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Riacutizzazione di BPCO. Celli B. ERJ 2004 Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper Riacutizzazioni:

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Presentazione sul tema: "Riacutizzazione di BPCO. Celli B. ERJ 2004 Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper Riacutizzazioni:"— Transcript della presentazione:

1 Riacutizzazione di BPCO

2 Celli B. ERJ 2004 Standards for the diagnosis and treatment 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 dell’espettorato, che eccede la variabilità quotidiana ed è tale da richiedere modifiche del trattamento

3 Sethi S, File TM. Curr Med Res Opin. 2004;20: 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 l’elevatissimo consumo di risorse sanitarie  Poiché la bronchite cronica è responsabile dell’85% 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

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; 23:

5 Cause di RIACUTIZZAZIONI Infezioni Batteriche Virali Allergie Inquinamento Anidride solforosa Polveri industriali Clima Inverno RIACUTIZZAZIONE Ball P. Chest. 1995;108:43S-52S. Gump DW, et al. Am Rev Respir Dis. 1976;113:

6 ALL EXACERBATIONS BY MONTH OF STUDY: from East London COPD cohort

7 Modifiable risk factors in patients with COPD exacerbation (EFRAM study) García Aymerich J et al. ERJ 2000; 16:  No influenza vaccination: 28 %  No rehabilitation program: 86 %  No home O 2 in pts with PaO 2 < 55 mm Hg: 28 %  Failed in inhaler maneuvers: 43 %  Current smokers: 26 %

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 LOAD n=57 * p= Bacterial Load Log cfu/ml

12 ,2 2,2 5,5 Healthy subjects Stable COPD Exacerb. COPD Bacterial index Culture + Bacterial infection and COPD Rosell et al. Arch Intern Med 2005; 165:

13 The “fall & rise” of bacterial AECB Modifying factors Bacterial load (CFU/ml) Time (days) Clinical threshold AB1 AB2 AB3 AE AB Cure Cure Cure Stop AB Time to relapse Miravitlles et al. Eur Respir J 2002: 20 (Suppl 36): 9s-19s

14 The usual suspects AECB Etiology Chlamydia pneumoniae

15 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. Persistent colonisation Sethi et al. AJRCCM 2004;170: Sputum cultures underestimate the frequency of colonisation by H.influenzae in COPD.

16 RELATIVE RISK OF EXACERBATION AND BACTERIAL STRAIN CHANGE 33% of exacerbation visits were assoaciated with a new strain, compared to 15% of visits when no new strain was found P<0.001 For H Influenzae, S pneumoniae, M Catarrhalis Sethi et al NEJM 2002 Exacerbation visits %

17 INTERACTION OF BACTERIAL AND VIRAL INFECTION Wilkinson et al Chest 2006; 129:

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 RIACUTIZZAZIONI OSTRUZIONE BRONCHIALE INSUFFLAZIONE DISPNEA LIMITAZIONE SFORZO PEGGIORAMENTO Q of L

21 Circolo vizioso del declino funzionale nei pazienti con BPCO

22 Upper lobes43.6% Middle lobe/lingula 46.2% Lower lobes76.9% 39 (72.2%) of patients had bronchiectasis on HRCT Median score was 3/24 (range 1-14) Patel et al AJRCCM2004

23 NATURAL HISTORY OF COPD Lung Function Time (Years) Exacerbation Never smoked Smoker Fletcher C. BMJ 1977;1:

24 Rodriguez-Roisin, R. Chest 2000;117:398S-401S Day-to-day variability of a patient with COPD Normal variation of clinical state Exacerbation threshold Time Function

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 Pauwels et al. Am J Respir Crit Care Med 2003; 167(7): A Day Mean PEF (L/min) FSC 50/500mcg bd Salmeterol 50mcg bd Fluticasone propionate 500mcg bd Placebo Onset of exacerbation 26 0

27 INTERACTION OF BACTERIAL AND VIRAL INFECTION Wilkinson et al, Chest 2006; 129:

28 Seemungal TAR et al, AJRCCM 2000; 161: patients - F/up 2.5 years FEV % Pred Daily Symptoms and PEFR FEV 1 (34) Time Course and Recovery of COPD Exacerbations Recovery 75.2% No recovery 7.1% (90 d.)

29 Impatto delle infezioni delle basse vie respiratorie sul declino annuale del FEV1 (ml/anno) >1.50 Ex fumatori Fumatori intermittenti Fumatori Kanner RE et al. AJRCCM 2001 indice

30 Decline in FEV 1 Over 12 Months in Patients with COPD Pauwels et al. AJRCCM 2001;163:A770

31 Variazione percentuale del FEV1 in 4 anni 0,75 0,8 0,85 0,9 0, Infrequente Frequente Anni Donaldson GC et al. Thorax 2002;57: indice

32 The risk of an exacerbation increases as lung function declines Hauber et al. Am J Respir Crit Care Med 2002; 165(8): A Percentage of patients remaining Mild Exacerbation-free time (days) Moderate Severe ATS stage

33 Exacerbation Rate by FEV 1 Donaldson & Wedzicha Thorax 2006;61:164

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 Pauwels et al. Am J Respir Crit Care Med 2003; 167(7): A Days Mean breathlessness score FSC 50/500mcg bd Salmeterol 50mcg bd Fluticasone propionate 500mcg bd Placebo Onset of exacerbation

36 Symptoms worsen during the 2 days preceding an exacerbation Pauwels et al. Am J Respir Crit Care Med 2003; 167(7): A949 % patients with worsening of one or two symptoms Breathlessness score Cough score Sputum colour Sputum production Breathlessness score 25%11% 12% Cough score 30%17%20% Sputum colour 34%19% Sputum production 28%

37 INTERACTION OF BACTERIAL AND VIRAL INFECTION Wilkinson et al Chest 2006; 129:

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 Spencer & Jones. Thorax 2003; 58: SGRQ total score Time after presentation with an exacerbation (weeks) 0426 Experiencing an exacerbation during the follow-up period Experiencing no further exacerbation 12 n = Improved health status n =133 n =116 n =115 n =299 n =280 n =233 n =221

40 Exacerbations and quality of life Exacerbations/year SGRQ Score Seemungal TAR et al, AJRCCM 1998; 157: 1418 P <

41 A higher frequency of exacerbations is related to greater impairment of health status Seemungal et al. Am J Respir Crit Care Med 1998; 157: Mean SGRQ score TotalActivityImpactsSymptoms p< exacerbations per year (n=38) 0-2 exacerbations per year (n=32) p=0.002 p=0.001 p< Improved health status 48,9 67,7 36,3 53,2 64,1 80,9 50,4 77,

42 Exacerbation category None in 3 years Infrequent <1.65/year Frequent >1.65/year * p< SGRQ slope (units/year) (Worse) Spencer S et al. Eur Respir J. 2004;23: COPD exacerbations: Health status mod. to severe COPD pts. followed for a maximum of 3 yrs # p<0.004 * #

43 Relationship between exacerbations and mortality Exacerbations increase the risk of death in patients with COPD.

44 Outcome delle AECB Mortalità Seneff MG, et al. JAMA. 1995;274: ; Connors et al. Am J Respir Crit Care Med Oct;154 (4 Pt 1): Murata GM, et al. Ann Emerg Med Feb;20(2):125-9; Adams SG, et al. Chest. 2000;117: Mortalità ospedaliera 24% Mortalità ospedaliera 11-49% Pazienti ospedalizzati Pazienti in UTI indice

45 Sopravvivenza associata a AECB grave Connors et al. Am J Respir Crit Care Med 1996;154:959 Giorni Sopravvivenza (%) indice

46 Hospital stay 60 days180 days1 year2 years Mortality (%) COPD Exacerbations : Mortality 11% 20% 33% 43% 49% Connors AF Jr et al. Am J Respir Crit Care Med. 1996;154: pts with severe COPD exacerbation (PaCO 2 > 50 mm Hg)

47 Soler-Cataluña JJ et al. Thorax. 2005;64: COPD exacerbations: Survival Time (months) Probability of surviving p< p<0.001 p=0.07 3–4 exacerbations1–2 exacerbationsNo exacerbation

48 COPD exacerbations: Survival Soler-Cataluña JJ et al. Thorax. 2005;64: Time (months) Probability of surviving p< p<0.01 p< NS No exacerbation1 hospitalizationER visitsReadmission

49

50 Sethi et al Chest 2000 Airway inflammation and aetiology of COPD exacerbations

51 SPUTUM IL-8 AT EXACERBATION AND MORAXELLA CATTARHALIS Powrie et al ERS 2005 P=0.018

52 EFFECT OF CHLAMYDIA INFECTION ON INDUCED SPUTUM IL-6 Seemungal et al Thorax 2002

53 2180 patients, 777 isolates of 673 patients % Inclusion criteria: age > 40 years  3 exacerb./year  3 comorbidities treatment failure or high prevalence of resistant pathogens Anzueto et al., Clin Ther, 1998 Microbial patterns in outpatients with COPD exacerbations and risk factors for a complicated course

54 GermiVariabile dipendente Rapporto di probabilità LC 95% H. influenzae vs fumatori Non- ed ex-fumatori FEV 1 > 50% vs <50% 8,16 6,85 1,9-43,0 1,6-52,6 P. aeruginosa FEV 1 > 50% vs <50% 6,621,21-123,6 S. pneumoniaeMesidall’ultima riacutizzazione 2 5,021,12-35,7 M. catarrhalis Miravilles et al, 1999 Fattori associati indipendentemente con l’isolamento dei più comuni patogeni

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 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 CLASSIFICAZIONE DELLE RIACUTIZZAZIONI DELLA BRONCHITE CRONICA BASATA SUI SINTOMI

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 ILevel IILevel 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 If applicable No Yes If applicable Yes If applicable 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; 7:74

63 Fixed Effect Meta-Analysis Results of Selected Spirometry Variables P < is indicated for statistical comparisons of Level I versus II (*), II versus III (†), and I versus III (#) as well as P < 0.05 for comparison of out- versus in-patient setting (*)

64 Fixed Effect Meta-Analysis Results of Selected Clinical Variables P < is indicated for statistical comparisons of Level I versus II (*), II versus III (†), and I versus III (#) as well as P < 0.05 for comparison of out- versus in-patient setting (*)

65 Fixed Effect Meta-Analysis Results of Selected Clinical Variables P < is indicated for statistical comparisons of Level I versus II (*), II versus III (†), and I versus III (#) as well as P < 0.05 for comparison of out- versus in-patient setting (*)

66 Franciosi et al, Respir Res 2006; 7:74 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.

67 PLASMA FIBRINOGEN AT EXACERBATION Wedzicha et al Thrombosis and Hemostasis 2000 Seemungal et al Am J Respir Crit Care Med Stable ExacerbationConvalescence Fibrinogen g/l Mean ± SEM P<0.001 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 = N = 120 Exacerbations

68 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 AE-COPD: Procalcitonin Standard groupProCT guided-groupp-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 bacteriology31/45 (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%) Antibiotic use (days)7 ± 54 ± Patient & Prescriber factors

69 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): Evidence in favor: Stockley Prescriber factors

70 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): Consequence: Stockley data Prescriber factors Bronko Test Chart Cut-off color

71 Relation of severity of COPD and acute exacerbation COPD mild moderate severe acute exacerbatio n mild moderate severe

72 Wilkinson TMA et al. Am J Respir Crit Care Med. 2004;169: Delay between onset and treatment (days) Symptom recovery time (days) 0.42 d/d-delay (p<0.001) COPD exacerbations: Early therapy and recovery

73 Bacterial Eradication vs Failure Rate y= x r=0.91 Clinical failure rate (%) Eradication failure rate (%) Pechere JC et al. J Antimicrob Chemo 2000;45:19-24

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 l’ausilio ospedaliero (BTS guidelines 1997)

77 Criteria for hospitalization ATS standards of care 1995 ERS / ATS guidelines 2004 ATS 1995ERS / ATS 2004 severe dyspneamarked 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 confusionchanges in mental status inadequate response to outpatient management uncertain diagnosis inadequate home care

78 INDICAZIONI PER L’AMMISSIONE 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 1995ERS / ATS 2004 severe dyspnea, not improved after 2 himpending or actual respiratory failure respiratory acidosis (pH < 7.3) despite oxagen supplementation signs of ventilatory fatigue confusionpresence 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 AECB: insuccesso terapeutico Pazienti ospedalizzati Pazienti ambulatoriali Tasso di insuccesso terapeutico Recidiva (ripetute visite di emergenza) 19-32% 19% Seneff MG, et al. JAMA. 1995;274: ; Connors et al. Am J Respir Crit Care Med Oct;154 (4 Pt 1): Murata GM, et al. Ann Emerg Med Feb;20(2):125-9; Adams SG, et al. Chest. 2000;117: indice

82 Predictors of outcome in outpatients with acute COPD exacerbations VariablesOdds of failure Home oxygen and one exacerbation0,311 Home oxygen and two exacerbations1,008 Home oxygen and three exacerbations3,274 Home oxygen and four exacerbations10,627 Home oxygen and five exacerbations34,707 Odds of failure in relation to home oxygen therapy and number of exacerbations over 24 months Dewan NA et al., Chest 2000

83 Predictors of outcome in hospitalized patients with acute COPD exacerbations 1400 admissions from 38 hospitals 14 % died within 3 months However: variation between hospitals 0-50% Predictors of LOS Age > 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 > 4 medications 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 >/=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 % OR95% CIp Age1,071,04 – 1, PA-aO 2 > 41 mm Hg2,331,39 – 3, Ventricular arrhythmias 1,911,1 – 3, Atrial fibrillation2,271,14 – 4, Fuso L et al., Am J Med 1995


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