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BPCO: dalle novit patogenetiche alla terapia Gianna Camiciottoli Dip. Di Scienze Biomediche, Sperimentali e Cliniche Mario Serio Universit degli Studi di Firenze Firenze, 11 novembre 2016 Conflict of interest disclosure X I have no

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Gianna Camiciottoli

  • Dip. Di Scienze Biomediche, Sperimentali e Cliniche “Mario

Serio” Università degli Studi di Firenze

BPCO: dalle novità patogenetiche alla terapia

Firenze, 11 novembre 2016

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SLIDE 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:

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SLIDE 3

Small Airways Disease

  • Airway infmammation
  • Airway fjbrosis, luminal plugs
  • Increased airway resistance

Parenchymal Destruction

  • Loss of alveolar attachments
  • 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 COPD Phenotypes Phenotypes

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SLIDE 4

COPD COPD Phenotypes Phenotypes

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SLIDE 5

COPD COPD Phenotypes Phenotypes

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SLIDE 6

COPD COPD Phenotypes Phenotypes

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SLIDE 7

COPD COPD Phenotypes Phenotypes

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SLIDE 8

COPD COPD

«I find it a step backward to grade the severity of COPD solely by the FEV1. COPD 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 2013

«I find it a step backward to grade the severity of COPD solely by the FEV1. COPD 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 2013

Treatment according to severity Treatment according to severity

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SLIDE 9

COPD COPD Phenotypes Phenotypes

  • The words ‘‘expiratory airfmow limitation’’ expresses
  • ur present inaccuracy in difgerentiating increased

airway resistance from increased lung compliance

  • Regardless of expiratory airfmow limitation, the

difgerent pathological changes seen in vivo by HRCT are brought by people with difgerent body habits

  • Let us jump over the hindering barrier of airfmow

limitation and explore the COPD world beyond

Beyond airfmow limitation: another look at COPD M.Pistolesi Thorax January 2009 Vol 64 No 1 Beyond airfmow limitation: another look at COPD M.Pistolesi Thorax January 2009 Vol 64 No 1

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SLIDE 10

COPD COPD

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.”

Phenotypes Phenotypes

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SLIDE 11

COPD COPD Phenotypes Phenotypes

  • Mean Lung attenuation
  • % area with attenuation values below a predetermine

threshold

  • Bronchial wall thickness
  • Cross sectional area of blood vessels

Quantitative CT

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SLIDE 12

%LAA-950 %LAA-950 AWT-Pi10 (mm) AWT-Pi10 (mm)

Vida Diagnostics, Coralville, Iowa, http://www.vidadiagnostics.com/ Vida Diagnostics, Coralville, Iowa, http://www.vidadiagnostics.com/

Phenotypes Phenotypes COPD COPD

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SLIDE 13

n=100

learning set

Principal Component Analysis

(mm) COPD COPD Phenotypes Phenotypes

Camiciottoli G, et al European Respiratory Journal Sep 2013, 42 (3) 626-635

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SLIDE 14

CT1 is proportional to the difgerence of the

  • riginal variables (%LAA-950 minus AWT-Pi10)

and refmects then the prevalent mechanism of airfmow obstruction (airways or emphysema CT phenotype) CT2 is proportional to the sum of the

  • riginal

variables (%LAA-950 plus AWT-Pi10) and refmects then the

  • verall CT severity
  • f COPD

Principal Component Analysis phenotype severity

COPD COPD Phenotypes Phenotypes

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SLIDE 15

n=100 Predictors Coefficients R Prediction errors mean mode

CT1

phenotyp e

DLCO%

purulent sputum

TLC%

intercept

  • 0.018
  • 0.580

0.011 0.324 0.6 4 6.7% 2.3%

CT2

severity

FEV1/VC

purulent sputum

FRC%

intercept

  • 0.030

0.775 0.013

  • 0.575

0.7 7 6.2% 2.1% Predictive models of CT1 and CT2 by multivariate analysis of clinical and pulmonary function variables Predictive models of CT1 and CT2 by multivariate analysis of clinical and pulmonary function variables

The models derived from the learning set of 100 patients were ten fold cross-validated and trained to estimate CT1 and CT2 in the prospective set

  • f 373 patients.

COPD COPD Phenotypes Phenotypes

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SLIDE 16

Prospective validation Prospective validation

n=373

testing set (patients who did not undergo CT)

n=373

testing set (patients who did not undergo CT) COPD severity and phenotype COPD severity and phenotype

A B C D

CT1= (-0.018 x DLCO% ) + (-0.580 x purulent sputum*) + (0.011 x TLC%) + 0.324 CT2= (-0.030 x FEV1/VC) + (0.775 x purulent sputum*) + (0.013 x FRC%) - 0.575

  • Sputum

purulence

  • FEV1/VC
  • TLC%
  • FRC%
  • DLCO%

severity phenotype

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SLIDE 17

Prospective validation Prospective validation COPD severity and phenotype COPD severity and phenotype

C D A B

n=373

testing set

n=373

testing set

n=80 FEV1/VC: 45% FRC: 132% DLCO: 78% n=73 FEV1/VC: 36% FRC: 162% DLCO: 49% n=143 FEV1/VC: 60% FRC: 100% DLCO: 88% n=77 FEV1/VC: 52% FRC: 118% DLCO: 61%

absent/

  • ccasional

0.30 chronic/ purulen t

  • 0.41

chronic/non purulent 0.07

mild severe moderate very severe

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SLIDE 18

Risk

(GOLD Classification of Airflow Limitation)

R i s k ( E x a c e r b a t i

  • n

h i s t

  • r

y ) H

  • s

p i t a l i z a t i

  • n

> 2 1

(C) (D)

(A)

(B)

mMRC 0-1 CAT < 10

4 3 2 1

mMRC > 2 CAT > 10

Symptoms

C A B

  • Purulent sputum
  • FEV1/VC
  • TLC%
  • FRC%
  • DLCO%

D

  • mMRC/CAT
  • FEV1%
  • Exacerbation history

COPD COPD Phenotypes Phenotypes

CT classifjcation versus GOLD 2015 classifjcation

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SLIDE 19

Risk

(GOLD Classification of Airflow Limitation)

Risk

( E x a c e r b a t i

  • n

h i s t

  • r

y )

> 2 1

(C) (D)

(A)

(B)

mMRC 0-1 CAT < 10

4 3 2 1

mMRC > 2 CAT > 10

Symptoms

Global Strategy for Diagnosis, Management and Prevention

  • f COPD

Combined COPD Assessment

H

  • s

p i t a l i z a t i

  • n
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SLIDE 20

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 A SAMA prn

  • r

SABA prn LAMA

  • r

LABA

  • r

SABA and SAMA Theophylline B LAMA

  • r

LABA LAMA and LABA SABA and/or SAMA Theophylline C ICS + LABA

  • r

LAMA LAMA and LABA PDE4-inh. SABA and/or SAMA Theophylline D ICS + LABA and/or LAMA 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

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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

  • ften

present with comorbid diseases, including cardiovascular disease, metabolic syndrome, osteoporosis, depression, and skeletal muscle wasting and dysfunction

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SLIDE 22

Risk

(GOLD Classification of Airflow Limitation)

Risk

( E x a c e r b a t i

  • n

h i s t

  • r

y )

> 2 1

(C) (D)

(A)

(B)

mMRC 0-1 CAT < 10

4 3 2 1

mMRC > 2 CAT > 10

Symptoms

Global Strategy for Diagnosis, Management and Prevention

  • f COPD

Combined COPD Assessment

H

  • s

p i t a l i z a t i

  • n
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SLIDE 23

Price BD et al. Inter J COPD 2014

65% 35% 12% 88%

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SLIDE 24

Risk

(GOLD Classification of Airflow Limitation)

Risk

( E x a c e r b a t i

  • n

h i s t

  • r

y )

> 2 1

(C) (D)

(A)

(B)

mMRC 0-1 CAT < 10

4 3 2 1

mMRC > 2 CAT > 10

Symptoms

Global Strategy for Diagnosis, Management and Prevention

  • f COPD

Combined COPD Assessment

H

  • s

p i t a l i z a t i

  • n
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SLIDE 25

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

  • ften

present with comorbid diseases, including cardiovascular disease, metabolic syndrome, osteoporosis, depression, and skeletal muscle wasting and dysfunction

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SLIDE 26

Exacerbations and phenotypes Exacerbations and phenotypes COPD COPD COPDGene study. Han MK et al. Radiology 201

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SLIDE 27

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

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SLIDE 28

COPD COPD Phenotypes Phenotypes Exacerbation severity

Mild: treated at home Severe: emergency room or hosptalized

23 %

Clinical manifestation

  • Dyspnoea (D)
  • Sputum (S)
  • Dyspnoea

+ sputum (D+S) 58% 18% 24% 77%

Exacerbations Frequency

Not frequent: <2 /year Frequent: ≥2 /year

68% 32%

CT1 and CT2 classifjcation versus exacerbation

Bigazzi F et al,European Respiratory Journal Sep 2014, 44 (Suppl 58) P571

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SLIDE 29

CT1 and CT2 classifjcation versus exacerbations

COPD COPD Phenotypes Phenotypes

Phenotype CT1 Severity CT2

<2 ≥2 mild severe D+S D S

COPD COPD

ns ns ns ns ns p<0.01 p<0.01 p<0.01 p<0.05 ns

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SLIDE 30

Exacerbation severity

Mild: treated at home Severe: emergency room or hosptalized

23 %

Clinical manifestation

  • Dyspnoea (D)
  • Sputum (S)
  • Dyspnoea

+ sputum (D+S) 58% 18% 24% 77%

Exacerbations Frequency

Not frequent: <2 /year Frequent: ≥2 /year

68% 32%

Bigazzi F et al,European Respiratory Journal (Suppl),on line first October 2016,

1/3 are frequent exacerbators at 3-year follow-up 1/16 have severe exacerbations at 3-year follow-up

Results

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SLIDE 31
  • Exacerbations are an index of clinical and functional

impairement in COPD

  • 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 COPD

Conclusions Conclusions

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SLIDE 32

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

  • ften

present with comorbid diseases, including cardiovascular disease, metabolic syndrome, osteoporosis, depression, and skeletal muscle wasting and dysfunction

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SLIDE 33

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

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SLIDE 34

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

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SLIDE 35

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

  • ften

present with comorbid diseases, including cardiovascular disease, metabolic syndrome, osteoporosis, depression, and skeletal muscle wasting and dysfunction

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SLIDE 36
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SLIDE 37

BPCO

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SLIDE 38
  • Idiopathic arterial hypertension (IAH),
  • Ischemic heart disease (IHD),
  • Heart failure (HF)
  • Peripheral vascular disease (PVD),
  • Diabetes (D),
  • Osteoporosis (O)
  • Anxious depressive syndrome (ADS)

Prevalence of comorbidities according to predominant Phenotype and Severity of COPD

Camiciottoli G et al, Intern. J. COPD 2016; 11: 2229-2236

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SLIDE 39

Prevalence of comorbidities according to predominant Phenotype and Severity of COPD

Camiciottoli G et al, Intern. J. COPD 2016; 11: 2229-2236

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SLIDE 40

Prevalence of comorbidities according to predominant Phenotype and Severity of COPD

Camiciottoli G et al, Intern. J. COPD 2016; 11: 2229-2236

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SLIDE 41

Prevalence of comorbidities according to predominant Phenotype and Severity of COPD

Camiciottoli G et al, Intern. J. COPD 2016; 11: 2229-2236

A B C D

B+D A+C

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SLIDE 42

Prevalence of comorbidities according to predominant Phenotype and Severity of COPD

Camiciottoli G et al, Intern. J. COPD 2016; 11: 2229-2236

A B C D

C+D A+B C+D

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SLIDE 43

Prevalence of comorbidities according to predominant Phenotype and Severity of COPD

Camiciottoli G et al, Intern. J. COPD 2016; 11: 2229-2236

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SLIDE 44

Prevalence of comorbidities according to predominant Phenotype and Severity of COPD

Camiciottoli G et al, Intern. J. COPD 2016; 11: 2229-2236

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SLIDE 45

Risk

(GOLD Classification of Airflow Limitation)

R i s k ( E x a c e r b a t i

  • n

h i s t

  • r

y ) H

  • s

p i t a l i z a t i

  • n

> 2 1

(C) (D)

(A)

(B)

mMRC 0-1 CAT < 10

4 3 2 1

mMRC > 2 CAT > 10

Symptoms

C A B

  • Purulent sputum
  • FEV1/VC
  • TLC%
  • FRC%
  • DLCO%

D

  • mMRC/CAT
  • FEV1%
  • Exacerbation history

COPD COPD Phenotypes Phenotypes

CT classifjcation versus GOLD 2015 classifjcation

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SLIDE 46

COPD COPD Phenotypes Phenotypes

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

GOLD D

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SLIDE 47

CT classifjcation versus Comorbidities

COPD COPD Phenotypes Phenotypes

CT1= (-0.018 x DLCO% ) + (-0.580 x purulent sputum*) + (0.011 x TLC%) + 0.324 CT2= (-0.030 x FEV1/VC) + (0.775 x purulent sputum*) + (0.013 x FRC%) - 0.5

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SLIDE 48

Chronic bronchitis/Bronchiolitis Emphysema

ICS + LABA+ LAMA+ PDE4Inh ICS + LAMA and/or LABA

severity

LAMA and/or LABA LABA + LAMA

Personalized therapy Personalized therapy COPD COPD

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SLIDE 49

COPD COPD Personalized medicine Personalized medicine

Lancet 2015

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SLIDE 50
  • 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 identifjcare il meccanismo fjsiopatologico predominante alla base dell’ostruzione.

  • T

ale identifjcazione è essenziale per indirizzare la terapia alle difgerenti presentazioni cliniche di ciascun paziente.

La terapia personalizzata della BPCO La terapia personalizzata della BPCO