lobal itiative for sthma

Transcription

1 lobal itiative for sthma

2 GINA Workshop Report Evidence Category A B C D Sources of Evidence Randomized clinical trials Rich body of data Randomized clinical trials Limited body of data Non-randomized trials Observational studies Panel judgment consensus

3 Definition of Asthma Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role Chronic inflammation causes an associated increase in airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment

4 Mechanisms Underlying the Definition of Asthma Risk Factors (for development of asthma) INFLAMMATION Airway Hyperresponsiveness Risk Factors (for exacerbations) Airflow Obstruction Symptoms

5 History of smoking History of Asthma History of smoking History of Asthma

6 MODERN VIEW OF ASTHMA Allergen Macrophage Mast cell Th2 cell Mucus plug Neutrophil Eosinophil Epithelial shedding Nerve activation Mucus Vasodilatation hypersecretion New vessels hyperplasia Plasma leak Oedema Subepithelial fibrosis Sensory nerve activation Cholinergic reflex Bronchoconstriction Hypertrophy/hyperplasia

7 Cytokine Mediators in Asthma Endothelium IL-1 IL-8 GM-CSF Epithelium IL-4 IL-5 IL-6 IL-8 IL-13 GM-CSF Macrophage Eosinophil T-lymphocyte Mast Cell IL-1 IL-6 IL-8 IL-12 GM-CSF TNF- INF- PDGF IL-3 IL-5 IL-6 GM-CSF TNF- TGF- /- IL-2 INF- GM-CSF IL-3 IL-4 IL5 IL-10 Il-13 IL-3 IL-4 IL-5 IL-6 TNF-

8 Asthma Diagnosis History and patterns of symptoms Physical examination Measurements of lung function Measurements of allergic status to identify risk factors

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10 Le prove di funzionalità respiratoria hanno un ruolo diagnostico fondamentale

11 Flusso espiratorio Flusso inspiratorio PEF CPT PIF Normale VR CPT PEF PIF Ostruzione intratoracica variabile V R PEF CPT PIF Ostruzione extratoracica variabile VR CPT PEF PIF Ostruzione fissa intra o extratoracica VR

12 TC spirale del torace con ricostruzione 3D dell immagine Stenosi congenita bilaterale dei bronchi principali

13 Non tutto quello che sibila è asma: un vecchio aforisma sempre attuale Prima della chirurgia Dopo chirurgia

14 Misura della concentrazione dei gas nell aria espirata Asma bronchiale CO=5.6 ppm NO=11.2 ppb L ossido nitrico come marcatore di infiammazione asmatica

15 Classification of Severity STEP 4 Severe Persistent STEP 3 Moderate Persistent STEP 2 Mild Persistent STEP 1 Intermittent CLASSIFY SEVERITY Clinical Features Before Treatment Symptoms Continuous Limited physical activity Daily Attacks affect activity > 1 time a week but < 1 time a day < 1 time a week Asymptomatic and normal PEF between attacks Nocturnal Symptoms Frequent > 1 time week > 2 times a month 2 times a month FEV 1 or PEF 60% predicted Variability > 30% 60-80% predicted Variability > 30% 80% predicted Variability 20-30% 80% predicted Variability < 20% The presence of one feature of severity is sufficient to place patient in that category.

16 Six-Part Asthma Management Program 1. Educate Patients 2. Assess and Monitor Severity 3. Avoid Exposure to Risk Factors 4. Establish Medication Plans for Chronic Management: Adults and Children 5. Establish Plans for Managing Exacerbations 6. Provide Regular Follow-up Care

17 Six-part Asthma Management Program Goals of Long-term Management Achieve and maintain control of symptoms Prevent asthma episodes or attacks Maintain pulmonary function as close to normal levels as possible Maintain normal activity levels, including exercise Avoid adverse effects from asthma medications Prevent development of irreversible airflow limitation Prevent asthma mortality

18 Six-part Asthma Management Program Control of Asthma Minimal (ideally no) chronic symptoms Minimal (infrequent) exacerbations No emergency visits Minimal (ideally no) need for as needed use of β 2 -agonist No limitations on activities, including exercise PEF circadian variation of less than 20 percent (Near) normal PEF Minimal (or no) adverse effects from medicine

19 Six-Part Asthma Management Program The most effective management is to prevent airway inflammation by eliminating the causal factors Asthma can be effectively controlled in most patients, although it can not be cured The major factors contributing to asthma morbidity and mortality are underdiagnosis and inappropriate treatment.

20 Six-Part Asthma Management Program Any asthma more severe than intermittent asthma is more effectively controlled by treatment to suppress and reverse airway inflammation than by treatment only of acute bronchoconstriction and symptoms

21 Six-part Asthma Management Program Part 1: Educate Patients to Develop a Partnership Patient education involves a partnership between the patient and health care professional(s) with frequent revision and reinforcement Aim is guided self-management giving patients the ability to control their asthma Interventions, including use of written action plans, have been shown to reduce morbidity in both children and adults

22 Six-part Asthma Management Program Part 1: Educate Patients to Develop a Partnership Educate continually Include the family Provide information about asthma Provide training on self-management skills Emphasize a partnership among health care providers, the patient, and the patient s family

23 Six-part Asthma Management Program Factors Associated with Non-Compliance in Asthma Care Medication Usage Difficulties associated with inhalers Complicated regimens Fears about, or actual side effects Cost Patient/Physician Misunderstanding/lack of information Underestimation of severity Attitudes toward ill health Cultural factors Poor communication

24 Six-part Asthma Management Program Part 2: Assess and Monitor Asthma Severity with Symptom Reports and Measures of Lung Function Symptom reports Use of reliever medication Nighttime symptoms Activity limitations Spirometry for initial assessment. Peak Expiratory Flow for follow-up: Assess severity Assess response to therapy PEF monitoring at home Important for those with poor perception of symptoms Daily measurement recorded in a diary Assesses the severity and predicts worsening Guides the use of a zone system for asthma self-management Arterial blood gas for severe exacerbations

25 Six-part Asthma Management Program Part 3: Avoid Exposure to Risk Factors Methods to prevent onset of asthma are not yet available but this remains an important goal Measures to reduce exposure to causes of asthma exacerbations (e.g. allergens, pollutants, foods and medications) should be implemented whenever possible

26 Part 4: Long-term Asthma Management Stepwise Approach to Asthma Therapy The choice of treatment should be guided by: Severity of the patient s asthma Patient s current treatment Pharmacological properties and availability of the various forms of asthma treatment Economic considerations Cultural preferences and differing health care systems need to be considered.

27 Part Part 4: 4: Long-term Long-term Asthma Asthma Management Management Stepwise Approach to Asthma Therapy - Adults Outcome: Best Possible Results Outcome: Asthma Control Controller: Controller: Controller: None Controller: Daily inhaled corticosteroid Daily inhaled corticosteroid Daily long acting inhaled β2agonist plus (if needed) Daily inhaled corticosteroid Daily long-acting -Theophylline-SR inhaled β2-leukotriene agonist When asthma is controlled, reduce therapy Monitor -Long-acting inhaled β2- agonist -Oral corticosteroid Reliever: STEP 1: Intermittent Rapid-acting inhaled β2-agonist prn STEP 2: Mild Persistent STEP 3: Moderate Persistent STEP 4: Severe Persistent STEP Down Alternative controller and reliever medications may be considered (see text).

28 Recommended Asthma Medications Step 1: Adults Severity Step 1: Intermittent Daily Controller Medications None Other Options (in order of cost) None Reliever Medication: Rapid-acting inhaled β 2 - agonist prn, not more than 3-4 times a day. Once control is achieved and maintained for at least 3 months, gradual reduction of therapy should be tried.

29 Recommended Asthma Medications Step 2: Adults Severity Step 2: Mild Persistent Daily Controller Medications Inhaled glucocorticoid (< 500 μgg BDP or equivalent) Other Options (in order of cost) Sustained-release theophylline, or Cromone, or Leukotriene modifier Reliever Medication: Rapid-acting acting inhaled β 2 - agonist prn, not more than 3-44 times a day. Once control is achieved and maintained for at leastl 3 months, gradual reduction of therapy should be tried.

30 Severity Step 3: Moderate persistent Recommended Asthma Medications Step 3: Adults Daily Controller Medications Inhaled glucocorticoid ( μgg BDP or equivalent) plus long-acting inhaled β 2 - agonist Other Options (in order of cost) Inhaled glucocorticoid ( μg BDP or equivalent) plus sustained- release theophylline, or Inhaled glucocorticoid ( μg BDP or equivalent) plus long-acting inhaled β 2 - agonist, or Inhaled glucocorticoid at higher doses (> 1000 μgg BDP or equivalent), or Inhaled glucocorticoid ( μg BDP or equivalent) plus leukotriene modifier Reliever Medication: Rapid-acting acting inhaled β 2 - agonist prn, not more than 3-44 times a day. Once control is achieved and maintained for at leastl 3 months, gradual reduction of therapy should be tried.

31 Recommended Asthma Medications Step 4: Adults Severity Step 4 Severe persistent Daily Controller Medications Inhaled glucocorticoid ( > 1000 μgg BDP or equivalent) plus long-acting inhaled β 2 - agonist plus one or more of the following, if needed: - Sustained-release theophylline - Leukotriene modifier - Long-acting inhaled β 2 - agonist - Oral glucocorticoid Other Options Reliever Medication: Rapid-acting acting inhaled β 2 - agonist prn, not more than 3-44 times a day. Once control is achieved and maintained for at leastl 3 months, gradual reduction of therapy should be tried.

32 Part 4: Long-term Asthma Management Allergen-specific Immunotherapy Greatest benefit of specific immunotherapy using allergen extracts has been obtained in the treatment of allergic rhinitis A number of questions must be addressed regarding the role of specific immunotherapy in asthma therapy Specific immunotherapy should be considered only after strict environmental avoidance and pharmacologic intervention, including inhaled glucocorticoids, have failed to control asthma Perform only by trained physician

33 LONG-ACTING 2-AGONIST MONOTHERAPY VS CONTINUED THERAPY WITH INHALED CORTICOSTEROIDS IN PATIENTS WITH PERSISTENT ASTHMA A Randomized Controlled Trial Patients with persistent asthma well controlled by low doses of triamcinolone cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control. Lazarus SC et al. JAMA 2001; 285:

34 3,4 Triamcinolone Salmeterol Placebo 3,2 FEV 1 Liters 3 2,8 2,6 Run-in Randomized treatment 2,4 Baseline Week Lazarus SC et al., JAMA 2001; 285:

35 LOW-DOSE FLUTICASONE PROPIONATE COMPARED WITH MONTELUKAST FOR FIRST-LINE TREATMENT OF PERSISTENT ASTHMA: A RANDOMIZED CLINICAL TRIAL Busse W, Raphael GD, Galant S, Kalberg C, Goode-Sellers PS, Srebro S, Edwards L, Rickard K For the Fluticasone Propionate Clinical Research Study Group J Allergy Clin Immunol 2001; 107:

36 Mean % change from baseline Low-dose Fluticasone is More Effective of Montelukast in Mild Persistent Asthma in FEV Baseline * * * * * * FP 88 µg BID MON 10 mg BID Treatment week Endpoint Busse W et al., J Allergy Clin Immunol 2001; 107: * *

37 Six-part Asthma Management Program Part 5: Establish Plans for Managing Exacerbations Primary therapies for exacerbations: Repetitive administration of rapid-acting inhaled β 2 -agonist Early introduction of systemic glucocorticoids Oxygen supplementation Closely monitor response to treatment with serial measures of lung function

38 Six-part Asthma Management Program Part 5: Managing Severe Asthma Exacerbations Severe exacerbations are life-threatening medical emergencies Care must be expeditious and treatment is often most safely undertaken in a hospital or hospital-based emergency department

39 Emergency Department Management Acute Asthma Initial Assessment History, Physical Examination, PEF or FEV 1 Good Response Observe for at least 1 hour If Stable, Discharge to Home Initial Therapy Bronchodilators; O 2 if needed Incomplete/Poor Response Add Systemic Glucocorticoids Good Response Discharge Poor Response Admit to Hospital Respiratory Failure Admit to ICU

40 Six-part Asthma Management Program Part 6: Provide Regular Followup Care Continual monitoring is essential to assure that therapeutic goals are met. Frequent follow-up visits are necessary to review: Home PEF and symptom records Techniques in use of medications Risk factors and their control Once asthma control is established, follow-up visits should be scheduled (at 1 to 6 month intervals as appropriate)

41 Six-part Asthma Management Program: Summary Asthma can be effectively controlled, although it cannot be cured Effective asthma management programs include education, objective measures of lung function, environmental control, and pharmacologic therapy A stepwise approach to pharmacologic therapy is recommended. The aim is to accomplish the goals of therapy with the least possible medication

42 Six-part Asthma Management Program: Summary (continued) Anything more than mild, occasional asthma is more effectively controlled by suppressing inflammation than by only treating acute bronchospasm The availability of varying forms of treatment, cultural preferences, and differing health care systems need to be considered

43 Inhaled Allergen Challenge Inhaled AG Proof of Concept for anti-inflammatories in asthma FEV 1 LAR Early AR 0-2 h mast cell Late Asthmatic Reaction 3-10 h multiple cells?

44 Biotechnology Approaches MoAbs and soluble receptors : -IgE, -IL-5, IL-4R cytokines and antagonists : chemokine antagonists : peptide allergens

45 Anti-IgE Omalizumab rhumoab-e25, Xolair, Novartis GT IV AGC : suppression of EAR (37%) and LAR (62%) Aerosolised AGC : inactive on EAR/LAR Study in mod-severe asthma : n = 317, 20 weeks Sig. effects on symptom scores serum IgE decreased by 95%

46 3 : 3 hexamer complexes Soluble IgE Anti-IgE E25

47 Anti-IL-5 Eos as a target in asthma If you could have one therapeutic target...??? eos are a prominent unifying pathological feature eos role in immunity : parasites IL-5 knock-out mice are healthy IL-5 drives the final stage of eosinopoiesis distinct surface proteins (eos vs neut) : CD 9, IL-5R, CCR3 (eotaxin-r), VLA-4 steroids inhibit eosinopoiesis and eos function

48 Anti IL-5 on Blood Eos 0.8 Dose IV AGC AGC Eos 0.4 Placebo 2.5mg/kg mg/kg Screen Predose 6 h 12 h 24 h Day 5 Day 8 Day 9 Day 15 Day 29 Day 30 Wk 8 Wk 16 Time

49 Th 1 and Th 2 cells SRL 172 Mycobact.vaccae Intracellular pathogens IL-12, IL-18 Th1 uncommitted CD4 + cell CpG pdna Extracellular pathogens IL-4,IL-13 Th2 IFN- IL-4 cell-mediated immunity humoral immunity

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