 34.5% experienced 1-2 exacerbations and 11.8% experienced ≥3 exacerbations.
Generally, patients with frequent exacerbations had later stages of COPD (GOLD Stages III to IV), although around 14% of patients who experienced ≥3 exacerbations had moderate COPD (GOLD Stage II).
The rate of mortality increased significantly with the frequency of exacerbations, with patients who experienced ≥3 exacerbations having a risk of death 4.3 times greater than patients who had no exacerbations.
Reference
Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60:925–931.
Soler-Cataluna JJ, Martinez-Garcia MÁ, Román Sánchez P, et al. Thorax 2005;60: 11

12. Frequenza delle riacutizzazioni e infarto del miocardio5 4
Myocardial Infarction
(per 100 patient per year) 3 2 1 1 2 3 4
>=5
Exacerbations (Prescriptions of Antibiotics and Steroids per year)
DATA FROM THIN GP DATABASE
Donaldson, et al. Chest 2010.

13. Riacutizzazioni della BPCO e declino del FEV1
FEV1, forced expiratory volume in 1 second
Pauwels et al. Am J Respir Crit Care Med 2001;163:1256–76 13

14. Riacutizzazioni: qualità della vita in pazienti (n=613) con BPCO moderata e severa seguiti per 3 anni *
*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 14

15. Riacutizzazioni della BPCO: mortalità
1016 pts with severe COPD exacerbation
(PaCO2 ≥ 50 mm Hg) 60
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 15

16. Impatto clinico delle riacutizzazioni
Poorer Quality of Life
Greater Airway Inflammation
“Frequent Exacerbator”
Higher Mortality
Faster Decline in Lung Function

17. Percentuale delle riacutizzazioni non riferite dai pazienti
50% not reported to
study team (UNREPORTED EXACERBATIONS)
Total
Reported
Unreported
Seemungal, et al. AJRCCM 1998.