aggiornamento linee guida gina 2003 1/4/2004 sala congressi hotel michelangelo sassuolo prof....

Aggiornamento Linee Guida GINA 2003

1/4/2004Sala Congressi Hotel Michelangelo

Sassuolo

Prof. Leonardo M. FabbriClinica di Malattie dell’Apparato Respiratorio

Università degli Studi di Modena e Reggio Emilia, Modena

ATTUALITA’ ED EVOLUZIONE NELLA GESTIONE CLINICA DELL’ASMA

GGloballobalININitiative foritiative forAAsthma 2003sthma 2003

www.ginasthma.comwww.ginasthma.com

Executive CommitteeExecutive CommitteeChair: Paul O’Byrne, MDChair: Paul O’Byrne, MDExecutive CommitteeExecutive CommitteeChair: Paul O’Byrne, MDChair: Paul O’Byrne, MD

Dissemination Dissemination CommitteeCommittee

Chair: Tan Chair: Tan Wan-ChengWan-Cheng, MD, MD

GINA StructureGINA Structure

Science Science CommitteeCommittee

Chair: Eric Bateman, MDChair: Eric Bateman, MD

GINA reports prepared during workshops conducted in cooperation with GINA reports prepared during workshops conducted in cooperation with the U.S. National Heart, Lung, and Blood Institute, NIH and the World the U.S. National Heart, Lung, and Blood Institute, NIH and the World

Health Organization.Health Organization.

GINA reports prepared during workshops conducted in cooperation with GINA reports prepared during workshops conducted in cooperation with the U.S. National Heart, Lung, and Blood Institute, NIH and the World the U.S. National Heart, Lung, and Blood Institute, NIH and the World

Health Organization.Health Organization.

G G lobal Initiative for Chroniclobal Initiative for Chronic

O O bstructivebstructive

L L ungung

D D iseaseisease

www.goldcopd.comwww.goldcopd.com

Global Initiative on Obstructive Global Initiative on Obstructive Lung DiseaseLung Disease

EXECUTIVE COMMITTEEEXECUTIVE COMMITTEEChair: Romain PauwelsChair: Romain Pauwels

S.Buist, USS.Buist, USP.Calverley, UKP.Calverley, UKB.Celli, USB.Celli, USL.Fabbri, ItalyL.Fabbri, ItalyY.Fukuchi, JapanY.Fukuchi, JapanL.Grouse, USL.Grouse, USS.Hurd, USS.Hurd, USC.Jenkins, AustraliaC.Jenkins, Australia

C.Lenfant, USC.Lenfant, USJ.Luna, GuatemalaJ.Luna, GuatemalaW.McNee, UKW.McNee, UKE.Nizankowska-Mogilnicka, E.Nizankowska-Mogilnicka,

PolandPolandK.Rabe, NLK.Rabe, NLR.Rodriguez Roisin, ER.Rodriguez Roisin, EP.Van Der Molen, NLP.Van Der Molen, NLN.Zhong, ChinaN.Zhong, China

Global Initiative on Obstructive Lung DiseaseGlobal Initiative on Obstructive Lung Disease

SCIENTIFIC COMMITTEESCIENTIFIC COMMITTEEChair: Leonardo M. FabbriChair: Leonardo M. Fabbri

P. Barnes, UKP. Barnes, UKS. Buist, USS. Buist, US

P. Calverley, UKP. Calverley, UKY. Fukuchi, GiapponeY. Fukuchi, Giappone

W. McNee, UKW. McNee, UKR. Pauwels, BelgiumR. Pauwels, Belgium

K. Rabe, GermanyK. Rabe, GermanyRoberto Rodrigues Roisin, SpainRoberto Rodrigues Roisin, Spain

N. Zielinski, PolandN. Zielinski, Poland

Third Quarter, 2000: Publication Date from 2000/07/01 to 2000/09/30Search COPD NOT ASTHMA: All Fields.

Limits: All Adult: 19+ years, only items with abstracts, English, Clinical Trial, Human Sort by: Authors (20 citations)

No star = Clinical Trial, One * = Randomized Clinical Trials (15 citations)Two ** = Randomized Clinical Trials and Core Clinical Journals (7 citations)

ASSIGNMENTS, REVIEWER, PUBLICATION NUMBER

Peter Barnes, 8Sonia Buist, 16, 17

Leo Fabbri, 14, 20, 10, 19Yoshi Fukuchi, 5, 7, 10, 12, 19, 20

Bill MacNee, 1, 5, 8, 15Romain Pauwels, 16, 17

Klaus Rabe, 2, 3, 4, 11, 14Roberto Rodriguez-Roisin, 2, 3, 4, 11, 13, 18

Jan Zielinski, 1, 7, 10, 15, 19

GOLD REPORT – Section 4Page 32, left column, end of para 2,

ORIGINAL TEXT…. tract inflammation57-61. It is likely that

indoor air pollution derived from the burning of biomass fuels will prove to

have similar effects.

SUGGESTED REVISION…. tract inflammation57-61. It is likely that indoor

air pollution derived from the burning of biomass fuels will prove to have similar effects. Also bacterial colonization

contributes to the airway inflammation in patients with stable COPD. The

degree of inflammation also relating to the bacterial load and to the bacterial

species (Hill at et al, 2000). Consequences of such colonization

and enhanced inflammation on morbidity and lung function is not clear

Hill AT, Campbell EJ, Hill SL, Bayley DL, Stockley RA. Association between airway bacterial load and markers of airway inflammation in patients with stable chronic

bronchitis. Am J Med 2000 Sep;109(4):288-95

PATIENTS AT HIGH RISK OF DEATH PATIENTS AT HIGH RISK OF DEATH AFTER LUNG-VOLUME–REDUCTION SURGERYAFTER LUNG-VOLUME–REDUCTION SURGERY

N Engl J Med 2001; 345: to be published on October 11N Engl J Med 2001; 345: to be published on October 11

National Emphysema Treatment Trial Research GroupNational Emphysema Treatment Trial Research Group

New Engl J Med 2001; to be published next Oct 11New Engl J Med 2001; to be published next Oct 11

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 6 12 18 24 30 36 42

Pro

bab

ility

of

dea

thP

rob

abili

ty o

f d

eath

Months since RandomizationMonths since Randomization

Medical therapyMedical therapy

SurgerySurgery

Patients at High Risk of Death after Patients at High Risk of Death after Lung-Volume-Reduction SurgeryLung-Volume-Reduction Surgery

P < 0.001P < 0.001

NATIONAL EMPHISEMA TREATMENT TRIAL RESEARCH GROUPNATIONAL EMPHISEMA TREATMENT TRIAL RESEARCH GROUP

Levels of evidenceLevels of evidenceLevelLevel SourceSource

AA Randomized clinical trials Randomized clinical trials (RCT). Several, consistent(RCT). Several, consistent

BB Randomized clinical trials Randomized clinical trials (RCT). Few, inconsistent(RCT). Few, inconsistent

CC Non-randomized clinical Non-randomized clinical trials. Small and/or trials. Small and/or observational studiesobservational studies

DD Opinion of expertsOpinion of experts

INSTITUTE OF SCIENTIFIC INSTITUTE OF SCIENTIFIC INFORMATION (ISI)INFORMATION (ISI)

ISI JOURNAL CITATION REPORTSISI JOURNAL CITATION REPORTShttp://jcrweb.com/http://jcrweb.com/

Impact Factor Impact Factor Number of Citations in 2002Number of Citations in 2002Number of articles 2000-2001Number of articles 2000-2001

IMPACT FACTOR 2002IMPACT FACTOR 2002

Medicine, General & Internal:Medicine, General & Internal:

1) New Engl J Med1) New Engl J Med 31.7431.742) JAMA – J Am Med Assoc2) JAMA – J Am Med Assoc 16.7816.783) Lancet3) Lancet 15.3915.394) Ann Intern Med 4) Ann Intern Med 11.4111.415) Annu Rev Med5) Annu Rev Med 7.95 7.956) Brit Med J 6) Brit Med J 7.58 7.587) Arch Intern Med7) Arch Intern Med 6.74 6.748) Medicine8) Medicine 5.18 5.18

IMPACT FACTOR 2002IMPACT FACTOR 2002

Respiratory SystemRespiratory System

1) Am J Resp Crit Care1) Am J Resp Crit Care 6.566.562) Am J Resp Cell Mol2) Am J Resp Cell Mol 4.174.173) Thorax3) Thorax 4.084.084) Am J Physiol-Lung C4) Am J Physiol-Lung C 3.903.905) Chest5) Chest 2.972.976) Eur Respir J6) Eur Respir J 2.942.947) J Thorac Cardiov Sur7) J Thorac Cardiov Sur 2.842.848) Sarcoidosis Vasc Dif8) Sarcoidosis Vasc Dif 2.832.83

Le linee guida GINA in Italia:passare dalla teoria ai fatti

Prof. L.M. Fabbri

Processo di aggiornamento delle linee guida

Trattamento farmacologico: 2003-2004

Asma grave/BPCO

Nuovi farmaci antiasmatici

GGloballobalININitiative foritiative forAAsthma 2003sthma 2003

www.ginasthma.comwww.ginasthma.com

Executive CommitteeExecutive CommitteeChair: Paul O’Byrne, MDChair: Paul O’Byrne, MDExecutive CommitteeExecutive CommitteeChair: Paul O’Byrne, MDChair: Paul O’Byrne, MD

Dissemination Dissemination CommitteeCommittee

Chair: Tan Chair: Tan Chen WanChen Wan, MD, MD

GINA StructureGINA Structure

Science Science CommitteeCommittee

Chair: Eric Bateman, MDChair: Eric Bateman, MD

GINA reports prepared during workshops conducted in cooperation with the U.S. National Heart, Lung, and Blood Institute, NIH and the World

Health Organization.

GINA reports prepared during workshops conducted in cooperation with the U.S. National Heart, Lung, and Blood Institute, NIH and the World

Health Organization.

Science CommitteeScience CommitteeScience CommitteeScience Committee

E. Bateman, E. Bateman, South AfricaSouth Africa, , ChairChair

P. Barnes, P. Barnes, UKUK S. Holgate, S. Holgate, UKUK

J. Bousquet, J. Bousquet, FranceFrance J. Kips, J. Kips, BelgiumBelgium

W. Busse, W. Busse, USAUSA P. O’Byrne, P. O’Byrne, CanadaCanada

J. Drazen, J. Drazen, USAUSA K. Ohta, K. Ohta, JapanJapan

M. FitzGerald, M. FitzGerald, CanadaCanada S. Pedersen, S. Pedersen, DenmarkDenmark

P. Gibson, P. Gibson, AustraliaAustralia E. von E. von Mutius,Mutius,GermanyGermany

E. Bateman, E. Bateman, South AfricaSouth Africa, , ChairChair

P. Barnes, P. Barnes, UKUK S. Holgate, S. Holgate, UKUK

J. Bousquet, J. Bousquet, FranceFrance J. Kips, J. Kips, BelgiumBelgium

W. Busse, W. Busse, USAUSA P. O’Byrne, P. O’Byrne, CanadaCanada

J. Drazen, J. Drazen, USAUSA K. Ohta, K. Ohta, JapanJapan

M. FitzGerald, M. FitzGerald, CanadaCanada S. Pedersen, S. Pedersen, DenmarkDenmark

P. Gibson, P. Gibson, AustraliaAustralia E. von E. von Mutius,Mutius,GermanyGermany


Prof. L.M. Fabbri



Asma grave/BPCO


Management of asthma:Management of asthma:updating the GINA guidelinesupdating the GINA guidelines

Systemic Systemic steroidssteroids

Ast

hm

a se

ver i

t yA

sth

ma

seve

rit y

MildMildIntermittentIntermittent

Mild Mild PersistentPersistent

Moderate Moderate PersistentPersistent

ModerateModeratePersistentPersistent(Severe?)(Severe?)SevereSevere

PersistentPersistent(Very severe?)(Very severe?)

Combination with higher Combination with higher doses inhaled corticosteroids, doses inhaled corticosteroids, theophylline, antileukotrienestheophylline, antileukotrienes

Avoidance of risk factors, immunotherapyAvoidance of risk factors, immunotherapyShort-acting beta-2 agonists as neededShort-acting beta-2 agonists as needed

Low-dose inhaled steroidsLow-dose inhaled steroids

Combination of long-acting beta2 agonists Combination of long-acting beta2 agonists with low dose inhaled steroidswith low dose inhaled steroids

Stepwise Approach to Asthma TherapyStepwise Approach to Asthma Therapy

Controlled by inhaledControlled by inhaledshort-acting beta-2 agonists prnshort-acting beta-2 agonists prn

ControllerController•• Not requiredNot required

RelieverReliever•• Inhaled beta2-agonistInhaled beta2-agonist

prn <3-4x a dayprn <3-4x a day

• • Inhaled beta2-agonist or Inhaled beta2-agonist or Cromolyn or Leukotriene Cromolyn or Leukotriene modifier prior to exercisemodifier prior to exercise or exposure to antigenor exposure to antigen

Step 1: Mild Intermittent Asthma

Avoid or Control Triggers

YearYear 11 22 33 44 55

VisitVisit

00

11 22 33 44 55

START – study outlineSTART – study outline

AdultsAdults

ChildrenChildren (6 (6––10 yrs)10 yrs)Budesonide 200 Budesonide 200 g g once dailyonce daily

+ usual + usual asthma asthma therapytherapy

Budesonide 400 Budesonide 400 g g once dailyonce daily+ usual + usual asthma asthma therapytherapy

Part BPart B

66 77 88 99 1010 1111 1212 1313 1414 1515 1616 1717 1818 1919 2020 2121 2222

Adults and Adults and CChildrenhildrenPlaceboPlacebo once daily once daily

+ usual + usual asthma asthma therapytherapy

Part APart A – Budesonide therapy – Budesonide therapyAdultsAdults

ChildrenChildren (6 (6––10 yrs)10 yrs)

Budesonide 400 Budesonide 400 g g once dailyonce daily+ usual + usual asthma asthma therapytherapy

Budesonide Budesonide 2200 00 g g once dailyonce daily+ usual + usual asthma asthma therapytherapy

Part APart A – Reference therapy – Reference therapy

Pauwels R et a. Lancet 2003; 371: 1071-1076

• Long-term, once-daily treatment Long-term, once-daily treatment with low-dose budesonide with low-dose budesonide

decreases the risk of severe decreases the risk of severe exacerbations by 44% and improves exacerbations by 44% and improves

asthma control compared with asthma control compared with placebo in patients with recent placebo in patients with recent onset, mild persistent asthma.onset, mild persistent asthma.

START START ConclusionsConclusions

Pauwels R et a. Lancet 2003; 371: 1071-1076


Controlled by low-doseControlled by low-doseinhaled steroidsinhaled steroids

ControllerController•• Daily inhaled cortico-Daily inhaled cortico-

steroid (200-500 mcg)steroid (200-500 mcg)

•• Cromolyn, Nedocromil, Cromolyn, Nedocromil,

sustained release sustained release

TheophyllineTheophylline

•• Consider LeukotrieneConsider Leukotriene

ModifiersModifiers

RelieverReliever•• Inhaled beta2-agonistInhaled beta2-agonist

prn <3-4x a dayprn <3-4x a day

• • Inhaled beta2-agonist or Inhaled beta2-agonist or Cromolyn or Leukotriene Cromolyn or Leukotriene modifier prior to exercise modifier prior to exercise or exposure to antigenor exposure to antigen

Step 2: Mild Persistent AsthmaStep 2: Mild Persistent Asthma

Avoid or Control TriggersAvoid or Control Triggers

0

2

4

6

Pre-BD 6 wk

Effects of Inhaled BeclomethasoneEffects of Inhaled BeclomethasoneDipropionate in Clinical AsthmaDipropionate in Clinical Asthma

Bronchial FunctionBronchial Function Bronchial SubmucosaBronchial Submucosa

Asthmaticsymptoms

Sev

erit

y

0,01

0,1

1

10

100

Pre-BD 6 wk

PC20 methacholine

(mg/ml)m

g/m

l

nu

mb

er o

f ce

lls/m

m2

of

sub

mu

cosa eosinophilsT lymphocytesmast cells

0

40

80

120

160

200

240

720

760

Pre-BD6 wk Pre-BD6 wk Pre-BD6 wk

Djukanovic et al, Am Rev Respir Dis 1992 Mar;145(3):669-74

JAMA 2001; 285: 2583-2593JAMA 2001; 285: 2583-2593

LONG-ACTING LONG-ACTING 2-AGONIST 2-AGONIST MONOTHERAPY MONOTHERAPY VSVS CONTINUED CONTINUED THERAPY WITH INHALED THERAPY WITH INHALED CORTICOSTEROIDS IN PATIENTS CORTICOSTEROIDS IN PATIENTS WITH PERSISTENT ASTHMAWITH PERSISTENT ASTHMAA Randomized Controlled TrialA Randomized Controlled Trial

Patients with persistent asthma well controlled by low doses of Patients with persistent asthma well controlled by low doses of triamcinolone cannot be switched to salmeterol monotherapy triamcinolone cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control.without risk of clinically significant loss of asthma control.

Lazarus SC et al.Lazarus SC et al.

0

5

10

15

20

25

30

4 8 12 16 20 24

FP 88 µg BID

MON 10 mg BID

Low-dose Fluticasone is More Effective of Low-dose Fluticasone is More Effective of Montelukast in Mild Persistent AsthmaMontelukast in Mild Persistent Asthma

Busse W et al., J Allergy Clin Immunol 2001; 107: 461-468Busse W et al., J Allergy Clin Immunol 2001; 107: 461-468

Treatment week

EndpointBaseline

Mea

n %

ch

ang

e fr

om

bas

elin

e

in F

EV

1

** *

* * * **

O’Byrne et al. Am. J. Respir. Crit. Care Med. 2001;164 1392-1397O’Byrne et al. Am. J. Respir. Crit. Care Med. 2001;164 1392-1397

Low Dose Inhaled Budesonide and Formoterol Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma . The OPTIMA in Mild Persistent Asthma . The OPTIMA

Randomized TrialRandomized Trial

Paul M. O‘Byrne, Peter J. Barnes, Roberto Rodriguez-roisin,Paul M. O‘Byrne, Peter J. Barnes, Roberto Rodriguez-roisin,

Eva Runnerstrom,Thomas Sandstrom, Klas Svensson, Eva Runnerstrom,Thomas Sandstrom, Klas Svensson,

and Anne Tattersfieldand Anne Tattersfield

Placebo

Budesonide200

Budesonide 200+ Formoterol

34/226

44/227

79/237

Time to first severe exacerbationTime to first severe exacerbationP

rop

ort

ion

Days


Rate for poorly controlled days

Rate for poorly controlled days

Placebo Budesonide200

Budesonide +Formoterol

Rate

0.00

0.05

0.10

0.150.144

0.0730.083


Mometasone furoate administered once daily Mometasone furoate administered once daily is as effective as twice-daily administration for is as effective as twice-daily administration for treatment of mild-to-moderate persistent treatment of mild-to-moderate persistent asthmaasthma

This is the first study demonstrating that a total daily dose of 400 g of mometasone furoate (MF) administered by dry powder inhaler is an effective treatment for patients with mild-to-moderate persistent asthma previously taking only 2-agonists

_________________________________________________

Kemp et al, J Allergy Clin Immunol. 2000 Sep;106(3):485-92


Controlled by inhaled steroidsControlled by inhaled steroidsplus long-acting bronchodilatorsplus long-acting bronchodilators

ControllerController

•• Add long acting broncho-Add long acting bronchodilators to low dose inhaled dilators to low dose inhaled steroidssteroids

•• Increase the dose of inhaled Increase the dose of inhaled corticosteroids 800-2,000corticosteroids 800-2,000gg

• • Add leukotriene modifiers if Add leukotriene modifiers if control is not achievedcontrol is not achieved

RelieverReliever

•• Inhaled beta2-agonist prnInhaled beta2-agonist prn <3-4x a day<3-4x a day

• • Inhaled beta2-agonist or Inhaled beta2-agonist or Cromolyn or Leukotriene Cromolyn or Leukotriene modifier prior to exercise ormodifier prior to exercise or

exposure to antigenexposure to antigen

Step 3: Moderate Persistent AsthmaStep 3: Moderate Persistent Asthma

Avoid or Control TriggersAvoid or Control Triggers

0

5

10

15

20

25

30

35

0 3 6 9 12 15 18 21

Time (weeks)

Salmeterol 50 g bid+ BDP 200 g bid

BDP 500 g bid

***

*****

*****

*p<0.05, **p<0.01, ***p<0.001 vs BDP

Addition of salmeterol to inhaled BDP is superior to increased dose of BDP in persistent asthma

Greening et al. Lancet 1994

Mea

n c

han

ge

fro

m b

asel

ine

in m

orn

ing

PE

F (

L/m

in)

BDP, beclomethasone dipropionate; ICS, inhaled corticosteroid PEF, peak expiratory flow

Weeks of treatment

Addition of salmeterol to inhaled BDP is superior to increased dose of BDP in moderate/severe asthma

0

1

2

3

4

5

6

7

8

9

10

0 2 8 16 24

Ch

ang

e in

FE

V1 (%

pre

dic

ted

)

Woolcock et al. Am J Respir Crit Care Med 1996Adapted with permission

Salmeterol 50 g bid+ BDP 500 g bid

BDP 1000 g bid

BDP, beclomethasone dipropionate

**

****

*p<0.001, **p<0.05

Pauwels RA et al., N Engl J Med 1997Pauwels RA et al., N Engl J Med 1997

Higher-dose budesonide plus formoterolLower-dose budesonide plus formoterolHigher-dose budesonideLower-dose budesonide

Changes in FEVChanges in FEV1 1 during the study during the study

90

85

80

75

-1 0 1 2 3 6 9 12

Month

FE

V1

(% o

f p

red

icte

d)

FACET

Estimates of severe exacerbation ratesEstimates of severe exacerbation rates

BUD200BUD200

h=0.91h=0.91

BUD800BUD800

h=0.46h=0.46

BUD200+FBUD200+F

h=0.67h=0.67

BUD800+FBUD800+F

h=0.34h=0.34

FORM: - 26% FORM: - 26% (p=0.014)(p=0.014)p=0.031p=0.031


BUDH:BUDH:- 49%- 49%(p<0.001)(p<0.001)

Estimates of mild exacerbation ratesEstimates of mild exacerbation rates

BUD200BUD200

h=35.4h=35.4

BUD800BUD800

h=22.3h=22.3

BUD200+FBUD200+F

h=21.3h=21.3

BUD800+FBUD800+F

h=13.4h=13.4

FORM: - 40% FORM: - 40% (p=0.001)(p=0.001) p=0.76p=0.76

FACET

BUDH:BUDH:- 37%- 37%(p<0.001)(p<0.001)


Classification of Asthma SeverityClassification of Asthma Severity

CLASSIFY SEVERITYClinical Features Before Treatment

Symptoms

STEP 4SeverePersistent

ContinuousLimited physicalactivity

Frequent≤60% predictedVariability >30%

Nighttime Symptoms PEF

STEP 3ModeratePersistent

Daily

Use 2-agonist dailyAttacks limit activity

>1 time week 60-80% predictedVariability >30%

STEP 2MildPersistent

≥1 time a weekbut <1 time a day >2times a months

≥80% predictedVariability 20-30%

STEP 1Intermittent

<1 time a week

Asymptomatic andnormal PEF betweenattacks

≤2 times a month≥80% predictedVariability <20%

One of the features of severity is sufficient to place a patient in that category

Inten

sity of treatm

ent

Inten

sity of treatm

ent

TreatmentTreatment

Management of AsthmaManagement of Asthma

Long-acting bronchodilators and/or LTRALong-acting bronchodilators and/or LTRA

Inhaled steroidsInhaled steroids

Short-acting Short-acting 2 agonists prn2 agonists prn

PREVENTIONPREVENTION

Severity of asthmaSeverity of asthma

Oral steroidsOral steroids

IMMUNOTHERAPY ?IMMUNOTHERAPY ?

Treatment Options for PatientsTreatment Options for PatientsNot Controlled on Inhaled SteroidsNot Controlled on Inhaled Steroids

Patients not controlled on inhaled steroidsPatients not controlled on inhaled steroidsPatients not controlled on inhaled steroidsPatients not controlled on inhaled steroids

Increase theIncrease thedose of inhaleddose of inhaled

steroidsteroid

Add leukotrieneAdd leukotrienereceptor receptor

antagonistsantagonistsAdd long-actingAdd long-actingbeta2-agonistsbeta2-agonists

Add Add theophyllinetheophylline

Montelukast + Budesonide vs higher-dose budesonide

Days relative to start of trial

Montelukast + budesonide 800 µg(n=433)Budesonide 1600 µg(n=425)

AM PEF

(L/min)

440

390

400

410

420

430

-14 -7 0 7 14 21 28 35 42 48 56 63 70 77 84

p=0.367between groups

during the last 10 weeks of the 12-week treatment period

Run-inPrice et al., Thorax 2003

Busse WW et al.Busse WW et al. J Allergy Clin Immunol 1999; 103: 1075-80 J Allergy Clin Immunol 1999; 103: 1075-80

COMPARISON OF INHALED SALMETEROL COMPARISON OF INHALED SALMETEROL AND ORAL ZAFIRLUKAST IN PATIENTS AND ORAL ZAFIRLUKAST IN PATIENTS

WITH ASTHMAWITH ASTHMA

In patients with persistent asthma, most of whom currently In patients with persistent asthma, most of whom currently using inhaled corticosteroids, treatment with inhaled using inhaled corticosteroids, treatment with inhaled

salmeterol provided significantly greater improvement that salmeterol provided significantly greater improvement that oral zafirlukast in overall clinical control over the 4-week oral zafirlukast in overall clinical control over the 4-week

treatment periodtreatment period

Biermer L t al.Biermer L t al. BMJ 2003; in press BMJ 2003; in press

A ONE-YEAR COMPARATIVE TRIAL OF A ONE-YEAR COMPARATIVE TRIAL OF MONTELUKAST AND FLUTICASONE VS MONTELUKAST AND FLUTICASONE VS SALMETEROL AND FLUTICASONE IN SALMETEROL AND FLUTICASONE IN

PROTECTING AGAINST ASTHMA ATTACKSPROTECTING AGAINST ASTHMA ATTACKS

The study demonstrates the equal clinical benefit of The study demonstrates the equal clinical benefit of including montelukast or salmeterol in asthma therapy for including montelukast or salmeterol in asthma therapy for

protection against asthma exacerbations of patients protection against asthma exacerbations of patients inadequately controlled by inhaled corticosteroids.inadequately controlled by inhaled corticosteroids.

ADDITION OF LEUKOTRIENE ANTAGONISTS ADDITION OF LEUKOTRIENE ANTAGONISTS TO THERAPY IN CHRONIC PERSISTENT TO THERAPY IN CHRONIC PERSISTENT

ASTHMA: A RANDOMISED DOUBLE-BLINDASTHMA: A RANDOMISED DOUBLE-BLINDPLACEBO-CONTROLLED TRIAL PLACEBO-CONTROLLED TRIAL

Used as additional therapy in a hospital outpatient clinic setting, Used as additional therapy in a hospital outpatient clinic setting, montelukast did not provide such additional benefit in patientsmontelukast did not provide such additional benefit in patients

with moderate or severe asthmawith moderate or severe asthma

Robinson DS et al Lancet 2001; 357: 2007-11Robinson DS et al Lancet 2001; 357: 2007-11


Prof. L.M. Fabbri



Asma grave/BPCO


Differences between asthma and COPDDifferences between asthma and COPD

ASTHMAASTHMASensitizing agentSensitizing agent

COPDCOPDNoxious agentNoxious agent

Asthmatic airwayAsthmatic airwayinflammationinflammation

CD4+ T-lymphocytesCD4+ T-lymphocytes

EosinophilsEosinophils

COPD airway inflammationCOPD airway inflammationCD8+ T-lymphocytesCD8+ T-lymphocytes

MarcrophagesMarcrophages

NeutrophilsNeutrophils

Airflow limitationAirflow limitationCompletelyCompletelyreversiblereversible

CompletelyCompletelyirreversibleirreversibleAirflow limitationAirflow limitation

AsthmaAsthmaA

B

C

B

D

COPDCOPD

Fabbri LM et al Am J Respir Crit Care Med Fabbri LM et al Am J Respir Crit Care Med 2003;167 418-4242003;167 418-424

ASTHMAASTHMA COPDCOPD

Mild Intermittent Mild Intermittent 2 prn 2 prn MildMild 2 prn 2 prn

Mild persistentMild persistent iGCS iGCS Moderate LABAModerate LABA

Moderate persistent Combination Severe Moderate persistent Combination Severe CombinationCombination

LABA+iGCS LABA+iGCS LABA+iGCSLABA+iGCS

Severe persistent Oral GCS Very Oxygen, SxSevere persistent Oral GCS Very Oxygen, Sx severesevere SurgerySurgery

Management of COPD and asthma:GOLD and GINA guidelines


Prof. L.M. Fabbri



Asma grave/BPCO


TREATMENT OPTIONS IN ASTHMATREATMENT OPTIONS IN ASTHMA

CURRENT OPTIONSCURRENT OPTIONSInhaled corticosteroidsInhaled corticosteroids

Long acting beta2-agonistsLong acting beta2-agonistsLeukotriene receptor antagonistsLeukotriene receptor antagonists

FUTURE OPTIONSFUTURE OPTIONSBetter corticosteroids and bronchodilatorsBetter corticosteroids and bronchodilators

Phosphodiesterase inhibitorsPhosphodiesterase inhibitorsAnti-IgEAnti-IgE

FUTURISTIC OPTIONSFUTURISTIC OPTIONSMediator antagonistsMediator antagonists

Non-steroidal antiinflammatory agentsNon-steroidal antiinflammatory agentsChemokine and chemokine receptor antagonistsChemokine and chemokine receptor antagonists

Gene therapyGene therapy

Modified by P.J. Barnes, 2003Modified by P.J. Barnes, 2003

YYYYIgEIgE

YY

YY

YY

IL-4, IL-13IL-4, IL-13

B lymphocyteB lymphocyte

YYYY

YY HistamineHistamineCys-LTsCys-LTsPGDPGD22

FcFcRIRI

Mast cellMast cell

YYYY

YY

YYYY

YY

YY

ChronicChronicinflammationinflammation

YYYY

FcFcRII (CD23)RII (CD23)

MacrophageMacrophage

T lymphocyteT lymphocyte

EosinophilEosinophil

rhuMAb-E25,rhuMAb-E25,omalizumabomalizumab

IgE AND ITS INHIBITION IN ATOPYIgE AND ITS INHIBITION IN ATOPY

Modified by P.J. Barnes, 2003Modified by P.J. Barnes, 2003

L 0

20

40

60

80

L

% P

atie

nts

Placebo

Anti-IgE (low dose)

Anti-IgE (high dose)

Milgrom H et al: NEJM 1999

>50% reduction Discontinuing

omalizumab: iv. 2x weekly x 12 weeks then reduction over 8 weeks

ANTI-IgE IN STEROID-DEPENDENT ASTHMAANTI-IgE IN STEROID-DEPENDENT ASTHMA

Oral steroids

0

20

40

60

80

100

Median BDP dosereduction (%)

Omalizumab sc 28wks

Placebo

Complete BDPwithdrawal (%)

p<0.001p<0.001

p<0.001p<0.001

Soler M et al: Eur Respir J 2001

Moderate to severe allergic asthmaModerate to severe allergic asthma

EFFECT OF ANTI-IgE IN EFFECT OF ANTI-IgE IN ASTHMAASTHMA

FEVFEV11, PEF, PEF

Exacerbations (58%)Exacerbations (58%)

POSITION OFPOSITION OF ANTI-IgE ANTI-IgE IN THE IN THE TREATMENT OF ASTHMATREATMENT OF ASTHMA

• Patients with more severe asthma steroid-dependent, steroid-resistant, brittle

• Patients with severe concomitant allergic diseases

• Poor compliance with existing therapy ?

• Cover for immunotherapy ?Cover for immunotherapy ? Modified by P.J. Barnes, 2003Modified by P.J. Barnes, 2003

Management of asthma:Management of asthma:updating the GINA guidelinesupdating the GINA guidelines

Systemic Systemic steroidssteroids

Ast

hm

a se

ver i

t yA

sth

ma

seve

rit y

MildMildIntermittentIntermittent

Mild Mild PersistentPersistent

Moderate Moderate PersistentPersistent

ModerateModeratePersistentPersistent(Severe?)(Severe?)SevereSevere

PersistentPersistent(Very severe?)(Very severe?)

Combination with higher Combination with higher doses inhaled corticosteroids, doses inhaled corticosteroids, theophylline, antileukotrienestheophylline, antileukotrienes

Avoidance of risk factors, immunotherapyAvoidance of risk factors, immunotherapyShort-acting beta-2 agonists as neededShort-acting beta-2 agonists as needed

Low-dose inhaled steroidsLow-dose inhaled steroids

Combination of long-acting beta2 agonists Combination of long-acting beta2 agonists with low dose inhaled steroidswith low dose inhaled steroids


Prof. L.M. Fabbri



Asma grave/BPCO


Aggiornamento Linee Guida GINA 2003

Prof. Leonardo M. FabbriClinica di Malattie dell’Apparato Respiratorio

Università degli Studi di Modena e Reggio Emilia, Modena

ATTUALITA’ ED EVOLUZIONE NELLA GESTIONE CLINICA DELL’ASMA

aggiornamento linee guida gina 2003 1/4/2004 sala congressi hotel michelangelo sassuolo prof....

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