Percorsi diagnostico-terapeutici dell'Asma bronchiale

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  • The GOLD guidelines suggest a stepwise approach to the management of COPD, depending upon the stage and severity of the disease.
    For patients at all stages, risk factors such as smoking should be avoided.
    Rapid-acting bronchodilators are recommended as needed for those with mild COPD. As the disease progresses regular treatment with one or more bronchodilators may be required to alleviate or prevent symptoms. Patients’ responses to different bronchodilators may vary and failure of a bronchodilator to control symptoms should prompt the trial of another bronchodilator. Combination treatment with several bronchodilators may be required if symptoms are still troublesome.
    Pulmonary rehabilitation and exercise training may improve exercise tolerance and the symptoms of dyspnoea and fatigue.
    Inhaled corticosteroids can be given to patients with moderate COPD. Corticosteroids and antibiotics may be utilised in the management of exacerbations.
    Oxygen therapy is the principal non-pharmacological treatment of severe COPD. Long-term oxygen therapy can increase survival as well as improve exercise capacity and mental state. The primary goal of oxygen therapy is to raise PaO2 from <7.3 kPa to 8 kPa.
    Surgery is an option reserved for select patients with severe or end-stage COPD.
    GOLD: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NIH publication No. 2701, March 2001.
    GOLD workshop report at: http://www.goldcopd.com/workshop
  • START – study outline
    START is a 5-year multinational, multicentre study with two phases: a 3-year double-blind randomized phase followed by a 2-year open-label phase.
    During the first 3 years (Part A), patients received either Budesonide Turbuhaler or placebo once daily plus their usual asthma therapy which could include, eg cromones, inhaled 2-agonists, oral steroid therapy and after study medication had been initiated, even inhaled steroids.
    During the final 2 years (Part B), all patients receive Budesonide Turbuhaler once daily plus their usual asthma therapy.
    Reference therapy = Placebo + usual asthma therapyBudesonide therapy = Budesonide Turbuhaler + usual asthma therapy
  • This plot shows the proportion of patients in the three treatment groups who at the time recorded on the horizontal axis have not experienced a severe exacerbation. In the P200 group there is no recorded event between day 126 and day 277, which explains the curve being parallel with time-axis in that segment.
    The numbers in the plot are Number of patients with at least one SEVEX /Total number of patients with data.
    Both P200 and P200+O are statistically significant from PLA. There is no difference between P200 and P200+O
  • This plot shows the rate (or proportion) of poorly controlled days for the three treatment groups. The calculations are based on the diary data recorded after visits 3-8. The estimates are based on the “group approach” that is intrinsic in the Poisson model and has been used for analysis: all poorly controlled days are summed for a treatment group and divided by the total number of days for that group.
    Both P200 and P200+O are significantly better than PLA. No difference between P200 and P200+O can be found.
  • Slide 5
    The figure shows mean AM PEF throughout the run-in and treatment periods. The last 2 weeks of the 4-week run-in period is indicated on the figure as the 14-day period before randomisation (day 0). AM PEF continued to improve in both treatment groups throughout the 12-week treatment period, with no indication of a plateau in treatment effect up to 12 weeks.
    In recognition that the effects of increasing the dose of corticosteroid may not appear for 1-2 weeks, the primary efficacy analysis considered the last 10 weeks of the 12-week active treatment period.
    Mean AM PEF at baseline (day 0) was 391.0 L/min in the montelukast plus budesonide 800 g group and 388.5 L/min in the budesonide 1600 g group.
    Mean change from baseline during the last 10 weeks of the treatment period was 33.5 L/min in the montelukast plus budesonide 800 g group and 30.1 L/min in the budesonide 1600 g group. There was no significant difference between treatment groups for mean change from baseline in AM PEF (P=0.367).
    The graph shows an obvious improvement in AM PEF in the montelukast plus budesonide 800 g group after the montelukast-placebo run-in period.
    These results show that montelukast added to budesonide 800 g was at least as effective as doubling the dose of budesonide to 1600 g, with respect to improvement in AM PEF during the last 10 weeks of the 12-week treatment period.
  • The GOLD guidelines suggest a stepwise approach to the management of COPD, depending upon the stage and severity of the disease.
    For patients at all stages, risk factors such as smoking should be avoided.
    Rapid-acting bronchodilators are recommended as needed for those with mild COPD. As the disease progresses regular treatment with one or more bronchodilators may be required to alleviate or prevent symptoms. Patients’ responses to different bronchodilators may vary and failure of a bronchodilator to control symptoms should prompt the trial of another bronchodilator. Combination treatment with several bronchodilators may be required if symptoms are still troublesome.
    Pulmonary rehabilitation and exercise training may improve exercise tolerance and the symptoms of dyspnoea and fatigue.
    Inhaled corticosteroids can be given to patients with moderate COPD. Corticosteroids and antibiotics may be utilised in the management of exacerbations.
    Oxygen therapy is the principal non-pharmacological treatment of severe COPD. Long-term oxygen therapy can increase survival as well as improve exercise capacity and mental state. The primary goal of oxygen therapy is to raise PaO2 from <7.3 kPa to 8 kPa.
    Surgery is an option reserved for select patients with severe or end-stage COPD.
    GOLD: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NIH publication No. 2701, March 2001.
    GOLD workshop report at: http://www.goldcopd.com/workshop
  • Percorsi diagnostico-terapeutici dell'Asma bronchiale

    1. 1. Aggiornamento Linee Guida GINA 2003 1/4/2004 Sala Congressi Hotel Michelangelo Sassuolo Prof. Leonardo M. Fabbri Clinica di Malattie dell’Apparato Respiratorio Università degli Studi di Modena e Reggio Emilia, Modena ATTUALITA’ ED EVOLUZIONE NELLA GESTIONE CLINICA DELL’ASMA
    2. 2. GGloballobal ININitiative foritiative for AAsthma 2003sthma 2003 www.ginasthma.comwww.ginasthma.com
    3. 3. Executive CommitteeExecutive Committee Chair: Paul O’Byrne, MDChair: Paul O’Byrne, MD Executive CommitteeExecutive Committee Chair: Paul O’Byrne, MDChair: Paul O’Byrne, MD DisseminationDissemination CommitteeCommittee Chair: TanChair: Tan Wan-ChengWan-Cheng, MD, MD GINA StructureGINA Structure ScienceScience CommitteeCommittee Chair: Eric Bateman, MDChair: Eric Bateman, MD GINA reports prepared during workshops conducted in cooperation withGINA reports prepared during workshops conducted in cooperation with the U.S. National Heart, Lung, and Blood Institute, NIH and the Worldthe U.S. National Heart, Lung, and Blood Institute, NIH and the World Health Organization.Health Organization.
    4. 4. GG lobal Initiative for Chroniclobal Initiative for Chronic OO bstructivebstructive LL ungung DD iseaseisease www.goldcopd.comwww.goldcopd.com
    5. 5. Global Initiative on ObstructiveGlobal Initiative on Obstructive Lung DiseaseLung Disease EXECUTIVE COMMITTEEEXECUTIVE COMMITTEE Chair: Romain PauwelsChair: Romain Pauwels S.Buist, USS.Buist, US P.Calverley, UKP.Calverley, UK B.Celli, USB.Celli, US L.Fabbri, ItalyL.Fabbri, Italy Y.Fukuchi, JapanY.Fukuchi, Japan L.Grouse, USL.Grouse, US S.Hurd, USS.Hurd, US C.Jenkins, AustraliaC.Jenkins, Australia C.Lenfant, USC.Lenfant, US J.Luna, GuatemalaJ.Luna, Guatemala W.McNee, UKW.McNee, UK E.Nizankowska-Mogilnicka,E.Nizankowska-Mogilnicka, PolandPoland K.Rabe, NLK.Rabe, NL R.Rodriguez Roisin, ER.Rodriguez Roisin, E P.Van Der Molen, NLP.Van Der Molen, NL N.Zhong, ChinaN.Zhong, China
    6. 6. Global Initiative on Obstructive Lung DiseaseGlobal Initiative on Obstructive Lung Disease SCIENTIFIC COMMITTEESCIENTIFIC COMMITTEE Chair: Leonardo M. FabbriChair: Leonardo M. Fabbri P. Barnes, UKP. Barnes, UK S. Buist, USS. Buist, US P. Calverley, UKP. Calverley, UK Y. Fukuchi, GiapponeY. Fukuchi, Giappone W. McNee, UKW. McNee, UK R. Pauwels, BelgiumR. Pauwels, Belgium K. Rabe, GermanyK. Rabe, Germany Roberto Rodrigues Roisin, SpainRoberto Rodrigues Roisin, Spain N. Zielinski, PolandN. Zielinski, Poland
    7. 7. Third Quarter, 2000: Publication Date from 2000/07/01 to 2000/09/30 Search 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, 8 Sonia Buist, 16, 17 Leo Fabbri, 14, 20, 10, 19 Yoshi Fukuchi, 5, 7, 10, 12, 19, 20 Bill MacNee, 1, 5, 8, 15 Romain Pauwels, 16, 17 Klaus Rabe, 2, 3, 4, 11, 14 Roberto Rodriguez-Roisin, 2, 3, 4, 11, 13, 18 Jan Zielinski, 1, 7, 10, 15, 19
    8. 8. GOLD REPORT – Section 4 Page 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
    9. 9. PATIENTS AT HIGH RISK OF DEATHPATIENTS 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
    10. 10. 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 ProbabilityofdeathProbabilityofdeath Months since RandomizationMonths since Randomization Medical therapyMedical therapy SurgerySurgery Patients at High Risk of Death afterPatients 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
    11. 11. Levels of evidenceLevels of evidence LevelLevel SourceSource AA Randomized clinical trialsRandomized clinical trials (RCT). Several, consistent(RCT). Several, consistent BB Randomized clinical trialsRandomized clinical trials (RCT). Few, inconsistent(RCT). Few, inconsistent CC Non-randomized clinicalNon-randomized clinical trials. Small and/ortrials. Small and/or observational studiesobservational studies DD Opinion of expertsOpinion of experts
    12. 12. INSTITUTE OF SCIENTIFICINSTITUTE OF SCIENTIFIC INFORMATION (ISI)INFORMATION (ISI) ISI JOURNAL CITATION REPORTSISI JOURNAL CITATION REPORTS http://jcrweb.com/http://jcrweb.com/ Impact FactorImpact Factor Number of Citations in 2002Number of Citations in 2002 Number of articles 2000-2001Number of articles 2000-2001
    13. 13. IMPACT FACTOR 2002IMPACT FACTOR 2002 Medicine, General & Internal:Medicine, General & Internal: 1) New Engl J Med1) New Engl J Med 31.7431.74 2) JAMA – J Am Med Assoc2) JAMA – J Am Med Assoc 16.7816.78 3) Lancet3) Lancet 15.3915.39 4) Ann Intern Med4) Ann Intern Med 11.4111.41 5) Annu Rev Med5) Annu Rev Med 7.957.95 6) Brit Med J6) Brit Med J 7.587.58 7) Arch Intern Med7) Arch Intern Med 6.746.74 8) Medicine8) Medicine 5.185.18
    14. 14. IMPACT FACTOR 2002IMPACT FACTOR 2002 Respiratory SystemRespiratory System 1) Am J Resp Crit Care1) Am J Resp Crit Care 6.566.56 2) Am J Resp Cell Mol2) Am J Resp Cell Mol 4.174.17 3) Thorax3) Thorax 4.084.08 4) Am J Physiol-Lung C4) Am J Physiol-Lung C 3.903.90 5) Chest5) Chest 2.972.97 6) Eur Respir J6) Eur Respir J 2.942.94 7) J Thorac Cardiov Sur7) J Thorac Cardiov Sur 2.842.84 8) Sarcoidosis Vasc Dif8) Sarcoidosis Vasc Dif 2.832.83
    15. 15. 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
    16. 16. 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
    17. 17. GGloballobal ININitiative foritiative for AAsthma 2003sthma 2003 www.ginasthma.comwww.ginasthma.com
    18. 18. Executive CommitteeExecutive Committee Chair: Paul O’Byrne, MDChair: Paul O’Byrne, MD Executive CommitteeExecutive Committee Chair: Paul O’Byrne, MDChair: Paul O’Byrne, MD DisseminationDissemination CommitteeCommittee Chair: TanChair: Tan Chen WanChen Wan, MD, MD GINA StructureGINA Structure ScienceScience 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.
    19. 19. Science 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 Mutius,E. von Mutius,GermanyGermany
    20. 20. 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
    21. 21. Management of asthma:Management of asthma: updating the GINA guidelinesupdating the GINA guidelines SystemicSystemic steroidssteroids AsthmaseverityAsthmaseverity MildMild IntermittentIntermittent MildMild PersistentPersistent ModerateModerate PersistentPersistent ModerateModerate PersistentPersistent (Severe?)(Severe?) SevereSevere PersistentPersistent (Very severe?)(Very severe?) Combination with higherCombination with higher doses inhaled corticosteroids,doses inhaled corticosteroids, theophylline, antileukotrienestheophylline, antileukotrienes Avoidance of risk factors, immunotherapyAvoidance of risk factors, immunotherapy Short-acting beta-2 agonists as neededShort-acting beta-2 agonists as needed Low-dose inhaled steroidsLow-dose inhaled steroids Combination of long-acting beta2 agonistsCombination of long-acting beta2 agonists with low dose inhaled steroidswith low dose inhaled steroids
    22. 22. Stepwise Approach to Asthma TherapyStepwise Approach to Asthma Therapy Controlled by inhaledControlled by inhaled short-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 orInhaled beta2-agonist or Cromolyn or LeukotrieneCromolyn 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
    23. 23. 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 200Budesonide 200 µµgg once dailyonce daily + usual+ usual asthmaasthma therapytherapy Budesonide 400Budesonide 400 µµgg once dailyonce daily + usual+ usual asthmaasthma therapytherapy Part BPart B 66 77 88 99 11 00 11 11 11 22 11 33 11 44 11 55 11 66 11 77 11 88 11 99 22 00 22 11 22 22 Adults andAdults and CChildrenhildren PlaceboPlacebo once dailyonce daily + usual+ usual asthmaasthma therapytherapy Part APart A – Budesonide therapy– Budesonide therapy AdultsAdults ChildrenChildren (6(6––10 yrs)10 yrs) Budesonide 400Budesonide 400 µµgg once dailyonce daily + usual+ usual asthmaasthma therapytherapy BudesonideBudesonide 220000 µµgg once dailyonce daily + usual+ usual asthmaasthma therapytherapy Part APart A – Reference therapy– Reference therapy Pauwels R et a. Lancet 2003; 371: 1071-1076
    24. 24. • Long-term, once-daily treatmentLong-term, once-daily treatment with low-dose budesonidewith low-dose budesonide decreases the risk of severedecreases the risk of severe exacerbations by 44% and improvesexacerbations by 44% and improves asthma control compared withasthma control compared with placebo in patients with recentplacebo in patients with recent onset, mild persistent asthma.onset, mild persistent asthma. STARTSTART ConclusionsConclusions Pauwels R et a. Lancet 2003; 371: 1071-1076
    25. 25. Stepwise Approach to Asthma TherapyStepwise Approach to Asthma Therapy Controlled by low-doseControlled by low-dose inhaled steroidsinhaled steroids ControllerController •• Daily inhaled cortico-Daily inhaled cortico- steroid (200-500 mcg)steroid (200-500 mcg) •• Cromolyn, Nedocromil,Cromolyn, Nedocromil, sustained releasesustained release TheophyllineTheophylline •• Consider LeukotrieneConsider Leukotriene ModifiersModifiers RelieverReliever •• Inhaled beta2-agonistInhaled beta2-agonist prn <3-4x a dayprn <3-4x a day •• Inhaled beta2-agonist orInhaled beta2-agonist or Cromolyn or LeukotrieneCromolyn or Leukotriene modifier prior to exercisemodifier 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
    26. 26. 0 2 4 6 Pre-BD 6 wk Effects of Inhaled BeclomethasoneEffects of Inhaled Beclomethasone Dipropionate in Clinical AsthmaDipropionate in Clinical Asthma Bronchial FunctionBronchial Function Bronchial SubmucosaBronchial Submucosa Asthmatic symptoms Severity 0,01 0,1 1 10 100 Pre-BD 6 wk PC20 methacholine (mg/ml)mg/ml numberofcells/mm2 ofsubmucosa 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
    27. 27. JAMA 2001; 285: 2583-2593JAMA 2001; 285: 2583-2593 LONG-ACTINGLONG-ACTING ββ2-AGONIST2-AGONIST MONOTHERAPYMONOTHERAPY VSVS CONTINUEDCONTINUED THERAPY WITH INHALEDTHERAPY WITH INHALED CORTICOSTEROIDS IN PATIENTSCORTICOSTEROIDS IN PATIENTS WITH PERSISTENT ASTHMAWITH PERSISTENT ASTHMA A Randomized Controlled TrialA Randomized Controlled Trial Patients with persistent asthma well controlled by low doses ofPatients with persistent asthma well controlled by low doses of triamcinolone cannot be switched to salmeterol monotherapytriamcinolone 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.
    28. 28. 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 ofLow-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 Mean%changefrombaseline inFEV1 * * * * * * * *
    29. 29. 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 FormoterolLow Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma . The OPTIMAin 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
    30. 30. Placebo Budesonide 200 Budesonide 200 + Formoterol 34/226 44/227 79/237 Time to first severe exacerbationTime to first severe exacerbation Proportion Days 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
    31. 31. Rate for poorly controlled days Placebo Budesonide 200 Budesonide + Formoterol Rate 0.00 0.05 0.10 0.15 0.144 0.073 0.083 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
    32. 32. Mometasone furoate administered once dailyMometasone furoate administered once daily is as effective as twice-daily administration foris as effective as twice-daily administration for treatment of mild-to-moderate persistenttreatment of mild-to-moderate persistent asthmaasthma This is the first study demonstrating that a total daily dose of 400 µg of mometasone furoate (MF) administered by dry powder inhaler is an effective treatment for patients with mild-to- moderate persistent asthma previously taking only β2-agonists _________________________________________________ Kemp et al, J Allergy Clin Immunol. 2000 Sep;106(3):485-92
    33. 33. Stepwise Approach to Asthma TherapyStepwise Approach to Asthma Therapy Controlled by inhaled steroidsControlled by inhaled steroids plus long-acting bronchodilatorsplus long-acting bronchodilators ControllerController •• Add long acting broncho-Add long acting broncho- dilators to low dose inhaleddilators to low dose inhaled steroidssteroids •• Increase the dose of inhaledIncrease the dose of inhaled corticosteroids 800-2,000corticosteroids 800-2,000µµgg •• Add leukotriene modifiers ifAdd 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 orInhaled beta2-agonist or Cromolyn or LeukotrieneCromolyn 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
    34. 34. 0 5 10 15 20 25 30 35 0 3 6 9 12 15 18 21 Time (weeks) Salmeterol 50 µg bid + BDP 200 µg bid BDP 500 µg 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 Meanchangefrombaseline inmorningPEF(L/min) BDP, beclomethasone dipropionate; ICS, inhaled corticosteroid PEF, peak expiratory flow
    35. 35. 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 ChangeinFEV1(%predicted) Woolcock et al. Am J Respir Crit Care Med 1996 Adapted with permission Salmeterol 50 µg bid + BDP 500 µg bid BDP 1000 µg bid BDP, beclomethasone dipropionate ** *** * *p<0.001, **p<0.05
    36. 36. Pauwels RA et al., N Engl J Med 1997Pauwels RA et al., N Engl J Med 1997 Higher-dose budesonide plus formoterol Lower-dose budesonide plus formoterol Higher-dose budesonide Lower-dose budesonide Changes in FEVChanges in FEV11 during the studyduring the study 90 85 80 75 -1 0 1 2 3 6 9 12 Month FEV1(%ofpredicted) FACET
    37. 37. 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 Pauwels RA et al., N Engl J Med 19Pauwels RA et al., N Engl J Med 19 BUDH:BUDH: - 49%- 49% (p<0.001)(p<0.001)
    38. 38. 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) Pauwels RA et al., N Engl J Med 19Pauwels RA et al., N Engl J Med 19
    39. 39. Classification of Asthma SeverityClassification of Asthma Severity CLASSIFY SEVERITY Clinical Features Before Treatment Symptoms STEP 4 Severe Persistent Continuous Limited physical activity Frequent ≤60% predicted Variability >30% Nighttime Symptoms PEF STEP 3 Moderate Persistent Daily Use β2-agonist daily Attacks limit activity >1 time week 60-80% predicted Variability >30% STEP 2 Mild Persistent ≥1 time a week but <1 time a day >2times a months ≥80% predicted Variability 20-30% STEP 1 Intermittent <1 time a week Asymptomatic and normal PEF between attacks ≤2 times a month ≥80% predicted Variability <20% One of the features of severity is sufficient to place a patient in that category IntensityoftreatmentIntensityoftreatment TreatmentTreatment
    40. 40. Management of AsthmaManagement of Asthma Long-acting bronchodilators and/or LTRALong-acting bronchodilators and/or LTRA Inhaled steroidsInhaled steroids Short-actingShort-acting ββ2 agonists prn2 agonists prn PREVENTIONPREVENTION Severity of asthmaSeverity of asthma Oral steroidsOral steroids IMMUNOTHERAPY ?IMMUNOTHERAPY ?
    41. 41. Treatment Options for PatientsTreatment Options for Patients Not 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 the dose of inhaleddose of inhaled steroidsteroid Add leukotrieneAdd leukotriene receptorreceptor antagonistsantagonists Add long-actingAdd long-acting beta2-agonistsbeta2-agonists AddAdd theophyllinetheophylline
    42. 42. 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=0.367 between groups during the last 10 weeks of the 12-week treatment period Run-in Price et al., Thorax 2003
    43. 43. Busse WW et al.Busse WW et al. J Allergy Clin Immunol 1999; 103: 1075-80J Allergy Clin Immunol 1999; 103: 1075-80 COMPARISON OF INHALED SALMETEROLCOMPARISON OF INHALED SALMETEROL AND ORAL ZAFIRLUKAST IN PATIENTSAND ORAL ZAFIRLUKAST IN PATIENTS WITH ASTHMAWITH ASTHMA In patients with persistent asthma, most of whom currentlyIn patients with persistent asthma, most of whom currently using inhaled corticosteroids, treatment with inhaledusing inhaled corticosteroids, treatment with inhaled salmeterol provided significantly greater improvement thatsalmeterol provided significantly greater improvement that oral zafirlukast in overall clinical control over the 4-weekoral zafirlukast in overall clinical control over the 4-week treatment periodtreatment period
    44. 44. Biermer L t al.Biermer L t al. BMJ 2003; in pressBMJ 2003; in press A ONE-YEAR COMPARATIVE TRIAL OFA ONE-YEAR COMPARATIVE TRIAL OF MONTELUKAST AND FLUTICASONE VSMONTELUKAST AND FLUTICASONE VS SALMETEROL AND FLUTICASONE INSALMETEROL AND FLUTICASONE IN PROTECTING AGAINST ASTHMA ATTACKSPROTECTING AGAINST ASTHMA ATTACKS The study demonstrates the equal clinical benefit ofThe study demonstrates the equal clinical benefit of including montelukast or salmeterol in asthma therapy forincluding montelukast or salmeterol in asthma therapy for protection against asthma exacerbations of patientsprotection against asthma exacerbations of patients inadequately controlled by inhaled corticosteroids.inadequately controlled by inhaled corticosteroids.
    45. 45. ADDITION OF LEUKOTRIENE ANTAGONISTSADDITION OF LEUKOTRIENE ANTAGONISTS TO THERAPY IN CHRONIC PERSISTENTTO THERAPY IN CHRONIC PERSISTENT ASTHMA: A RANDOMISED DOUBLE-BLINDASTHMA: A RANDOMISED DOUBLE-BLIND PLACEBO-CONTROLLED TRIALPLACEBO-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
    46. 46. 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
    47. 47. Differences between asthma and COPDDifferences between asthma and COPD ASTHMAASTHMA Sensitizing agentSensitizing agent COPDCOPD Noxious agentNoxious agent Asthmatic airwayAsthmatic airway inflammationinflammation CD4+ T-lymphocytesCD4+ T-lymphocytes EosinophilsEosinophils COPD airway inflammationCOPD airway inflammation CD8+ T-lymphocytesCD8+ T-lymphocytes MarcrophagesMarcrophages NeutrophilsNeutrophils Airflow limitationAirflow limitation CompletelyCompletely reversiblereversible CompletelyCompletely irreversibleirreversibleAirflow limitationAirflow limitation
    48. 48. Asthma A B C B D COPD Fabbri LM et al Am J Respir Crit Care MedFabbri LM et al Am J Respir Crit Care Med 2003;167 418-42003;167 418-4
    49. 49. ASTHMAASTHMA COPDCOPD Mild IntermittentMild Intermittent ββ2 prn2 prn MildMild ββ2 prn2 prn Mild persistentMild persistent iGCSiGCS Moderate LABAModerate LABA Moderate persistent Combination SevereModerate persistent Combination Severe CombinationCombination LABA+iGCSLABA+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
    50. 50. 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
    51. 51. TREATMENT OPTIONS IN ASTHMATREATMENT OPTIONS IN ASTHMA CURRENT OPTIONSCURRENT OPTIONS Inhaled corticosteroidsInhaled corticosteroids Long acting beta2-agonistsLong acting beta2-agonists Leukotriene receptor antagonistsLeukotriene receptor antagonists FUTURE OPTIONSFUTURE OPTIONS Better corticosteroids and bronchodilatorsBetter corticosteroids and bronchodilators Phosphodiesterase inhibitorsPhosphodiesterase inhibitors Anti-IgEAnti-IgE FUTURISTIC OPTIONSFUTURISTIC OPTIONS Mediator antagonistsMediator antagonists Non-steroidal antiinflammatory agentsNon-steroidal antiinflammatory agents Chemokine and chemokine receptor antagonistsChemokine and chemokine receptor antagonists Gene therapyGene therapy Modified by P.J. Barnes, 2003Modified by P.J. Barnes, 2003
    52. 52. YY YY IgEIgE YY YY YY IL-4, IL-13IL-4, IL-13 εε B lymphocyteB lymphocyte YYYY YY HistamineHistamine Cys-LTsCys-LTs PGDPGD22 FcFcεεRIRI Mast cellMast cell YYYY YY YYYY YY YY ChronicChronic inflammationinflammation YYYY FcFcεεRII (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
    53. 53. L0 20 40 60 80 L %Patients 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
    54. 54. 0 20 40 60 80 100 Median BDP dose reduction (%) Omalizumab sc 28wks Placebo Complete BDP withdrawal (%) 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 INEFFECT OF ANTI-IgE IN ASTHMAASTHMA ↑ FEVFEV11, PEF, PEF ↓↓ Exacerbations (58%)Exacerbations (58%)
    55. 55. POSITION OFPOSITION OF ANTI-IgEANTI-IgE IN THEIN 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
    56. 56. Management of asthma:Management of asthma: updating the GINA guidelinesupdating the GINA guidelines SystemicSystemic steroidssteroids AsthmaseverityAsthmaseverity MildMild IntermittentIntermittent MildMild PersistentPersistent ModerateModerate PersistentPersistent ModerateModerate PersistentPersistent (Severe?)(Severe?) SevereSevere PersistentPersistent (Very severe?)(Very severe?) Combination with higherCombination with higher doses inhaled corticosteroids,doses inhaled corticosteroids, theophylline, antileukotrienestheophylline, antileukotrienes Avoidance of risk factors, immunotherapyAvoidance of risk factors, immunotherapy Short-acting beta-2 agonists as neededShort-acting beta-2 agonists as needed Low-dose inhaled steroidsLow-dose inhaled steroids Combination of long-acting beta2 agonistsCombination of long-acting beta2 agonists with low dose inhaled steroidswith low dose inhaled steroids
    57. 57. 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
    58. 58. Aggiornamento Linee Guida GINA 2003 Prof. Leonardo M. Fabbri Clinica di Malattie dell’Apparato Respiratorio Università degli Studi di Modena e Reggio Emilia, Modena ATTUALITA’ ED EVOLUZIONE NELLA GESTIONE CLINICA DELL’ASMA

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