Riacutizzazione di BPCO

1
Riacutizzazione di BPCO
2
Standards for the diagnosis andtreatment of
patients with COPD a summary of the ATS/ERS
position paper

• Riacutizzazioni definizione
• La riacutizzazione della BPCO è un evento, che si
  verifica nel corso della storia naturale della
  malattia, caratterizzato da un cambiamento
  rispetto al basale di dispnea e/o
  dellespettorato, che eccede la variabilità
  quotidiana ed è tale da richiedere modifiche del
  trattamento

Celli B. ERJ 2004
3
Costi delle AECB

• In generale, solo una minima parte della spesa
  sanitaria pro capite è generata da pazienti con
  BPCO lieve o moderata
• La malattia grave e molto grave, di competenza
  prevalentemente specialistica, spiega
  lelevatissimo consumo di risorse sanitarie
• Poiché la bronchite cronica è responsabile
  dell85 dei casi di BPCO, una rilevante porzione
  della spesa sanitaria pro capite per questi
  pazienti è generata dalle riacutizzazioni,
  indipendentemente dalla gravità della malattia
  di base

Sethi S, File TM. Curr Med Res Opin.
2004201511-21
4
Definition
EXACERBATION Defined as an increase in the
baseline symptoms of the disease in the absence
of an identifiable cause.
ATS/ERS Statement ERJ 2004 23932-946
5
Cause di RIACUTIZZAZIONI
Infezioni Batteriche Virali
Allergie
RIACUTIZZAZIONE
Inquinamento Anidride solforosa Polveri
industriali
Clima Inverno
Ball P. Chest. 199510843S-52S. Gump DW, et al.
Am Rev Respir Dis. 1976113465-74.
6
ALL EXACERBATIONS BY MONTH OF STUDY from East
London COPD cohort
7
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 lt 55 mm Hg 28 ? Failed in inhaler
maneuvers 43 ? Current smokers 26
García Aymerich J et al. ERJ 2000 16 1037-1042
8
AECB ETIOLOGY
Papi A et al. AJRCCM 2006
9
RESPIRATORY VIRUSES AND EXACERBATIONS
Seemungal et al Am J Respir Crit Care Med 2001
10
RSV (PCR) IN STABLE COPD AND AT EXACERBATION
Seemungal et al Am J Respir Crit Care Med 2001

• EXACERBATIONS
• RSV found in 26 of exacerbations
• Detection of RSV not related to exacerbation
  parameters
• STABLE
• RSV found in 24 of stable samples

11
CHANGES IN BACTERIAL LOADn57
p0.0001
Bacterial Load Log cfu/ml
12
Bacterial infection and COPD
Bacterial index
Culture
Rosell et al. Arch Intern Med 2005 165 891-897
13
The fall rise of bacterial AECB
Modifying factors
Clinical threshold
Bacterial load (CFU/ml)
AB1
AB2
AB3
Time (days)
AE AB Cure Cure Cure Stop AB
Time to relapse
Miravitlles et al. Eur Respir J 2002 20 (Suppl
36) 9s-19s
14
AECB Etiology
Chlamydia pneumoniae
15
Persistent colonisation

• During a 7-year study, 122 instances of gaps in
  sputum cultures for H.influenzae were observed.
• 17 periods of prolonged periods of negative
  sputum cultures preceded and followed by an
  identical strain of H.influenzae.
• H.influenzae DNA present in negative sputum
  samples.

Sputum cultures underestimate the frequency of
colonisation by H.influenzae in COPD.
Sethi et al. AJRCCM 2004170266-272
16
RELATIVE RISK OF EXACERBATION AND BACTERIAL
STRAIN CHANGE
Exacerbation visits

• 33 of exacerbation visits were assoaciated with
  a new strain, compared to 15 of visits when no
  new strain was found
• Plt0.001
• For H Influenzae,
• S pneumoniae, M Catarrhalis

Sethi et al NEJM 2002
17
INTERACTION OF BACTERIAL AND VIRAL
INFECTION Wilkinson et al Chest 2006 129317-324
18
Rapporti tra infiammazione e infezione nei
pazienti con BPCO
19
BACTERIAL ERADICATION AND INFLAMMATION White et
al Thorax 2003
20
ALTERAZIONI STRUTTURALI VIE AEREE-PARENCHIMA
COLONIZZAZIONE BATTERICA
OSTRUZIONE BRONCHIALE INSUFFLAZIONE
RIACUTIZZAZIONI
DISPNEA LIMITAZIONE SFORZO
PEGGIORAMENTO Q of L
21
Circolo vizioso del declino funzionale nei
pazienti con BPCO
22
39 (72.2) of patients had bronchiectasis on
HRCT Median score was 3/24 (range 1-14) Patel et
al AJRCCM2004
Upper lobes 43.6 Middle lobe/lingula
46.2 Lower lobes 76.9
23
NATURAL HISTORY OF COPD
Never smoked
Exacerbation
Lung Function
Smoker
Exacerbation
Exacerbation
Time (Years)
Fletcher C. BMJ 197711645-1648.
24
Day-to-day variability of a patient with COPD
Normal variation of clinical state
Exacerbation threshold
Function
Time
Rodriguez-Roisin, R. Chest 2000117398S-401S
25
Relationship between lung function and
exacerbations
Exacerbations increase as lung function declines.
26
Lung function shows a small decline in the days
immediately preceding an exacerbation
Fluticasone propionate 500mcg bd
FSC 50/500mcg bd
270
Salmeterol 50mcg bd
Placebo
260
250
240
Mean PEF (L/min)
230
220
210
Onset of exacerbation
0
-14
14
-12
-10
-8
-6
-4
-2
0
2
4
6
8
10
12
Day
Pauwels et al. Am J Respir Crit Care Med 2003
167(7) A949
27
INTERACTION OF BACTERIAL AND VIRAL
INFECTION Wilkinson et al, Chest 2006
129317-324
28
Time Course and Recovery of COPD Exacerbations
101 patients - F/up 2.5 years FEV1 41.9
Pred Daily Symptoms and PEFR FEV1 (34)
Recovery 75.2
No recovery 7.1 (90 d.)
Seemungal TAR et al, AJRCCM 2000 161 1608
29
Impatto delle infezioni delle basse vie
respiratorie sul declino annuale del FEV1
(ml/anno)
Ex fumatori
Fumatori intermittenti
70
Fumatori
60
50
40
30
20
10
0
0-0.24
0.25-0.49
0.50-0.99
1.00-1.49
gt1.50
indice
Kanner RE et al. AJRCCM 2001
30
Decline in FEV1 Over 12 Months in Patients with
COPD
Pauwels et al. AJRCCM 2001163A770
31
Variazione percentualedel FEV1 in 4 anni
0,95
Infrequente
Frequente
0,9
0,85
0,8
0,75
0
1
2
3
4
Anni
indice
Donaldson GC et al. Thorax 200257847-852
32
The risk of an exacerbation increases as lung
function declines
100
Percentage of patients remaining
80
60
ATS stage
40
Mild
Moderate
20
Severe
0
400
300
200
100
0
Exacerbation-free time (days)
Hauber et al. Am J Respir Crit Care Med 2002
165(8) A271.
33
Exacerbation Rate by FEV1
Donaldson Wedzicha Thorax 200661164
34
Relationship between symptoms and exacerbations
Symptoms worsen before and during an
exacerbation, prompting presentation to a
physician, but their resolution is not sufficient
for recovery.
35
Breathlessness increases during an exacerbation
FSC 50/500mcg bd
2.4
Salmeterol 50mcg bd
Fluticasone propionate500mcg bd
2.2
Placebo
2.0
Mean breathlessness score
1.8
1.6
Onset of exacerbation
1.4
0
-14
14
-12
-10
-8
-6
-4
-2
0
2
4
6
8
10
12
Days
Pauwels et al. Am J Respir Crit Care Med 2003
167(7) A949.
36
Symptoms worsen during the 2 days preceding an
exacerbation
patients with worsening of one or two symptoms patients with worsening of one or two symptoms patients with worsening of one or two symptoms patients with worsening of one or two symptoms
Breathlessness score Cough score Sputum colour Sputum production
Breathlessness score 25 11 11 12
Cough score 30 17 20
Sputum colour 34 19
Sputum production 28
Pauwels et al. Am J Respir Crit Care Med 2003
167(7) A949
37
INTERACTION OF BACTERIAL AND VIRAL
INFECTION Wilkinson et al Chest 2006 129317-324
38
Relationship between exacerbations and health
status
Exacerbations have a pronounced detrimental
impact on health status, while low health status
is linked with increased probability of
exacerbations
39
Recovery of health status after an exacerbation
is prolonged, particularly if another
exacerbation occurs during the recovery period
Experiencing an exacerbation during the follow-up
period
Experiencing no further exacerbation
n 133
SGRQ total score
Improved health status
60
55
n 133
n 115
n 116
50
n 299
45
40
n 280
35
n 233
30
n 221
0
4
26
12
Time after presentation with an exacerbation
(weeks)
Spencer Jones. Thorax 2003 58 589-93.
40
Exacerbations and quality of life
P lt 0.0005
SGRQ Score
3 - 8
Exacerbations/year
Seemungal TAR et al, AJRCCM 1998 157 1418
41
A higher frequency of exacerbations is related to
greater impairment of health status
0-2 exacerbations per year (n32)
3-8 exacerbations per year (n38)
Mean SGRQ score
Improved health status
100
p0.001
plt0.0005
80
plt0.0005
80,9
77,0
p0.002
67,7
60
64,1
53,2
50,4
48,9
40
36,3
20
0
Total
Activity
Impacts
Symptoms
Seemungal et al. Am J Respir Crit Care Med 1998
157 1418-22
42
COPD exacerbations Health status
613 mod. to severe COPD pts. followed for a
maximum of 3 yrs

plt0.0001
(Worse)

3.0
plt0.004
235
285
2.0
91
SGRQ slope (units/year)
1.0
0
None in 3 years
Infrequent lt1.65/year
Frequent gt1.65/year
Exacerbation category
Spencer S et al. Eur Respir J. 200423698-702
43
Relationship between exacerbations and mortality
Exacerbations increase the risk of death in
patients with COPD.
44
Outcome delle AECBMortalità
Mortalità ospedaliera 24 Mortalità
ospedaliera 11-49
Pazienti in UTI
Pazienti ospedalizzati
Seneff MG, et al. JAMA. 1995274852-1857
Connors et al. Am J Respir Crit Care Med. 1996
Oct154(4 Pt 1)959-67. Murata GM, et al. Ann
Emerg Med. 1991 Feb20(2)125-9 Adams SG, et
al. Chest. 20001171345-1352
indice
45
Sopravvivenzaassociata a AECB grave
100
80
60
Sopravvivenza ()
40
20
0
0
100
300
350
Giorni
indice
Connors et al. Am J Respir Crit Care Med
1996154959
46
COPD Exacerbations Mortality
1016 pts with severe COPD exacerbation (PaCO2 gt
50 mm Hg)
60
49
50
43
40
33
30
Mortality ()
20
20
11
10
0
Hospital stay
60 days
180 days
1 year
2 years
Connors AF Jr et al. Am J Respir Crit Care Med.
1996154959-67
47
COPD exacerbations Survival
1.0
0.8
0.6
plt0.001
Probability of surviving
plt0.0001
0.4
p0.07
0.2
0.0
0
10
20
30
40
50
60
Time (months)
Soler-Cataluña JJ et al. Thorax. 200564925-31
48
COPD exacerbations Survival
1.0
0.8
NS
0.6
plt0.0001
Probability of surviving
plt0.01
plt0.0001
0.4
NS
0.2
0.0
0
10
20
30
40
50
60
Time (months)
Soler-Cataluña JJ et al. Thorax. 200564925-31
49
(No Transcript)
50
Airway inflammation and aetiology of COPD
exacerbations
Sethi et al Chest 2000
51
SPUTUM IL-8 AT EXACERBATION AND MORAXELLA
CATTARHALISPowrie et al ERS 2005
P0.018
52
EFFECT OF CHLAMYDIA INFECTION ON INDUCED SPUTUM
IL-6 Seemungal et al Thorax 2002
53
Microbial patterns in outpatients with COPD
exacerbations and risk factors for a complicated
course
2180 patients, 777 isolates of 673 patients
Inclusion criteria age gt 40 years ? 3
exacerb./year ? 3 comorbidities treatment
failure or high prevalence of resistant pathogens

Anzueto et al., Clin Ther, 1998
54
Fattori associati indipendentemente con
lisolamento dei più comuni patogeni
Germi
Variabile dipendente
Rapporto di
LC 95
probabilità
Non- ed ex-fumatori
H. influenzae
8,16
1,9-43,0
vs fumatori
FEV1
6,85
1,6-52,6
gt 50 vs lt50
P. aeruginosa
6,62
1,21-123,6
FEV1
gt 50 vs lt50
S. pneumoniae
Mesi
dallultima
5,02
1,12-35,7
riacutizzazione
lt2 vs gt2
------
------
------
M. catarrhalis
Miravilles et al, 1999
55
Predictors of pathogens in hospitalized patients
with COPD exacerbations

Eller et al., Chest 1998
56
Predictors of pathogens in patients with COPD
exacerbations treated in the ICU

57
Heterogeneity of COPD exacerbations

• The cause of an exacerbation can include acute
  viral bronchitis, environmental pollutants, and
  allergic responses as well as bacterial
  infections.
• Patients with similar degree of airflow
  limitation may have different rates of
  exacerbations, with a minority of the patients
  presenting with more than two exacerbations per
  year (frequent exacerbators).

58

• Le manifestazioni cliniche non permettono di
  identificare le cause della riacutizzazione,
  perché virus e atipici sono associati con gli
  stessi sintomi e grado di risposta infiammatoria.
  
• Solo la presenza di escreato purulento è stata
  associata ad elevata carica batterica nelle
  secrezioni respiratorie durante le riacutizzazioni

59
CLASSIFICAZIONE DELLE RIACUTIZZAZIONI DELLA
BRONCHITE CRONICA BASATA SUI SINTOMI
Esacerbazioni Sintomi
cardinali Tipo I Tutti Aumento
dispnea Aumento volume escreato Aumento
escreato purulento Tipo II Due dei sintomi
sopra citati Tipo III Uno dei sintomi del
Tipo I uno tra i seguenti Infezione delle
vie respiratorie superiori nei 5 giorni
precedenti Febbre senza altre
cause Incremento del wheezing Incremento
della tosse Incremento della frequenza
respiratoria o cardiaca
Anthonisen 1987
60
Possibile classificazione della severità delle
riacutizzazioni di BPCO
61
Operational Classification of Severity of
Exacerbations

• The Operational Classification of Severity is as
  follows ambulatory (Level I), requiring
  hospitalisation (Level II) and acute respiratory
  failure (Level III).

Level I Level II Level III
Clinical history Co-morbid conditions History of frequent exacerbations Severity of COPD Mild/moderate Moderate/severe Severe
Physical findings Haemodynamic evaluation Use accessory respiratory muscles, tachypnoea Persistent symptoms after initial therapy Stable Not present No Stable Stable/unstable
Diagnostic procedures Oxygen saturation Arterial blood gases Chest radiograph Blood tests Serum drug concentrations Sputum gram stain and culture Electrocardiogram Yes No No No If applicable No No Yes Yes Yes Yes If applicable Yes Yes Yes Yes Yes Yes If applicable Yes Yes
unlikely to be present likely to be
present very likely to be present
ERS-ATS COPD Guidelines
62
Meta-analyses of typical study demographics
showed that there was significant overlap in 95
CI and study data distributions for the three
exacerbation severity levels
Franciosi et al, Respir Res 2006 774
63
Fixed Effect Meta-Analysis Results of Selected
Spirometry Variables
P lt 0.017 is indicated for statistical
comparisons of Level I versus II (), II versus
III (), and I versus III () as well as P lt 0.05
for comparison of out- versus in-patient setting
()
64
Fixed Effect Meta-Analysis Results of Selected
Clinical Variables
P lt 0.017 is indicated for statistical
comparisons of Level I versus II (), II versus
III (), and I versus III () as well as P lt 0.05
for comparison of out- versus in-patient setting
()
65
Fixed Effect Meta-Analysis Results of Selected
Clinical Variables
P lt 0.017 is indicated for statistical
comparisons of Level I versus II (), II versus
III (), and I versus III () as well as P lt 0.05
for comparison of out- versus in-patient setting
()
66

• The current management and treatment of COPD
  exacerbations is primarily dependent on the
  evaluation of the symptoms rather than the signs
  related to the exacerbation event.
• Arterial carbon dioxide tension and breathing
  rate consistently varied with the severity of
  COPD exacerbations and with in- versus
  out-patients.
• Other commonly-accepted measures and suggested
  biomarkers for exacerbations failed to show
  consistent trends or lacked sufficient data to
  permit any meta-analysis.

Franciosi et al, Respir Res 2006 774
67
PLASMA FIBRINOGEN AT EXACERBATIONWedzicha et al
Thrombosis and Hemostasis 2000Seemungal et al Am
J Respir Crit Care Med 2001

• Increased fibrinogen with colds P 0.02
• Increased fibrinogen with sputum purulence P
  0.03
• Rise 0.56 g/l during viral Exs
• Rise in 0.27 g/l during non-viral Exs
• P 0.056

N 120 Exacerbations
Plt0.001
Plt0.001
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
68
AE-COPD Procalcitonin
Patient Prescriber factors
Standard group ProCT guided-group p-value
Age, male gender () 71 y, 48 (53) 70 y, 48 (53) ns
Antibiotics at admission () 19 (21) 20 (22) ns
Anthonisen Typ I () 43 (48) 49 (54) ns
Positive bacteriology 31/45 (67) 28/57 (49) ns
GOLD III IV 68 83 0.039
FEV1 mean (L) () 0.99 0.48 (44.9) 0.85 0.32 (38.4) ns
Antibiotic use () 62 (68.8) 35 (38.8) 0.0001
Antibiotic use (days) 7 5 4 5 0.0001
Procalcitonin-guided antibiotic therapy in acute
exacerbations of COPD a randomised trial - The
ProCOLD Study D. Stolz, M. Christ-Crain, R.
Bingisser, M. Gencay, J. Leuppi, D. Miedinger, C.
Müller, P. Huber, B. Müller, M. Tamm. ERS
Copenhagen, 2005
69
Prescriber factors
Evidence in favor Stockley
Stockley RA, O'Brien C, Pye A, Hill SL.
Relationship of sputum color to nature and
outpatient management of acute exacerbations of
COPD. Chest 2000 117(6)1638-1645.
70
Prescriber factors
Consequence Stockley data
Bronko Test Chart
Cut-off color
Stockley RA, O'Brien C, Pye A, Hill SL.
Relationship of sputum color to nature and
outpatient management of acute exacerbations of
COPD. Chest 2000 117(6)1638-1645.
71
Relation of severity of COPD and acute
exacerbation
COPD
mild
moderate
severe
acute exacerbation
mild
moderate
severe
72
COPD exacerbations Early therapy and recovery
24
0.42 d/d-delay (plt0.001)
18
12
Symptom recovery time (days)
6
0
0
14
7
Delay between onset and treatment (days)
Wilkinson TMA et al. Am J Respir Crit Care Med.
20041691298-303
73
Bacterial Eradication vs Failure Rate
y 0.5785x 5.7679
r0.91
Clinical failure rate ()
Eradication failure rate ()
Pechere JC et al. J Antimicrob Chemo 20004519-24
74
Criteri per decidere se trattare una
riacutizzazione di BPCO a casa o in ospedale.
I.(BTS guidelines 1997)
75
Criteri per decidere se trattare una
riacutizzazione di BPCO a casa o in ospedale.
II.(BTS guidelines 1997)
76
Criteri per decidere se trattare una
riacutizzazione di BPCO a casa o in ospedale.
III.Da valutare con lausilio ospedaliero(BTS
guidelines 1997)
77
Criteria for hospitalization ATS standards of
care 1995 ERS / ATS guidelines 2004
ATS 1995 ERS / ATS 2004
severe dyspnea marked increase in dyspnea
worsening hypoxemia / hypercapnia
inability to eat or to sleep due to symptoms
new onset of immobility
significant, potentially unstable comorbidity presence of high risk comorbid conditions
confusion changes in mental status
inadequate response to outpatient management
uncertain diagnosis
inadequate home care
78
INDICAZIONI PER LAMMISSIONE A REPARTI
SPECIALIZZATI O DI TERAPIA INTENSIVA
Presenza di gravi disfunzioni respiratorie
Ammissione nel reparto di terapia intensiva
INDICAZIONI PER RICOVERO IN ICU

• insufficienza respiratoria
• presenza di altre disfunzioni di end-organ
• shock
• disturbi renali, epatici o neurologici
• instabilità emodinamica

79
Criteria for ICU admission ATS standards of care
1995 ERS / ATS guidelines 2004
ATS 1995 ERS / ATS 2004
severe dyspnea, not improved after 2 h impending or actual respiratory failure
respiratory acidosis (pH lt 7.3) despite oxagen supplementation
signs of ventilatory fatigue
confusion presence of other end-organ dysfunction neurological disturbance
presence of other end-organ dysfunction
hemodynamic instability
80
Quanto maggiore è la presenza dei succitati
indicatori, tanto più pressante è la necessità di
ospedalizzare il paziente
81
Outcome delle AECBinsuccesso terapeutico
Pazienti ospedalizzati
Recidiva (ripetute visite di emergenza)
19
Pazienti ambulatoriali
Tasso di insuccesso terapeutico
19-32
Seneff MG, et al. JAMA. 1995274852-1857
Connors et al. Am J Respir Crit Care Med. 1996
Oct154(4 Pt 1)959-67. Murata GM, et al. Ann
Emerg Med. 1991 Feb20(2)125-9 Adams SG, et
al. Chest. 20001171345-1352
indice
82
Predictors of outcome in outpatients with acute
COPD exacerbations
Odds of failure in relation to home oxygen
therapy and number of exacerbations over 24 months
Variables Odds of failure
Home oxygen and one exacerbation 0,311
Home oxygen and two exacerbations 1,008
Home oxygen and three exacerbations 3,274
Home oxygen and four exacerbations 10,627
Home oxygen and five exacerbations 34,707
Dewan NA et al., Chest 2000
83
Predictors of outcome in hospitalized patients
with acute COPD exacerbations
Predictors of LOS
Age gt 65
Low FEV1
Poor performance status

Predictors of death
Poor performance status
Acidosis
Presence of leg edema

Predictors of readmission
Low FEV1
Previous admission
Readmission with gt 4 medications
1400 admissions from 38 hospitals 14 died
within 3 months However variation between
hospitals 0-50
Roberts CM et al., Thorax 2002
84
LOWER LOBE BRONCHIECTASIS AND EXACERBATION
RECOVERY Patel et al AJRCCM 2004
Patients with lower lobe score 0 or 1/8 time to
recovery of symptoms 10 days
Patients with lower lobe score gt/2/8 time to
recovery of symptoms 12 days
p 0.001
85
Predictors of outcome (mortality) in hospitalized
patients with acute COPD exacerbations
590 patients hospitalized in a university
hospital Mortality rate 14,4
OR 95 CI p
Age 1,07 1,04 1,11 0.0001
PA-aO2 gt 41 mm Hg 2,33 1,39 3,9 0.001
Ventricular arrhythmias 1,91 1,1 3,31 0.0022
Atrial fibrillation 2,27 1,14 4,51 0.019
Fuso L et al., Am J Med 1995