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
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:
COPD Phenotypes COPD Phenotypes Small Airways Disease Parenchymal Destruction • Airway infmammation • Airway fjbrosis, luminal plugs • Loss of alveolar attachments • Increased airway resistance • Decrease of elastic recoil Airfmow limitation • Both mechanisms concur to determine the overall severity of COPD • Their relative predominance determines the clinical phenotype of COPD
COPD Phenotypes COPD Phenotypes
COPD Phenotypes COPD Phenotypes
COPD Phenotypes COPD Phenotypes
COPD Phenotypes COPD Phenotypes
COPD Treatment according to severity COPD Treatment according to severity «I find it a step backward to grade the «I find it a step backward to grade the severity of COPD solely by the FEV1. COPD severity of COPD solely by the FEV1. COPD consists of two (or more) separate diseases, consists of two (or more) separate diseases, chronic bronchitis and emphysema. Each of chronic bronchitis and emphysema. Each of these has its own pathophysiology and these has its own pathophysiology and therefore management. To lump them therefore management. To lump them together is misleading.» together is misleading.» John B West. Am J Respir Crit Care Med John B West. Am J Respir Crit Care Med 2013 2013
COPD COPD Phenotypes Phenotypes Beyond airfmow limitation: another look at Beyond airfmow limitation: another look at COPD COPD M.Pistolesi Thorax January 2009 Vol 64 No 1 M.Pistolesi Thorax January 2009 Vol 64 No 1 • Regardless of expiratory airfmow limitation, the difgerent pathological changes seen in vivo by HRCT are brought by people with difgerent body habits • The words ‘‘expiratory airfmow limitation’’ expresses our present inaccuracy in difgerentiating increased airway resistance from increased lung compliance • Let us jump over the hindering barrier of airfmow limitation and explore the COPD world beyond
COPD Phenotypes COPD Phenotypes James C Hogg • “ Progress toward specifjc treatments for COPD might be accelerated by moving beyond measurements of airfmow limitation to the precise diagnosis of the specifjc targets responsible for the airfmow 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.”
COPD Phenotypes COPD Phenotypes Quantitative CT • Mean Lung attenuation • % area with attenuation values below a predetermine threshold • Bronchial wall thickness • Cross sectional area of blood vessels
Phenotypes COPD Phenotypes COPD AWT-Pi10 %LAA-950 AWT-Pi10 %LAA-950 (mm) (mm) Vida Diagnostics, Coralville, Iowa, Vida Diagnostics, Coralville, Iowa, http://www.vidadiagnostics.com/ http://www.vidadiagnostics.com/
Phenotypes COPD Phenotypes COPD n=100 learning set (mm) Principal Component Analysis Camiciottoli G, et al European Respiratory Journal Sep 2013, 42 (3) 626-635
Phenotypes COPD Phenotypes COPD Principal Component Analysis CT2 is proportional severity to the sum of the original variables (%LAA-950 plus AWT-Pi10) and refmects then the overall CT severity phenotype of COPD CT1 is proportional to the difgerence of the original variables (%LAA-950 minus AWT-Pi10) and refmects then the prevalent mechanism of airfmow obstruction (airways or emphysema CT phenotype)
Phenotypes COPD Phenotypes COPD Predictive models of CT1 and CT2 by Predictive models of CT1 and CT2 by multivariate analysis of clinical and pulmonary multivariate analysis of clinical and pulmonary function variables function variables n=100 Predictors Coefficients R Prediction errors mean mode CT1 DL CO % -0.018 -0.580 0.6 6.7% 2.3% purulent phenotyp sputum 0.011 4 e TLC% 0.324 intercept CT2 FEV 1 /VC -0.030 0.775 0.7 6.2% 2.1% purulent severity 0.013 7 sputum FRC% -0.575 The models derived from the learning set of 100 patients were ten fold intercept cross-validated and trained to estimate CT1 and CT2 in the prospective set of 373 patients.
COPD severity and phenotype Prospective validation COPD severity and phenotype Prospective validation CT1= (-0.018 x DLCO% ) + (-0.580 x purulent sputum*) + (0.011 x TLC%) + 0.324 C D CT2= (-0.030 x FEV1/VC) + (0.775 x purulent sputum*) + (0.013 x FRC%) - 0.575 • Sputum purulence • FEV 1 /VC severity • TLC% • FRC% • DLCO% n=373 n=373 phenotype testing set testing set A B (patients who did (patients who did not undergo CT) not undergo CT)
COPD severity and phenotype Prospective validation COPD severity and phenotype Prospective validation n=373 n=373 C D testing set testing set n=80 n=73 very severe FEV1/VC: 45% FEV1/VC: 36% FRC: 132% FRC: 162% DL CO : 78% DL CO : 49% severe chronic/ chronic/non absent/ purulen purulent occasional t 0.07 0.30 -0.41 moderate n=77 n=143 FEV1/VC: 52% FEV1/VC: 60% FRC: 118% FRC: 100% mild DL CO : 61% DL CO : 88% A B
COPD Phenotypes COPD Phenotypes CT classifjcation versus GOLD 2015 classifjcation (GOLD Classification of Airflow Limitation ) C D 4 H (C) o ( (D) E s > 2 p x i a 3 t a c l e i Risk z r b a R a t i i o t s i o n k n 1 h i s 2 t (A) o r (B) y ) 0 1 A B mMRC 0-1 mMRC > 2 CAT < 10 CAT > 10 Symptoms • Purulent sputum • mMRC/CAT • FEV 1 /VC • FEV 1 % • TLC% • FRC% • Exacerbation history • DL CO %
Global Strategy for Diagnosis, Management and Prevention of COPD Combined COPD Assessment (GOLD Classification of Airflow Limitation) ( 4 H E o s x (C) (D) > 2 p a i t c a l e i z 3 Risk a r b t i o a n t i o Risk n h 2 i s (A) 1 t (B) o r y ) 1 mMRC > 2 mMRC 0-1 CAT > 10 CAT < 10 Symptoms
Global Strategy for Diagnosis, Management and Prevention of COPD Manage Stable COPD: 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 LAMA SAMA prn or A or LABA Theophylline SABA prn or SABA and SAMA LAMA SABA and/or SAMA B or LAMA and LABA Theophylline LABA ICS + LABA PDE4-inh. or C LAMA and LABA SABA and/ or SAMA LAMA Theophylline ICS and LAMA or ICS + LABA ICS + LABA and LAMA or C arbocysteine and/or D ICS+LABA and PDE4-inh. or SABA and/ or SAMA LAMA LAMA and LABA or Theophylline LAMA and PDE4-inh .
Phenotype: a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes: symptoms, exacerbations, response to therapy, rate of disease progression, or death Patients with COPD often present with comorbid diseases, including cardiovascular disease, metabolic syndrome, osteoporosis, depression, and skeletal muscle wasting and dysfunction
Global Strategy for Diagnosis, Management and Prevention of COPD Combined COPD Assessment (GOLD Classification of Airflow Limitation) ( 4 H E o s x (C) (D) > 2 p a i t c a l e i z 3 Risk a r b t i o a n t i o Risk n h 2 i s (A) 1 t (B) o r y ) 1 mMRC > 2 mMRC 0-1 CAT > 10 CAT < 10 Symptoms
65% 35% 12% 88% Price BD et al. Inter J COPD 2014
Global Strategy for Diagnosis, Management and Prevention of COPD Combined COPD Assessment (GOLD Classification of Airflow Limitation) ( 4 H E o s x (C) (D) > 2 p a i t c a l e i z 3 Risk a r b t i o a n t i o Risk n h 2 i s (A) 1 t (B) o r y ) 1 mMRC > 2 mMRC 0-1 CAT > 10 CAT < 10 Symptoms
Phenotype: a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes: symptoms, exacerbations, response to therapy, rate of disease progression, or death Patients with COPD often present with comorbid diseases, including cardiovascular disease, metabolic syndrome, osteoporosis, depression, and skeletal muscle wasting and dysfunction
COPD Exacerbations and phenotypes COPD Exacerbations and phenotypes COPDGene study. Han MK et al. Radiology 201
COPD Exacerbations and phenotypes COPD Exacerbations and phenotypes Nishimura M et al. Am J Resp Crit Care Med 2012
COPD Phenotypes COPD Phenotypes CT1 and CT2 classifjcation versus exacerbation Exacerbations Frequency Exacerbation severity Not frequent: <2 /year Mild: treated at home Frequent: ≥2 /year Severe: emergency room or hosptalized 32% 68% 23 % 77% 18% Clinical manifestation Dyspnoea (D) 24% 58% Sputum (S) Dyspnoea + sputum (D+S) Bigazzi F et al,European Respiratory Journal Sep 2014, 44 (Suppl 58) P571
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