BPCO: dalle novità patogenetiche alla terapia

Transcription

1 BPCO: dalle novità patogenetiche alla terapia Gianna Camiciottoli Dip. Di Scienze Biomediche, Sperimentali e Cliniche Mario Serio Università degli Studi di Firenze Firenze, 11 novembre 2016

2 Conflict of interest disclosure X I have no, real or perceived, direct or indirect conflicts of interest that relate to this presentation. I have the following, real or perceived direct or indirect conflicts of interest that relate to this presentation:

3 Phenotypes Small Airways Disease Airway inflammation Airway fibrosis, luminal plugs Increased airway resistance Parenchymal Destruction Loss of alveolar attachments Decrease of elastic recoil Airflow limitation Both mechanisms concur to determine the overall severity of Their relative predominance clinical phenotype of determines the

4 Phenotypes

5 Phenotypes

6 Phenotypes

7 Phenotypes

8 Treatment according to severity «I find it a step backward to grade the severity of solely by the FEV1. consists of two (or more) separate diseases, chronic bronchitis and emphysema. Each of these has its own pathophysiology and therefore management. To lump them together is misleading.» John B West. Am J Respir Crit Care Med

9 Phenotypes Beyond airflow limitation: another look at M.Pistolesi Thorax January 2009 Vol 64 No 1 Regardless of expiratory airflow limitation, the different pathological changes seen in vivo by HRCT are brought by people with different body habits The words expiratory airflow limitation expresses our present inaccuracy in differentiating increased airway resistance from increased lung compliance Let us jump over the hindering barrier of airflow limitation and explore the world beyond

10 Phenotypes James C Hogg Progress toward specific treatments for might be accelerated by moving beyond measurements of airflow limitation to the precise diagnosis of the specific targets responsible for the airflow limitation. This step will require precise, safe, non-invasive quantitative methods of diagnosis that will allow both the airway-obstructive and emphysema phenotypes to serve as measurable endpoints in clinical trials.

11 Phenotypes Quantitative CT Mean Lung attenuation % area with attenuation values below a predetermine threshold Bronchial wall thickness Cross sectional area of blood vessels

12 %LAA-950 %LAA-950 Vida VidaDiagnostics, Diagnostics,Coralville, Coralville,Iowa, Iowa, Phenotypes AWT-Pi10 AWT-Pi10 (mm) (mm)

13 Phenotypes n=100 learning set (mm) Principal Component Analysis Camiciottoli G, et al European Respiratory Journal Sep 2013, 42 (3)

14 Phenotypes CT2 is proportional to the sum of the original variables (%LAA-950 plus AWT-Pi10) and reflects then the overall CT severity of severity Principal Component Analysis phenotype CT1 is proportional to the difference of the original variables (%LAA-950 minus AWT-Pi10) and reflects then the prevalent mechanism of airflow obstruction (airways or emphysema CT

15 Phenotypes Predictive Predictive models models of of CT1 CT1 and and CT2 CT2 by by multivariate multivariate analysis analysis of of clinical clinical and and pulmonary pulmonary function variables function variables Predictors Coefficients R Prediction errors n=100 mean mode CT1 phenotyp e DLCO% purulent sputum TLC% % 2.3% % 2.1% intercept CT2 severity FEV1/VC purulent sputum FRC% derived from The models the learning set of 100 patients were ten fold cross-validated intercept and trained to estimate CT1 and CT2 in the prospective set

16 severity and phenotype Prospective validation CT1= ( x DLCO% ) + ( x purulent sputum*) + (0.011 x TLC%) C D CT2= ( x FEV1/VC) + (0.775 x purulent sputum*) + (0.013 x FRC%) Sputum severity purulence FEV1/VC TLC% FRC% DLCO% n=373 n=373 testing testing set set (patients (patients who who did did not not undergo undergo CT) CT) A phenotype B

17 severity and phenotype n=373 n=373 testing testing set set very severe severe C D n=80 FEV1/VC: 45% FRC: 132% DLCO: 78% chronic/ purulen t moderate mild Prospective validation n=143 FEV1/VC: 60% FRC: 100% DLCO: 88% A n=73 FEV1/VC: 36% FRC: 162% DLCO: 49% chronic/non absent/ purulent occasional n=77 FEV1/VC: 52% FRC: 118% DLCO: 61% B

18 Phenotypes D 4 Risk A B (C) (D) (B) 0 mmrc 0-1 CAT < 10 mmrc > 2 CAT > 10 Symptoms Purulent sputum FEV1/VC TLC% FRC% DLCO% >2 1 (A) mmrc/cat FEV1% Exacerbation history Risk (Exacerbation history) Hospitalization C (GOLD Classification of Airflow Limitation) CT classification versus GOLD 2015 classification

19 Global Strategy for Diagnosis, Management and Prevention of (GOLD Classification of Airflow Limitation) (D) >2 (A) (B) mmrc 0-1 CAT < 10 mmrc > 2 CAT > 10 Symptoms Risk (C) (Exacerbation history) 4 Hospitalization Risk Combined Assessment

20 Global Strategy for Diagnosis, Management and Prevention of Manage Stable : Pharmacologic Therapy (Medications in each box are mentioned in alphabetical order, and therefore not necessarily in order of preference.) Patient First choice Second choice Alternative Choices A SAMA prn or SABA prn LAMA or LABA or SABA and SAMA Theophylline B LAMA or LABA LAMA and LABA SABA and/or SAMA Theophylline LAMA and LABA PDE4-inh. SABA and/or SAMA Theophylline ICS and LAMA or ICS + LABA and LAMA or ICS+LABA and PDE4-inh. or LAMA and LABA or LAMA and PDE4-inh. Carbocysteine SABA and/or SAMA Theophylline C D ICS + LABA or LAMA ICS + LABA and/or LAMA

21 Phenotype: a single or combination of disease attributes that describe differences between individuals with as they relate to clinically meaningful outcomes: symptoms, exacerbations, response to therapy, rate of disease progression, or death Patients with often present with comorbid diseases, including cardiovascular disease, metabolic syndrome, osteoporosis, depression, and skeletal muscle wasting and dysfunction

22 Global Strategy for Diagnosis, Management and Prevention of (GOLD Classification of Airflow Limitation) (D) >2 (A) (B) mmrc 0-1 CAT < 10 mmrc > 2 CAT > 10 Symptoms Risk (C) (Exacerbation history) 4 Hospitalization Risk Combined Assessment

23 65% 35% 12% 88% Price BD et al. Inter J 2014

24 Global Strategy for Diagnosis, Management and Prevention of (GOLD Classification of Airflow Limitation) (D) >2 (A) (B) mmrc 0-1 CAT < 10 mmrc > 2 CAT > 10 Symptoms Risk (C) (Exacerbation history) 4 Hospitalization Risk Combined Assessment

25 Phenotype: a single or combination of disease attributes that describe differences between individuals with as they relate to clinically meaningful outcomes: symptoms, exacerbations, response to therapy, rate of disease progression, or death Patients with often present with comorbid diseases, including cardiovascular disease, metabolic syndrome, osteoporosis, depression, and skeletal muscle wasting and dysfunction

26 Exacerbations and phenotypes Gene study. Han MK et al. Radiology 201

27 Exacerbations and phenotypes Nishimura M et al. Am J Resp Crit Care Med 2012

28 Phenotypes CT1 and CT2 classification versus exacerbation Exacerbations Frequency Exacerbation severity Not frequent: <2 /year Mild: treated at home Frequent: 2 /year Severe: emergency room or hosptalized 68% 32% 23 % 77% 18% Clinical manifestation 58% 24% Dyspnoea (D) Sputum (S) Dyspnoea + sputum (D+S) Bigazzi F et al,european Respiratory Journal Sep 2014, 44 (Suppl 58) P571

29 Phenotype CT1 CT1 and CT2 classification versus exacerbations ns ns <2 Severity CT2 Phenotypes ns 2 p<0.01 mild ns severe p<0.05 D ns S D+S ns p<0.01 p<0.01

30 Results 1/3 are frequent exacerbators Exacerbations Frequency at 3-year follow-up 1/16 have severe exacerbations Exacerbation severity at 3-year follow-up Not frequent: <2 /year Mild: treated at home Frequent: 2 /year Severe: emergency room or hosptalized 68% 32% 23 % 77% 18% Clinical manifestation 58% 24% Dyspnoea (D) Sputum (S) Dyspnoea + sputum Bigazzi F et al,european(d+s) Respiratory Journal (Suppl),on line first October 2016,

31 Conclusions Exacerbations are an index of clinical and functional impairement in Exacerbation frequency and severity are not related to predominant phenotype as assed by quantitative CT while could be considered as an index of disease severity The so called frequent exacerbator and severe exacerbator are not stable phenotypes and these clinical caracteristics cannot be taken into account to personalize therapy in patients with

32 Phenotype: a single or combination of disease attributes that describe differences between individuals with as they relate to clinically meaningful outcomes: symptoms, exacerbations, response to therapy, rate of disease progression, or death Patients with often present with comorbid diseases, including cardiovascular disease, metabolic syndrome, osteoporosis, depression, and skeletal muscle wasting and dysfunction

33 FEV1 decline Nishimura M et al. Am J Resp Crit Care Med 2012

34 FEV1 decline Nishimura M et al. Am J Resp Crit Care Med 2012

35 Phenotype: a single or combination of disease attributes that describe differences between individuals with as they relate to clinically meaningful outcomes: symptoms, exacerbations, response to therapy, rate of disease progression, or death Patients with often present with comorbid diseases, including cardiovascular disease, metabolic syndrome, osteoporosis, depression, and skeletal muscle wasting and dysfunction

36

37 BPCO

38 Prevalence of comorbidities according to predominant Phenotype and Severity of Idiopathic arterial hypertension (IAH), Ischemic heart disease (IHD), Heart failure (HF) Peripheral vascular disease (PVD), Diabetes (D), Osteoporosis (O) Anxious depressive syndrome (ADS) Camiciottoli G et al, Intern. J. 2016; 11:

39 Prevalence of comorbidities according to predominant Phenotype and Severity of Camiciottoli G et al, Intern. J. 2016; 11:

40 Prevalence of comorbidities according to predominant Phenotype and Severity of Camiciottoli G et al, Intern. J. 2016; 11:

41 Prevalence of comorbidities according to predominant Phenotype and Severity of C D A B A+C B+D Camiciottoli G et al, Intern. J. 2016; 11:

42 Prevalence of comorbidities according to predominant Phenotype and Severity of A+B C D A B C+D C+D Camiciottoli G et al, Intern. J. 2016; 11:

43 Prevalence of comorbidities according to predominant Phenotype and Severity of Camiciottoli G et al, Intern. J. 2016; 11:

44 Prevalence of comorbidities according to predominant Phenotype and Severity of Camiciottoli G et al, Intern. J. 2016; 11:

45 Phenotypes D 4 Risk A B (C) (D) (B) 0 mmrc 0-1 CAT < 10 mmrc > 2 CAT > 10 Symptoms Purulent sputum FEV1/VC TLC% FRC% DLCO% >2 1 (A) mmrc/cat FEV1% Exacerbation history Risk (Exacerbation history) Hospitalization C (GOLD Classification of Airflow Limitation) CT classification versus GOLD 2015 classification

46 Phenotypes GOLD D FEV1 19%, FEV1/VC 26, TLC 151%, RV 312%, RV/TLC 79% FRC 132%, DLCO 19% Absent sputum mmrc 4 CAT20 Hospitalized FEV1 50%, FEV1/VC 63, TLC 83%, RV 102%, RV/TLC 43% FRC 90%, DLCO 77% Purulent sputum Pheripheral oedema mmrc 2 CAT20 Hospitalized

47 Phenotypes classification versus CT2= ( xct FEV1/VC) + (0.775 x purulent sputum*) + (0.013 x FRC%) Comorbidities CT1= ( x DLCO% ) + ( x purulent sputum*) + (0.011 x TLC%)

48 severity Personalized therapy ICS + LABA+ LAMA+ PDE4Inh LABA + LAMA ICS + LAMA and/or LABA LAMA and/or LABA Chronic bronchitis/bronchiolitis Emphysema

49 Personalized medicine Lancet 2015

50 La terapia personalizzata della BPCO La terapia della BPCO non dovrebbe basarsi soltanto sui sintomi, la frequenza di riacutizzazioni ed il FEV1. Ciascun paziente dovrebbe essere sottoposto ad una valutazione clinica e funzionale completa allo scopo di identificare il meccanismo fisiopatologico predominante alla base dell ostruzione. Tale identificazione è essenziale per indirizzare la terapia alle differenti presentazioni cliniche